Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:17])[CH3:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1.[F-].[K+]>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:1][C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:17])[CH3:16])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1
Reactant: CC(=O)Nc1cc(N)cc(-c2ccccc2)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Nc2ccc(Br)cc2[N+](=O)[O-])cc(-c2ccccc2)c1
Yield: 52 %

Procedure:
A solution of N-(5-aminobiphenyl-3-yl)acetamide (1 g, 4.54 mmol), 4-bromo-1-fluoro-2-nitrobenzene (1.03 g, 4.54 mmol, 1.0 eq.) and potassium fluoride (0.26 g, 4.54 mmol, 1.0 eq.) in DMF (5 ml) was heated at 100° C. for 12 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the product in 52% yield (1 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)(O)[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6](/[CH:14]=[C:15](/[C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)\[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: COc1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
To a stirred solution of 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(4-methoxyphenyl)propan-2-ol (0.145 g, 0.39 mmol) in DCM (10 mL) at −78° C. was added borontribromide (0.293 g in 5 mL DCM). The reaction mixture was stirred at −78° C. for 30 min. and then at 25° C. for 1 h. The solution was poured into ice water, basified with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by HPLC to obtain 12 mg of product as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.50 (d, 2H), 7.30 (s, 1H), 7.16 (d, 1H), 7.08 (d, 1H), 6.90 (s, 1H), 6.82 (d, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 3.80 (m, 1H), 3.60 (m, 1H), 3.10 (m, 5H), 2.40 (s, 3H), 1.85 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:20]([C:21](=[O:23])[CH3:22])=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:30])[CH:17]=3)[C:12]2=[O:31])=[CH:6][CH:5]=1.CO.[OH-].[Na+]>C1COCC1>[C:21]([C:20]1[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:17][C:16]([Cl:30])=[CH:15][CH:14]=2)(=[O:23])[CH3:22]
Reactant: COC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Reaction time: 12 h
Yield: 82.6 %

Procedure:
To a solution of 4-[(3-acetyl-6-chloro-1-oxo-4-phenyl-1H-isoquinolin-2-yl)methyl]benzoic acid methyl ester (1.5 g) in THF (15 ml) were added methanol (15 ml) and 8N-aqueous sodium hydroxide solution (0.8 ml) at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure, water and 10% hydrochloric acid were added to the residue. The aqueous layer was acidified and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization (ethyl acetate-hexane) to give the title compound (1.2 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[C:12](=[CH:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1>CO.[C].[Pd]>[CH3:1][C:2]1[S:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)NCC=C1CCc2ccc3nc(C)sc3c21
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCC1CCc2ccc3nc(C)sc3c21
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
N-[2-(2-Methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]thiazol-8-ylidene)ethyl]acetamide (61.0 mg, 0.224 mmol) was dissolved in methanol (3 mL), a 10% palladium-carbon powder (10 mg) was added, and the mixture was stirred at room temperature for 15 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0-95/5) to give the title compound (49.6 mg, yield 81%).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:21])[CH:3]=1.C=O.[OH-].[K+].[O:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O.C(O)=O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:26][CH2:30][CH:29]4[CH2:4][CH2:5][N:6]([CH3:7])[CH2:27][CH2:28]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:21])[CH:3]=1
Reactant: COc1ccc2ncnc(Nc3ccc(Br)cc3F)c2c1
Reactant: C1CCOC1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 81 °C
Reaction time: 5 h

Procedure:
7-(1-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (40 g), water (16 ml), formic acid (43 ml) and aqueous formaldehyde (37% w/w, 33 ml) were added to a vessel equipped with overhead stirrer, reflux condenser and thermometer. The reaction mixture was heated to 81° C. and stirred at this temperature for 5 hours. The reaction mixture was cooled to 60° C. and tetrahydrofuran (178 ml) was added. The temperature of the reaction mixture was adjusted to 40° C. and potassium hydroxide (49% w/w, 84 ml) was added, followed by water (22 ml). The aqueous phase was separated and discarded. The organic phase was adjusted to 60° C. and water (107 ml) and butyl acetate (107 ml) were added. The aqueous phase was separated and discarded. The organic phase was filtered, following through with tetrahydrofuran (18 ml) wash. The temperature of the filtrates was adjusted to 60° C. and butyl acetate (107 ml) was added. The reaction mixture was set for distillation at ambient pressure. The distillation was stopped when the contents temperature reached 106° C. The slurry was cooled to 65° C. and tetrahydrofuran (107 ml) was added. The slurry was cooled to 0-5° C. and held for 1 hour before isolating the product by filtration. The product was washed with ethyl acetate (72 ml) and dried at 50° C. Yield: 24.82 g, 80.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:23])OCC)[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1.[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][NH:28][CH3:29]>C1(C)C=CC=CC=1>[Cl:17][C:6]1[CH:5]=[C:4]([NH:18][C:19]([N:28]([CH2:27][CH:26]([O:30][CH3:31])[O:25][CH3:24])[CH3:29])=[O:23])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: CNCC(OC)OC
Reactant: CCOC(=O)Nc1cc(Cl)c(Oc2cc(Cl)cc(Cl)c2)c(Cl)c1
Solvent: Cc1ccccc1
Product: COC(CN(C)C(=O)Nc1cc(Cl)c(Oc2cc(Cl)cc(Cl)c2)c(Cl)c1)OC

Procedure:
Ethyl [3,5-dichloro-4-(3,5-dichlorophenoxy)phenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[3,5-dichloro-4-(3,5-dichlorophenoxy)phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[O:20].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:23][N:24]([CH3:26])[CH3:25])[N:6]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[O:20]
Reactant: Cc1ncccc1-n1c(C)nc2ccc(F)cc2c1=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cc1ncccc1-n1c(C=CN(C)C)nc2ccc(F)cc2c1=O
Temperature: 140 °C
Yield: 56.1 %

Procedure:
A mixture of 6-fluoro-3,4-dihydro-2-methyl-3-(2-methyl-pyridin-3-yl)-quinazolin-4-one (1.02 g, 3.79 mmol) and dimethylformamide dimethyl acetal (1.01 mL, 7.58 mmol) in dimethylformamide (5 mL) was heated to 140° C. for 24 hours. Additional dimethylformamide dimethyl acetal (2 mL) was added and the reaction was heated at 140° C. for 16 hours. The reaction was cooled to ambient temperature and concentrated at reduced pressure. The dark residue was triturated with ether and the dark purple crystalline solid which formed was collected and dried to give 0.69 g (56%) of 6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-3-(2-methyl-pyridin-3-yl)-quinazolin-4-one which had: 1H NMR δ 8.61 (dd, J=1.5, 5 Hz, 1 H), 7.87 (d, J=12.3 Hz, 1 H), 7.78 (dd, J=3, 8.5 Hz, 1 H), 7.50-7.45 (m, 2 H), 7.39-7.29 (m, 2 H), 3.97 (d, J=12.3 Hz, 1 H), 2.86 (br s, 6 H), 2.35 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1.[N:50]1(C(OC(C)(C)C)=O)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(CN4CCNCC4)c3)c2)c1

Procedure:
N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.034 g, 0.05 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (0.0112 g, 0.06 mmol), and acetic acid (0.0036 g, 0.06 mmol) were combined in 1,2-dichloroethane (2 mL), and the mixture stirred for thirty min. Sodium triacetoxyborohydride (0.0148 g, 0.07 mmol) was added and the mixture stirred overnight at room temperature. Some starting material still remained, so additional 1,1-dimethylethyl 1-piperazinecarboxylate (0.004 g, 0.02 mmol) and sodium triacetoxyborohydride (0.005 g, 0.024 mmol) were added and the mixture again stirred overnight at room temperature. Solvents were concentrated, and the residue taken up in EtOAc, washed with 1N NaOH, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the protected product. This was treated with 10% TFA in CH2Cl2 for 3 h. The product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 2.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound as a white solid. LC-MS m/z 749.1 (M+H)+, 1.47 min (ret time); mp 127-130° C. Analytical HPLC shows 98.8% purity, (ret time 10.129 min).
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([CH3:14])[S:13][C:7]=2[S:6]1(=[O:16])=[O:15])(C)(C)C.ClC1C=CC=CC=1Cl.C(=O)(O)[O-].[Na+]>CCOCC>[CH3:14][C:12]1[S:13][C:7]2[S:6](=[O:16])(=[O:15])[NH:5][C:9](=[O:10])[C:8]=2[CH:11]=1
Reactant: Cc1cc2c(s1)S(=O)(=O)N(C(C)(C)C)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: Clc1ccccc1Cl
Product: Cc1cc2c(s1)S(=O)(=O)NC2=O
Yield: 83.1 %

Procedure:
A mixture of 0.2 gm (0.77 millimols) of N-tert. butyl-5-methyl-thieno[3,2-d]isothiazole-3(2H)-one-1,1-dioxide and o-dichloro-benzene was refluxed for 8 hours. After cooling, the reaction mixture was distributed between a mixture of ether and aqueous sodium bicarbonate solution. The separated aqueous solution was acidified and extracted with methylene chloride. After evaporation and recrystallization from methanol, 0.13 gm (83% of theory) of 5-methyl-thieno[3,2-d]isothiazole-3(2H)-one-1,1-dioxide was obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][C:19]=3[CH:20]=2)=[O:15])=[CH:6][CH:5]=1.[NH2:34][OH:35].[OH-].[Na+]>CO.O1CCCC1.O>[OH:35][NH:34][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:21][C:19]=3[CH:20]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCCNC(=O)c2cc3cc(OCCN4CCCC4)ccc3o2)cc1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1ccc(OCCNC(=O)c2cc3cc(OCCN4CCCC4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino]-ethoxy}-benzoic acid methyl ester (169 mg, 0.37 mmol) in methanol (8 ml) and tetrahydrofuran (4 ml) was added hydroxylamine in water (2.9 ml of a 50 wt. % solution) and 4.0 M aqueous solution of sodium hydroxide (0.65 ml). After stirring for 18 h, the organics were removed and the aqueous solution was cooled in an ice/water bath and the pH was adjusted to ˜8 with 4.4 ml 1.0 M hydrochloric acid to give precipitates. The heterogeneous solution was warmed to room temperature and acetonitrile was added till the precipitates dissolved. The solution was chromatographed on C-18 reverse phase HPLC. Fractions with absorbance at 214 nm, were collected, frozen, and lyophilize to give the title compound (31 mg). 1H NMR (400 MHz, DMSO-d6) δ: 11.05 (s, 1H), 10.4 (s, 1H), 8.91 (s, 2H), 7.70 (d, 2H, J=7.4), 7.59 (dd, 1H, J=3.7, 9.1 Hz), 7.51 (d, 1H, J=3.7 Hz), 7.35 (s, 1H), 7.13 (d, 1H, J=9.0 Hz), 7.00 (d, 2H, J=7.4 Hz), 4.37 (m, 2H), 4.18 (m, 2H), 3.62 (m, 6H), 3.12 (m, 2H), 2.02 (m, 2H), 1.89 (m, 2H). EM (calc.): 453.2; MS (ESI) rate (M+1H)+: 454.1, (M−1H)−: 452.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]=O)=[CH:6][C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[CH:6][C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(CCC=O)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN(CCCc2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)CC1
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
Tert-butyl (2-chloro-5-cyano-3-(3-oxopropyl)phenyl)carbamate (113 mg, 0.366 mmol) was taken up in THF (2 mL) and 1-methylpiperazine (0.081 mL, 0.732 mmol) and acetic acid (0.042 mL, 0.732 mmol) were added. The reaction was stirred for 10 min, and then sodium triacetoxyborohydride (233 mg, 1.098 mmol) was added. The reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-10% MeOHIDCM; 24 g column). Tert-butyl (2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)carbamate (120 mg) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][NH:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[CH3:9][C:4]1[N:5]=[C:6]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH:7]=[C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[N:3]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CNc1cccc(O)c1
Product: Cc1nc(N(C)c2cccc(O)c2)cc(N(C)c2cccc(O)c2)n1
Yield: 45 %

Procedure:
This compound was obtained (yield 45%) based on the method described in Production Example 2B using 4,6-dichloro-2-methylpyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-methylaminophenol instead of the 3-aminophenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH2:11][CH:12]([OH:17])[CH2:13][CH:14]=[CH:15][CH3:16].[Br:18]N1C(=O)CCC1=O>C(Cl)Cl>[Br:18][CH2:16][CH:15]1[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10][C:4]2[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[O:17]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC=CCC(O)CCc1cc(F)ccc1OC
Solvent: ClCCl
Product: COc1ccc(F)cc1CCC1CCC(CBr)O1
Temperature: 25 °C

Procedure:
To a solution of 1-(2′-methoxy-5′-fluorophenyl)hept-5-en-3-ol (3.5 g, 14.7 mmol) in dry CH2Cl2 (90 mL) at 0° C. was added N-bromosuccinimide (NBS, 3.15 g, 17.0 mmol) portionwise and the reaction was warmed to room temperature for 12 h. Solvent was then removed in vacuo and the residue was purified by flash column chromatography (5% EtOAc in Hexane, Rf=0.12) to result in the trans isomer (2.05 g, 44%) as an oil; and the cis isomer (743 mg, 16%) as an oil; and mixture of both isomers (1.35 g, 29%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.F[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>CS(C)=O>[N:3]1([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: c1ccc2c(c1)CCN2
Reactant: N#Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1cccc(N2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
4.63 g (0.0193 mole, 1.1 equiv.) 99% NaH was added in one portion to a stirred solution of 19.8 ml (0.175 mole) indoline in 90 ml sieve dried DMSO under nitrogen at room temperature. After 65 minutes, the mixture was cooled in an ice bath and treated dropwise with a solution of 23.43 g (0.193 mole, 1.1 equiv.) 3-fluorobenzonitrile in 34 ml dry DMSO. The product was permitted to stir overnight at room temperature, poured onto 300 ml ice and extracted with CHCl3. The organic layer was washed five times with water (800 ml portions), dried over MgSO4, and concentrated to give 42.75 l g (38.6 g theory) of oil. 2.0 g of the crude product was chromatographed on silica gel (104 g) using ether-hexane thus affording a 0.99 g sample of an oil of pure 3-(1-indolinyl)benzonitrile.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C.[C:23]([CH2:25][C:26]([OH:28])=O)#[N:24].[C:29]([N:37]1[CH2:42][CH2:41][NH:40][C@H:39]([CH3:43])[CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[C:29]([N:37]1[CH2:42][CH2:41][N:40]([C:26](=[O:28])[CH2:25][C:23]#[N:24])[C@H:39]([CH3:43])[CH2:38]1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: N#CCC(=O)O
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)CC#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
DCC (2.43 g) and triethylamine (5 ml) were added into a solution of cyanoacetic acid (1.00 g) and (R)-N-benzoyl-3-methylpiperazine (2.84 g) in THF (50 ml). After reaction stirred at room temperature for 12 hours, solvents were removed under vacuum to give a residue which was purified by silica gel column chromatography to afford 3 g of (R)-N-benzoyl-3-methyl-N′-(2-cyano-acetyl)piperazine. MS m/z: (M+H)+ calcd for C15H18N3O2 272.14, found 272.17. HPLC retention time: 0.93 minutes (column H).
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)=[O:6])([CH3:4])[CH3:3].[CH3:20][Mg]Br.CCOC(C)=O.CCCCCCC>C(Cl)Cl.CCOCC>[CH3:4][C:2]([S@:5]([NH:7][C@H:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:17])([F:18])[F:19])=[CH:11][CH:10]=1)[CH3:20])=[O:6])([CH3:1])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of (R,E)-2-methyl-N-(4-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (7.7 g, 26.3 mmol) in CH2Cl2 (150 mL), cooled to 0° C. (water/ice bath), under nitrogen, was added 3M methyl magnesium bromide (35 mL, 105 mmol) in Et2O. The reaction mixture was stirred at 0° C. for 30 min, then allowed to warm up to room temperature and stirred additional 4 hrs. The reaction mixture was cooled again to 0° C. and quenched with the slow addition of a saturated NH4Cl solution. The by-phasic mixture was diluted with DCM and Water and the aqueous extracted with DCM two times. The organic phases were combined, washed with brine, dried (Na2SO4), filtered and concentrated to 11.5 g crude white solid. Silica gel column chromatography (EtOAc/Heptane 0 to 30%) afforded (R)-2-methyl-N—((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (5.08 g, 16.2 mmol, 62% yield) as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 1.21 (s, 9H) 1.53 (d, J=6.70 Hz, 3H) 3.31 (d, J=2.74 Hz, 1H) 4.59 (qd, J=6.67, 3.37 Hz, 1H) 7.18 (d, J=8.02 Hz, 2H) 7.36 (d, J=8.66 Hz, 2H). LCMS m/z 310.2 (M+H)+, Rt 0.90 min.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([NH2:29])=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=3)=[CH:18][CH:17]=2)=[CH:13][C:12]=1[O:32][CH3:33]>C1COCC1>[F:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]4=[N:29][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]4[CH:25]=[C:26]([CH3:28])[CH:27]=3)=[CH:20][CH:21]=2)=[CH:13][C:12]=1[O:32][CH3:33]
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1cc(Oc2ccc(-c3cc(C)cnc3N)cc2)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(C3=CC(C)=CN4CCS(=O)(=O)N=C34)cc2)ccc1F
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 222 mg) in THF (dry) (20 mL) was added 2-chloroethanesulfonyl chloride (0.233 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(4-fluoro-3-methoxyphenoxy)phenyl)-5-methylpyridin-2-amine (360 mg) in THF (dry) (20 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added to the mixture and the organic phase was separated. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give 9-[4-(4-fluoro-3-methoxyphenoxy)phenyl]-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide as a white solid. This product was subjected to the next reaction without further purification. A part of the product was crystallized from EtOAc/IPE to give the title compound as a colorless solid.