Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH:20]1([CH2:23][NH2:24])[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Reactant: NCC1CC1
Product: O=[N+]([O-])c1cc(S(=O)(=O)c2ccccc2)ccc1NCC1CC1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-2-nitro-4-(phenylsulfonyl)benzene (J. Chem. Soc. Perkin Trans. 1, 1988, 991-998) and cyclopropylmethylamine.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]2[N:22]([CH:23]=[O:24])[CH2:21][CH2:20][C:19]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][N:35]([CH3:42])[CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:30][CH:29]=3)=[O:26])=[CH:18][C:17]=2[CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:23]([N:22]1[C:16]2[CH:15]=[CH:14][C:13]([C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=3)=[CH:43][C:17]=2[CH:18]=[C:19]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]([CH3:42])[CH:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:30][CH:29]=2)=[O:26])[CH2:20][CH2:21]1)=[O:24]
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3N(C=O)CC2)cc1)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
In water/ethanol/toluene (1:1:10, 60.0 ml) were dissolved 4-methylphenyl borate (658 mg) and 7-bromo-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4- carboxamide (2.01 g), and to the mixture was added potassium carbonate (1.34 g). Under argon atmosphere, the mixture was stirred for 30 minutes, and to the mixture was added tetrakistriphenylphosphine palladium(186 mg). Under argon atmosphere, the mixture was refluxed for 17 hours, and the mixture was dilute with ethyl acetate (750 ml). The mixture was washed with water (200 ml) and saturated brine (100 ml), and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (150 g, ethyl acetate→ethyl acetate/ethanol=20:1) and recrystallized from ethanol to give 1-formyl-7-(4-methylphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 317) (669 mg, 33%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH2:27][C@H:28]([OH:32])[C:29]([OH:31])=[O:30].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][CH2:27][C@H:28]([OH:32])[C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCC[C@H](O)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)NCC[C@H](O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 93.5 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 4-amino-2-(S)-hydroxy-butyric acid (112 mg, 0.94 mmol) (Aldrich) in 0.5 M NaOMe/MeOH (1.25 mL, 0.63 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was diluted with water (60 mL), acidified by 1 N HCl to pH=3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound 119 mg (0.29 mmol) in 93% yield. LC-MS ESI−: 406.00 (M−1)−.
Reaction SMILES: [CH3:1][Si:2]([CH3:32])([CH3:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:22])/[C:17]([O:19]CC)=[O:18])=[C:11]([F:23])[CH:10]=1)=[O:7].[OH-].[Na+].Cl>C(O)C>[CH3:30][Si:27]([CH3:28])([CH3:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([Si:2]([CH3:1])([CH3:32])[CH3:31])[CH:26]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:22])/[C:17]([OH:19])=[O:18])=[C:11]([F:23])[CH:10]=1)=[O:7]
Reactant: CCOC(=O)/C(C)=C/c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C/C(=C\c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F)C(=O)O
Temperature: 50 °C
Yield: 1.9 %

Procedure:
Compound 14e (18.9 g) was dissolved in ethanol (302 ml), and a 2N sodium hydroxide aqueous solution (100 ml) was added thereto. The obtained mixture was stirred under heating at 50° C. for 2 hours. The reaction mixture was ice-cooled, and a 1N hydrochloric acid aqueous solution (300 ml) was added to neutralize the mixture. The precipitated solid was filtered off and dried under reduced pressure to obtain Crude Compound 14 (16.6 g) as a white solid. Crude Compound 14 (400 mg) was recrystallized with ethanol (4.0 ml) and purified water (4.0 ml) to obtain Compound 14 (344 mg, 86%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1>>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]([CH3:13])=[C:2]([N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Product: COc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(C)cc1[N+](=O)[O-]

Procedure:
Starting Materials: 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (INTERMEDIATE 7) and tert-butyl piperidin-4-ylcarbamate.
Reaction SMILES: [CH2:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:25]([O:27][CH2:28][CH2:29][CH:30]=[CH2:31])=[O:26])=[O:19])=[O:7])[CH2:2]C=C>ClCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[N:20]12[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:25](=[O:26])[O:27][CH2:28][CH2:29][CH:30]=[CH:31][CH2:2][CH2:1][O:5][C:6](=[O:7])[C@@H:8]1[N:9]([CH2:10][CH2:11][CH2:12]1)[C:13](=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]2=[O:19]
Reactant: C=CCCOC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCCC=C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: O=C1OCCC=CCCOC(=O)[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@H]12
Temperature: 50 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
A mixture of 410 mg (0.92 mmol) (R)-1-[6-[(R)-2-but-3-enyloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid but-3-enyl ester and 40 mg benzylidene-bis(tricyclohexylphosphine)dichlororuthenium in 30 ml dry dichloromethane was stirred at 50° C. overnight. Removal of the solvent and chromatography on silicagel with ethylacetate/acetone with a ratio of 8/2 gave 200 mg (51%) (12R,23R)-14,21-dioxa-1,8-diaza-tricyclo[21.3.0.0 8,12]hexacos-17-ene-2,7,13,22-tetraone as an oil, MS m/e (%): 421 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:21]=1[C:22](Cl)=[O:23].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:19][C:20]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:21]=1[C:22]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][C:9]=2[F:11])[C:5]([C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=2)=[CH:6]1)=[O:23]
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(C(=O)c3cc(Cl)ccc3Cl)c3c(F)cc(F)cc23)CC1

Procedure:
(5.6 mg, 33%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and 2,5-dichlorobenzoyl chloride (12.6 mg, 0.06 mmol) with 1M NaN(TMS)2 (60 μL, 0.06 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>>[N:35]1[C:36]([NH2:37])=[C:31]2[C:32]([N:28]=[CH:29][NH:30]2)=[N:33][CH:34]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: Nc1ncnc2nc[nH]c12

Procedure:
reacting hydrogen peroxide with alcohol in the presence of catalase to form an aldehyde, reacting the aldehyde with the reduced form of nicotineamide adenine dinucleotide (hereinafter referred to as NADH) to form nicotineamide adenine dinucloeotide (hereinafter referred to as NAD) and determining NAD colorimetrically.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.CO.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:13][OH:14])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=Cc1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
5-Bromo-pyridine-2-carbaldehyde (X. Wang et al, Tetrahedron Letters 41 (2000), 4335–4338) (60 g, 322 mmol) was added to methanol (700 ml) and then water was added (700 ml) followed by addition of hydroxylamine hydrochloride (28 g, 403 mmol). Sodium carbonate (20.5 g, 193.2 mmol) in water (200 ml) was added and the reaction was stirred for 30 minutes. Water (500 ml) was then added and the precipitate was filtered and washed with water (2×300 ml) to give the desired product (60 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>C1COCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:10][CH:11]=1
Reactant: COCCO
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc(Br)cn1

Procedure:
0.25 mL 2-methoxyethanol (3.17 mmol) are added to a mixture of 80 mg (3.17 mmol) sodium hydride in 5 mL THF. The reaction mixture is stirred at r.t. for 10 min before 500 mg (2.11 mmol) 2,5-dibromopyridine are added. After 5 h at 75° C. the reaction mixture is diluted with half sat.aq. NaHCO3 solution and extracted with EtOAc. The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc 85/15).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.C([O-])(O)=O.[Na+].[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18]>CN(C=O)C.C(N(CC)CC)C.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:20][C:16](=[O:19])[CH:17]=[CH:18][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=Cc1ccc(C=O)c(F)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A solution of 4-bromo-2-fluoro benzaldehyde (2 g, 9.9 mmol) in DMF (50 ml) and triethylamine (6 ml) was degassed flushing N2 for 30 min. PPh3 (130 mg, 0.459 mmol), Pd(OAc)2 (44.3 mg, 0.20 mmol), NaHCO3 (1.6 g, 18.6 mmol) and tert-butyl acrylate (1.27 g, 9.9 mmol) were added and the resulting mixture was heated to reflux for 4 h. Additional tert-butyl acrylate (633 mg) and Pd(OAc)2 (20 mg) were added and the mixture was stirred at 100° C. for 3 h then the solution was diluted with H2O and extracted with Et2O. The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuo to give the crude product that was purified by silica gel chromatography (petroleum ether/EtOAc 95:5). The collected fractions gave 2 g of 3-(3-fluoro-4-formyl-phenyl)-acrylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:20].O>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:20])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)CO)ccc1OCCCCl
Yield: 32.8 %

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodo]benzene (15.6 g, 36.2 mmol), H2O (18 ml), OF3CO2H (2.8 ml) and CH3CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99-101° C.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19]C)=[O:18])=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+].Cl>O.O1CCCC1>[C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1cccc(C(=O)N2CCN(C(=O)C(C)C)CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C(=O)O)c2)CC1
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of methyl 3-(4-isobutyrylpiperazine-1-carbonyl)benzoate (1.25 g, 3.9 mmol) in water (10 mL) and tetrahydrofuran (10 mL) at 0° C., lithium hydroxide monohydrate (250 mg, 6 mmol) was added. The mixture was stirred at that temperature for 2 h. The resulting mixture was neutralized to pH=5 with hydrochloric acid, and extracted with ethyl acetate (100 mL×4) and concentrated to obtain a white solid of 3-(4-isobutyrylpiperazine-1-carbonyl)benzoic acid (1.1 g, yield 76%). LC-MS (ESI) m/z: 305 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[N:12]1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:51][C:52]1[CH:63]=[CH:62][C:55]2[NH:56][C:57]([C@@H:59]([NH2:61])[CH3:60])=[N:58][C:54]=2[CH:53]=1.ClCl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[N:12]1)[C:5]([NH:61][C@H:59]([C:57]1[NH:56][C:55]2[CH:62]=[CH:63][C:52]([Cl:51])=[CH:53][C:54]=2[N:58]=1)[CH3:60])=[O:7]
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(-n2ncc3c2CCCC3)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc(-n2ncc3c2CCCC3)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 10 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(4,5,6,7-tetrahydroindazol-1-yl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 10%; Rf value: 0.70 (silica gel: ethyl acetate); C23H21Cl2N5O (454.359); mass spectrum: (M+H)+=454/456/458 (chlorine isotope).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C@@H:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:14][S:13]2)=[C:7]([CH3:25])[CH:6]=1)=[O:4].[Li+].[OH-]>CO.O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C@@H:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:14][S:13]2)=[C:7]([CH3:25])[CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(N=C2SC[C@H](CC(C)C)N2CC(C)C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine (prepared in a manner analogous to that described in Method D2a; 0.035 g, 0.097 mmol) in a mixture of MeOH (1.5 mL) and H2O (1.5 mL) was added LiOH (0.016 g, 0.39 mmol). The resulting mixture was stirred for 2 d at room temp., then was concentrated under reduced pressure. The residue was adjusted to pH 1 with a 1% HCl solution, then extracted with EtOAc (4×10 mL). The combined organic layers were sequentially washed with H2O (15 mL), a saturated NaCl solution (15 mL), and dried (Na2SO4). Concentration under reduced pressure gave (4S)-2-(4-carboxy-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine (0.034 g, 100%): TLC (40% EtOAc/hex) Rf 0.08. This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13].[CH3:15][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1.CS(O)(=O)=O>C(O)C>[CH3:15][C:16]1[N:20]([CH:12]([CH3:13])[CH2:11][C:10](=[O:14])[NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:19][CH2:18][N:17]=1
Reactant: C/C=C/C(=O)Nc1c(C)cccc1C
Reactant: CC1=NCCN1
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CC1=NCCN1C(C)CC(=O)Nc1c(C)cccc1C

Procedure:
Combine 1.89 gm. (0.01 M) N-(2,6-dimethylphenyl)crotonamide, 0.90 gm. (0.0107 M) lysidine, 0.01 gm. (~0.001 M) methanesulphonic acid and about 40 ml. of ethanol in a pressure bottle and heat (bath temp. 100°-110° C.) for about 100 hours. Remove the solvent in vacuo, add about 50 ml. of water. Adjust the pH to 8.0 with concentrated HCl, and extract the aqueous phase with 2×25 ml. methylene chloride. Then adjust the aqueous phase to pH 13 with 50% sodium hydroxide and extract with 3×30 ml. of methylene chloride. Wash the combined methylene chloride extracts with 2×5 ml. of water. Dry the methylene chloride extracts over sodium sulfate. Evaporate off the solvents to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([CH:18]=[CH2:19])=[CH:4][N:3]=1.CS(C)=O.[OH-].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:18][CH2:19][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:17])[C:15]=4[CH:16]=[C:8]3[C:6]=2[CH:7]=1
Reactant: C=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1cccc2c1cc1n2CCc2cnc(Cl)cc2-1
Temperature: 100 °C
Reaction time: 3 h
Yield: 22.4 %

Procedure:
A solution of 2-(2-chloro-5-vinylpyridin-4-yl)-4-fluoro-1H-indole (50 mg, 0.18 mmol), Bu4NCl (0.07 mL of 50% a.q. solution), DMSO (0.25 mL) and KOH (0.6 mL of 60% a.q. solution) was stirred at 100° C. for 3 hours. Then the mixture was diluted with H2O, extracted with EtOAc, then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. It was purified by column (PE:EA=3:1) to obtain the product of 2-chloro-11-fluoro-5,6-dihydroindolo[2,1-a][2,6]naphthyridine (11 mg, yield: 20%). 1H-NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 7.62 (s, 1H), 7.18˜7.21 (m, 2H), 7.12 (s, 1H), 6.81 (t, J=8.4 Hz, 1H), 4.29 (t, J=6.0 Hz, 2H), 3.20 (t, J=6.0 Hz, 2H). MS (M+H)+: 273/275.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.C(N)(=O)C1C=CC=CC=1.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:43]3[CH:44]=[CH:45][C:40]([C:39]([F:50])([F:49])[F:38])=[CH:41][CH:42]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Agent: NC(=O)c1ccccc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3ccc(C(F)(F)F)cc3)C2=O)cc1
Yield: 85 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-(4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-(trifluoromethyl)phenyl boronic acid instead of phenyl boronic acid to obtain the title compound (85%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:20][CH2:19]2)=[O:17])=[C:9]([CH3:30])[CH:8]=1>C1COCC1.O>[CH3:27][C:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[CH:8][C:9]=2[CH3:30])[CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(CCCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
Lithium hydroxide monohydrate (108 mg, 2.6 mmol) was added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid methyl ester from Example E43.1 (500 mg, 1.3 mmol) in THF (12 ml) and water (6 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% acetic acid:4% methanol:94% dichloromethane) then recrystallised from chloroform and pet. ether to yield the title compound (439 mg, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([O:27]CC4C=CC=CC=4)=[CH:22][C:21]=3[Cl:35])[C:15]2=[O:36])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([OH:27])=[CH:22][C:21]=3[Cl:35])[C:15]2=[O:36])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(O)cc3Cl)C2=O)CC1
Yield: 88 %

Procedure:
Treat a solution of 4-[(R)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-2-oxo-pyrrolidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Preparation 13) (2.2 g, 4.1 mmol) in EtOAc (50 mL) with Palladium Hydroxide on carbon (0.1 g). Purge the solution with Hydrogen and stir the reaction overnight under 1 atm of hydrogen. Filter the reaction through celite to remove the catalyst. Remove the solvent to afford 1.6 g (87%) of desired product. MS (m/e): 441 (M−1).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4]1.O.NN>C(O)C>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CO[C@H]1CC[C@H](N)CC1

Procedure:
A mixture of 2-(trans-4-methoxycyclohexyl)-1H-isoindole-1,3(2H)-dione (0.27 g, 1.0 mmol), and hydrazine hydrate (63.3 uL, 0.00130 mol) in ethanol (2.0 mL) was heated at reflux for 1 h. After cooling, the solid was filtered off, and the filtrate was concentrated to yield the desired product (0.12 g, 89%).