Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[H-].[Na+].[CH3:31]I.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)[CH2:19][CH2:20]2)=[O:14])=[C:6]([N:8]([CH3:31])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3NS(C)(=O)=O)CC2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N(C)S(C)(=O)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-{5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (634 mg) described in Preparation Example 226 was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (65.1 mg, 60% in oil) was added under ice-cooling. After stirring at room temperature for 10 min, methyl iodide (93 μL) was added, and the mixture was stirred overnight. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (670 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N=C=N.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)Cl.CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][N:34]([C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=2)[CH2:33][CH2:32]1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Agent: N=C=N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Cc4ccc(C(C)C)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
To a solution of 4-isopropylphenylacetic acid (36 mg, 0.2 mmol) in anhydrous DCM (1 mL) was added PS-carbodiimide (100 mg, 0.3 mmol) and the mixture was shaken at rt for 15 min. Then, a solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (27.5 mg, 0.1 mmol), as prepared in Example 1d, in anhydrous DMF (1 mL) was added to the mixture and it was shaken overnight at rt. It was then filtered and the resin was washed with THF/DCM and the combined filtrate and washings were concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 1% MeOH/DCM) to yield 13.4 mg (31%) of pure 1-[4-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-1-yl]-2-(4-isopropyl-phenyl)-ethanone. 1H-NMR (300 MHz, CDCl3): δ 9.06 (s, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 7.23-7.19 (m, 4H), 4.82 (d, 1H), 4.17-4.00 (m, 7H), 3.76 (m, 2H), 3.57 (m, 1H), 3.23 (m, 1H), 2.96-2.80 (m, 2H), 2.06-1.80 (m, 4H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 433.2, found 434.4 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1>>[Br:1][C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)nicotinamide (Stage 212.2) and (R)-pyrrolidin-3-ol to afford a solid. UPLC-MS (Condition 3) tR=1.05 min, m/z=478.1 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[N:26]3)=[CH:21][C:20]=2[CH3:34])[C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40].C(=O)=O.C(O)C>>[CH:1]1([N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:27]=[N:26]3)=[CH:21][C:20]=2[CH3:34])[C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1
Reactant: COC(=O)CCN
Agent: Cl
Agent: O=C=O
Solvent: CCO
Product: COC(=O)CCNC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1

Procedure:
The title compound was prepared by a method analogous to that described in Steps B-C of Example 82, using (+/−)-methyl 6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinate in Step B and methyl 3-aminopropanoate hydrochloride in Step C. Racemic methyl 3-(6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinamido)propanoate was purified by chiral SFC to afford Isomer 1 and Isomer 2, which were used in conversion to the final enantiopure products. Chiral SFC: Chiralpak AD-H, 4.6×250 mm, 5 μm. Modifier: 0.05% DEA. Mobile Phase: 60/40 CO2/ethanol. Flow: 2.35 mL/min. Retention time: 5.19 minutes (Isomer 1) and 7.83 minutes (Isomer 2).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11]>>[CH3:14][O:13][C:9]([CH2:10][CH2:11][N:1]([CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH2:11][CH2:10][C:9]([O:13][CH3:14])=[O:12])=[O:12]
Reactant: NCc1cccnc1
Reactant: C=CC(=O)OC
Product: COC(=O)CCN(CCC(=O)OC)Cc1cccnc1

Procedure:
52.06 Grams of 3-aminomethylpyridine was refluxed with 200 milliliters of methyl acrylate for 96 hours. The excess methyl acrylate was evaporated off to give 137.6 grams of 3-[N,N-di(2-methoxycarbonylethyl)aminomethyl] pyridine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>O1CCCC1.C(N(CC)CC)C>[CH3:8][S:9]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tetrahydro-2H-pyran-4-ol (20 g) in tetrahydrofuran (150 mL) and triethylamine (28.5 mL) is slowly added methanesulfonyl chloride (15.5 mL), while keeping the temperature below 30° C. The mixture is stirred for 12 hours at room temperature. The precipitate is filtered off and washed twice with tetrahydrofuran. The combined organic phases are concentrated and partitioned between ethyl acetate and water. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 29.4 g; TLC: rf=0.36 (silicagel, petrole ether/ethyl acetate 1:1); Mass spectrum (ESI+): m/z=198 [M+NH4]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (466 mg, 1.5 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (446 mg, 1.5 mmol) according to the general procedure M. Obtained as an orange oil (310 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4](F)[C:3]=1[NH2:10].S(=O)(O)[O-].[Na+].[CH3:16]N(C)C(=O)C>C(OCC)(=O)C>[N:10]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:16]=1
Reactant: Nc1cc(F)cc(F)c1N
Reactant: CC(=O)N(C)C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: c1ccc2[nH]cnc2c1
Temperature: 120 °C

Procedure:
Aldehyde 1e (2.05 g, 4.28 mmol), 1,2-diamino-3,5-difluorobenzene (617 mg, 4.28 mmol) and sodium bisulfite (891 mg, 8.57 mmol) were dissolved in N,N-dimethylacetamide (43 mL) and heated in a 120° C. oilbath for 21 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with half-saturated aqueous sodium chloride solution (75 mL, a 1:1 mixture of deionized water and saturated aqueous sodium chloride solution). The aqueous layer was back-extracted with ethyl acetate (2×100 mL). All the organic extracts were combined, dried over magnesium sulfate, and concentrated to a brown tar (3.39 g). This crude material was purified by silica gel chromatography (eluting with a gradient of 70% to 100% ethyl acetate in hexanes), to give benzoimidazole product 1f (2.11 g, 81%) as a tan foam: 1H NMR (CD3OD) δ 8.46 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.46 (dd, J=1.3, 8.6 Hz, 1H), 7.13 (m, 1H), 6.84 (m, 1H), 5.99 (dd, J=2.3, 9.9 Hz, 1H), 4.60 (s, 2H), 4.01 (m, 1H), 3.86 (m, 1H), 3.32 (m, 2H, obscured by solvent peak) 2.67 (m, 1H), 2.28 (s, 3H), 2.18 (m, 2H), 1.89 (m, 1H), 1.73 (m, 2H), 1.47 (s, 9H), 1.13 (t, J=7.1 Hz, 1H). Anal. (C33H36F2N6O3.0.4 H2O) C, H, N, F.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.CON(C)[C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1)=[O:33]>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cc(F)c(OCc2ccccc2)c(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc(F)cc(F)c2OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of 2-(benzyloxy)-1-bromo-3,5-difluorobenzene (13.7 g, 46 mmol) in anhydrous THF (100 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (18.4 mL, 46 mmol). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (10.43 g, 38.3 mmol) in anhydrous THF (40 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl solution (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with AcOEt/hexane (1:20→1:10) to provide (R)-tert-butyl 3-(2-(benzyloxy)-3,5-difluorobenzoyl)piperidine-1-carboxylate (6.4 g, 32%) as a light yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][NH2:8])=[O:4].[Cl:32][CH2:33][CH2:34][CH2:35][S:36](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:38])=[O:37]>>[Cl:32][CH2:33][CH2:34][CH2:35][S:36]([NH:8][CH2:7][CH:6]([O:5][C:3](=[O:4])[NH:2][CH3:1])[CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:38])=[O:37]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC(=O)NC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC(=O)NC

Procedure:
2-Methylcarbamoyloxy-3-octadecylcarbamoyloxypropylamine IVc2 is allowed to react and worked up by the same procedure as described in (4). m.p. 102°-104° C. The summary of the experimental condition and the physical data of the product are listed in the Table 7.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:17])C(OCC)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]([NH2:21])[CH2:19][NH2:20]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11](=[O:17])[NH:20][CH2:19][CH2:18][N:21]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NCCN
Reactant: CCOC(=O)C(=O)Cc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: O=C1NCCN=C1c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with ethyl 4-nitrophenylpyruvate (223 mg, 1.00 mmol), 3 pieces of molecular sieves (4-8 mesh, 3A) and anhydrous methanol (10 mL). The resulting solution was cooled to 0° C. with an ice bath and 1,2-ethylenediamine (63 mg, 1.05 mmol) was added dropwise. After addition was complete the reaction was stirred at room temperature for 1 h. After this time the resulting suspension was filtered and the filter cake washed with cold methanol (2×5 mL). The filter cake was dried in an oven at 50° C. overnight under vacuum to afford 31 in 89% yield (196 mg) as a white solid: mp 191-192° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.63 (bs, 1H), 8.26 (d, 2H, J=8.0 Hz), 8.09 (d, 2H, J=8.0 Hz), 3.88 (t, 2H, J=6.5 Hz), 3.37 (m, 2H); MS (ESI+) m/z 220 (M+H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16]2=[CH:19][NH:20][CH:21]=[C:15]2[C:14]1=[O:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].CN([CH:26]=[O:27])C>>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16]2=[C:19]([CH:26]=[O:27])[NH:20][CH:21]=[C:15]2[C:14]1=[O:22])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]cc2C1=O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2c(c[nH]c2C=O)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
POCl3 (0.646 mL, 6.93 mmol) was added dropwise to the ice-cooled DMF (1.5 mL, 18.9 mmol). After stirring at room temperature for 30 minutes, the mixture was re-cooled to −5° C. and to it was added a solution of the above 4-oxo-2,4,6,7-tetrahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester (1.5 g, 6.3 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with ice cubes followed by the addition of 10 N potassium hydroxide, adjusting pH to 11-12. After stirring for 30 minutes, the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried, and concentrated to give 1.2 g of 1-formyl-4-oxo-2,4,6,7-tetrahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]([Cl:11])[CH2:9][CH:8]([CH2:12][CH3:13])[CH2:7][C:5]=2[N:6]=1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>N1C=CC=CC=1>[CH2:12]([CH:8]1[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:15](=[O:16])[O:17][CH2:18][CH3:19])[S:3][C:4]=2[CH:10]([Cl:11])[CH2:9]1)[CH3:13]
Reactant: CCC1Cc2nc(N)sc2C(Cl)C1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2c(s1)C(Cl)CC(CC)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-5-ethyl-7-chloro-4,5,6,7-tetrahydrobenzothiazole (0.10 mol) dissolved in pyridine (125 ml.) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. Ethyl chloroformate (0.12 mol) is then added dropwise to the reaction mixture with stirring and cooling. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is poured into ice water to form a precipitate. The precipitate is recovered by filtration, is dried and recrystallized to yield the desired product ethyl N-(5-ethyl-7-chloro-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14](O)=O)=[CH:12][N:11]=[C:10]([CH2:17][N:18]2[N:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]2)[N:9]=1.N1C(C)=CC=CC=1C.CS(Cl)(=O)=O.[NH2:40][C:41]1[C:49]([CH3:50])=[CH:48][C:47]([Cl:51])=[CH:46][C:42]=1[C:43]([OH:45])=[O:44]>C(#N)C>[Cl:51][C:47]1[CH:48]=[C:49]([CH3:50])[C:41]2[N:40]=[C:14]([C:13]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:9][C:10]([CH2:17][N:18]4[N:22]=[N:21][C:20]([C:23]([F:24])([F:26])[F:25])=[N:19]4)=[N:11][CH:12]=3)[O:44][C:43](=[O:45])[C:42]=2[CH:46]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cnc(Cn4nnc(C(F)(F)F)n4)nc3-c3ccccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
At RT, 385 mg (1.30 mmol) of 4-(2-chlorophenyl)-2-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl}pyrimidine-5-carboxylic acid was initially charged in 5 ml of acetonitrile, and 0.27 ml (2.33 mmol) of lutidine was added. With stirring, the solution was then cooled to 0° C., 0.14 ml (1.78 mmol) of methanesulphonyl chloride, dissolved in 2 ml of acetonitrile, was added dropwise and the mixture was stirred at 0° C. for another 15 min. A little at a time, an acetonitrile suspension (3 ml) of 0.53 ml (4.54 mmol) of lutidine and 289 mg (1.56 mmol) of 2-amino-5-chloro-3-methylbenzoic acid was then added to this reaction mixture, and stirring was continued for another 15 min. 0.14 ml (1.78 mmol) of methanesulphonyl chloride, dissolved in 2 ml of acetonitrile, was then added dropwise. The reaction was stirred overnight, with the temperature increasing to RT. The solvent was removed under reduced pressure. The residue was then poured into ice-water and mixed in an ultrasonic bath. The residue was filtered off, again taken up in water and sonicated once more. The residue is filtered off, washed with water and dried under reduced pressure. 708 mg (88% of theory; content 86%) of the desired product were isolated. There was not further purification.
Reaction SMILES: [OH:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[S:6][C:7]([C:9]#[N:10])=[CH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH:27]([F:29])[F:28]>O>[F:28][CH:27]([F:29])[O:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[S:6][C:7]([C:9]#[N:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: FC(F)Cl
Reactant: COc1cc2sc(C#N)cc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2sc(C#N)cc2cc1OC(F)F
Temperature: 40 °C

Procedure:
A mixture of 5-hydroxy-6-methoxy-benzo[b]thiophene-2-carbonitrile (10.30 g) and anhydrous potassium carbonate (7.63 g) was treated with a solution of dry dimethylformamide (110 ml) which has been previously saturated with chlorodifluoromethane gas. The mixture was then sealed in an autoclave, stirred, and heated to 40° C. After 3 days the reaction mixture was cooled and poured into water (700 ml). The resultant precipitate was iiltered off, dried, and extracted with hot dichloromethane (300 ml). The organic extract was concentrated then poured through a column of fine silica (200 g). The appropiate fractions were combined and evaporated to dryness to give 5-difluoromethyloxy-6-methoxy-benzo[b]thiophene-2-carbonitrile as an off-white solid (5.49 g), m.p. 99°-101° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Br[C:19]1[C:28]2[C:23](=C[CH:25]=[C:26](OC)[N:27]=2)[N:22]=[CH:21]C=1N>CN(C)C=O>[CH3:19][C@H:28]1[CH2:23][N:22]([CH3:21])[CH2:25][CH2:26][N:27]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C)CCN1c1nccc(N)n1
Temperature: 220 °C
Yield: 27.5 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (200 mg, 1.544 mmol), Hunig's base (1348 μl, 7.72 mmol) and (3S)-1,3-dimethylpiperazine (Ref.: WO2009061879 (A1)) (318 mg, 1.698 mmol) in N,N-dimethylformamide (DMF) (1.7 ml) was heated to 220° C. via a microwave reactor for 15 min. The reaction mixture was purified by RP-HPLC to yield 2-[(2S)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (88 mg, 0.425 mmol, 28% yield). MS (ES+) m/z 208.0 (MH+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.S(Cl)([Cl:16])(=O)=O>>[Cl:16][C:9]1[CH:8]=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1cccc(OC(F)(F)F)c1
Product: Oc1ccc(Cl)c(OC(F)(F)F)c1

Procedure:
A solution of 3-trifluoromethoxyphenol and sulfuryl chloride is stirred at room temperature until conversion of starting material to product is complete. The excess of sulfuryl chloride is evaporated using a rotary evaporator. The residue is dissolved in dichloromethane and washed with water. The organic layer is separated, dried over MgSO4, filtered and concentrated to yield crude 4-chloro-3-trifluoromethoxyphenol. The crude product is purified over a silica gel column using to give purified product that is used with or without further purification in the following reaction.
Reaction SMILES: [CH3:1][NH:2][NH2:3].Cl[C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1>CCOCC>[CH3:1][N:2]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[NH2:3]
Reactant: Clc1nc2ccccc2o1
Reactant: CNN
Solvent: CCOCC
Product: CN(N)c1nc2ccccc2o1
Temperature: 0 °C

Procedure:
To an ice cooled solution of 16.2 ml. of methylhydrazine in 100 ml. of dry ether is added 10.8 g. of 2-chlorobenzoxazole at a dropwise rate, keeping the temperature below 25° C. The mixture is stirred 30 min. in the ice bath and 2 hours at room temperature and then carefully evaporated. The residue is slurried with 200 ml. cold water, filtered, washed and dried to give 9.5 g. of 2-(1-methylhydrazine)benzoxazole, m.p. 128°-31°.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3([CH3:20])[O:19][CH2:18][CH2:17][O:16]3)[C:10]=2[F:21])[CH2:5][CH2:4]1)[CH3:2].Cl>[Pd].CO>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3([CH3:20])[O:16][CH2:17][CH2:18][O:19]3)[C:10]=2[F:21])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(C3(C)OCCO3)c2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCC(c2cccc(C3(C)OCCO3)c2F)CC1

Procedure:
Preparation according to preparation 18: 1-ethyl-4-[2-fluoro-3-(2-methyl-1,3-dioxolan-2-yl)phenyl]-1,2,3,6-tetrahydropyridine (0.73 g, 2.5 mmol), methanol (20 ml), palladium on carbon (0.32 g) and hydrochloric acid (0.2 ml, conc). Yield: 0.7 g. MS m/z (relative intensity, 70 eV) 293 (M+, 23), 292 (12), 279 (15), 278 (bp) 84 (16).
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+].[CH2:24]([NH2:27])[CH2:25][NH2:26]>>[NH2:26][CH2:25][CH2:24][NH:27][C:12]1[CH:13]=[C:14]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3
Reactant: NCCN
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Product: NCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (1.58 g, 4.0 mmol) in ethylenediamine (Aldrich, 70 mL) was added NaH (Aldrich, 95%, 1.0 g, 40 mmol) in small portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated to 120° C. for 1.5 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (3×150 mL). The combined organic extracts were successively washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude 5-(2-amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a brown solid. (Yield 1.1 g, 88.7%).