Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:19][CH2:18]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46].[ClH:47]>>[ClH:28].[ClH:47].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]3[NH:16][CH:17]2[CH2:22][CH2:21][CH:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:19][CH2:18]2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CCN(CC)C1CCC(Nc2c(S(C)(=O)=O)cnc3ccc(Br)cc23)CC1
Agent: Cl
Product: CCN(CC)C1CCC(Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1
Yield: 50 %

Procedure:
Following general procedure D, N1-[6-bromo-3-(methylsulfonyl)quinolin-4-yl]-N4,N4-diethylcyclohexane-1,4-diamine (40 mg, 0.088 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.176 mmol) to afford, after treatment with 1M HCl, the desired product (24.5 mg, 50%) as an orange-brown solid: 1H NMR (500 MHz, DMSO-d6+D2O) δ 8.91 (d, J=8.0 Hz, 1H), 8.44-8.32 (m, 2H), 8.08 (d, J=8.5 Hz, 1H), 7.48-7.27 (m, 2H), 3.98-3.95 (m, 3H), 3.46 (d, J=11.4 Hz, 5H), 3.28-3.03 (m, 5H), 2.38 (s, 2H), 2.27 (d, J=13.0 Hz, 1H), 2.15 (s, 1H), 2.10-1.96 (m, 2H), 1.90-1.69 (m, 3H), 1.33-1.23 (m, 6H); ESI MS m/z 532 [C27H34ClN3O4S+H]+; HPLC 98.9% (AUC), tR=10.49 min.
Reaction SMILES: [C:1]1(=[N:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3][CH2:2]1.O1CCCC1.B>C1COCC1>[CH:1]1([NH:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)NN=C1CCC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC1CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of tert-butyl 2-cyclobutylidenehydrazinecarboxylate (5.0 g, 27.1 mmol) in THF (50 mL) was added dropwise over 1.5 hours to a solution of borane tetrahydrofuran complex (33.9 mL, 33.9 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2.5 hours. Borane tetrahydrofuran (3 mL, 3 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The resulting mixture was quenched cautiously by the addition of water (50 mL) and the mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (2×200 mL), using brine to aid the separation. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-10% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:10](=[O:29])[N:11]([CH:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)[C:12]3[N:13]([N:18]=[C:19]([CH3:21])[N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:30]1[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=1.O1CCCC1.[BH4-].[Na+]>CO>[OH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([N:11]2[C:10](=[O:29])[C:9]([CH2:8][C:6]3[CH:5]=[CH:4][C:3]([C:30]4[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[C:2]([CH3:1])[CH:7]=3)=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]3[N:18]=[C:19]([CH3:21])[N:20]=[C:12]23)[CH2:23][CH2:24]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n(C2CCC(=O)CC2)c2nc(C)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2′-methyl-4′-{[2-methyl-5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.10 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride (0.05 g) at 0° C., and the mixture was stirred at room temperature for 30 min. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (1.01 g, 91%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][CH:51]1[CH2:56][NH:55][CH2:54][CH:53]([CH3:57])[NH:52]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][C@H:53]([CH3:57])[NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC1CNCC(C)N1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-4-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.15 mmol) in DCM (2 mL) was added 2,6-dimethylpiperazine (predominantly cis) (26 mg, 0.23 mmol), AcOH (0.01 mL, 0.18 mmol) followed by NaBH(OAc)3 (64.3 mg, 0.30 mmol). The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was purified using a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 90% CH3CN in water at a flowrate of 20 mL/min. Fractions containing product were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}-4-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide as a white solid (23 mg, 20%). LC-MS m/z 757 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:15][CH:14]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(Cl)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 4-chloroaniline to yield 2-[(4-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=2[CH:22]=1.B([O-])([O-])O[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[C:12]1([N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=4)=[CH:22][C:6]=3[CH:7]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[CH2:9][CH2:10]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(c2ccccc2)CC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A mixture of methyl 7-bromo-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.27 g), 4-(2-propoxyethoxy)phenyl borate (0.23 g), 1M potassium carbonate solution (3 ml), ethanol (3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed under argon atmosphere overnight, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-phenyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.26 g) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:24])=[CH:3][CH2:4][CH:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23].[OH-].[Na+].O.O.O.O.O.O.O.O.O.O.O.O.P([O-])([O-])(O)=[O:40].[Na+].[Na+]>O>[C:11]1([N:8]([C:9](=[O:10])[CH:5]([CH2:4][CH:3]=[C:2]([CH3:24])[CH3:1])[C:6]([OH:23])=[O:40])[NH:7][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=P([O-])([O-])O
Reactant: CC(C)=CCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)=CCC(C(=O)O)C(=O)N(Nc1ccccc1)c1ccccc1

Procedure:
103.8 gm (0.324 mol) of 4-(3-methyl-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine were dissolved in a solution of 12.96 gm (0.324 mol) of sodium hydroxide pellets and 57.3 gm (0.16 mol) of disodium hydrogen phosphate dodecahydrate in 400 ml of water. The reaction mixture was heated for 30 hours in an atmosphere of nitrogen, then cooled, diluted with 600 ml of water, and filtered. The filtered solution was neutralized (pH 7 to 7.5) with 2 N hydrochloric acid and extracted several times with chloroform. The combined chloroform extracts were evaporated, leaving crude 2-(3-methyl-2-butenyl)propanedioic acid mono(1,2-diphenylhydrazide) which was dissolved in 500 ml of 10% aqueous ammonium hydroxide. To this solution a solution of 17.9 gm (0.162 mol) of calcium chloride in 50 ml of water was added while stirring.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:21])[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C(O)(C)C.[Pd]>[CH3:21][C:9]1[C:10]([CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])=[C:5]2[N:4]=[CH:3][C:2]([C:29]#[C:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][N:6]2[N:8]=1
Reactant: C#Cc1ccccc1
Reactant: CCCC1CC(=O)N(Cc2c(C)nn3cc(Br)cnc23)C1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CCCC1CC(=O)N(Cc2c(C)nn3cc(C#Cc4ccccc4)cnc23)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
To a solution of 1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 184 (0.66 mmol, 1 eq, 0.26 g) in 2 ml of water and 2 ml of isopropyl alcohol are added successively palladium on activated carbon (10%, 0.284 mmol, 0.5 eq, 30 mg), phenyl acetylene (0.68 mmol, 1.2 eq, 70 mg), and K3PO4 (1.13 mmol, 2 eq, 0.24 g) dissolved in 2 ml of water. The mixture is degassed and stirred vigorously overnight at 100° C. The solvent is removed under reduce pressure. The crude product is purified by chromatography on silicagel (AcOEt/hexane: 4/6) to afford 25 mg of 1-{[2-methyl-6-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one 199.
Reaction SMILES: Cl.[C:2]([S:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:32]=[CH:31][C:25](/[CH:26]=[CH:27]/[C:28](Cl)=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:2]([S:5][CH:6]1[CH2:11][CH2:10][N:9]([C:28](=[O:29])/[CH:27]=[CH:26]/[C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:33])([F:34])[F:19])=[CH:32][CH:31]=2)[CH2:8][CH2:7]1)(=[O:4])[CH3:3]
Reactant: O=C(Cl)/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)SC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SC1CCN(C(=O)/C=C/c2ccc(OC(F)(F)F)cc2)CC1
Yield: 95.2 %

Procedure:
In 17 ml of dichloromethane were suspended 1.28 g (6.53 mmol) of 4-(acetylthio)piperidine hydrochloride, and 2.27 ml (16.3 mmol) of triethylamine were added dropwise to the suspension with stirring under ice-cooling. Then, a solution in which 1.80 g (7.18 mmol) of (E)-4-(trifluoromethoxy)cinnamoyl chloride were dissolved in 6 ml of dichloromethane was added dropwise to the reaction mixture, followed by stirring of the mixture at the same temperature for 1 hour. The reaction mixture was subjected to silica gel column chromatography and eluted with a mixed solvent of hexane-ethyl acetate (2:1 to 1:1) to obtain 2.32 g (yield: 95%) of the desired compound as a slightly yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:18])[C:15](O)=[O:16])=[O:7]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:7])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:18])[CH2:15][OH:16]
Reactant: O=C(CCCCCCC(O)C(=O)O)c1ccco1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC(O)CCCCCCC(O)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 640 ml. of 1.0 M. boranetetrahydrofuran complex in tetrahydrofuran is added a solution of 81 g. of 8-(2-furoyl)-2-hydroxyoctanoic acid in 240 ml. of tetrahydrofuran during one hour while maintaining a temperature of 0°-10° C. After the addition, the solution is stirred at room temperature for 3 hours, is cooled to 0° C., and treated cautiously with 80 ml. of 1:1 aqueous tetrahydrofuran. The resulting mixture is diluted with ethyl acetate. The solution is washed successively with an ice-cold brine-hydrochloric acid mixture, brine, brine-sodium bicarbonate solution and brine. The solution is dried over magnesium sulfate and concentrated to give an oil; pmr (CDCl3)δ4.70 (triplet).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[NH:11][C:6]=2[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:20]
Reactant: COC(=O)c1cc(Cl)cc(N=Cc2cccc(Br)c2)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)cc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-5-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-7-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[C:3]1=O.[CH3:14][O:15][C:16](=[O:19])[CH2:17]Br>>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([C:3]=1[CH2:17][C:16]([O:15][CH3:14])=[O:19])=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2
Reactant: COC(=O)CBr
Reactant: CC1Cc2cc(C#N)ccc2C1=O
Product: COC(=O)CC1=C(C)Cc2cc(C#N)ccc21

Procedure:
The above reactions of Example 1C are repeated except that the starting materials are 2-methyl-5-cyanoindanone and methylbromoacetate. Using the same reaction conditions and techniques there is obtained methyl 2-methyl-6-cyano-3-indenylacetate.
Reaction SMILES: C(O[C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14]Br)C.[CH3:17][O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.NC1C=CC=CC=1>>[CH3:17][O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:14][C:6]3[C:5](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=3)[C:4]2=[O:16])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1CBr
Reactant: COC(=O)COc1ccc(N)cc1
Solvent: Nc1ccccc1
Product: COC(=O)COc1ccc(N2Cc3ccc([N+](=O)[O-])cc3C2=O)cc1

Procedure:
By using 2-bromomethyl-5-nitrobenzoic acid ethyl ester and (4-amino-phenoxy)-acetic acid methyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain [4-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-acetic acid methyl ester (Compound 25) as a yellow green powdery substance.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[NH:3][CH2:2]1.[N:10]([O-])=[O:11].[Na+]>Cl>[N:10]([N:3]1[CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6][O:1][CH2:2]1)=[O:11]
Reactant: O=C(O)C1CCOCN1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: O=NN1COCCC1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tetrahydro-2H-1,3-oxazine-4-carboxylic acid (i.e. the product of Step A) (2.00 g, 15.3 mmol) was dissolved in 1 N hydrochloric acid (12.4 mL), and the solution was cooled to 0° C. Sodium nitrite (1.42 g, 20.6 mmol) was then added portionwise, and the reaction mixture was stirred for 1 h. The reaction mixture was then extracted twice with dichloromethane and once with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1.29 g of the title compound as a solid. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N+:15]([O-:26])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccc(-c2ccncc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2ccc(OCCCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A mixture of 4-[4-(3-chloropropoxy)phenyl]pyridine (1.22 g) and metachloroperbenzoic acid (1.82 g) in chloroform (25 mL) is stirred at room temperature for four hours, then concentrated under reduced pressure and purified by column chromatography over silica gel using a gradient dichloromethane/methanol from 100/0 to 95/5. Fractions containing the expected product are pooled and concentrated under reduced pressure to give 1.09 g of 4-[4-(3-chloropropoxy)phenyl]pyridine 1-oxide as a pale yellow solid used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:44])[CH2:20][CH2:21][C:22](=[O:43])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)=[C:25]([CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])[CH:24]=1)C>C(O)C.C(OCC)(=O)C>[C:38]([CH2:37][CH2:36][C:25]1[CH:24]=[C:23]([C:22](=[O:43])[CH2:21][CH2:20][C:19]([OH:44])=[O:18])[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15])([OH:40])=[O:39]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCC(=O)c1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCc1c(OCCCCCOc2ccc(C(=O)CCC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 57.7 %

Procedure:
Starting with 0.156 g (0.76 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.357 g (0.76 mmol) of 4-[(5-bromopentyl)oxy]-3-(3-ethoxy-3-oxopropyl)-γ-oxobenzenebutanoic acid ethyl ester, the title compound (0.237 g; 63.8% overall yield) was obtained as a white solid, mp 181.5°-184° C. (recrystallized from ethanol-ethyl acetate), using the procedure of example 22.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:28][C@@:26]3([CH3:27])[C@@H:22]([CH2:23][C@H:24]4[CH2:29][C@:25]43[O:30][CH3:31])[C@H:21]3[C:12]2=[C:13]2[C@@:18](O)([CH2:19][CH2:20]3)[CH2:17][C:16]3(OCC[O:33]3)[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)C.O>C(O)(=O)C>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[CH2:28][C@@:26]3([CH3:27])[C@@H:22]([CH2:23][C@H:24]4[CH2:29][C@:25]43[O:30][CH3:31])[C@H:21]3[C:12]2=[C:13]2[C:18]([CH2:19][CH2:20]3)=[CH:17][C:16](=[O:33])[CH2:15][CH2:14]2)=[CH:9][CH:10]=1)=[O:3]
Reactant: CCOC(OCC)c1ccc([C@H]2C[C@@]3(C)[C@@H](C[C@H]4C[C@]43OC)[C@@H]3CC[C@@]4(O)CC5(CCC4=C32)OCCO5)cc1
Solvent: CC(=O)O
Solvent: O
Product: CO[C@@]12C[C@@H]1C[C@H]1[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(C=O)cc3)C[C@@]12C

Procedure:
0.6 g of 11beta-(4-(diethoxymethyl)-phenyl)-3,3-ethylenedioxy-17beta-methoxy-16alpha,17alpha-methylene-estr-9-en-5alpha-ol is dissolved in 10 ml of 70% aqueous acetic acid and heated on the water bath for about 2 hours at 70° C. Then, the steroid is precipitated by adding water and some ammonia. The isolated crude product is flash chromatographed with benzene/ethyl acetate (10:1) on neutral aluminum oxide. 0.41 g of the target compound, which can be crystallized from ether or acetonitrile, is obtained, melting point: 196° C. to 199.5° C., [α]D =315.9°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-:30])=O)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[C:28]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:28](=[O:30])[C:27]4[CH:26]=[CH:25][C:24]([N:21]5[CH2:20][CH2:19][O:18][CH2:23][CH2:22]5)=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1)(=[O:30])[CH:27]=[CH2:26]
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Product: C=CC(=O)Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc32)cc1

Procedure:
Compound 390 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-morpholinobenzoate. 1H NMR (500 MHz, Acetone-d6) δ 9.59 (s, 1H), 9.47 (s, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 7.98 (dd, J=2, 9 Hz, 4H), 7.81 (m, 2H), 7.77 (d, J=9 Hz, 1H), 7.05 (d, J=9 Hz, 2H), 6.52-6.38 (m, 2H), 5.75 (dd, J=2, 10 Hz, 1H), 3.80 (m, 4H), 3.29 (m, 4H).