Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:23]=[N:22][C:10]3[S:11][CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:14]1[CH2:13][CH2:12][S:11][C:10]2[N:22]=[CH:23][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][C:9]1=2
Reactant: CC(C)(C)OC(=O)N1CCSc2ncc(N3CCOCC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1nc2c(cc1N1CCOCC1)NCCS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 7-morpholino-2,3-dihydro-1H-pyrido[2,3-b]-[1,4]thiazine-1-carboxylate (280 mg, 0.83 mmol) in DCM (2.0 mL) was added TFA (3.2 mL, 41.5 mmol). The reaction was stirred at rt for 2 h and evaporated in vacuo. The resulting residue was dissolved in DCM (40 mL) and washed with NaHCO3 (20 mL, saturated aqueous solution). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo to give 4-(2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl)morpholine as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.62 (1H, d, J=2.5 Hz), 6.26 (1H, d, J=2.5 Hz), 3.82-3.87 (4H, m), 3.59-3.63 (2H, m), 3.13-3.17 (2H, m), 3.06-3.10 (4H, m). Mass Spectrum (ESI) m/e=238.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1>C(N)CC>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:8][CH2:7][CH2:6][CH3:11])=[N:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1cccc(F)c1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1
Solvent: CCCN
Product: CCCNC(=Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-[3-(2,6-difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.0 g, 0.0025 mol), yellow mercuric oxide (0.64 g, 0.003 mol) and n-propylamine (20 ml) was stirred at room temperature for 48 hours. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 0.60 g (48%), m.p. 99°-100 ° C.
Reaction SMILES: [Cl-].[C:2]([CH2:5][O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH3+:13])([OH:4])=[O:3].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[OH-].[Na+]>[C:14]1([NH:20][C:21](=[O:22])[NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]2[O:6][CH2:5][C:2]([OH:4])=[O:3])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: [NH3+][C@@H]1CCCC[C@H]1OCC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CO[C@@H]1CCCC[C@H]1NC(=O)Nc1ccccc1
Yield: 39.3 %

Procedure:
To a solution of trans-2-carboxymethoxy-cyclohexyl ammonium chloride (0.419 g, 2 mmoles) in 2N NaOH (10 ml), phenylisocyanate (0.476 g, 4 mmoles) was added under stirring. After 1 hour the solution was extracted with diethyl ether (10 ml) and the aqueous phase was acidified with HCl 18% to pH 3. The title compound separated in the form of white crystals, which were filtered off and dried over P2O5. Thus, there were obtained 0.23 g (40%) of the title compound, melting point 166°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[C:6]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:5]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH:14]([CH3:15])[CH3:16])[CH3:13])[C:6]([C:17]([OH:19])=[O:18])=[C:5]2[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)N(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A solution of tert-butyl 6-chloro-2-(isopropyl(methyl)amino)-4-phenylquinoline-3-carboxylate (75 mg, 183 μmol), in DCM (1 ml) and TFA (1 ml) was stirred at room temperature for 2 h followed by a further 2 h at 40° C. The reaction mixture was concentrated in vacuo and the crude residue was dissolved in ethyl actetate and washed with water. The ethyl acetate layer was washed with 0.1N NaOH solution (2×) and then the aqueous layer was made acidic (pH 3-4) with 1N HCl and then further extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product as a light yellow solid (48 mg, 74%). MS (ESI): 355 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C:10]1=[O:23].[Cl:24][C:25]1[CH:38]=[CH:37][C:28]2[S:29][C:30]([S:33](Cl)(=[O:35])=[O:34])=[C:31]([CH3:32])[C:27]=2[CH:26]=1>>[C:21]([C:17]1[CH:16]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][C@H:9]([NH:8][S:33]([C:30]3[S:29][C:28]4[CH:37]=[CH:38][C:25]([Cl:24])=[CH:26][C:27]=4[C:31]=3[CH3:32])(=[O:35])=[O:34])[C:10]2=[O:23])[CH:20]=[CH:19][N:18]=1)#[N:22]
Reactant: N#Cc1cc(CN2CC[C@H](N)C2=O)ccn1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(S(=O)(=O)N[C@H]2CCN(Cc3ccnc(C#N)c3)C2=O)sc2ccc(Cl)cc12

Procedure:
The title compound is prepared as described in EXAMPLE 125, Part C using 4-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)pyridine-2-carbonitrile trifluoroacetate in place of 4-(3-(S)-amino-2-oxopyrrolidine-1-ylmethyl)-thiophene-2-carbonitrile hydrochloride and with 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride in place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with gradient of 25% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([OH:25])([CH3:24])[CH3:23])[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Br:36]N1C(=O)CCC1=O>CC#N.CCOC(C)=O>[Br:36][C:21]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)=[CH:12][CH:13]=2)[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])=[N:19][C:20]=1[C:22]([OH:25])([CH3:24])[CH3:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(O)c1nc(-c2ccccc2C(F)(F)F)n(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c1Br
Reaction time: 2 h
Yield: 86291.9 %

Procedure:
To a solution of 2-[1-(3′-methanesulfonyl-biphenyl-4-yl)-2-(2-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-propan-2-ol (100 mg, 0.20 mmol) in MeCN (2 mL, anhyd) was added N-bromosuccinimide (45 mg, 0.25 mmol). After 2 h, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, water (3×10 mL) and brine, then dried (Na2SO4) and concentrated. The residue was purified by chromatography (silica), eluting with EtOAc/hexanes (65:40 to 95:5) to yield the title compound (100 g, 86%) as a white solid. 1H-NMR (CD2Cl2): δ 8.10 (1H, m), 7.92 (1H, m), 7.86 (1H, m), 7.60-7.74 (4H, m), 7.47 (2H, m), 7.25-7.31 (3H, m), 3.56 (1H, s), 3.06 (3H, s), 1.66 (6H, s); MS (ES): 579, 581 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH2:28])=[N:10][CH:11]=[N:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([C:31]1([C:34](O)=[O:35])[CH2:33][CH2:32]1)#[N:30]>>[NH2:28][C:9]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:34]([C:31]3([C:29]#[N:30])[CH2:33][CH2:32]3)=[O:35])[CH:7]=[CH:6][CH:5]=2)=[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[N:12]=[CH:11][N:10]=1
Reactant: Nc1cccc(-c2c(N)ncnc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: N#CC1(C(=O)O)CC1
Product: N#CC1(C(=O)Nc2cccc(-c3c(N)ncnc3Oc3ccc(Oc4ccccc4)cc3)c2)CC1
Yield: 66 %

Procedure:
N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-1-cyanocyclopropanecarboxamide was prepared from 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and 1-cyanocyclopropanecarboxylic acid using Method E (66% yield). HPLC: 100%, RT=4.485 min. MS: m/z=465 [M+H]+, RT=2.26 min. 1H-NMR (DMSO-d6) δ 10.07 (s, 1H), 8.10 (s, 1H), 7.64-7.61 (m, 2H), 7.43-7.36 (m, 3H), 7.18 (d, 1H), 7.11 (t, 1H), 7.06 (d, 2H), 7.00-6.97 (m, 4H), 6.58 (broad s, 2H), 1.65 (s, 4H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]([CH3:18])([CH2:15][NH:16][NH2:17])[C:13]#[N:14].C(N(CC)CC)C>O1CCOCC1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:16]([CH2:15][C:12]([CH3:18])([CH3:11])[C:13]#[N:14])[NH2:17]
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C#N)CNN
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C#N)CN(N)c1nc2ccccc2o1
Reaction time: 8 h

Procedure:
A solution of 2,2-dimethyl-2-cyanoacetaldehyde (9.4 g.) in ethanol (100 ml.) is added dropwise to a solution of hydrazine hydrate (40 g.) in ethanol (400 ml.), heated under reflux over a period of 3 hours. The solvent and excess of reagent are removed in vacuo to give 2,2-dimethyl-2-cyanoacetaldehyde hydrazone. This is dissolved in ethanol (100 ml.) and treated at room temperature with sodium borohydride (3.7 g.). The reaction mixture is stirred for two hours, acidified with acetic acid to pH 5, diluted with water and extracted with methylene chloride. The organic phase is dried and concentrated in vacuo to give 2,2-dimethyl-3-hydrazinopropanenitrile. A solution of 2-chlorobenzoxazole (15.3 g.) in dioxane (150 ml.) is added dropwise at 0° C. to a solution of 2,2-dimethyl-3-hydrazinopropanenitrile (11.3 g.) and triethylamine (10.1 g.) in dioxane (400 ml.). Stirring is continued overnight at room temperature. The precipitate is filtered and the filtrate concentrated in vacuo. The residue is washed with water and crystallized to give 3-[1-(2-benzoxazolyl) hydrazino)-2,2-dimethylpropanenitrile.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:1]
Reactant: OCc1ccc(OCc2ccccc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
A mixture of 4-hydroxymethylphenoxy phenyl methane (1.07g.; 0.005 mole) and active manganese dioxide (0.44g.; 0.005 mole) in dry acetone (20ml) was stirred under dry nitrogen for 18 hrs. at room temperature. The inorganic salts were then filtered off to yield 4-formylphenoxy phenyl methane identified by TLC.
Reaction SMILES: [K].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([SH:13])=[N:10][N:9]=1.Br[C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18](O)=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=1.CN(C=[O:34])C>O>[C:21]([C:19]1[CH:20]=[C:15]([OH:34])[CH:16]=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:18]=1[S:13][C:11]1[O:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)=[N:9][N:10]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Reactant: Sc1nnc(-c2ccccn2)o1
Agent: [K]
Solvent: O
Product: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1Sc1nnc(-c2ccccn2)o1
Temperature: 110 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
To a stirring heterogeneous mixture of 5-(2-pyridyl)-1,3,4-oxadiazole-2-thiol potassium salt (2.17 g, 0.19 mol) in DMF (25 ml) under an N2 atmosphere, was added 2.85 g (0.01 mol) of 4-bromo-2,6-ditertbutylphenol. The mixture was stirred for 24 h at 110° C. After cooling, the slurry was diluted with water (100 ml) and extracted with Et2O (4×35 ml). The Et2O extracts were combined and washed with water (2×50 ml) and saturated NaCl solution (50 ml) and then dried (MgSO4). The solvent was removed in vacuo to give a solid. Chromatography on silica gel using 1/4 ethyl acetate/hexanes gave 2-(2,6-ditertbutyl-4-hydroxyphenyl)thio-5-(2-pyridyl)-1,3,4-oxadiazole (45) as a white solid (1.5 g, 40% yield; mp 128°-129° C.).
Reaction SMILES: C([N+](CC)(CC)S(NC(=O)OC)(=O)=O)C.[C:16]([NH:24][C:25]1[S:26][CH2:27][C@@H:28]2[CH2:34][C@H:33]([C:35]([NH:37][CH:38]([CH3:41])[CH:39]=O)=[O:36])[O:32][CH2:31][C@:29]2([C:42]2[CH:47]=[C:46]([Br:48])[CH:45]=[CH:44][C:43]=2[F:49])[N:30]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br:48][C:46]1[CH:45]=[CH:44][C:43]([F:49])=[C:42]([C@:29]23[CH2:31][O:32][C@@H:33]([C:35]4[O:36][CH:39]=[C:38]([CH3:41])[N:37]=4)[CH2:34][C@H:28]2[CH2:27][S:26][C:25]([NH:24][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:30]3)[CH:47]=1
Reactant: CC(C=O)NC(=O)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Solvent: Cc1ccccc1
Product: Cc1coc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(Br)ccc3F)CO2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl N-(triethylammoniumsulfonyl)carbamate (Burgess reagent) (0.811 g, 3.40 mmol) was added to a solution of (4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-N-(1-oxopropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxamide (C39) (0.747 g, 1.36 mmol) in toluene (34 mL). The resulting solution was stirred at room temperature for 10 minutes, followed by heating to 65° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a yellow oily residue. Yield: 417 mg, 58%. LCMS m/z 532.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.17 (br s, 2H), 7.36-7.54 (m, 5H), 7.36 (q, J=1.2 Hz, 1H), 7.01-7.06 (m, 1H), 4.83 (dd, J=12.0, 2.4 Hz, 1H), 4.31 (dd, J=11.9, 1.6 Hz, 1H), 3.07 (dd, J=13.0, 3.8 Hz, 1H), 2.70 (m, 1H), 2.58-2.54 (m, 1H), 2.17 (d, J=1.7 Hz, 3H), 2.08-2.14 (m, 1H).
Reaction SMILES: C(O[K])(C)(C)C.[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>O1CCOCC1.O>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([O:18][C:20]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=2[CH:22]=[O:23])[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)(C)O[K]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2C=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.9 %

Procedure:
tBuOK (948 mg; 8.44 mmol; 1.2 eq.) was added to a solution of 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.46 g; 8.44 mmol; 1.2 eq.) in 1,4-dioxane (5 mL) and the solution was stirred at room temperature for 15 minutes whereupon a solution of 2,4-difluoro-benzaldehyde (1 g; 7.04 mmol; 1 eq.) in 1,4-dioxane (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 5 minutes then diluted with water. The solution was extracted with DCM (2×) and the combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptanes/EA) afforded the title compound (705 mg, 34%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.41 (d, J=0.8 Hz, 1H), 7.93 (dd, J=8.7, 6.8 Hz, 1H), 6.99-6.72 (m, 1H), 6.33 (dd, J=10.2, 2.2 Hz, 1H), 5.07-4.85 (m, 1H), 4.40 (ddd, J=9.9, 6.4, 1.1 Hz, 2H), 4.10 (ddd, J=9.9, 4.0, 1.1 Hz, 2H), 1.48 (s, 9H). HPLC (max plot) 96.4%; Rt 4.22 min.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:36])[F:37])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[CH2:7]1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.8 %

Procedure:
To a solution of 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (2.95 g, 14.73 mmol) in DCM (120 ml) was added DIPEA (5.40 ml, 30.9 mmol) and then 4-(trifluoromethyl)benzenesulfonyl chloride (3.96 g, 16.20 mmol). The reaction mixture was stirred 2.5 hours at room temperature then washed with water (250 ml), dried on a phase separation cartridge and concentrated in vacuo. The obtained product was dissolved in 1,4-dioxane (60 ml) and treated with 4M aq. HCl in 1,4-dioxane (18.41 ml, 73.6 mmol) overnight. The mixture was concentrated under vacuo then dissolved in EtOAc (150 ml), washed with 2N aq. NaOH solution (200 ml) then dried on a phase separation cartridge and concentrated in vacuo. The product was then dissolved in EtOAc (100 ml) and extracted with 2M aq. HCl (2×200 ml). 2M aq. NaOH solution was added to the aqueous layer until basic pH then the product was extracted with EtOAc (500 ml). The organic layer was dried on a phase separation cartridge and concentrated under vacuo to give the title compound (3.76 g).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[C:8]([CH3:18])=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2[NH:10][N:9]=[C:8]([CH3:18])[C:7]=2[N:6]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccccc1Cl
Solvent: O
Product: Cc1n[nH]c2c1nc(-c1ccccc1Cl)c1ccccc12

Procedure:
The preparation took place in analogy to Example 33 (B), using 401 mg of 2-chloro-N-(3-methyl-5-phenyl-1H-pyrazol-4-yl)-benzamide. The reaction mixture was diluted with water and extracted with dichloromethane. The organic portion was concentrated under reduced pressure and purified by MPLC (4 g SiO2, dichloromethane/methanol=99/1→50/50) to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]2([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:4]=[CH:3]1.Cl.[F:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]2([NH:14][C:15](=[O:18])[CH2:16][N:30]3[CH2:31][CH2:32][CH:27]([C:25](=[O:26])[C:24]4[CH:23]=[CH:22][C:21]([F:20])=[CH:34][CH:33]=4)[CH2:28][CH2:29]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:4]=[CH:3]1
Reactant: O=C(CCl)NC1(c2ccc(=O)[nH]c2)CCCCC1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(C(=O)c2ccc(F)cc2)CC1)NC1(c2ccc(=O)[nH]c2)CCCCC1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A mixture of N-[1-(1,6-dihydro-6-oxo-3-pyridinyl)cyclohexyl]chloroacetamide (1.74 g), 4-(4-fluorobenzoyl)piperidine hydrochloride (1.57 g) and diisopropylethylamine (1.67 g) was heated in 35 ml of refluxing acetonitrile for 1 hour. The resulting suspension was cooled to room temperature and the solid was collected, yielding 1.8 g of solid. Recrystallization from methanol gave 1.1 g of product as a solid, m.p. 243°-245° C. (dec).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)CCC.Br[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:10]=1
Reactant: Brc1ccccn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(-c3ccccn3)c2)cc1
Yield: 77.9 %

Procedure:
The crude 4-tributylstannyl-1-trityl-1H-imidazole (1.37g) in toluene (10 mL) was treated sequentially with 2-bromopyridine (0.33 mL, 3.43 mmol) and Pd(PPh3)4 (0.26 g, 0.23 mmol). The reaction mixture was heated at reflux under an argon atmosphere for 4 hours. After cooling, the reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform (50 mL) and sequentially washed with aqueous saturated potassium fluoride (75 mL), water (75 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in-vacuo to afford 0.69 g of crude 4-(2-pyridyl)-1-trityl-1H-imidazole.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[C:5]([F:18])=[CH:4][CH:3]=1.[NH3:19]>C(O)CO.[Cu-]=O>[NH2:19][C:2]1[N:7]=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[C:5]([F:18])=[CH:4][CH:3]=1
Reactant: C[C@]1(c2nc(Br)ccc2F)N=C(N)OCC1(F)F
Reactant: N
Agent: O=[Cu-]
Solvent: OCCO
Product: C[C@]1(c2nc(N)ccc2F)N=C(N)OCC1(F)F
Temperature: 60 °C

Procedure:
To a solution of (R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (8.73 g, 23.17 mmol) in ethylene glycol (139 ml) and aq. NH3 (w=25%, 108 ml) in an autoclave was added copper(I) oxide (497 mg, 3.47 mmol) and the mixture was warmed to 60° C. over night. After cooling to rt the mixture was extracted with EtOAc, the organic layer was washed with aq. NH3 (w=12%, 2×), the combined organic layers were washed with sat. aq. NaCl, dried with Na2SO4 and evaporated. The residue was dissolved in TBME and extracted with 1N HCl (2×). The combined aq. layers were basified by addition of solid Na2CO3 some NaCl was added and the aq. solution extracted with DCM (4×). The combined DCM extracts were dried with K2CO3 and evaporated to provide the title compound as greyish resin. The crude material was used for the next step without further purification.
Reaction SMILES: Cl.[CH:2]([N:5]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:6][CH2:7]Cl)([CH3:4])[CH3:3].[NH:15]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[C:16]1=[O:17]>>[CH:2]([N:5]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:6][CH2:7][N:15]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[C:16]1=[O:17])([CH3:4])[CH3:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)N(CCCl)C1CCCCC1
Agent: Cl
Product: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C1CCCCC1
Yield: 75.5 %

Procedure:
By using the 2-(N-isopropylcyclohexylamino)ethyl chloride hydrochloride obtained and isatin, a method analogous to that described in Reference Example 1 was carried out to obtain 1-[2-(N-isopropylcyclohexylamino)ethyl]isatin having a melting point of 103°-106° C (yield: 75.5%, recrystallizing solvent: ethyl acetatehexane).