Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[C:16](=O)[C:15]3[C:14]([C:18]([O:20]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][CH:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][N:4]=[CH:3]1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[C:6]([CH:7]2[C:16]3=[N:30][NH:31][C:18](=[O:20])[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([C:15]=43)[NH:9][CH:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][N:4]=[CH:3]1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1cncn1C)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: Cn1cncc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46 %

Procedure:
A mixture of ethyl 3-(1-methyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (170 mg) in 85% hydrazine monohydrate (3 mL) and methanol (3 mL) was stirred at room temperature for 5 h. Filtered and washed the cake by methanol (2 mL) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain 9-(1-methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (70 mg, yield 46%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.50 (s, 3H), 4.52-4.54 (d, J=9.2 Hz, 1H), 4.83-4.85 (d, J=9.2 Hz, 1H), 6.66 (s, 1H), 7.17-7.19 (d, J=7.6 Hz, 1H), 7.25-7.32 (m, 3H), 7.36-7.44 (m, 5H), 7.56-7.60 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 348 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][O:4][C:5]([N:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]4[O:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C:20]=4[CH:33]=3)[CH:14]=2)[N:9]=[CH:8]1)=[O:6].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:25]1[C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[C:15]4[N:7]([C:5]([O:4][CH2:3][CH:2]([CH3:34])[CH3:1])=[O:6])[CH:8]=[N:9][C:10]4=[N:11][CH:12]=3)=[CH:33][C:20]=2[CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: CC(C)COC(=O)n1cnc2ncc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)n1cnc2ncc(-c3ccc4c(c3)CNCCO4)cc21
Temperature: 80 °C
Yield: 117.4 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(1-{[(2-methylpropyl)oxy]carbonyl}-1H-imidazo[4,5-b]pyridine-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.40 g, 0.86 mmol) in chloroform (4 mL) was added dropwise trifluoroacetic acid (5 mL) and the solution then warmed to 80° C. for 45 minutes. After cooling, the solution was concentrated and dried to give 2-methylpropyl 6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate (0.37 g, 90% yield) as the trifluoroacetic acid salt. MS (EI) for C20H25N4O3: 367 (MH+).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].[Cl:14][C:15]([Cl:19])=[CH:16][CH2:17]Cl>>[Cl:14][C:15]([Cl:19])=[CH:16][CH2:17][N:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: ClCC=C(Cl)Cl
Product: COC(=O)c1c(C=O)c(C)c(C)n1CC=C(Cl)Cl

Procedure:
The title compound was prepared as grayish-white crystals in 87.1% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1,1, 3-trichloro-1-propene.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[N:3]1.Cl.[Cl:15][C:16]1[C:17]([CH2:22][NH2:23])=[N:18][CH:19]=[CH:20][N:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH2:22][NH:23][C:11]([CH:6]2[CH2:7][CH2:8][CH2:9][C:10]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]2=3)=[O:13])=[N:18][CH:19]=[CH:20][N:21]=1
Reactant: Cn1ncc2c1CCCC2C(=O)O
Reactant: NCc1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cn1ncc2c1CCCC2C(=O)NCc1nccnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.9 %

Procedure:
To a solution of 1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxylic acid (6 g, 33 mmol) and (3-chloropyrazin-2-yl)methanamine hydrochloride (6 g, 33 mmol) in 200 mL of DCM was added TEA (9 g, 88 mmol) dropwise. The resulting mixture was stirred at room temperature for 5 mins, and then HATU (12.5 g, 33 mmol) was added to the solution in portions at 0° C. The mixture was stirred at room temperature for 2 hours. Water was added, the DCM layers was separated, and washed with brine, dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography on silica gel (PE/THF=5/1 v/v %) to afford N-((3-chloropyrazin-2-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxamide (1.5 g, 15%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[O:11][N:10]=1.C[CH2:21][N:22](CC)CC.[Si](C#N)(C)(C)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([O:16][C:14]([C:13]1[C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[C:21]#[N:22])=[N:10][O:11][C:12]=1[CH3:19])=[O:15])[CH3:18]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(-c2c(F)cccc2I)noc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)C#N
Solvent: O
Product: CCOC(=O)c1c(-c2c(F)cccc2C#N)noc1C
Temperature: 25 °C
Yield: 82 %

Procedure:
To a mixture of ethyl 3-(2-Fluoro-6-iodo-phenyl)-5-methyl-isoxazole-4-carboxylate (0.25 g, 0.67 mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.067 mmol), and Et3N (5 mL) under N2 was added TMSCN and heated at reflux overnight. The reaction was cooled to room temperature, diluted with H2O, and extracted with EtOAc (2×). The combined extracts were washed (H2O then brine), dried (MgSO4), filtered, and concentrated. Flash chromatography (silica gel, EtOAc/hexanes gradient) gave the title compound (0.15 g, 82%). Mass Spectrum (ES+) (m/z) 275.0 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[Cl:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.CN(C=O)C>[Cl:31][C:30]1[C:25]([NH:24][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[CH:9]=[CH:10][C:2]=2[F:1])=[C:26]([F:33])[C:27]([OH:32])=[CH:28][CH:29]=1
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Reactant: Nc1c(Cl)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1c(Cl)ccc(O)c1F)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a mixture of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (478 mg, 2.04 mmol, 1.0 eq) and (COCl)2 (777 mg, 6.13 mmol, 3.0 eq) in DCM (20 mL) was added DMF (0.3 mL). The reaction mixture was stirred at 0° C. for 1 h, then the solvent removed in vacuo. The residue obtained was dissolved in THF (20 mL) and added dropwise to a solution of 3-amino-4-chloro-2-fluoro-phenol (intermediate X(d)) (330 mg, 2.04 mmol, 1.0 eq) and NaHCO3 (515 mg, 6.13 mmol, 3.0 eq) in THF (20 mL). After the addition, the reaction mixture was stirred at room temperature for 30 min. The THF was evaporated in vacuo and the aqueous solution adjusted to pH 3 by addition of 1M HCl. The mixture was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:1) to give the title compound as a yellow solid (200 mg, 26%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]([OH:26])[CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[CH2:7]1)=[O:5])C.O.CO.[OH-].[Li+:31]>O1CCCC1>[OH:26][CH:13]([CH2:14][O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2)[CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([O-:5])=[O:3])[CH2:7]1.[Li+:31]
Reactant: CCOC(=O)[C@@H]1CCCN(CC(O)COc2cccc3ncccc23)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])[C@@H]1CCCN(CC(O)COc2cccc3ncccc23)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-[2-Hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-3-carboxylic acid ethyl ester (44) (0.739 g; 2.06 mmol) is dissolved in 20 mL of a 2:2:1 mixture of tetrahydrofuran:water:methanol. Lithium hydroxide (52 mg; 2.17 mmol) is added and the mixture stirred at ambient temperature. After 16 hours, the mixture is concentrated in vacuo at 40° C. Further drying on the vacuum pump affords the desired product (45) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1.CCOC(C)=O.CCCCCC>C(#N)C>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:40]=[CH:41][C:32]([CH2:31][N:11]([CH:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:23])[CH:8]([CH3:10])[CH3:9])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:33][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: COC(=O)c1ccc(CN(C(C(=O)OC(C)(C)C)C(C)C)S(=O)(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
To a stirring solution of 2-(4-Methoxy-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester (140 mg, 0.41 mmol) in acetonitrile (5 ml) at ambient temperature was added cesium carbonate (1.33 g, 4.10 mmol). Then methyl 4-(bromomethyl)benzoate (115 mg, 0.60 mmol) was added to the suspension and the reaction mixture was stirred at 70° C. for 1 hour by which time TLC (EtOAc/Hexane 1:1) monitoring showed the reaction to be completed. After cooling to ambient temperature, the mixture was filtered to remove excess cesium carbonate and evaporated to dryness. The residue was purified by flash chromatography (EtOAc/Hexane 1:1) to furnish the pure product as slightly yellow oil. Yield 153 mg (76%).
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[C:3]=1[C:12]([O:14]CC)=O.[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:18]>Cl.C(O)(=O)C>[O:14]=[C:12]1[NH:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:1][C:2]2[S:6][CH:5]=[C:4]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)[C:3]1=2
Reactant: CCOC(=O)c1c(-c2cccs2)csc1N
Reactant: CCOC(=O)C#N
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2scc(-c3cccs3)c2c(=O)[nH]1
Temperature: 90 °C
Yield: 88.5 %

Procedure:
Ethyl 5′-amino-2,3′-bithiophene-4′-carboxylate (3.00 g, 11.842 mmol) was suspended in 1N hydrogen chloride-acetic acid solution (30 mL), ethyl cyanoformate (1.29 g, 13.026 mmol) was added, and the mixture was stirred under heating at 90° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was suspended in diethyl ether, and the insoluble material was collected by filtration, washed with water to give the title compound as a brown powder (3.21 g, 88%).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[F:22][C:23]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][C:24]=1[C:25]#[N:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:29]=[CH:30][C:23]=2[F:22])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCCc1ccc(F)c(C#N)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCCCCc1ccc(F)c(-c2nc(-c3ccccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (1.27 g), 2-fluoro-5-undecylbenzonitrile (1.09 g), anhydrous aluminum chloride (0.55 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.85 g of desired compound (melting point: 35.0°-37.0° C.).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[NH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[S:17]>>[BrH:1].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:16]3[S:17][CH:2]=[C:3]([C:5]4[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=4[CH3:10])[N:15]=3)=[CH:24][CH:23]=2)=[CH:27][CH:28]=1
Reactant: NC(=S)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3ccc(Oc4ccc(Cl)cc4)cc3)n2)c(C)s1
Yield: 74 %

Procedure:
Methyl 4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2arboxylate hydrobromide: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (309 mg, 1.0 mmol) was allowed to react with amino{[4-(4-chlorophenoxy)phenyl]amino}methane-1-thione (297 mg) as described in Example 154, step (a) to give 410 mg (72% yield) of methyl 4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C22H17ClN2O3S3, 489.1 (M+H), found 489.1.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[S:6][C:5](/[CH:7]=[CH:12]/[N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)s1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(/C=C/[N+](=O)[O-])s1
Temperature: 10 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 10.3 g (80 mmol) 5-methyl-2-thiophenecarboxaldehyde (commercially available) and 13.5 mL nitromethane in 160 mL methanol was cooled to −5° C. A 50% sodium hydroxide solution (80 mL) was added drop wise maintaining the temperature between 5 and 10° C. (formation of a yellow precipitate). After complete addition the mixture was stirred at 10° C. for 1 h. The suspension was poured onto an ice-cold solution of HCl 37% (340 mL) and water (560 mL). The crude product separated as a yellow solid, which was filtered and dissolved in dichloromethane. The solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified on a silica eluting with a gradient formed from heptane and ethyl acetate. Evaporation of the product fractions yielded 6.9 g (51%) of the title compound as yellow solid.
Reaction SMILES: COC1C=CC=C2C=1C=CN2C1C=CC(N)=CC=1.[I:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:34]3[C:29](=[C:30]([O:35][CH3:36])[CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[CH:22][CH:21]=1.[Na]>>[I:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:34]3[C:29](=[C:30]([O:35][CH3:36])[CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: COc1cccc2c1ccn2-c1ccc(I)cc1
Agent: COc1cccc2c1ccn2-c1ccc(N)cc1
Agent: [Na]
Product: COc1cccc2c1CCN2c1ccc(I)cc1

Procedure:
The synthesis of 1-(4-iodophenyl)indolin-4-ol (92) is provided in Reaction Scheme 4b. The reaction of 1-fluoro-4-nitrobenzene and 4-methoxy-1H-indole in the presence of Cs2CO3 gave 4-methoxy-1-(4-nitrophenyl)-1H-indole (88), which was reduced with H2/Pd to yield 4-(4-methoxy-1H-indol-1-yl)benzenamine (89). The amino group of 89 was converted via the Sandmeyer reaction to 1-(4-iodophenyl)-4-methoxy-1H-indole (90) which on reduction with sodium borocyanohyride gave 1-(4-iodophenyl)-4-methoxyindoline (91). The indoline 91 was demethylated with BBr3 to provide the desired 92.
Reaction SMILES: CC([O-])(C)C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=O.CO>C1COCC1.O>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][C:17]#[N:18])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(CC#N)cc1F
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a suspension of t-BuOK (25.3 g, 0.207 mol) in TI-1F (150 mL) was added a solution of TosMIC (20.3 g, 0.104 mol) in TI-IF (50 mL) at −78° C. The mixture was stirred for 15 minutes, treated with a solution of 3-fluoro-4-methoxy-benzaldehyde (8.00 g, 51.9 mmol) in THF (50 mL) dropwise, and continued to stir for 1.5 hours at −78° C. To the cooled reaction mixture was added methanol (50 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (200 mL). The aqueous phase was extracted with EtOAc (100 mL×3). The combined organic layers were dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to afford 2-(3-fluoro-4-methoxyphenyl)acetonitrile (5.0 g, 58%). 1H NMR (400 MHz, CDCl3) δ 7.02-7.05 (m, 2 H), 6.94 (t, J=8.4 Hz, 1 H), 3.88 (s, 3 H), 3.67 (s, 2 H). 13C NMR (100 MHz, CDCl3) δ 152.3, 147.5, 123.7, 122.5, 117.7, 115.8, 113.8, 56.3, 22.6.
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([F:9])[CH2:7][NH:6][CH2:5]1)=[N+:2]=[N-:3].CCN(C(C)C)C(C)C.[C:19](Cl)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[N:1]([C@H:4]1[C@H:8]([F:9])[CH2:7][N:6]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [N-]=[N+]=N[C@@H]1CNC[C@H]1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a stirred mixture of (trans)-3-azido-4-fluoropyrrolidine (18 g) in CH2Cl2 (120 mL) was added DIPEA (35 g, 0.27 mol, 2.5 eq), then CBZ-Cl (22 g, 0.13 mol) was added dropwise at 0-5° C. After addition, the resulting mixture was stirred at rt overnight. The mixture was washed with sat. aq. NH4Cl (150 mL), sat. aq. NaHCO3 (3×40 mL) and brine (40 mL). The organic layer was concentrated and purified by column (petroleum ether/EtOAc=10:1˜5:1) to give the title compound (30 g, ˜100% yield in two steps, containing residual EtOAc and DCM) as a light yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:13][CH:12]=1
Reactant: Clc1ccc(I)cc1
Reactant: c1ccc2[nH]ccc2c1
Product: Clc1ccc(-n2ccc3ccccc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-chloro-4-iodobenzene: ESMS m/e: 227.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.COC1C=C2C(=CC=1)NCC2.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Cc1ccc2[nH]ccc2c1
Agent: COc1ccc2c(c1)CCN2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CCN2
Yield: 99 %

Procedure:
5-Methylindoline was prepared from 5-methylindole using the procedure described for the preparation of 5-methoxyindoline. 5-Methylindole (11 g, 0.0835 mol) in glacial acetic acid (150 mL) in a 1 L 3-necked flask was reduced at 10-15° C. with sodium cyanoborohydride (15.8 g, 0.251 mol). Extraction with ethyl acetate provided 5-methylindoline (11 g, 0.0832 mol, 99% yield) as a thick oil which was used without further purification. The structure was corroborated by NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44]([C:46]1[N:50]([CH3:51])[N:49]=[CH:48][CH:47]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:44][C:46]4[N:50]([CH3:51])[N:49]=[CH:48][CH:47]=4)[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Reactant: Cn1nccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3Cc2ccnn2C)cc1
Reaction time: 120 h
Yield: 60.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 5-formyl-1-methylpyrazole (0.23 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 5 days. To the reaction solution, 5-formyl-1-methylpyrazole (0.23 g) and sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) were added, and the mixture was further stirred for 24 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:3) and further recrystallized from ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-(1-methylpyrazol-5-ylmethyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 89) (140.1 mg) as yellow crystals.
Reaction SMILES: [O:1]([CH:8]=[CH:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[N:15][N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:12]2[CH2:13][CH2:14][N:10]([CH:9]=[CH:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:22][N:21]=1
Reactant: O=[N+]([O-])N=C1NCCN1C=COc1ccccc1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])N=C1N(C=COc2ccccc2)CCN1Cc1ccc(Cl)nc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
A mixture comprising 2.8 g of 1-(2-phenoxyvinyl)2-nitroiminoimidazolidine, 3.6 g of 2-chloro-5chloromethylpyridine, 3.2 g of potassium carbonate and 15 ml of dimethylsulfoxide was stirred at 70° C. for one hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluet: ethyl acetate) to give 3.0 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2-phenoxyvinyl)-imidazolidine.