Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@:9]23[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:10]2[N:11]([CH3:17])[C:12](=O)[C@@H:13]([CH3:15])[O:14]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@:9]23[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:10]2[N:11]([CH3:17])[CH2:12][C@@H:13]([CH3:15])[O:14]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@]23CCCC[C@@H]2N(C)C(=O)[C@@H](C)O3)c1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1cccc([C@]23CCCC[C@@H]2N(C)C[C@@H](C)O3)c1
Yield: 98.1 %

Procedure:
The crude product of Example 10 (1.36 g) in dry ether (25 cm3) was added dropwise to a stirred, refluxing suspension of lithium aluminium hydride (0.45 g) in dry ether (10 cm3). The mixture was heated to reflux for 6 hr. and was then allowed to cool. Saturated Rochelle salt solution (50 cm3) was added and the mixture was stirred to dissolve aluminium salts. The phases were separated and the aqueous phase was extracted with further ether. The extracts were dried (Na2SO4) and evaporated, leaving the title product as an oil (1.27 g). The crude title base (1.1 g) was converted in ethyl acetate to its hydrogen oxalate salt, which was recrystallised from ethyl acetate-methanol giving crystals (0.73 g), m.p. 213°-5° (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][N:4]=1.[F:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([F:26])[C:15]=1[C:16](O)=[O:17].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[F:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([F:26])[C:15]=1[C:16]([NH:12][C:9]1[CH:10]=[C:11]2[C:3]([O:2][CH3:1])=[N:4][NH:5][C:6]2=[N:7][CH:8]=1)=[O:17]
Reactant: COc1n[nH]c2ncc(N)cc12
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1n[nH]c2ncc(NC(=O)c3c(F)ccc([N+](=O)[O-])c3F)cc12
Reaction time: 24 h
Yield: 68.5 %

Procedure:
3-Methoxy-1H-pyrazolo[3,4-b]pyridin-5-amine (563 mg, 3.43 mmol) in N,N-dimethylformamide (17.1 mL) was sequentially treated with 2,6-difluoro-3-nitrobenzoic acid (766.2 mg, 3.772 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (723.2 mg, 3.772 mmol), and 1-hydroxybenzotriazole (509.7 mg, 3.772 mmol) at ambient temperature. After 24 hours, the reaction mixture was diluted with ethyl acetate, washed with water (4×), sodium bicarbonate (2×), and brine (1×), dried over sodium sulfate, and concentrated. The crude product was triturated with dichloromethane to provide 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-nitrobenzamide (820.6 mg, 2.350 mmol, 68.5% yield) as a solid. MS (APCI-neg) m/z=347.8 (M−H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]([OH:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[H-].[H-].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:21][C:20]([F:22])([F:23])[C:19]([C:15]1[CH:14]=[C:13]([CH3:29])[C:12]([O:11][CH2:10][CH2:9][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:17]([CH3:18])[CH:16]=1)([OH:28])[C:24]([F:25])([F:27])[F:26]
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC(=O)NCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCCNCc1ccccc1
Reaction time: 16 h

Procedure:
To N-benzyl-2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetamide (3.0 g=6.0 mmol) in 75 ml toluene add sodium bis-2-methoxyethoxy)aluminum hydride (70% solution in benzene, 8.0 g=28 mmol) over 1/2 hour. Stir 16 hours, treat with 1.0 N NaOH, and extract with ethyl acetate. Dry and concentrate the organic layer. Recrystallize from ether-hexane to give 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]ethylbenzylamine, as white crystals, m.p. 117°-120° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:16](=O)OC(C)(C)C)[CH2:9][CH2:8]1>O1CCCC1>[CH3:16][NH:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][O:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)NCCN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCN1CCOCC1
Temperature: 2.5 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed a solution of LiAlH4 (7.72 g, 208.65 mmol, 3.00 equiv) in tetrahydrofuran (60 mL). This was followed by the addition of a solution of tert-butyl 2-morpholinoethylcarbamate (16 g, 62.61 mmol, 1.00 equiv, 90%) in tetrahydrofuran (40 mL) dropwise with stirring at 0-5° C. The resulting solution was stirred for 2 h at 70° C. in a oil bath. The reaction was then quenched by the addition of 7.7 mL of water, 7.7 mL of 15% sodium hydroxide, and 23.1 mL of water. The solids were filtered out. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (0.5% triethylamine) (20:1). This resulted in 4.2 g (42%) of N-methyl-2-morpholinoethanamine as brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33]Cl)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:36]([O-:39])(=[O:38])[CH3:37].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:35])[N:27]3[C:30]([O:32][CH2:33][O:38][C:36](=[O:39])[CH3:37])=[O:31])=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OCCl
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1.20 g, 2.22 mmol) in dimethyl formamide (20 mL) was added cesium acetate (639 mg, 3.33 mmol). The reaction was then stirred at ambient temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and quenched with water/brine (1:1, 50 mL). The reaction was extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL) then brine (50 mL) and dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 0-10% tetrahydrofuran/dichloromethane with 1% Et3N to give the product which required further purification. The product was purified by column chromatography on silica eluting with 0.5% Et3N/ethyl acetate to give acetoxymethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-87 (243 mg, 19% over 2 steps).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].[C:29]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)(=[O:31])[CH3:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([N:4]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2][NH:1][C:38]([CH:35]3[CH2:34][CH2:33][N:32]([C:29](=[O:31])[CH3:30])[CH2:37][CH2:36]3)=[O:39])([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[C:6](=[O:15])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)CN(CCN)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)NCCN(CC(C)(C)C)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Yield: 32.9 %

Procedure:
The mixture 3-[(2-Amino-ethyl)-(2,2-dimethyl-propyl)-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (120 mg, 0.286 mmol), 1-Acetyl-piperidine-4-carboxylic acid (59 mg, 0.344 mmol), EDC.HCl (66 mg, 0.344 mmol), HOBt (46 mg, 0.344 mmol) and DIPEA (111 mg, 0.860 mmol) in dichloro-methane (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give 54 mg rac-1-Acetyl-piperidine-4-carboxylic acid{2-[[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide of as a white solid. Then 18 mg rac-1-Acetyl-piperidine-4-carboxylic acid{2-[[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide was separated by chiral preparative HPLC to obtain 7 mg 1-Acetyl-piperidine-4-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide MS: [M+H]+=573.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:28][O:29][CH3:30])[C:10]([NH:12][CH:13]2[C:26](=[O:27])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:31]>CO.O1CCCC1.C(OC(C)C)(C)C>[ClH:31].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:28][O:29][CH3:30])[C:10]([NH:12][CH:13]2[C:26](=[O:27])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a suspension of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.52 g) in a mixture of methanol (3 ml) and tetrahydrofuran (2 ml) was added conc. hydrochloric acid (0.18 g), and the mixture was stirred at 30° C. for 4 hours. After the reaction mixture was cooled and diluted with diisopropyl ether, the precipitated crystals were collected by filtration, washed with diisopropyl ether and then dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (0.45 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15]([CH3:21])([C:18](O)=[O:19])[CH2:14][CH2:13]1.C(Cl)(=O)C([Cl:25])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15]([CH3:21])([C:18]([Cl:25])=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C(=O)O)CCC(N2C(=O)c3ccccc3C2=O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C(=O)Cl)CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-(1,3-Dioxoisoindolin-2-yl)-1-methylcyclohexanecarboxylic acid (Intermediate 74, 220 mg, 0.786 mmol) was dissolved in DCM (5 mL), and oxalyl chloride (146 mg, 0.1 mL, 1.149 mmol) was added slowly, followed by addition of a drop of DMF. The mixture was stirred at room temperature for 20 min, then concentrated under vacuum to provide the product as a yellow solid that was used as is in the next step.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][CH2:4][C@H:3]1[N:7]([CH3:11])[C:8](=[O:10])[CH3:9].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1>>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:5]2[CH2:6][CH:2]([OH:1])[CH:3]([N:7]([CH3:11])[C:8](=[O:10])[CH3:9])[CH2:4]2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)N(C)[C@@H]1CNC[C@H]1O
Product: CC(=O)N(C)C1CN(c2ccc(N)cc2)CC1O

Procedure:
trans-N-(4-Hydroxypyrrolidin-3-yl)-N-methylacetamide was reacted with 4-fluoronitrobenzene by method C, and the product was subsequently hydrogenated by method B. This resulted in the product with the molecular weight of 249.32 (C13H19N3O2); MS (ESI): 250 (M+H+).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[C:30]3[O:29][CH2:28][CH2:27][N:26]([CH3:31])[C:25]=3[CH:24]=[C:23]([Cl:32])[CH:22]=2)=[O:20])[CH2:11]1)=[O:7])(C)(C)C.[NH2:33][C:34]1[C:42]([Cl:43])=[CH:41][C:37](C(O)=O)=[C:36]([O:44][CH3:45])[CH:35]=1>>[NH2:33][C:34]1[C:42]([Cl:43])=[CH:41][C:37]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:30]4[O:29][CH2:28][CH2:27][N:26]([CH3:31])[C:25]=4[CH:24]=[C:23]([Cl:32])[CH:22]=3)=[O:20])[CH2:11]2)=[O:7])=[C:36]([O:44][CH3:45])[CH:35]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN1CCOc2c(C(=O)NCCCN3CCC(CNC(=O)OC(C)(C)C)C3)cc(Cl)cc21
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)c2cc(Cl)cc3c2OCCN3C)C1

Procedure:
N-(3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propyl)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide (1.5 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.65 g) to give N-(3-(3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)-pyrrolidin-1-yl)propyl)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[N:19]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)O1.N>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:17][C:18]2[N:19]=[C:20]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)[CH:21]=[CH:22][CH:23]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cccc(Br)n1)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: [Pd]
Agent: N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(Cc1cccc(-c2ccncc2)n1)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 86 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-{[(6-bromopyridin-2-ylmethyl)methylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester (Preparation 4, 88 mg, 0.28 mmol) in toluene (5 mL, anhydrous) was added palladium tetrakis(triphenylphosphine) (13 mg, 0.01 mmol) and sodium carbonate (53 mg in 1.5 mL water, deoxygenated). To the vigorously stirred biphasic mixture was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine 57 mg, 0.28 mmol) and the reaction mixture heated to 86° C. (bath) for 3 days. The reaction mixture was allowed to cool to rt then aqueous ammonia (2M, 15 mL) was added with vigorous stirring. After 10 min, ethyl acetate (30 mL) was added and the layers separated. The aqueous was extracted with ethyl acetate (2×20 mL) and the combined organics washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification via flash chromatography (5% MeOH/CH2Cl2) afforded the title compound: δH (CDCl3): 0.96-1.12 (2H, m), 1.43 (9H, s), 1.63-1.73 (1H, m), 1.78 (2H, d), 2.26-2.32 (5H, m), 2.69 (2H, t), 3.72 (2H, s), 4.00-4.14 (2H, m), 7.51 (1H, d), 7.65 (1H, d), 7.77 (1H, t), 7.88 (2H, d), 8.69 (2H, d). RT=2.38 min; m/z (ES+)=397 [M+H]+.
Reaction SMILES: C(C1C=CC(C(O)=O)=CC=1)#N.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=3)=[CH:35][CH:34]=2)=[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[C:22]2=[O:31])=[CH:16][CH:15]=1)#[N:13].C1COCC1>N.[Ni]>[NH2:13][CH2:12][C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=3)=[CH:35][CH:34]=2)=[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[C:22]2=[O:31])=[CH:18][CH:19]=1
Reactant: CN1C(=O)C(=C(Nc2ccc(-c3cn(C)cn3)cc2)c2ccc(C#N)cc2)c2ccccc21
Agent: [Ni]
Agent: N
Agent: N#Cc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: CN1C(=O)C(=C(Nc2ccc(-c3cn(C)cn3)cc2)c2ccc(CN)cc2)c2ccccc21
Reaction time: 10 h

Procedure:
Starting from 4-cyanobenzoic acid, synthesis was carried out analogously to Example 40. Only the final step differed as follows. 6.15 g of 3-{(4-cyanophenyl)-[4-(1-methyl-1H-imidazol-4-yl)phenylamino]methylene}-1-methyl-1,3-dihydroindol-2-one was dissolved in 200 mL of methanolic ammonia and THF and hydrogenated with 5 g of Raney nickel at RT and under a pressure of 50 psi. After about 10 hours, the catalyst was removed by suction filtering and the filtrate was again filtered through a glass filter, evaporated down, and the crystalline residue was filtered with diisopropyl ether suction. The crystals were suspended in 400 mL of methanol, adjusted to pH 1 with 10% ethanolic hydrochloric acid, and heated to boiling temperature. The mixture was filtered and the filtrate was evaporated down to a residual volume of about 100 mL and combined with 300 mL of ethanol. After further evaporation to approximately 100 mL residual volume, the substance crystallized out. After cooling, it was suction filtered and washed with ice-cold ethanol. Yield: 6.15 yellow crystals; melting point>300° C.; Rf value=0.32 (dichloromethane/methanol/ammonia (85:15:1)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:5]=3)[NH:1][CH:2]=2)=[CH:32][CH:33]=1
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Product: COC(=O)c1ccc2[nH]cc(Cc3ccc(OCc4ccc5ccccc5n4)cc3)c2c1

Procedure:
This compound was prepared from methyl indole-5-carboxylate and 4-(quinolin-2-ylmethoxy)benzyl chloride (Example 1a) by the method described in Example 12, part i, m.p. 179°-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.1 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (78 mg, 60%).
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[C:4]#[N:5].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=2[C:4]#[N:5])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: N#Cc1c(Br)cncc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cncc(Br)c2C#N)CC1
Temperature: 100 °C
Yield: 42.6 %

Procedure:
3,5-Dibromo-isonicotinonitrile (500 mg, 1.9 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (710 mg, 2.3 mmol) and 2.0 M Na2CO3 aqueous solution (1.9 mL, 3.8 mmol) are added into the 1,4-dioxane (20 mL). Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (140 mg, 0.19 mmol) is added and the mixture is heated at 100° C. for 3.5 hrs. The reaction mixture is filtered and the filtrate is concentrated to give the crude product. Purification by flash column chromatography affords 295 mg of 5-bromo-4-cyano-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[F:10][C:11]1[CH:22]=[CH:21][C:14]([CH:15]([OH:20])[C:16](OC)=[O:17])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH3:2][N:3]([O:4][CH3:5])[C:16](=[O:17])[CH:15]([OH:20])[C:14]1[CH:13]=[CH:12][C:11]([F:10])=[CH:22][CH:21]=1
Reactant: COC(=O)C(O)c1ccc(F)cc1
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CON(C)C(=O)C(O)c1ccc(F)cc1
Temperature: 3.5 °C
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
Cool a mixture of N-methyl-O-methyl hydroxylamine hydrochloride (118 mmol) and toluene (125 mL) to −5° C. Slowly add trimethylaluminum (2 M in heptane, 59.2 mL, 118 mmol) to the mixture over 20 minutes, maintaining the reaction temperature from −1 to 8° C. After about 5 minutes slowly warm the mixture to room temperature and stir for 1.5 hours. Add a solution of methyl p-fluoromandelate (11.1 g, 60 mmol) in 75 mL of toluene over 30 min without external cooling. Cool the reaction to 0° C. and quench with 10% hydrochloric acid. Extract with ethyl acetate (4×250 mL). Wash the combined ethyl acetate layers sequentially with water and saturated aqueous sodium chloride, dry over sodium sulfate and concentrate under reduced pressure to provide 12.1 g (82%) of the desired compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[O:16][CH:15]([CH3:18])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26](OCC)(=[O:28])C.Cl>>[CH3:26][O:28][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[O:16][CH:15]([CH3:18])[CH2:14][NH:13][CH2:12][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(-c3cccc(F)c3)c2O1
Agent: Cl
Product: COc1cccc(-c2csc3c2OC(C)CNC3)c1
Yield: 92 %

Procedure:
tert-Butyl 8-(3-fluorophenyl)-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (274 mg) was stirred in 4N hydrogen chloride-ethyl acetate solution (5 mL) for 30 min. The precipitated crystals were washed with ethyl acetate to give 8-(3-fluorophenyl)-2-methyl-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride (207 mg, 92%) as colorless crystals.
Reaction SMILES: O.[C:2]([OH:6])(=O)[CH:3]=O.Br.[NH2:8][C:9]1[S:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([OH:25])=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=2)=[N:13][N:14]=1>O.C(O)(=O)C.Cl>[C:26]([C:17]1[CH:16]=[C:15]([C:12]2[N:14]3[N:13]=[CH:3][C:2](=[O:6])[N:8]=[C:9]3[S:10][CH:11]=2)[CH:20]=[C:19]([C:21]([CH3:24])([CH3:22])[CH3:23])[C:18]=1[OH:25])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(C2=NN=C(N)SC2)cc(C(C)(C)C)c1O
Reactant: O=CC(=O)O
Agent: Br
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2csc3nc(=O)cnn23)cc(C(C)(C)C)c1O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
4.8 g (0.05 mol) of glyoxylic acid monohydrate in 75 ml of water were added dropwise to a solution of 10.0 g (0.025 mol) of 2-amino-5-(3,5-di-tert.butyl-4-hydroxyphenyl)-6H-1,3,4-thiadiazine hydrobromide from step (c1) in 250 ml of glacial acetic acid and 25 ml of 4N hydrochloric acid at 80° C. After the mixture had been stirred at 80° C. for 20 hours, it was evaporated under reduced pressure. It was advantageously possible to purify the solid residue by column chromatography on silica gel using methylene chloride/methanol (25:1) as the eluent and subsequent recrystallization from ethanol, and, from analytical and spectroscopic investigations, the product proved to be identical to that prepared by procedures (a) and (b).