Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[OH-].[Na+]>P([O-])(O)(O)=O.[K+].O.C1(C)C=CC=CC=1>[C:12]([N:6]1[CH2:7][CH2:8][C:3]([NH2:2])([C:9]([OH:11])=[O:10])[CH2:4][CH2:5]1)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1(C(=O)O)CCNCC1
Agent: Br
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: NC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
4-amino-4-carboxy-piperidine hydrobromide ([P. Jacobsen, K. Schaumburg, P. Krogsgaard-Larsen, Acta. Chem. Scandinavica B34, 319-326 (1980)]; 2.25 g, 10 mmoles) was dissolved in a solution of 18 ml potassium dihydrogen phosphate buffer (0.05 Molar potassium dihydrogen phosphate in 1N aqueous sodium hydroxide) and 6 ml of water. The solution was chilled with an ice-bath over an hour period during which solutions of carbobenzyloxy chloride (1.57 ml, 11 mmoles) in 3.0 ml of toluene and aqueous 1N sodium hydroxide were simultaneously added dropwise so as to maintain a pH of 7.0. The mixture was then stirred for one hour at 5° C., and for four additional hours at ambient temperature. The precipitate formed during the reaction was filtered and the filter cake washed with 3 (30 ml) portions of diethyl ether. The amorphous colorless solid was dried in vacuo affording 1.4 g of the title compound (50% yield). 1Hnmr (60 mHz; CF 3 CO2D) delta 2.0-2.7 (4H, broad m), 3.5-4.5 (4H, broad m), 5.28 (2H, s), 7.4 (5H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH:6]=[C:5]([C:18]2[S:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[N:23]=2)[N:4]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[C:5]([C:18]2[S:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[N:23]=2)[N:4]=1
Reactant: CSc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CSc1cc(CCC(=O)O)cc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
tert-Butyl 3-[2-(methylthio)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.12 g, 0.29 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 0.5 hr. Diisopropyl ether was combined with the reaction mixture to give precipitates, which were recrystallized from ethanol to give the titled compound (0.09 g, 87%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27].C(OCC)(=O)C.CCOCC>CN(C)C1C=CN=CC=1.CN(C=O)C>[N+:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN1CCN(c2cccc3ccc(Nc4ccccc4[N+](=O)[O-])cc23)CC1
Yield: 7.1 %

Procedure:
The title product was obtained following the procedure of example 27 by reacting 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.225 g, 0.93 mmol), 2-fluoronitrobenzene (0.255 g, 1.8 mmol), and 4-dimethylaminopyridine (0.167 g, 1.37 mmol) in dry DMF (5 mL) with an overnight reflux. The product was isolated by silica gel flash chromatography and recrystallization from ethyl acetate/ether to yield 0.024 g (7%) of the title compound as orange crystals: mp 87°-94° C.; 1H NMR δ 9.70 (br s, 1H), 8.26 (dd, J=1.5, 8.5 Hz, 1H), 8.07 (d, J=2 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.57 (s, J=8 Hz, 1H), 7.44-7.32 9m, 4H), 7.16 (dd, J=1,7.5 Hz, 1H), 6.82 (dd, J=6.5, 8.5 Hz, 1H), 3.15 (br s, 4H), 2.70 (br s, 4H), 2.41 (s, 3H). HRMS m/e calculated for C21H22N4O2 ; 362.1738. Observed m/e: 362.1736.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH3:19])[C:13](SCCC)=[N:12]3)[CH2:10][CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:30].[I-]>N.CCO>[NH2:30][C:13]1[N:14]([CH2:17][CH2:18][CH3:19])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CCCSC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CCC
Agent: N
Agent: [I-]
Solvent: CCO
Product: CCCN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Yield: 18.1 %

Procedure:
A solution of 6-bromo-2-phenyl-1′-propyl-2′-(propylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (280 mg, 0.6 mmol) and NH4I (172 mg, 1.2 mmol) in NH3/EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-phenyl-1′-propylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (45 mg, 18%). 1H-NMR (MeOD): 0.93 (m, 3H), 1.66 (m, 2H), 2.04 (m, 1H), 2.25 (m, 1H), 3.56 (m, 2H), 5.83 (m, 1H), 6.87 (m, 1H), 7.06 (m, 1H), 7.31 (m, 2H), 7.40 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][C:25]([O:29][CH3:30])([CH3:28])[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:31][C:32]1[CH:57]=[CH:56][C:35]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42](B3OC(=O)CN(C)CC(=O)O3)=[CH:41][CH:40]=2)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:42]2[CH:41]=[CH:40][C:39]([O:38][CH2:37][CH2:36][C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:57][CH:56]=3)=[CH:44][CH:43]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][C:25]([O:29][CH3:30])([CH3:28])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC1(C)CCN(c2c(Br)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)OC(C)C)CC1
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC1(C)CCN(c2c(-c3ccc(OCCc4ccc(F)cc4)cc3)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)OC(C)C)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
PD(Ph3P)4 (143 mg, 0.124 mmol) was added to an argon-degassed solution of (S)-isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (300 mg, 0.618 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (177 mg, 0.68 mmol), potassium phosphate tribasic (984 mg, 4.63 mmol) in dioxane (5 ml) and water (1 ml) stirred in a screw-capped pressure vessel for 16 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate 300 mg (78%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.37 (m, 2H), 7.21-7.12 (m, 3H), 7.04-7.00 (m, 3H), 5.98 (br. s, 1H), 4.96-4.93 (m, 1H), 4.24-4.21 (m, 2H), 3.42-3.40 (m, 2H), 3.26-3.21 (m, 1H), 3.07-3.05 (m, 2H), 2.90-2.86 (m, 1H), 2.81 (s, 3H), 2.44 (s, 3H), 2.05 (s, 3H), 1.53-1.42 (m, 2H), 1.33-1.25 (m, 2H), 1.18 (d, J=6.2 Hz, 3H), 1.14-1.12 (m, 12H), 1.00/0.81 (s, 3H). UPLC (M+H)=621.6.
Reaction SMILES: [N:1]([C@@H:4]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:5](=[O:11])[N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][C@@H:4]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:5](=[O:11])[N:6]1[CH2:10][CH2:9][S:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H](N=[N+]=[N-])C(=O)N2CCSC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC([C@H](N)C(=O)N2CCSC2)CC1
Temperature: 60 °C

Procedure:
Acid (Example 95, step A. 4.01 g) was converted to tert-butyl 4-[(1S)-1-azido-2-oxo-2-(1,3-thiazolidin-3-yl)ethyl]piperidine-1-carboxylate (1.3 g) in 4 steps using the procedures outlined in Example 6. 1H NMR (500 MHz, CD3OD, HCl salt) δ 4.71–4.49 (m, 2H), 4.09 (bs, 2H), 3.98–3.74 (m, 2H), 3.42 (d, 0.4H, J=7 Hz), 3.40 (d, 0.6H, J=7 Hz), 3.18 (t, 1.2H, J=5.6 Hz), 3.02 (t, 0.8H, J=5.6 Hz), 2.72 (bs, 2H), 2.18 (m, 1H), 1.99 (d, 1H, J=13 Hz), 1.61 (d, 1H, J=13.5 Hz), 1.42 (s, 9H), 1.24 (m, 1H), 1.19 (m, 1H). A portion of this material (30 mg) was dissolved in wet THF and triphenyl phosphine (26 mg) was added to the solution. The mixture was heated at 60° C. for 5 h, cooled, concentrated and purified by preparative TLC on silica gel (eluent: 5 to 10% methanol in CH2Cl2) to give the title compound. 1H NMR (500 MHz, CDCl3) δ 4.68–4.48 (m, 2H), 4.18 (bs, 2H), 3.99–3.69 (m, 2H), 3.36 (d, 0.4H, J=7 Hz), 3.29 (d, 0.6H, J=7 Hz). 3.1 (t, 1.2H, J=5.6 Hz), 3.0 (t, 0.8H, J=5.6 Hz), 2.61 (bs, 2H), 1.92 (bd, 1H, J=13.5 Hz), 1.65 (m, 1H), 1.58 (m, 1H), 1.42 (s, 9H), 1.25 (m, 1H), 1.20 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:5]#[N:6].CCN(CC)CC.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>CN(C=O)C>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:10]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11]2)=[C:2]([NH:1][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(C2CCc3cncn32)c(N)c1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(=O)Nc1cc(C#N)ccc1C1CCc2cncn21

Procedure:
A DMF (3 mL) solution of 3-Amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (0.095 g, 0.42 mmol), given as example 6B, is treated with Et3N (0.09 mL, 0.64 mmol) and butyryl chloride (0.05 mL, 0.51 mmol) at room temperature. After 1 h the solution is concentrated. Purification via prep HPLC gives N-[5-Cyano-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-phenyl]-butyramide. MS (ESI) m/z 295.1 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.01 (t, J=7.3 Hz, 3H), 1.67-1.80 (m, 2H), 2.35 (t, J=7.5 Hz, 2H), 2.49-2.61 (m, 1H), 2.88-3.01 (m, 2H), 3.05-3.18 (m, 1H), 5.56 (dd, J=8.0, 5.9 Hz, 1H), 6.84 (s, 1H), 6.97 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.45 (dd, J=8.1, 1.5 Hz, 1H), 7.70 (br s, 1H), 7.91 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:10]Br>CC(O)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1
Reactant: N#Cc1cccnc1N
Reactant: BrBr
Solvent: CC(=O)O
Product: N#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-aminopyridine-3-carbonitrile 1 (0.56 g, 4.6 mmol) was dissolved in 10 mL HOAc, to which one equivalent of Na2CO2 was added. Then, 1.1 equivalent of Br2 was added dropwise and reaction mixture was stirred at room temperature for 30 minutes. Orange precipitation was formed and filtered off to obtain the desired compound 2 in quantitative yield. The compound was carried on without further purification.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:16]2[CH2:19][CH:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:17]2)=[CH:11][CH:10]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[N:16]2[CH2:19][CH:18]([N:20]([CH2:21][C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[S:36]([CH3:35])(=[O:38])=[O:37])[CH2:17]2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CC(NCc3ccncc3)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(Cc1ccncc1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
346 mm3 of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 398 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(pyrid-4-ylmethyl)amine in 8 cm3 of dichloromethane. The mixture is cooled to around 0° C. before adding thereto 155 mm3 of methylsulfonyl choride, and then it is stirred at room temperature for 3 hours. The reaction mixture is diluted with 35 cm3 of dichloromethane and is then washed with twice 20 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent:dichloromethane/methanol (97/3 by volume)]. 288 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(pyrid-4-ylmethyl)methylsulfonamide are obtained in the form of a cream-colored foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm):2.83 (s:3H); 3.02 (broad t, J=7.5 Hz: 2H); 3.40 (broad t, J=7.5 Hz: 2H); 4.23 (s: 1H); 4.43 (mt: 1H); 4.57 (s: 2H); from 7.20 to 7.35 (mt: 8H); 7.32 (broad d, J=5.5 Hz: 2H); 8.60 (broad d, J=5.5 Hz: 2H)].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9])[C:6]([OH:19])=[CH:5][CH:4]=1.O1CC[CH2:23]OO1>FC(F)(F)C(O)=O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:19][CH2:23][N:10]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:8](=[O:9])[C:7]=2[CH:18]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)ccc1O
Reactant: C1COOOC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCN1COc2ccc(Cl)cc2C1=O

Procedure:
8.00 Grammes (26.1 mmoles) of 5-chloro-N-[2-(diethylamino)ethyl]salicylamide hydrochloride are dissolvedin 100 ml of trifluoroacetic acid with 2.35 grammes (26.1 mmoles) of trioxane and left to react for 20 hours at a temperature of 50° C.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:23])[CH2:19][CH2:20][C:21]#[CH:22]>C(#N)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:23][CH2:18][CH2:19][CH2:20][C:21]#[CH:22])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: C#CCCCN
Solvent: CC#N
Product: C#CCCCN=C(NC#N)NCCSCc1[nH]cnc1C
Reaction time: 96 h

Procedure:
A mixture of N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea (3.00 g., 0.0111 mole) and 4-pentyn-1-amine (3.69 g., 0.0445 mole) in 60 ml. of acetonitrile was stirred at reflux for 24 hours, and then allowed to stand at room temperature for 96 hours. The solvent and excess amine were removed under reduced pressure and the residual yellow gum was purified by chromatography on 50 g. of 100-200 mesh silica gel, using gradient elution with methylene chloride/methanol (99:1-96:4). The middle fractions indicated by TLC to be pure were combined and evaporated to give 1.91 g. of yellow gum which was crystallized at -15° C from 18 ml. of ethyl acetate. The resulting white solid (1.25 g.) was recrystallized at -15° C from 10 ml. of acetonitrile to give 1.063 g. of product; m.p. 99°-103° C.
Reaction SMILES: C(=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[C:16]=1[F:26])(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:27].O>CCOCC>[ClH:27].[F:26][C:16]1[C:17]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:18][CH:19]=[CH:20][C:15]=1[NH2:14]
Reactant: Fc1c(N=C(c2ccccc2)c2ccccc2)cccc1OC(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: Nc1cccc(OC(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of benzhydrylidene-(2-fluoro-3-trifluoromethoxy-phenyl)-amine (7.5 g, 20 mmol) in Et2O (40 mL) was added 3N aqueous HCl (10 mL). The reaction mixture was stirred for 4 h at RT, followed by addition of water. The aqueous layer was extracted with Et2O (2×10 mL), the combined organic layers were washed with brine and then dried over MgSO4. After removal of solvent in vacuo, the residue was purified by preparative HPLC (stationary phase: Gimini 300×50 mm, particle size 10 μm; solvent: A H2O+BCH3CN, pressure: 60-70 bar). The product was extracted with Et2O as the free base from the combined fractions. HCl gas was bubbled through the organic phase, and the solvent was removed under vacuum to afford the title compound. Recrystallisation from EtOH/diisopropylether gave a white solid. 1H NMR (D2O, 400 MHz): δ 7.40-7.35 (m, 1H, ArH), 7.32-7.27 (m, 1H, ArH), 7.27-7.19 (m, 1H, ArH). HRMS: 196.03801 [M]+ (calcd. 196.03800 for C7H5F4NO); Anal. Calcd. for C7H5F4NO: C, 36.31; H, 2.61; N, 6.05; Cl, 15.31; F, 32.82. Found: C, 35.78; H, 2.63; N, 6.14; Cl, 15.69; F, 31.99.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:11]([F:21])=[C:12]3[C:17](=[CH:18][C:19]=2[F:20])[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:22])=[N:4][CH:3]=1.[N:23]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[C:11]([F:21])=[C:12]4[C:17](=[CH:18][C:19]=3[F:20])[N:16]=[CH:15][CH:14]=[CH:13]4)[N:23]=[N:22][C:5]2=[N:4][CH:3]=1
Reactant: Nc1ncc(Br)nc1NCc1c(F)cc2ncccc2c1F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc2ncccc2c(F)c1Cn1nnc2ncc(Br)nc21
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 6-bromo-N2-(5,7-difluoroquinolin-6-ylmethyl)pyrazine-2,3-diamine (1.5 g, 4.10 mmol) in acetic acid (50 mL) and water (10 mL) was added a solution of sodium nitrite (283 mg, 4.10 mmol) in water (3 mL). After stirring at it for 3 h, the solvent was removed in vacuo, the residue was taken with NaHCO3 (aq.), extracted with CH2Cl2. The organic layer was washed with NH4Cl (aq.), dried over Na2SO4, filtered and concentrated in vacuo and purified by silica gel chromatography with hexanes:EtOAc to provide 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline (1.02 g, 65%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.99 (d, 1H), 8.79 (s, 1H), 8.43 (d, 1H), 7.65 (d, 1H), 7.49 (m, 1H), 6.13 (s, 2H). LCMS (method B): [MH]+=376.8, tR=2.23 min.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.BrBr.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=1
Reactant: Cc1ccc2cc(F)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2cc(CBr)ccc2c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of 2-fluoro-6-methylnaphthalene (0.750 g, 4.68 mmol) in carbon tetrachloride (20 mL) was added NBS (0.917 g, 5.15 mmol) and bromine (0.265 mL, 5.15 mmol) followed by AIBN (0.077 g, 0.47 mmol). The reaction mixture was heated to 70° C. and allowed to stir for 4 hours. It was then cooled to room temperature, partitioned between water and EtOAc, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo and subjected to silica gel chromatography eluting with 5-50% EtOAc in hexanes to yield 2-(bromomethyl)-6-fluoronaphthalene.
Reaction SMILES: [K].[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[NH:8][C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=1>CN(C)C=O>[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[N:8]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:8]4[C:7](=[O:12])[C:6]5([CH2:13][C:14]([CH3:16])([CH2:17][CH3:18])[NH:15][C:4]([CH3:20])([CH2:2][CH3:3])[CH:5]5[CH3:19])[NH:10][C:9]4=[O:11])=[CH:25][CH:24]=3)[C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3]
Reactant: BrCc1ccc(CBr)cc1
Reactant: CCC1(C)CC2(NC(=O)NC2=O)C(C)C(C)(CC)N1
Agent: [K]
Solvent: CN(C)C=O
Product: CCC1(C)CC2(NC(=O)N(Cc3ccc(CN4C(=O)NC5(CC(C)(CC)NC(C)(CC)C5C)C4=O)cc3)C2=O)C(C)C(C)(CC)N1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 80 ml of dimethylformamide were added 8.0 g of the potassium salt of 7,9-diethyl-6,7,9-trimethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 3.1 g of α,α'-dibromo-p-xylene; the mixture was heated, with stirring, at 60° C for 3 hours. The mixture was then concentrated by evaporation under reduced pressure and the residue was dissolved in chloroform. The chloroform solution was washed with water and dried over magnesium sulphate; the chloroform was then removed. The residue was purified first by column chromatography on silica gel (eluent: a 6 : 3 : 0.5 by volume mixture of ethyl acetate, benzene and triethylamine) and then by recrystallization from ethanol, giving 5.0 g of Compound 43 as crystals melting at 272° - 274° C.
Reaction SMILES: O=[C:2]1[CH2:21][NH:20][CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[NH:13][CH2:12][C:11](=O)[NH:10][CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.O>O1CCCC1>[CH:9]12[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH:3][CH2:2][CH2:21][NH:20][CH:19]1[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]1)[NH:13][CH2:12][CH2:11][NH:10]2
Reactant: O=C1CNC2CCCCC2NCC(=O)NC2CCCCC2N1
Solvent: O
Solvent: C1CCOC1
Product: C1CCC2NCCNC3CCCCC3NCCNC2C1
Reaction time: 24 h

Procedure:
A 1M solution of BH3 in tetrahydrofuran (265 ml.) was slowly added to 10.2 g. (33.1 mmol.) of compound (A). The solution was boiled for 24 hours. Water was then added dropwise to destroy the excess BH3 and the reaction mixture was brought to dryness. The solid residue was added to 265 ml. of a 6M hydrochloric acid solution and the mixture was refluxed overnight. Hydrochloric acid was eliminated under vacuum. The residue was digested in ethanol, filtered and dissolved in water. Concentrated ammonia was added until the pH became strongly basic. The inorganic precipitate that formed was filtered off and the filtrate was extracted with methylene chloride yielding 6.3 g. of compound (B) as a white solid after elimination of the solvent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18](OC)=[O:19])[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:19][CH2:18][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(CO)CSc1ccccc1
Temperature: 25 °C

Procedure:
A solution of Example 175A (1.22 g, 3.91 mmol) in toluene (10 mL) at −78° C. was treated with 1M DIBAL-H in toluene (8.6 mL), warmed to room temperature over 4 hours, diluted with ethyl acetate (100 mL), washed sequentially with 0.1N HCl (30 mL), water (15 mL), and brine (50 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product. MS (DCI) m/e 284 (M+H)+.
Reaction SMILES: C.Cl[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O.[NH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C)C=O>[C:4]1([C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCNCC1
Agent: C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Yield: 103.5 %

Procedure:
After the portionwise addition of 18.1 g (65.1 mmol) of chlorotriphenylmethane methane to a 150 ml dimethylformamide solution of 10.0 g (65.1 mmol) of 4-piperidone monohydrate hydrochloride and 20.0 g (198 mmol) of triethylamine at 60° C. under stirring, the resulting mixture was stirring further for 5 hours at the same temperature. The triethylamine hydrochloride precipitated by cooling was filtered out and the filtrate was concentrated under reduced pressure. To the residue was added 150 ml of water, followed by extraction with 300 ml of ethyl acetate. The organic layer was then washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, whereby 23.0 g (yield: 98.3%) of 1-triphenylmethyl-4-piperidone were obtained.