Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24](/[CH:26]=[CH:27]/[C:28](OCC)=[O:29])[CH:23]=[C:22]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=3)[CH:21]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([C:22]2[CH:23]=[C:24](/[CH:26]=[CH:27]/[CH2:28][OH:29])[CH:25]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=3)[CH:21]=2)=[CH:38][CH:37]=1)([CH3:41])([CH3:42])[CH3:40]
Reactant: CCOC(=O)/C=C/c1cc(-c2ccc(C(C)(C)C)cc2)cc(-c2ccc(C(C)(C)C)cc2)c1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C)c1ccc(-c2cc(/C=C/CO)cc(-c3ccc(C(C)(C)C)cc3)c2)cc1

Procedure:
The colourless gum (E)-3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-prop-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-acrylate by a procedure analogous to that described for example 52b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=2.[I-].C[N+]1C=CN([C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)C=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:31](=[O:40])[N:32]([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:15]=2
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: COc1ccc(OC)c(-c2c(C)c3ccc(O)cc3oc2=O)c1
Agent: [I-]
Product: COc1ccc(OC)c(-c2c(C)c3ccc(OC(=O)N(C)c4ccccc4)cc3oc2=O)c1
Yield: 13.5 %

Procedure:
The title compound (30 mg, 13% yield, white solid) was prepared from 3-(2,5-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=[C:4]([O:15][CH3:16])[N:3]=1.[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[Na+].[Na+]>CC#N>[CH2:19]([N:8]([C:7]1[C:2]([Br:1])=[N:3][C:4]([O:15][CH3:16])=[CH:5][CH:6]=1)[C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])[CH:18]=[CH2:17]
Reactant: COc1ccc(NC(=O)C(F)(F)F)c(Br)n1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=CCN(C(=O)C(F)(F)F)c1ccc(OC)nc1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
A mixture of N-(2-bromo-6-methoxy-pyridin-3-yl)-2,2,2-trifluoro-acetamide (5.52 g, 18.5 mmol), allyl bromide (3.57 g, 27.7 mmol) and sodium carbonate (5.1 g, 11 mmol) in CH3CN (60 mL) is stirred at 80° C. for 3 h. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 0-60% DCM in heptane to afford N-allyl-N-(2-bromo-6-methoxy-pyridin-3-yl)-2,2,2-trifluoro-acetamide (5.55 g) as an oil. 1H NMR (300 MHz, CDCl3): δ 3.66 (q, H), 4.00 (s, H), 5.95 (q, H), 5.08-5.30 (q, 2H), 5.75-5.94 (m, H), 6.74 (d, H), 7.38 (d, H).
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].CO>[CH:32]([Si:25]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:31])[CH3:30])[N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH2:8])=[CH:14][CH:13]=2)=[CH:17]1)([CH3:33])[CH3:34]
Reactant: [H][H]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NCc3ccccc3)cc2)c2cccnc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(N)cc2)c2cccnc21

Procedure:
Benzyl-[4-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenyl]-amine (112, 210.0 mg, 0.447 mmol), methanol (15.0 mL) and palladium hydroxide (30.0 mg, 0.214 mmol) were combined. The reaction mixture was hydrogenated under under an atmosphere of hydrogen (1 atm) at room temperature for 2 hours. Filtration and concentration gave the compound (113, 154 mg, 91%).
Reaction SMILES: C1(C(C2CCCCC2)=O)C=CC=CC=1.C=CC=C.C(O)(=O)C=C.[CH:24]1([C:30]([OH:32])=[O:31])[CH2:29][CH2:28][CH:27]=[CH:26][CH2:25]1>>[CH:24]1([C:30]([OH:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)C1CC=CCC1
Agent: C=CC(=O)O
Agent: C=CC=C
Agent: O=C(c1ccccc1)C1CCCCC1
Product: O=C(O)C1CCCCC1

Procedure:
In the synthesis mechanism of cyclohexyl phenyl ketone, a [2+4] Diels-Alder reaction using a 1,3-butadiene and an acrylic acid is carried out in the presence or absence of a solvent under the condition that no side reaction occurs, to prepare a 3-cyclohexene-1-carboxylic acid. The 3-cyclohexene-1-carboxylic acid is subjected to a hydrogenation reaction to yield a cyclohexanecarboxylic acid with a high conversion rate.
Reaction SMILES: Cl.[Cl-].[NH2:3][C:4]1[C:5]([NH:13][CH2:14][CH2:15][N+:16]([CH3:19])([CH3:18])[CH3:17])=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12.[NH2:20][C:21]1[C:22]([Cl:29])=[C:23]([OH:28])[C:24]([CH3:27])=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl-:29].[NH2:20][C:21]1/[C:26](=[N:3]/[C:4]2[C:5]([NH:13][CH2:14][CH2:15][N+:16]([CH3:19])([CH3:18])[CH3:17])=[N:6][N:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=23)/[CH:25]=[C:24]([CH3:27])[C:23](=[O:28])[C:22]=1[Cl:29]
Reactant: Cc1ccc(N)c(Cl)c1O
Reactant: C[N+](C)(C)CCNc1nn2ccccc2c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Product: CC1=C/C(=N\c2c(NCC[N+](C)(C)C)nn3ccccc23)C(N)=C(Cl)C1=O

Procedure:
5.83 mmol of 2-[(3-aminopyrazolo[1,5-a]pyridin-2-yl)amino]-N,N,N-trimethylethanaminium chloride hydrochloride dissolved in 30 ml of water were placed in a 100 ml one-necked round-bottomed flask. 5.83 mmol of 3-amino-2-chloro-6-methylphenol and then 17.5 mmol of sodium carbonate were added to this solution.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]4[CH2:32][O:31]4)=[CH:23][CH:24]=3)[O:19][CH:18]=2)=[CH:13][CH:12]=1>O1CCCC1>[OH:31][CH:30]([CH2:32][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:29][O:28][C:22]1[CH:21]=[C:20]2[C:25]([C:26](=[O:27])[C:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=3)=[CH:18][O:19]2)=[CH:24][CH:23]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2coc3cc(OCC(O)Cc4ccccc4)ccc3c2=O)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of cuprous iodide (0.14 g, 0.74 mmol) in tetrahydrofuran (2 ml) was added phenylmagnesium bromide in tetrahydrofuran (1M, 2.22 ml, 2.22 mmol) dropwise at −40° C. After 5 minutes 3-(4-methoxyphenyl)-7-(oxiran-2-ylmethoxy)chromen-4-one (0.24 g, 0.74 mmol) in tetrahydrofuran (4 ml) was added slowly, and stirred at −40° C. for 1 hour. The mixture was quenched with saturated ammonium chloride and water, extracted with ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was purified by preparative thin layer chromatography, eluting with 10% methanol/methylene chloride, followed by ethyl acetate/hexane 2/3, to provide 7-(2-hydroxy-3-phenylpropoxy)-3-(4-methoxyphenyl)chromen-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[N:12][OH:13])=[CH:7][CH:6]=1)=[O:4].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C>O1CCCC1.ClCCl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:19][CH:18]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: C#Cc1ccc(OCCCCCCOC)cc1
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of 4-methoxycarbonylphenylhydroxyiminomethyl chloride (975 mg) and 1-ethynyl-4-(6-methoxyhexyloxy)benzene (1.06 g) in tetrahydrofuran (10 ml) was added triethylamine (0.83 ml) in tetrahydrofuran (10 ml) over a period of 30 minutes at 40° C., and the mixture was stirred at 40° C. for 3 hours and 30 minutes. The mixture was diluted with dichloromethane and washed with water and brine. The separated organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with acetonitrile. The precipitate was collected by filtration and dried to give 4-[5-[4-(6-methoxyhexyloxy)phenyl]isoxazol-3-yl]benzoic acid methyl ester (1.37 g).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:11])[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[CH3:12]CN(C(C)C)C(C)C>[Pd].C=O>[CH3:12][N:6]1[CH2:7][C:3]([CH3:11])([CH3:2])[CH2:4][C@H:5]1[C:8]([OH:10])=[O:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1(C)CN[C@H](C(=O)O)C1
Agent: [Pd]
Agent: C=O
Agent: Cl
Product: CN1CC(C)(C)C[C@H]1C(=O)O
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A suspension of 4,4-dimethyl-L-proline hydrochloride (900 mg, 5.00 mmol), formaldehyde (37% aqueous, 450 μL), DIPEA (645 mg, 5.00 mmol) and palladium on carbon (10%, 400 mg) in IMS (50 mL) was stirred under an atmosphere of hydrogen (1 atm) for 4 h. The suspension was filtered and concentrated in vacuo to give the title compound as a viscous pink oil (780 mg, 99%). 1H NMR (400 MHz, CDCl3): 1.47 (3H, s), 1.49 (3H, s), 2.04-2.16 (1H, m), 2.23-2.34 (1H, m), 2.93 (3H, s), 3.10 (2H, m), 3.78-3.89 (1H, m), 4.86 (1H, br s).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]2[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][CH2:10][S:11][C:5]=2[CH:4]=1.C([Li])(C)(C)C.FC(F)(F)C1C=CC(NC(=O)OC(C)(C)C)=CC=1.[S].ClCCCI>CCCCC.O1CCCC1.O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:20]=[CH:19][C:6]2[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:9][CH2:10][S:11][C:5]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCCSc2cc(C(F)(F)F)ccc21
Agent: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: ClCCCI
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: CC(C)(C)OC(=O)N1C=CCSc2cc(C(F)(F)F)ccc21
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Tert-butyl 8-trifluoromethyl-2,3,4,5-tetrahydro-[1,5]benzothiazepine-5-carboxylate may be prepared in the following manner: 102 ml of a 1.5 M solution of tert-butyllithium in pentane are added dropwise over 1 hour to a solution, kept at −70° C. under argon, of 20 g of tert-butyl 4-trifluoromethylphenylcarbamate in 250 ml of anhydrous tetrahydrofuran. The mixture is stirred for 4 hours at −20° C., cooled to around −60° C., supplemented with 2.5 g of sulphur and then stirred for 45 minutes at −20° C. The mixture is cooled to around −60° C., supplemented with 15.6 g of 1-chloro-3-iodopropane, and then stirred for 16 hours at a temperature close to 20° C., heated for 7 hours under reflux, and then at a temperature close to 20° C. for 48 hours. The mixture is hydrolysed with 200 ml of distilled water and extracted twice with 180 ml of ethyl acetate in total. The combined organic extracts are dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa). The product is chromatographed under nitrogen pressure (150 kPa) on 450 g of 20-45 μm silica gel contained in a column 6 cm in diameter, eluting with a mixture of cyclohexane and ethyl acetate (90-10 by volume). 13 g of tert-butyl 8-trifluoromethyl-[1,5]benzothiazepine-5-carboxylate are thus obtained in the form of a pale yellow oil [1H NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 Mhz): 1.50 (9H, s, (CH3)3), 1.95 (2H, m, CH2), 3.05 (2H, t, J=6 Hz, SCH2), 3.70 (2H, t, J=6 Hz, CH2Cl), 7.60 (1H, dd, J=8 and 2 Hz, arom. CH), 7.75 (1H, d, J=2 Hz, arom. CH), 7.85 (1H, d, J=8 Hz, arom. CH), 8.60 (1H, s, NHCO)].
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Product: COc1ccc(NC(=O)OC(C)(C)C)c(N)c1

Procedure:
The title compound was prepared from (4-methoxy-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A10) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a white solid (19.377 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[CH:27][CH:26]=3)[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:14]([CH3:42])[C:13]=2[CH:43]=1)C1C=CC=CC=1>C(O)C.[Pt]=O>[CH:18]1([CH:17]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:43][C:13]=3[C:14]=2[CH3:42])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccccc4)cc3c2C)C2CCCCC2)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Ethyl 3-[{[4-({[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}(methyl)amino]-propanoate (2.46 g) synthesized in Example A154(2) was dissolved in ethanol (50 mL), and platinum oxide (0.33 g) was added to the solution. The reaction mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The reaction mixture was filtered, and the residue was washed with ethanol. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (1.64 g, 79%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[ClH:15]>C(O)C.[Pd]>[ClH:15].[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(-c2nnn[nH]2)c1
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of 5-(3-nitrophenyl)tetrazole (22 g, 0.12 mol) in ethanol (500 ml) was added 10% palladium on carbon (1.5 g, 7% (w/w)) in hydrochloric acid (23 ml of a 5M solution). The mixture was hydrogenated at 40 psi for 10 min, then the catalyst filtered off and washed with water. The solvents were evaporated in vacuo and the brown solid azeotroped with toluene (4×100 ml). The resulting solid was triturated with hot ethanol to give 5-(3-aminophenyl)tetrazole hydrochloride (16.3 g, 71%) as a beige powder; mp 203°-205° C.; δH (360 MHz, D2O) 7.63 (1H, d, J=9 Hz), 7.75 (1H, t, J=8 Hz), 8.00 (2H, m).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[C:12]([NH2:18])=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)=O.[H-].[Na+]>CS(C)=O.O>[Br:17][C:15]1[CH:14]=[N:13][C:12]2[NH:18][C:3](=[O:2])[C@@H:5]3[N:6]([CH2:7][CH2:8][CH2:9]3)[CH2:10][C:11]=2[CH:16]=1
Reactant: COC(=O)[C@H]1CCCN1Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1Nc2ncc(Br)cc2CN2CCC[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
A solution of (R)-1-(2-amino-5-bromo-pyridin-3-ylmethyl)pyrrolidine-2-carboxylic acid methyl ester (6.52 g, 20.8 mmol) in DMSO (200 mL) was treated with NaH (60% dispersion in mineral oil, 0.83 g, 20.7 mmol). After stirring at room temperature for 3 h, the mixture was stored in the freezer for 3 d. The mixture was allowed to warm to room temperature, diluted with H2O (400 mL), and extracted with EtOAc (4×200 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2,/MeOH, 99:1) gave the title compound (3.94 g, 67%) as an off-white solid: MS (ESI) m/e 282 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:36][OH:37])=[C:5]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH3:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9].[C:38](Cl)(=[O:40])[CH3:39].C1C=CC=CC=1.C(OCC)(=O)C>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH2:36][O:37][C:38](=[O:40])[CH3:39])=[C:5]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH3:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1=C(CO)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(COC(C)=O)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Yield: 90.9 %

Procedure:
To a mixture of 2-(N-methyl-N-benzylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate (630 mg) in pyridine (10 ml) was added a solution of acetyl chloride (146 mg) in methylene chloride (3 ml) under stirring and ice-cooling. The resultant mixture was further stirred at 50° to 60° C. for 2 hours. After removing the pyridine, water and ethyl acetate were added to the residue and the aqueous layer was adjusted to pH 4. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give an oily substance (800 mg). This oily substance was subjected to column chromatography on silica gel with an eluent [a mixture of 2 parts of benzene and 1 part of ethyl acetate by volume] to give an oil (620 mg) of 2-(N-methyl-N-benzylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-acetoxymethyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[C:8]([NH:13]C(=O)C(C)(C)C)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=1.Cl.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1-n1cc(Br)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncccc1-n1cc(Br)cn1
Temperature: 105 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A mixture of N-(3-(4-bromo-pyrazol-1-yl)-pyridin-2-yl)-2,2-dimethyl-propionamide (380 mg, 1.2 mmol) described in Manufacturing Example 39-1-3 and aqueous 2.5 N hydrochloric acid solution (2 mL) was stirred overnight at 105° C. The reaction mixture was cooled to 0° C., and 5 N sodium hydroxide solution (1 mL) was added. The resulting solids were filtered to obtain the title compound (100 mg, 72%).
Reaction SMILES: [C:1](Cl)(=O)C.[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([Cl:15])[CH:7]=1>CO>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:1])=[O:11])=[C:8]([Cl:15])[CH:7]=1
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(N)cc1Cl

Procedure:
Acetyl chloride (35.2 mmol, 2.5 mL) was added dropwise to a stirring solution of 4-amino-2-chloro-benzoic acid 70l (12.9 mmol, 2.22 g) in methanol (50 mL). The mixture was heated at reflux for 18 h, cooled, and concentrated under vacuum. The residue was taken up in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried, and concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 30% EtOAc/hexanes) to give compound 70m.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:9].[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][C:19]=1[S:28]([N:6]1[CH2:5][CH2:4][N:3]([C:8]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[O:9])[C@@H:2]([CH3:1])[CH2:7]1)(=[O:30])=[O:29]
Reactant: Cc1ccc(C(=O)N2CCNC[C@@H]2C)cn1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)C[C@@H]2C)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.8 %

Procedure:
To a solution of (2S)-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (may be prepared as described in Description 13) (200 mg, 0.912 mmol) in DCM (10 mL) was added 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (295 mg, 0.912 mmol) followed by DIPEA (0.159 mL, 0.912 mmol). The reaction mixture was left stirring at room temperature for 15 h. The solvent was removed by evaporation and the crude residue was dissolved in DCM (30 ml), washed with saturated sodium bicarbonate (40 ml), dried (hydrophobic frit) and evaporated under vacuum. The crude product was purified by silica chromatography using a gradient EtOAc/iso-hexane from 20/80 to 100/0. The desired fractions were combined and concentrated under vacuum to give the title compound (216 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9]#[N:10])=[CH:4][C:3]=1[O:18][CH3:19].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]#[N:10])=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: COc1cc(/C(C#N)=C/c2ccccc2)ccc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(C#N)Cc2ccccc2)ccc1F
Temperature: 25 °C
Yield: 110.8 %

Procedure:
To a suspension of (Z)-2-(4-fluoro-3-methoxyphenyl)-3-phenylacrylonitrile (14.23 g, 56.2 mmol) in EtOH was added sodium borohydride (2.66 g, 70.2 mmol) and stirred at room temperature over night. Poured into ice-water, added 5% citric acid and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to obtain 15.9 g of an orange oil.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].O.[PH2]([O-])=O.[Na+:13].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[C:26]1(=[O:36])[O:35][P:32]([OH:34])(=[O:33])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.[Na]>O>[C:1]([O:8][P:32]([O:31][C:29](=[O:30])[CH2:28][CH2:27][C:26]([O-:36])=[O:35])([OH:34])=[O:33])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[Na+:13].[Na+:13]
Reactant: O=C1CCC(=O)OP(=O)(O)O1
Reactant: O=C(O)/C=C\C(=O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[PH2][O-]
Agent: [NH4+]
Solvent: O
Product: O=C([O-])CCC(=O)OP(=O)(O)OC(=O)CCC(=O)[O-]
Reaction time: 2 h

Procedure:
Maleic acid 25.5g, 0.22m) was dissolved in 30 gm. of H2O, and sodium hypophosphite monohydrate (11.33g 0.11m) was added. At 60° C., the solution was treated over 4 hours with small portions of ammonium persulfate (1.9g in all). Heating was continued 2 hours more. The solution contained monosodium phosphinico succinate. Infra-red and NMR examination showed disappearance of the maleic double bond, indicating complete adduction.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([OH:23])[C:21]2[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(=O)C(=C(O)c2ccc(C)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 10(a) from 1-acetyl-5-nitro-2-indolinone and 4-methyl-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hunig's base (20° C., overnight) and final purification by column chromatography on silica gel with CH2Cl2 as eluant.