Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2.C1CCCCCC=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>C(O)CC>[N:16]1([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[OH:8])[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: C1CCC2OC2CC1
Reactant: c1nc[nH]n1
Agent: C1=CCCCCC1
Solvent: CCCO
Product: OC1CCCCCC1n1cncn1
Yield: 35.8 %

Procedure:
Cycloheptene oxide (Vb) prepared from cycloheptene (10 g) in the same manner as in Example 23(1), propanol (25 ml) and 1,2,4-triazole (8.6 g) were made to react at 100° C. for 4 hours and the propanol was removed by evaporation. After addition of a small amount of water, the reaction mixture was extracted with chloroform. The residue was washed with a saturated aqueous solution of sodium chloride, dried and evaporated. The residue was recrystallized from ether-hexane to give 2-(1,2,4-triazole-1-yl)cycloheptanol (IVd) (13.3 g) melting at 85°-86° C. (yield 35.8%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:22]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and 2-(R)-methylpyrrolidine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 420 (M+H)+;
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:15]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:12])=[O:13])[CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CS(=O)(=O)c1ccc2[nH]nc(I)c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cc(S(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
To a solution of 3-iodo-5-(methylsulfonyl)-1H-indazole (400 mg, 1.24 mmol) in THF (15 mL) was added t-BuOK (208 mg, 1.86 mmol) slowly at 0° C., mixture stirred for 30 minutes, then iodomethane (262 mg, 1.86 mmol) was added at 0° C., then warmed to room temperature and stirred for 2 hours. Reaction quenched with water (40 mL) and product extracted with EtOAc (3×30 mL), organics combined dried with sodium sulfate, filtered and concentrated under reduced pressure to afford a solid which was purified by column chromatography (silica gel, 200-300 mesh, eluting with dichloromethane/methanol=10:1) to give 3-iodo-1-methyl-5-(methylsulfonyl)-1H-indazole (210 mg, 50.6%) as a white solid. LCMS: (M+H)+=337; 1H NMR (300 MHz, DMSO): δ 7.97-7.94 (m, 3H), 4.13 (s, 3H), 3.26 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
Methyl 2-amino-4-chlorobenzoate (1.5 g, 8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH (429 mg, 11.3 mmol) in THF (10 mL) under N2 at 0° C. over 10 min. The resulting mixture was stirred at room temperature for 2 hrs, then the reaction was quenched at 0° C. with saturated Na2SO4 (50 mL), extracted with Et2O (2×70 mL). The combined organic solutions were washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a white solid (874 mg, 69% yield); 1H NMR (400 MHz, MeOD) δ ppm 4.50 (s, 2 H), 6.58 (dd, J=8.06, 2.01 Hz, 1 H), 6.70 (d, J=2.01 Hz, 1 H), 7.01 (d, J=8.06 Hz, 1 H); Mass spec. 157.06 (MH+), Calc. for C7H8ClNO 157.03.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:16])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared by a similar method to Example 1 from L-proline benzyl ester hydrochloride and 4-fluorobenzenesulphonyl chloride. The crude product was purified by column chromatography on silica gel eluting with dichloromethane to afford benzyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarboxylate as a clear oil.
Reaction SMILES: [F:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.[CH2:26]([O:28][CH2:29][CH2:30][NH2:31])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:26]([O:28][CH2:29][CH2:30][NH:31][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[C:3]([F:25])[C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:22])[CH3:27]
Reactant: Cn1c(Nc2nc3cc(F)c(F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)c(F)cc3s1)n2C

Procedure:
2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (31 mg) was prepared by following General Procedure F using 2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (36 mg), 2-ethoxy-ethyl amine (0.1 ml), HBTU (38 mg), and DIEA (0.2 ml). LCMS: m/z 433; and 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (m, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.76 (m, 1H), 7.65 (d, 1H), 7.48 (m, 2H), 3.66 (s, 3H), 3.47 (t, 2H), 2.88 (m, 4H), and 1.09 (t, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:16])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH3:15].[S:17](Cl)(Cl)=[O:18]>C1(C)C=CC=CC=1>[CH3:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[CH2:4][C:3]1[NH:16][S:17](=[O:18])[O:1][N:2]=1
Reactant: Cc1c(CC(N)=NO)ccc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(CC2=NOS(=O)N2)ccc2ccccc12
Temperature: 80 °C
Yield: 55.7 %

Procedure:
A suspension of N'-hydroxy-2-(1-methylnaphthalenyl)ethanimidamide (2.8 g, 13.1 mmol) in toluene (250 mL) was heated to 80° C. until all of the solid had dissolved. Thionyl chloride (1.86 g, 15.7 mmol) was added dropwise to the above solution under a stream of nitrogen, and a white precipitate was formed. The mixture was heated to reflux for 15 minutes, during which the precipitate dissolved to give an orange solution. The hot solution was filtered to remove trace solids and the filtrate was concentrated in vacuo to give a yellow solid. Recrystallization from toluene gave the desired product (1.90 g, 56%) as a light yellow solid, m.p. 118°-119° C. (dec.).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)C>[NH2:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Nc1ncnc(Cl)c1C(=O)O
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)O)n(-c3ccccc3)c(=O)c12
Yield: 29.7 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (270 mg, 0.89 mmol), 4-amino-6-chloropyrimidine-5-carboxylic acid (190 mg, 0.88 mmol, prepared according to Lan, Ruoxi et al from PCT Int. Appl. (2013), WO 2013040059 A1 20130321), DIEA (1.54 ml, 8.84 mmol) and cesium fluoride (403 mg, 2.65 mmol) were suspended in ethanol (10 ml) and the mixture was heated to reflux for 72 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography using SP1® Purification System (0% to 70%, ethyl acetate-methanol) to obtain 106 mg (27% yield) of the title compound. Purity: 90%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH3:20]I>CN(C=O)C>[CH3:20][O:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5]
Reactant: CI
Reactant: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC2CCCCO2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
An ice-cold yellow solution of 2-hydroxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (7.60 g, 32.17 mmol) in DMF (150 mL), was treated with NaH (0.93 g, 38.63 mmol) in portions over 30 min. The suspension was stirred for 15 min, then methyl iodide (3.0 mL, 48.09 mmol) was added dropwise. The mixture was warmed to rt, stirred for 1 h, then quenched with water and extracted with EtOAc. The extracts were washed with brine, dried (Na2SO4), filtered and concentrated to a yellow liquid. The crude product of 2-methoxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 6.50 (s, 1H), 6.49 (s, 1H), 5.54-5.52 (m, 1H), 3.87 (s, 1H), 3.88-3.80 (m, 1H), 3.67-3.61 (m, 1H), 2.57 (s, 3H), 2.10-1.95 (m, 1H), 1.95-1.82 (m, 2H), 1.80-1.58 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35](Br)=[CH:36][CH:37]=1)(=[O:32])=[O:31]>>[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=4)=[N:8][C:7]=23)=[CH:36][CH:37]=1)(=[O:32])=[O:31]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and 5-bomo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (180 mg, 63%). MS (ISN) 568.2 [(M−H)−]; mp 170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C@@H:13]1[CH2:15][O:14]1.[O:16]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>ClCCl>[O:16]1[C:20]2([CH2:25][CH2:24][N:23]([CH2:15][C@@H:13]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)[OH:14])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1ccc2nccc([C@@H]3CO3)c2c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Product: COc1ccc2nccc([C@@H](O)CN3CCC4(CC3)OCCO4)c2c1
Reaction time: 6 h

Procedure:
[R]-2-(6-Methoxyquinolin-4-yl)oxirane (1b) (470 mg) and 1,4-dioxa-8-azaspiro-[4,5]-decane (0.33 ml) were dissolved in dry dichloromethane (5 ml) and ytterbium triflate (30 mol %) was added. The mixture was stirred for 6 hours, filtered through celite, evaporated and chromatographed on silica gel (dichloromethane then methanol-dichloromethane) to afford the title compound (690 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:14][OH:15])=[CH:11][S:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].C(C1C=CC(C2C=C(C(F)(F)F)SC=2CO[C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])=[C:37]([CH3:48])[C:36]=2[CH3:49])=CC=1)C>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([CH2:14][O:15][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[C:37]([CH3:48])[C:36]=3[CH3:49])=[CH:11][S:12][CH:13]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2cscc2CO)cc1
Reactant: CCOC(=O)CCc1ccc(OCc2sc(C(F)(F)F)cc2-c2ccc(CC)cc2)c(C)c1C
Product: CCc1ccc(-c2cscc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 208 step 6 and 7 by coupling of (4-(4-ethylphenyl)thiophen-3-yl)methanol and ethyl 3-(4-hydroxy-2,3-dimethyl phenyl) propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-(trifluoromethyl)thiophen-2-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H), 7.36 (d, J=7.0 Hz, 2H), 7.28 (s, 1H), 7.22 (d, J=7.0 Hz, 2H), 6.95 (d, J=6.5 Hz, 1H), 6.67 (d, J=6.5 Hz, 1H), 4.98 (s, 2H0, 2.94 (t, J=7.0 Hz, 2H), 2.70 (m, 2H), 2.60 (t, J=7.0 Hz, 2H), 2.24 (s, 3H), 2.20 (s, 3H), 1.28 (t, J=6.5 Hz, 3H).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:23])[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O>C(O)C>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:23])[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CC(=O)c2cccs2)CC1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: O=C(CC1CCN(Cc2ccc[nH]c2=O)CC1)c1cccs1
Yield: 97.9 %

Procedure:
9.6 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-oxo-2-(2-thienyl)ethyl]piperidine obtained in Example 54 and 8.5 ml of thionyl chloride were dissolved in 60 ml of ethanol, and the mixture was heated under reflux for 3 hours. The solvent was evaporated, and then the residue was dissolved in chloroform and a 1N aqueous sodium hydroxide. The organic layer was separated, washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was recrystallized from ethanol, to give 9.0 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([N:10]2[CH2:31][C@H:30]([OH:32])[CH2:29][C@H:11]2[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH2:16][CH2:15]2)=[O:13])=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[C:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([N:10]2[CH2:31][C@H:30]([OH:32])[CH2:29][C@H:11]2[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:15]2)=[O:13])=[O:9])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)c2ccc(C(=N)N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)c1ccc(C(=O)N2C[C@H](O)C[C@H]2C(=O)N2CCC(OCC(=O)O)CC2)cc1

Procedure:
A solution of 1.60 g of t-butyl [[1-[(4R)-1-(p-amidino-benzoyl)-4-hydroxy-L-prolyl]-4-piperidinyl]oxy]acetate in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid is stirred at room temperature for 2 hours and evaporated. The residue is dissolved in ethanol and treated with ether. Suction filtration and drying of the precipitate gives 1.25 g of [[1-[(4R)-1-(p-amidinobenzoyl)-4-hydroxy-L-prolyl]-4-piperidinyl]oxy]acetic acid trifluoroacetate. M.p. 220° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][CH2:15][C:16](Cl)=[O:17]>>[Cl:14][CH2:15][C:16]([N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Product: O=C(CCl)N1CCCc2ccc([N+](=O)[O-])cc21

Procedure:
Using the procedure outlined in Description 4, the title compound was prepared from 7-nitro-1,2,3,4-tetrahydroquinoline (D1) (4.41 g, 25 mmol) and chloroacetyl chloride (2.2 ml, 27.6 mmol) as a dark brown solid (5.853 g). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.49 (br, 1H), 8.00 (dd, 1H), 7.33 (d, 1H), 4.27 (s, 2H), 3.86 (m, 2H), 2.90 (t, 2H), 2.09 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][C:7]([N+:16]([O-])=O)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Cl[Sn]Cl.O>C(O)C>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([NH2:16])=[CH:8][C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnc(C2CC2)c(-c2ccccc2)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cnc(C2CC2)c(-c2ccccc2)c1
Temperature: 80 °C
Yield: 57.1 %

Procedure:
A mixture of 2-cyclopropyl-5-nitro-3-phenylpyridine (0.25 mmol, 0.06 g) and SnCl2.H2O (0.89 mmol, 0.2 g) in ethanol (2 ml) was heated at 80° C. for 1 hour. The solvent was evaporated and the crude residue was dissolved in water. The solution neutralised with 6N NaOH aqueous solution and extracted with dichloromethane. The solid residue was purified by chromatography over SiO2 eluting with dichloromethane/methanol mixtures affording 6-cyclopropyl-5-phenylpyridin-3-amine (0.03 g, 57% of yield) of the expected product.
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:38]2[CH2:39][CH2:40][CH2:41][CH:36]([C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=4)[NH:32][CH:31]=3)[CH2:37]2)=[O:25])[CH2:15][CH2:14]1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Reactant: Fc1ccc2[nH]cc(C3CCCNC3)c2c1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)N2CCCC(c3c[nH]c4ccc(F)cc34)C2)CC1

Procedure:
The polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (338 mg, 1 mmole) was added to a solution of 5-fluoro-3-piperidine-3-yl-1H-indole (218 mg, 1 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×15 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The polar diastereoisomer of 3-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was purified by column chromatography [silica gel 60 (25 g); methanol (250 ml)]. It was obtained as a colourless solid in a yield of 200 mg (43%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.[C:28]1([C@@H:34]([NH2:36])[CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>O1CCOCC1>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:36][C@H:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:35])=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C[C@H](NC(=O)C1COCCN1c1nc(Cl)ncc1Br)c1ccccc1

Procedure:
To a 50 mL round-bottom flask were added 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 300 mg, 0.930 mmol), 1-hydroxybenzotriazole (126 mg, 0.930 mmol), and (S)-1-phenylethanamine (118 μl, 0.930 mmol) in 1,4-dioxane (9.3 mL) to give a green solution. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (178 mg, 0.930 mmol) was added to the solution, which was allowed to react at room temperature for 6 hours. The mixture was subsequently partitioned between aqueous saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C17H18BrClN4O2, 425.03. found 425.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([NH2:19])[CH:14]=1)[C:9]=2[NH2:20])(=[O:3])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(O)(=O)C>[C:21]([NH:19][C:13]1[CH:12]=[CH:11][C:10]2[C:15]([CH:14]=1)=[N:16][C:17]1[C:8](=[CH:7][CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:18]=1)[C:9]=2[NH2:20])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1ccc2c(N)c3ccc(N)cc3nc2c1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(N)c3ccc(NC(C)=O)cc3nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Acetamidyl-6,9-diaminoacridine (10 mg, 0.048 mmol) was dissolved in acetic acid (5 mL) and heated at reflux under a nitrogen atmosphere. Acetic anhydride (4.7 μL, 0.05 mmol) was added and reflux was continued for 10 min. On cooling to room temperature, the solution was concentrated to dryness and the residue was dissolved in water (10 mL) and washed with DCM (3×10 mL). The aqueous layer was lyophilised to give a brown solid.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19].Cl>CCO.[OH-].[Na+].CCOC(C)=O>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:12]([C:9]2[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=2)[N:13]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)n(-c2ccc(S(C)(=O)=O)cc2)n1
Reaction time: 0.08 h

Procedure:
4-(methylsulfonyl)phenylhydrazine hydrochloride (1.133 g, 5.09 mmol) and 4,4-dimethyl-3-oxopentanenitrile (0.697 g, 5.57 mmol) were weighed into a 100 mL RBF. 0.2 M HCl in EtOH (42 mL) was added and the suspension was heated to reflux for 27 h, during which time all solids gradually dissolved to give a yellow solution. The solution was diluted with 1 M NaOH(aq) (˜16 mL) to pH 12-13, EtOAc (70 mL) was added and the biphasic system was vigorously stirred for 5 min. The organic layer was isolated, dried (MgSO4), filtered and concentrated to give a yellow crystalline solid. Yield: 1.42 g (95%).