Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.O.[NH2:13][NH2:14].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:4]1(=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]=2[C:1](=[O:6])[NH:14][NH:13]1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c1CCCC2
Temperature: 100 °C

Procedure:
A mixture of 3,4,5,6-tetrahydrophthalic anhydride (3.5 g, 23 mmol), hydrazine hydrate (2.0 mL), sodium acetate (15.4 g, 188 mmol) in 100 mL of acetic acid is heated at 100° C. overnight. Upon cooling, a white solid is formed and collected by filtration. The solid is washed with water and dried to give 2,3,5,6,7,8-hexahydro-phthalazine-1,4-dione. The solid is taken up in 15 mL of POCl3. The resultant mixture is heated at reflux overnight. After cooled, the excess POCl3 is removed under reduced pressure. Crushed ice is added to the residue followed by careful addition of solid Na2CO3 to pH 9. The product is extracted with EtOAc twice. The combined extract is washed with brine, dried and concentrated. The residue is purified by flash silica gel column (Hexanes/EtOAc 4:1) to give 1,4-dichloro-5,6,7,8-tetrahydro-phthalazine as a white solid. 1H NMR: (CDCl3) 2.74 (m, 4H), 1.87 (m, 4H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:29][CH3:30])=[CH:20][C:21]([CH:27]=[O:28])=[C:22]([C:23]([F:26])([F:25])[F:24])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:29][CH3:30])=[CH:20][C:21]([CH2:27][OH:28])=[C:22]([C:23]([F:24])([F:25])[F:26])[C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C(F)(F)F)c(C=O)cc(OC)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C(F)(F)F)c(CO)cc(OC)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a solution of 710 mg (1.69 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole-5-carbaldehyde (example 54c) in 5 ml ethanol, 128 mg (3.38 mmol) NaBH4 are added at 0° C. The mixture is stirred for 30 min at room temperature. Then the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is crystallized from hexane/EtOAc to afford 655 mg of the title compound as a colorless crystalline solid.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([OH:24])[CH2:14][NH:15][CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:42]([NH:45][C:46]1[CH:47]=[C:48]([S:52](Cl)(=[O:54])=[O:53])[CH:49]=[CH:50][CH:51]=1)(=[O:44])[CH3:43]>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([OH:24])[CH2:14][N:15]([S:52]([C:48]2[CH:49]=[CH:50][CH:51]=[C:46]([NH:45][C:42](=[O:44])[CH3:43])[CH:47]=2)(=[O:54])=[O:53])[CH2:16][C:17]([CH3:22])([CH3:23])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1
Reactant: CC(=O)Nc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCC#N)c1
Yield: 59.1 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid (3R,3aS,6aR)hexahydro-furo[2,3-b]furan-3-yl ester (0.020 g, 0.05 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.025 ml, 0.13 mmol) and 3-acetamidobenzenesulfonyl chloride (0.012 g, 0.05 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by preparative thin layer chromatography (3% MeOH in CH2Cl2) gave 0.019 g of a white solid. MS (ES): 643 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[C@@H:10]([NH:17][C:18]1[C:27]2[C:22](=[C:23]([O:28][CH2:29][CH2:30][NH2:31])[CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:32])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:2]=[CH2:3].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[C@@H:10]([NH:17][C:18]1[C:27]2[C:22](=[C:23]([O:28][CH2:29][CH2:30][NH:31][S:34]([CH3:33])(=[O:36])=[O:35])[CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:32])[CH:19]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCN1CCCC[C@H]1[C@@H](Nc1cc(C)nc2c(OCCN)cccc12)c1ccccc1
Product: C=CCN1CCCC[C@H]1[C@@H](Nc1cc(C)nc2c(OCCNS(C)(=O)=O)cccc12)c1ccccc1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [(S)—((S)-1-allylpiperidin-2-yl)-phenylmethyl]-[8-(2-aminoethoxy)-2-methylquinolin-4-yl]-amine (example 34) and methanesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][CH2:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23](N(CC)CC)[CH3:24].ClC(OCC)=O.C(O)C>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:23][CH3:24])=[O:9])=[C:6]([O:11][CH2:12][C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(COc2cccc(Cl)c2C(=O)O)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(Cl)cccc1OCc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
1.0 g of 6-chloro-2-[(4,6-dimethoxy-2-pyrimidyl)methyloxy]benzoic acid was dissolved in 20 ml of tetrahydrofuran and cooled with ice. 0.35 g of triethylamine dissolved in 1 ml of tetrahydrofuran and 0.40 g of ethyl chloroformate dissolved in 1 ml of tetrahydrofuran were added thereto, and the mixture was stirred under ice cooling for about 30 minutes. Then, a solution of 1 g of ethanol and 0.35 g of triethylamine in 2 ml of tetrahydrofuran was added, and the temperature was raised up to room temperature in about one hour. After the removal of the solvent, the residue was purified using column chromatography to obtain 1.0 g of ethyl 6-chloro-2-[(4,6-dimethoxy-2-pyrmidyl)methyloxy]benzoate (yield 92%).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[C:13]([CH2:15][C@@H:16]2[C@H:20]([O:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:12]=[C:11]([CH3:40])[CH:10]=1)=O)(C)(C)C.Cl>CO>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][NH:24][CH2:23][CH2:22][O:21][C@@H:20]1[CH2:19][NH:18][CH2:17][C@@H:16]1[CH2:15][C:13]1[N:14]=[C:9]([NH2:8])[CH:10]=[C:11]([CH3:40])[CH:12]=1
Reactant: Cc1cc(C[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2OCCNCc2ccccc2F)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Product: Cc1cc(N)nc(C[C@H]2CNC[C@H]2OCCNCc2ccccc2F)c1
Reaction time: 12 h
Yield: 106 %

Procedure:
To a solution of 7a (70 mg, 0.10 mmol) in MeOH (2 mL) was added 6 N HCl (4 mL) at room temperature. The mixture was stirred for 12 h and then concentrated. The crude product was purified by recrystallization (EtOH/H2O) to give inhibitor 3a (38 mg, 97%): 1H NMR (500 MHz, D2O) δ 2.18 (s, 3H), 2.68-2.73 (m, 1H), 2.76-2.82 (dd, J=7.0, 15.5 Hz, 1H), 2.85-2.90 (dd, J=8.0, 15.0 Hz, 1H), 3.04-3.09 (t, J=11.5 Hz, 1H), 3.15-3.25 (m, 2H), 3.39-3.43 (dd, J=8.5, 11.5 Hz, 1H), 3.50-3.53 (d, J=13.5 Hz, 1H), 3.53-3.60 (m, 1H), 3.73-3.80 (m, 1H), 4.05-4.10 (m, 1H), 4.22 (s, 2H), 6.47 (s, 1H), 6.53 (s, 1H), 7.12-7.14 (dd, J=1.0, 8.5 Hz, 1H), 7.16-7.18 (dd, J=1.0, 8.0 Hz, 1H), 7.35-7.40 (m, 1H); 13C NMR (125 MHz, D2O) δ 21.0, 28.8, 41.3, 44.67, 44.70, 46.4, 47.1, 49.3, 63.9, 78.0, 110.3, 114.0, 115.8, 115.9, 117.4, 117.5, 125.0, 125.1, 132.1, 132.2, 132.3, 132.4, 145.7, 153.8, 158.1, 160.1, 162.0; LC-TOF (M+H) calcd for C20H28FN4O 359.2247. found 359.2253.
Reaction SMILES: C([O:8][C:9]1[C:35]([O:36][CH3:37])=[CH:34][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[N:18]=[CH:17][C:16]([C:21]#[N:22])=[C:15]3[NH:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([F:32])=[CH:26][C:25]=1[Cl:33])C1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.[Pd]>[Cl:33][C:25]1[CH:26]=[C:27]([F:32])[C:28]([O:30][CH3:31])=[CH:29][C:24]=1[NH:23][C:15]1[C:14]2[C:19](=[CH:20][C:11]3[CH:10]=[C:9]([OH:8])[C:35]([O:36][CH3:37])=[CH:34][C:12]=3[CH:13]=2)[N:18]=[CH:17][C:16]=1[C:21]#[N:22]
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCc5ccccc5)c(OC)cc4cc23)c(Cl)cc1F
Agent: [Pd]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2cc3c(Nc4cc(OC)c(F)cc4Cl)c(C#N)cnc3cc2cc1O
Reaction time: 15 h
Yield: 95.7 %

Procedure:
A mixture of 8-(benzyloxy)-4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-7-methoxybenzo[g]quinoline-3-carbonitrile (1.88 g, 3.70 mmol) and 280 mg of 15% Pd on carbon in a mixture of 50 mL of methylene chloride and 70 mL of N,N-dimethylformamide is hydrogenated at 50–40 psi for 15 hours. The mixture is filtered through Celite and concentrated in vacuo to a small volume. The yellow solid is collected by filtration to provide 1.50 g (95%) of 4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, mp 239–242° C. dec.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[S:28])[NH:6]2.[C:29](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[N:8]=[C:7]3[C:3]([NH:4][C:5]([S:28][CH3:29])=[N:6]3)=[C:2]([NH2:1])[N:10]=2)=[N:12]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=S)[nH]c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c2[nH]1
Temperature: 70 °C
Reaction time: 48 h
Yield: 17.4 %

Procedure:
100 mg (0.255 mmol) of the compound from example 28 were dissolved in 5 ml of dimethylformamide, and 49 mg (0.357 mmol) of potassium carbonate were added. The mixture was heated to 70° C. for 10 min and, after cooling, 18 μl (0.291 mmol) of iodomethane were added and the mixture was stirred at RT for 48 h. The mixture was concentrated and the residue was taken up in water and acidified with acetic acid. A solid precipitates out, which was filtered off and washed with water. The purification was effected by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 18 mg of the title compound were obtained (17% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[C:27]([O:35][CH3:36])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].NC1C=CC(N2C(=O)CC(=O)NC3C(CC)=CC=CC2=3)=CC=1>>[Cl:25][C:26]1[C:27]([O:35][CH3:36])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: COc1c(Cl)cccc1C(=O)Cl
Agent: CCc1cccc2c1NC(=O)CC(=O)N2c1ccc(N)cc1
Product: COc1c(Cl)cccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 9 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 3-chloro-2-methoxybenzoyl chloride, the title compound (yield 9%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)C1C(=CC=CC=1)C(N)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2c[nH]cn2)cc1
Reactant: NC(=O)c1ccccc1C(=O)NCCCCBr
Agent: [H-]
Agent: [Na+]
Product: NCCCCn1cnc(-c2ccc(F)cc2)c1
Yield: 81.8 %

Procedure:
Using the procedure of Stage A of Example 1, 10 g of the product of Stage A, 1.95 g of sodium hydride and 11.80 g of N-4-bromobutyl-phthalamide were reacted to obtain 7.53 g of the expected product melting at 138°-140° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:30]([NH:20][S:17]([C:15]2[CH:14]=[CH:13][C:10]3[CH2:11][CH2:12][N:6]([C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:21][CH3:22])[CH2:7][CH2:8][C:9]=3[CH:16]=2)(=[O:18])=[O:19])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCN(CC)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Reactant: O=C=NC1CCCCC1
Product: CCN(CC)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
In a manner analogous to that described in Example 1, from 3-diethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide and cyclohexylisocyanate, there is obtained 1-cyclohexyl-3-[(3-diethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 168°-169° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride with diethylcarbamoyl chloride in a manner analogous to that described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]1([CH:33]([O:35][C:36]2[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=2)[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:41][CH2:40][C:39]1[CH:42]=[CH:43][C:36]([O:35][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])=[CH:37][CH:38]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(Oc1ccc(CN)cc1)c1ccccc1
Product: CC(Oc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)c1ccccc1
Yield: 69.8 %

Procedure:
Use a method similar to the General Procedure 5-3, to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (851 mg, 2.0 mmol) and (±)-4-(1-phenyl-ethoxy)-benzylamine (721 mg, 2.6 mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to give (±)-7-chloro-6-[4-(1-phenyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (702 mg, 69%). MS (ES+) m/z: 503 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:10][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Fc1ccc(NCc2c[nH]cn2)cc1F
Temperature: 50 °C
Reaction time: 4 h
Yield: 29.2 %

Procedure:
To a solution of 3,4-difluoroaniline (0.60 g, 4.65 mmol) in 1,2-dichloroethane (5 ml) were added 4-formylimidazole (0.67 g, 6.97 mmol), sodium triacetoxyborohydride (1.97 g, 9.29 mmol) and acetic acid (0.05 ml). The reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was then concentrated in vacuo and the residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/dichloromethane gradient) to yield an off-white solid (284 mg, 29%); MS (ISP): 210.1 ((M+H)+.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([O:15]C)=O)[N:7]2[CH3:12].[CH3:17][NH2:18]>CO>[CH3:17][NH:18][C:13]([C:6]1[N:7]([CH3:12])[C:8]2[C:4]([CH:5]=1)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)=[O:15]
Reactant: COC(=O)c1cc2c(OC)cccc2n1C
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc2c(OC)cccc2n1C
Temperature: 57.5 °C

Procedure:
A solution of methyl 4-methoxy-1-methyl-1H-indol-2-carboxylate (1.03 g, 4.7 mmole) in 2.0 M methylamine in methanol (40 mL) was sealed in a pressure bottle and heated at 55-60° C. for 60 hr. Concentration in vacuo yielded the title compound (1.05 g, quantitative) as a white solid: MS (ES) m/e 219.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4](C1C=CC(C)=CC=1)=[O:5].ClC1C=CC=C(C(OO)=[O:26])C=1.P([O-])([O-])(O)=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([OH:5])=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2C)cc1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(F)ccc1C(=O)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
2.3 g (10 mmol) of 2-methyl-4-fluoro-4'-methylbenzophenone were added dropwise at 20° C., under inert gas, to 3.8 g (12 mmol) of 3-chloroperbenzoic acid (55%) in 40 ml of dichloromethane and 14.2 g (0.1 mol) of disodium hydrogenphosphate and the reaction mixture was then heated for 8 h at 40° C. It was monitored by gas chromatography and, if the conversion was incomplete, a further 2.5 g (8 mmol) of 3-chloroperbenzoic acid were added. 100 g of water were added 4 hours later and the mixture was neutralized with sodium hydrogencarbonate solution. The phases were separated, the aqueous phase was extracted with dichloromethane and the solvent was distilled off. The residue was boiled for 4 h with 100 g of 70% sulfuric acid and then poured on to 200 g of ice. Extraction and crystallization gave 1.15 g (7.5 mmol, 5%) of 2-methyl-4-fluorobenzoic acid. If the reaction is carried out under these conditions with 9.2 g (15 mmol) of ®Oxone (=potassium peroxomonosulfate) instead of with 3-chloroperbenzoic acid, essentially the same result is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1C(=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[Si:7]([CH3:17])([CH3:16])[CH2:6]1.C[Si]1(C)C2C=CC=CC=2[S:22](=[O:30])(=[O:29])NC1.C([Li])CCC.ClCCCBr>O1CCCC1>[CH3:16][Si:7]1([CH3:17])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:22](=[O:30])(=[O:29])[N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[CH2:6]1
Reactant: C[Si]1(C)CN(CCCCl)C(=O)c2ccccc21
Reactant: C[Si]1(C)CNS(=O)(=O)c2ccccc21
Agent: ClCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si]1(C)CN(CCCCl)S(=O)(=O)c2ccccc21

Procedure:
4,4-Dimethyl-2-(3-chloropropyl)-3H-1,2,4-benzothiazasiline 1,1-dioxide may be obtained in a manner similar to that described in Example 4 for the preparation of 3-(3-chloropropyl)-1,1-dimethyl-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline, but using 3.2 g of 4,4-dimethyl-3H-1,2,4-benzothiazasiline 1,1-dioxide, 10.5 cm3 of n-butyllithium, 5.3 g of 1-chloro-3-bromopropane and 50 cm3 of tetrahydrofuran. After purification by flash chromatography on a silica column under a nitrogen stream at moderate pressure (0.5-1.5 bar) with a dichloromethane-cyclohexane mixture (50--50 by volume) as eluent, 1.95 g of 4,4-dimethyl-2-(3-chloropropyl) 3H-1,2,4-benzothiazasiline 1,1-dioxide are obtained.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)(Cl)Cl>[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A 20% dispersion of pyridinium chlorochromate in basic alumina (50 g) was added to a solution of tert-butyl N-[2-(hydroxymethyl)phenyl]carbamate (11.0 g, 0.0493 mol) in anhydrous chloroform and the resulting suspension was stirred under an atmosphere of nitrogen at ambient temperature for 1 hour. Additional 16 g of a 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 45 min. At this point in time, additional 15 g of of 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 25 min. The resulting suspension was filtered through a silica gel pad, the filtrate was concentrated under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (2:98) as mobile phase to yield tert-butyl N-(2-formylphenyl)carbamate (8.67 g, 0.0392 mol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[I:11].[CH2:12]([O:19][C:20](=[O:27])[C:21]#[C:22][C:23]([F:26])([F:25])[F:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:19][C:20](=[O:27])/[CH:21]=[C:22](/[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[I:11])\[C:23]([F:26])([F:25])[F:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(C#CC(F)(F)F)OCc1ccccc1
Reactant: Nc1ccc(CCO)cc1I
Solvent: CO
Product: O=C(/C=C(/Nc1ccc(CCO)cc1I)C(F)(F)F)OCc1ccccc1
Reaction time: 1 h
Yield: 84.1 %

Procedure:
2-(4-Amino-3-iodo-phenyl)-ethanol (6.0 g, 23 mmol, 1.0 eq) was added to the solution of the 4,4,4-trifluoro-but-2-ynoic acid benzyl ester (5.7 g, 25 mmol, 1.1 eq) obtained from previous step in methanol (20 mL) at room temperature. The reaction mixture was stirred for 1 hour. After the solvent was removed, the residue was purified by flash chromatography (SiO2, hexanes-ethyl acetate) to yield 9.5 g of the desired enamine as pale yellow liquid (84.0% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[C:21]([O:31][CH3:32])=[N:22][C:23]([C:27]([F:30])([F:29])[F:28])=[C:24]([Br:26])[CH:25]=1.[CH:33](OC)=[O:34]>C1COCC1>[Br:19][C:20]1[C:21]([O:31][CH3:32])=[N:22][C:23]([C:27]([F:30])([F:29])[F:28])=[C:24]([Br:26])[C:25]=1[CH:33]=[O:34]
Reactant: COC=O
Reactant: COc1nc(C(F)(F)F)c(Br)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COc1nc(C(F)(F)F)c(Br)c(C=O)c1Br
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a flame-dried 100 mL round-bottomed flask, was added dry THF (15 mL). The solution was cooled to −78° C. before diisopropylamine (460 μL, 3.28 mmol), 2.5 M n-butyllithium in hexane (1.31 mL, 3.28 mmol), and a solution of 3,5-dibromo-2-methoxy-6-(trifluoromethyl)pyridine (1.00 g, 2.99 mmol) in dry THF (10 mL), were added sequentially. The reaction mixture was stirred at −78° C. for 10 min before methyl formate (276 μL, 4.49 mmol) was slowly added. After the reaction was stirred for another 2 hr, the mixture was warmed and stirred for 30 min at room temperature. Then the mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, washed by water and brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to yield 3,5-dibromo-2-methoxy-6-(trifluoromethyl)isonicotinaldehyde (985 mg, 90.5%). 1H-NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 4.11 (s, 3H).