Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8]O)[CH2:5][CH2:4][O:3]1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[Br:12][CH2:8][CH:6]1[CH2:5][CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7]1
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)CC(CO)CCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(CBr)CCO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.6 %

Procedure:
To a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol (2.50 g) in dichloromethane (30 mL) were added carbon tetrabromide (6.80 g) and triphenylphosphine (5.40 g), and the mixture was stirred at room temperature for 20 hr. Water was added and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give the title compound (1.10 g) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C.C(Cl)Cl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:7]1
Reactant: CC1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: C[C@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)+-2-methylpiperazine (10 g) was dissolved in acetonitrile (140 ml) and cooled to 5-10° C. whereupon triethylamine (35 ml) was added, followed by drop wise addition of a solution of trityl chloride 27.9 (g) in DCM (80 ml). The reaction was stirred for 1 h at room temperature. The resulting slurry was cooled to approximately 0° C. then filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography (silica, 1-4% MeOH/DCM as eluent) to give the sub-title compound (29 g).
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11](=[O:14])[N:10]([CH3:15])[CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[OH:16])[CH:2]=[CH2:3].[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:4]1[C:13]2[O:12][C:11](=[O:14])[N:10]([CH3:15])[CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[O:16][CH3:17])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)ccc2c1OC(=O)N(C)C2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: C=CCc1c(OC)ccc2c1OC(=O)N(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
0.66 g of 8-allyl-7-hydroxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-one was dissolved in 6 ml of N,N-dimethylformamide. 0.63 g of potassium carbonate and 0.94 ml of methyl iodide were added to the above solution, and the obtained mixture was then stirred at room temperature overnight under nitrogen atmosphere. Thereafter, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a sodium thiosulfate aqueous solution, water, and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 0.58 g of the subject compound.
Reaction SMILES: C[O-].[Na+].Cl.[CH2:5]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([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)[CH2:13][C@H:12]1[CH2:36][C:37](=[NH:39])[NH2:38])=[O:10])[CH:6]=[CH2:7].CN(C)[CH:42]=[CH:43][CH:44]=O.C(OCC)(=O)C>CO.O>[CH2:5]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@H:12]1[CH2:36][C:37]1[N:38]=[CH:44][CH:43]=[CH:42][N:39]=1)=[O:10])[CH:6]=[CH2:7]
Reactant: CN(C)C=CC=O
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1Cc1ncccn1
Yield: 7.5 %

Procedure:
To a solution of 28% sodium methoxide in methanol solution (104 mg) in methanol (10 ml) were added (2R,4S)-1-allyloxycarbonyl-2-amidinomethyl-4-(triphenylmethylthio)pyrrolidine hydrochloride (1.0 g) and 3-dimethylaminoacrylaldehyde (190 mg). After stirring under reflux for 8 hours, the solution was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel to give (2R,4S)-1-allyloxycarbonyl-2-(pyrimidin-2-ylmethyl)-4-(triphenylmethylthio) pyrrolidine (75 mg).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH:12](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:12]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2C(c1ccccc1)c1ccccc1

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-4-carbaldehyde and benzhydryl chloride instead of the benzyl bromide used in Example 1 to give 1.14 g of 1-benzhydrylindole-4-carbaldehyde as an orange-colored oily substance. The yield thereof was found to be 61%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([B:7]([OH:9])[OH:8])[S:5][CH:6]=1.[CH3:10][C:11]([CH2:15]O)([CH2:13]O)[CH3:12]>>[CH3:10][C:11]1([CH3:15])[CH2:13][O:9][B:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=2)[O:8][CH2:12]1
Reactant: CC(C)(CO)CO
Reactant: Cc1csc(B(O)O)c1
Product: Cc1csc(B2OCC(C)(C)CO2)c1
Yield: 60 %

Procedure:
The title compound (60%, yellow crystals) was prepared from 4-methylthiophen-2-boronic acid and neopentylglycol.
Reaction SMILES: [CH2:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:13]=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=4[C:18]=3[CH2:19][CH2:20][C@:4]12[CH3:5])[CH3:2].[Li].N.[Cl-].[NH4+]>O1CCCC1.NC1C=CC=CC=1.O>[CH3:2][CH2:1][C:3]1([OH:23])[C:4]2([CH3:5])[CH2:20][CH2:19][CH:18]3[C:17]4[CH:16]=[CH:15][C:14]([O:21][CH3:22])=[CH:13][C:12]=4[CH2:11][CH2:10][CH:9]3[CH:6]2[CH2:7][CH2:8]1
Reactant: CC[C@]1(O)CC[C@H]2C3=C(CC[C@@]21C)c1ccc(OC)cc1CC3
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: Nc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCC1(O)CCC2C3CCc4cc(OC)ccc4C3CCC21C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Add dl-17α-ethyl-3-methoxyestra-1,3,5(10),8-tetraen-17-ol (3 g) in tetrahydrofuran (50 ml) to lithium (0.8 g) in aniline (8 ml) and liquid ammonia (200 ml). Stir for 2 hours, decompose by adding ammonium chloride and water, and extract with ether. Wash, dry and evaporate the organic extract, and crystallize from ethyl acetatehexane to obtain dl-17α-ethyl-3-methoxyestra-1,3,5(10)-trien-17β-ol (2 g), m.p. 133°-135°; ultraviolet absorption maximum at 279 mμ (ε2,120).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:36])[C:21]([CH2:33][CH2:34][CH3:35])([CH2:30][CH2:31][CH3:32])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH3:35])[C:20](=[O:36])[C:19]=1[C:14]1[NH:13][C:12]2[CH:37]=[CH:38][C:9]([OH:8])=[CH:10][C:11]=2[S:16](=[O:17])(=[O:18])[N:15]=1
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Agent: [Pd]
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A suspension of the compound of Example 2F (110 mg, 0.21 mmol) in 1:1:1 tetrahydrofuran-ethyl acetate-methanol (20 mL) was treated with 10% palladium on carbon (30 mg) and stirred at 25° C. under hydrogen atmosphere for 18 hours. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford the title compound (86 mg, 94%). 1H NMR (300 MHz, DMSO-d6): δ 13.87 (m, 1 H), 10.33 (s, 2 H), 8.15 (d, J=7.72 Hz, 1 H), 7.72 (m, 2 H), 7.52 (m, 2 H), 7.16 (m, 2 H), 2.15 (m, 2 H), 1.97 (m, J=11.77 Hz, 2H), 0.89 (m, 2 H), 0.60 (m, 8 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:19]2[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: C1CSCCN1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CCSCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 98.3 %

Procedure:
A solution of 240 mg (0.90 mmol) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester and 0.189 ml (2.00 mmol) of thiomorpholine in 2.5 ml of tetrahydrofuran is heated at reflux for 2 hours. After evaporation of the tetrahydrofuran the residue is distributed between water and ethyl acetate, the organic phase separated and washed with water and brine, dried over Na2SO4 and concentrated yielding 310 mg of 2-nitro-5-thiomorpholin-4-yl-4-trifluoromethyl-benzoic acid methyl ester as brown powder, m.p. 68-82° C.
Reaction SMILES: [C:1]12([O:21][CH2:20][CH2:19][O:18]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2]2>C(OCC)(=O)C.[Pd]>[C:1]12([O:18][CH2:19][CH2:20][O:21]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2]2
Reactant: CCOC(=O)C=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC[C@@H]1Cc2ccccc2C2(C1)OCCO2
Reaction time: 2 h

Procedure:
To a stirred solution of Pd/C (0.535 g, 0.251 mmol) in ethyl acetate (25 mL), (R)-ethyl 3-(3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-3′-yl)acrylate (2.5 g, 8.67 mmol) was added under nitrogen. Reaction mixture was stirred for 2 h under hydrogen balloon. After completion of reaction, reaction mixture was filtered through celite, concentrated to get the crude compound. This crude compound was used directly in next reaction (2.3 g, 91%); m/z 290.7
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]1=[O:13].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][C:7]1=[O:13]
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Reactant: BrCCc1ccccc1
Solvent: CC#N
Product: O=c1cc(OCCc2ccccc2)ccn1Cc1cccc(F)c1
Yield: 56.5 %

Procedure:
According to Scheme 13 Method A: The title compound was prepared from 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (1 eq, 0.23 mmol, 0.05 g, Example 19 Step 2) and 1-(2-bromoethyl)benzene (2 eq, 0.46 mmol, 0.06 mL) according to the procedure described for Example 1 Step 2. Microwave conditions: 180° C. for 900s in acetonitrile (2 mL). The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 80/20 and by recrystallization in pentane to afford 1-(3-fluorobenzyl)-4-phenethoxypyridin-2(1H)-one (0.13 mmol, 43 mg, 58%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[OH-].[Na+].C=O.[C:19](O)(=O)C.C([BH3-])#N.[Na+]>ClC(Cl)C>[CH3:19][N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(Cl)Cl
Product: CN1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
Into a 125 mL Erlenmeyer flask was charged 7-nitro-1,2,3,4-tetrahydroisoquinoline, hydrochloric acid (3.17 g, 14.77 mmol) in dichloroethane (148 ml). The solution was stirred 10 minutes with 1 N NaOH, and the layers were separated. Paraformaldehyde (2.217 g, 73.8 mmol), acetic acid (4.23 ml, 73.8 mmol) and sodium cyanoborohydride (4.64 g, 73.8 mmol) were added. The reaction was heated at 90° C. overnight. The reaction was cooled to room temperature, and quenched with saturated aqueous sodium bicarbonate. The layers were separated, and the organic layer was dried over MgSO4, filtered, and concentrated onto silica gel. The reaction was purified by flash chromatography (50% ethyl acetate:hexanes for 20 minutes, then to 100% ethyl acetate:hexanes over 30 minutes) to provide the title compound. MS (DCI) m/e 193 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO.[Fe]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)c1cccc(N)c1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
40 g of methyl 2-methyl-3-nitrobenzoate was dissolved in 120 ml of methanol, and 157 g of concentrated hydrochloric acid was added thereto. Then, 36.8 g of iron powder was gradually added while maintaining the mixture at a temperature of not higher than 60° C. The mixture was stirred at room temperature for 4 hours and then poured into 1 liter of ice water. The solution was neutralized with sodium carbonate and extracted with chloroform (after filtering off insolubles). The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 27.8 g of the desired product as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1.[CH3:34][O:35][C:36]([NH:38][C:39](=NC(OC)=O)SC)=[O:37]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]4[N:32]=[C:39]([NH:38][C:36](=[O:37])[O:35][CH3:34])[NH:33][C:28]=4[CH:27]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: COc1cc2nccc(N3CCOc4ccc(-c5ccc(N)c(N)c5)cc4C3)c2cc1OC
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5cc(OC)c(OC)cc35)CCO4)cc2[nH]1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
A solution of 4-{-4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-2-nitroaniline (56 mg, 0.12 mmol) in methanol (20 mL) was hydrogenated at 30 psi over 10% Pd—C (25 mg) for 4 h. The catalyst was filtered off, and the filtrate was concentrated to give 4-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}benzene-1,2-diamine (40 mg, 77% yield) as a brown oil. MS (EI) for C26H26N4O3: 443 (MH STEP 5: To a solution of 4-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}benzene-1,2-diamine (40 mg, 0.09 mmol) in acetic acid (2 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (19 mg, 0.09 mmol) and the reaction mixture was stirred at 80° C. for 30 min. After cooling to room temperature the mixture was concentrated, and purified by preparative reverse phase HPLC to provide methyl (6-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-benzimidazol-2-yl)carbamate (17 mg, 25% yield) as a brown solid. 1H NMR (400 MHz, CD3OD): 8.30 (d, 1H), 7.78 (m, 2H), 7.68 (m, 2H), 7.60 (m, 1H), 7.27 (d, 2H), 7.11 (d, 1H), 7.04 (d, 1H), 5.17 (s, 2H), 4.64 (m, 2H), 4.25 (m, 2H), 4.01 (s, 3H), 3.96 (s 3H), 3.63 (s, 3H); MS (EI) for C29H27N5O5: 526 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]12[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]1[CH2:24][NH:23][CH2:22]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([O:29][C:27]([CH:26]1[CH:25]2[CH:21]1[CH2:22][N:23]([C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=1)=[O:14])[CH2:24]2)=[O:28])[CH3:31]
Reactant: CCOC(=O)C1C2CNCC21
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1C2CN(C(=O)c3ccc(N4CC(F)(F)C4)c(OCC4CC4)n3)CC21

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with ethyl 3-azabicyclo[3.1.0]hexane-6-carboxylate (179236-79-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=422.5 [MH+].
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[C:8]([C:11](=[CH:17]N(C)C)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[CH3:9]>C(O)C>[CH3:9][C:8]1[N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[N:7]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C
Yield: 87.5 %

Procedure:
tert-Butylhydrazine hydrochloride (33.6 grams, 0.27 mole) and α-acetyl-α-(dimethylaminomethylene)acetic acid, ethyl ester (50 grams, 0.27 mole) were added to 150 ml. of ethanol and the resulting reaction mixture was refluxed for two hours. The reaction mixture was then cooled, and the solvent was removed in vacuo. The residue was taken up in 300 ml. of ether, washed with water, washed with saturated sodium bicarbonate, washed with saturated brine, and dried using sodium sulfate and filter paper. The solvent was then removed in vacuo. The residue was distilled at 110° C. at 1.2 mm mercury pressure to provide 49.7 grams of 5-methyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 88.0%.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:29][O:30][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:11]3=[O:28].Cl.[NH2:32][OH:33].C(N(CC)CC)C>C(O)C>[OH:33][N:32]=[C:8]([C:7]1[C:2]([OH:1])=[CH:3][C:4]2[O:30][CH2:29][C:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[C:11]3=[O:28])[C:5]=2[CH:6]=1)[NH2:9]
Reactant: COc1ccc(CN2C(=O)C3(COc4cc(O)c(C#N)cc43)c3ccccc32)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CN2C(=O)C3(COc4cc(O)c(C(N)=NO)cc43)c3ccccc32)cc1
Yield: 99.3 %

Procedure:
To a stirred solution of 6-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.84 g, 2.10 mmol) and hydroxylamine hydrochloride (0.20 g, 2.9 mmol) in ethanol (50 mL) was added triethylamine (0.40 mL, 2.9 mmol). The reaction mixture was stirred at reflux for 18 h and concentrated in vacuo. The residue was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford N′,6-dihydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carboximidamide (0.90 g, 99%): MS (ES+) m/z 431.9 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:20]1[C:24]2C=CC=CC=2N=N1.CN.C(O)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([NH:20][CH3:24])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccccc1OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
2-(2-Benzyloxyphenyl)acetic acid (15.0 g, 62 mmol) was dissolved in dichloromethane (270 ml) and N,N-dimethylformamide (70 ml). 1-Hydroxybenzotriazole (8.37 g, 62 mmol) was added. The solution was cooled to 0 IC. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (11.89 g, 62 mmol) was added. The reaction mixture was stirred for 20 min. A 8.0 M solution of methylamine in ethanol (38.8 ml, 310 mmol) was added. The solution was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (500 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate solution (500 ml). The aqueous phase was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (400 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The remaining crystalIs were washed with a mixture of ethyl acetatelheptane 1:4 (100 ml). They were dried in vacuo. They were dissolved in ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate (2×500 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give 10.24 g of 2-(2-benzyloxyphenyl)-N-methylacetamide
Reaction SMILES: [Cl:1]Cl.[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[Cl-:1].[Cl-:1].[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCl
Solvent: ClC(Cl)Cl
Solvent: Ic1ccccc1
Product: [Cl-]
Temperature: -5 °C

Procedure:
Chlorine gas is bubbled through a solution of iodobenzene (20.4 g; 0.1 mole) in chloroform (100 ml) while the temperature of the reaction mixture is maintained at -5° C. In about 10 minutes a yellow solid precipitates and is removed by filtration. The filtrate is then further treated with chlorine gas until the formation of yellow solid ceases. The solid fractions are combined and air dried to afford 25.9 g (94.2%) of title product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4](/[CH:8]=[C:9](/[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])\[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[CH3:21][C:22]([CH3:32])([CH3:31])[CH2:23]/[CH:24]=[N:25]/[CH2:26][Si](C)(C)C.C(O)(=O)C.O>CN(C)P(N(C)C)(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:8]2[CH2:26][NH:25][CH:24]([CH2:23][C:22]([CH3:32])([CH3:31])[CH3:21])[C:9]2([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/C[Si](C)(C)C
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)CC1NCC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
To a solution of (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.2 g, 3.87 mmol) in hexamethylphosphoramide (20 mL) was added [3,3-dimethyl-but-(E)-ylidene]-trimethylsilanylmethyl-amine (1.1 g, 5.9 mmol), acetic acid (60 mg, 1 mmol) and H2O (0.1 g, 5.6 mmol) sequentially. The reaction mixture was stirred at room temperature for 18 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4, 1;3) to give rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile as a white foam (0.4 g, 24%).