Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1>C(O)(=O)C.CCO>[CH3:18][C:16]1[S:17][C:13]([CH:12]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: Cc1ccc(C=O)s1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C=NNC(=O)c2ccc(O)cc2)s1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.25 g, 0.0016 mol) and 5-methyl-2-thiophenecarboxaldehyde (0.20 g, 0.0016 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.24 g, in 57% yield, mp: 215.7° C. 1H NMR (CD3OD) δ 8.38 (s, 1H), 7.79 (d, 2H), 7.17 (s, 1H), 6.86 (d, 2H), 6.77 (s, 1H), 2.49 (s, 3H), 1.31. 13C NMR (CDCl3) δ166.5, 162.8, 145.6, 144.8, 138.1, 132.4, 130.7, 127.1, 124.8, 116.3, 15.6. Anal. Calcd for C13H12N2O2S: C, 59.98; H, 4.65; N, 10.76. Found: C, 59.98; H, 4.45; N, 10.40.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH:24]([CH2:31]Br)[C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:24]([C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:31]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NC(=O)C(Br)CBr
Reactant: COc1ccc(CNCCNc2cccc(Cl)c2)cc1OC
Product: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2C(=O)NC(C)C)cc1OC

Procedure:
In a manner similar to Preparation 23, react N-(3-chlorophenyl)-N'-[(3,4-dimethoxyphenyl)methyl]-1,2-ethanediamine with 2,3-dibromo-N-(1-methylethyl)propanamide to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[C:5]2[C:20]([CH3:21])=[N:19][NH:18][C:6]=2[NH:7][C:8]=1[C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=1[F:17])#[N:2]>ClCCl.[O-2].[Mn+2]>[C:1]([C:3]1[C:4]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)=[CH:24][CH:23]=2)=[C:5]2[C:20]([CH3:21])=[N:19][NH:18][C:6]2=[N:7][C:8]=1[C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=1[F:17])#[N:2]
Reactant: Cc1n[nH]c2c1C(c1ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc1)C(C#N)=C(c1c(F)ccc(F)c1F)N2
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1n[nH]c2nc(-c3c(F)ccc(F)c3F)c(C#N)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
To 2.48 g (4.50 mmol) of tert-butyl 4-(4-(5-cyano-3-methyl-6-(2,3,6-trifluorophenyl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate diluted in 20 ml of dichloromethane are added 1.96 g (22.5 mmol) of manganese oxide. The reaction mixture is sonicated for 5 min then stirred at room temperature for 18 h. It is next filtered on Celite (cyclohexane/ethyl acetate eluent: 5:5) to yield 1.86 g of tert-butyl 4-(4-(5-cyano-3-methyl-6-(2,3,6-trifluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate in the form of a light yellow solid.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:3][C:4]#[N:5].[SH2:12]>N1C=CC=CC=1.C(N(CC)CC)C>[NH2:1][C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:3][C:4](=[S:12])[NH2:5]
Reactant: N#CC=C(N)c1cccnc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)C=C(N)c1cccnc1
Reaction time: 672 h

Procedure:
A solution of 20 g of 3-amino-3-(3-pyridinyl)-2-propenenitrile [J. Med. Chem., 18, 441 (1975)] in 100 ml of pyridine and 14 ml of triethylamine was saturated with hydrogen sulfide and set aside under nitrogen at room temperature for 28 days. The solution was kept saturated by passing hydrogen sulfide into the reaction mixture at intervals during this time. After evaporation the crude product was purified by chromatography and crystallization from ethyl acetate to give 3.65 g of 3-amino-3-(3-pyridinyl)-2-propenethioamide, which was suspended in 80 ml of diethyl ether together with 5.21 g of potassium carbonate. A solution of 5.21 g of iodine in 80 ml of diethyl ether was added dropwise in 10 min to this suspension, keeping the temperature at 3±2° C. After 45 min the reaction mixture was diluted with brine and extracted with dichloromethane. The extract was washed, dried, and evaporated to give 2.19 g of 3-(3-pyridinyl)-5-isothiazolamine.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][N:15]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([C:9]([F:10])([F:11])[F:12])=[CH:8][C:2]=2[F:1])=[O:19])=[CH:16][N:15]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(C(F)(F)F)cc1F
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: O=C(Nc1ccc(C(F)(F)F)cc1F)c1ccc(Cl)nc1

Procedure:
6-Chloro-N-(2-fluoro-4-trifluoromethyl-phenyl)-nicotinamide was prepared from 2-fluoro-4-trifluoromethyl aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C13H7N2OClF4 [M+H]+: 319.0256. Found: 319.0255.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:28][C:29]([C:31]1[S:32][C:33]([C:36]([NH:38][NH2:39])=[O:37])=[CH:34][CH:35]=1)=[O:30]>CS(C)=O>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:28][C:29]([C:31]1[S:32][C:33]([C:36]([NH:38][N:39]=[C:18]([C:3]2[C:2]([OH:1])=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:5]([CH3:17])[N:4]=2)[CH3:19])=[O:37])=[CH:34][CH:35]=1)=[O:30]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NCc2ccccn2)s1
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccccn2)s1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 80.9 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (50 mg, 0.18 mmol) in dimethyl sulfoxide (1.0 mL) was heated with 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-picolylamide (58 mg, 0.21 mmol) prepared in Reference Synthetic Example 2 at 110° C. for 21 hours. The solvent was evaporated, and the residue was washed with water and chloroform to give 79 mg of the desired product (yield 83%).
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.C1CCN2C(=NCCC2)CC1.[OH:42][CH2:43][CH2:44][O:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[CH:48]=O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:48]/[C:47]2[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=2[O:45][CH2:44][CH2:43][OH:42])=[N:3]1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccccc1OCCO
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: OCCOc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a solution of (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.10 g, 0.21 mmol) in methanol (0.60 mL), DBU (0.079 mL, 0.53 mmol) was added and 2-(2-hydroxyethoxybenzaldehyde (0.039 g, 0.23 mmol) was further added, followed by stirring at room temperature for 2.0 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5). The obtained compound was added with 2.0 mol/L hydrogen chloride-ethyl acetate solution (2.0 mL) and washed, then the precipitated solid was collected by filtration. The obtained solid was added with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution to separate the mixture into organic layer and aqueous layer. The organic layer was concentrated under reduced pressure and the residue was dried under reduced pressure to obtain Compound 134 (0.024 g, 9%).
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]([C:7]1[CH:29]=[N:28][C:10]2[O:11][CH2:12][CH2:13][N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:9]=2[CH:8]=1)=O.C([O-])(=O)C.[NH4+:40].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:30]1([C:2]2[NH:40][C:5]([C:7]3[CH:29]=[N:28][C:10]4[O:11][CH2:12][CH2:13][N:14]([S:15]([C:18]5[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:23]=5)(=[O:17])=[O:16])[C:9]=4[CH:8]=3)=[N:4][CH:3]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [NH4+]
Reactant: O=C(CNC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2)c1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCOc2ncc(-c3ncc(-c4ccccc4)[nH]3)cc21
Yield: 860.8 %

Procedure:
To a solution of N-(2-oxo-2-phenylethyl)-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide (40 mg, 0.079 mmol) in DMF (1 mL) was added ammonium acetate (61 mg, 0.791 mmol). The reaction was subjected to microwave irradiation (150° C., 30 min). The reaction mixture was treated with saturated aqueous NaHCO3 (1 mL) and extracted with EtOAc (2×1 mL). The combined organic layers were dried with sodium sulfate, filtered and evaporated. The residue was purified by flash column chromatography using a gradient elution of hexanes with 25-100% EtOAc Providing 7-(5-phenyl-1H-imidazol-2-yl)-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (33 mg, 0.68 mmol, 86% yield) as a white/brown solid. LCMS (+ESI) m/z=487.0 [M+H]+; 1H-NMR (CDCl3) δ 8.69-8.67 (m, 2H), 7.82 (d, 2H), 7.75 (d, 2H), 7.72 (d, 2H), 7.42 (s, 1H), 7.36 (t, 2H) 7.26 (m, 2H) 3.95 (m, 2H), 3.84 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[C:22]([CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.CN(C)C=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[C:22]([CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(CC(=O)N(C)C)n3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(CC(=O)N(C)C)n3)cc12
Reaction time: 5 h
Yield: 14.1 %

Procedure:
2-{6-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazin-2-yl}-N,N-dimethyl-acetamide (56.6 mg, 0.104 mmol) was dissolved in methanol (0.5 mL) and dimethylformamide (0.5 mL) and 50% w/v aqueous potassium hydroxide (0.2 mL) was added. After 5 hours, the reaction was quenched by addition of acetic acid (0.2 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford 2-{6-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazin-2-yl}-N,N-dimethyl-acetamide (5.7 mg, 14.1%). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 2.74 (s, 3H), 2.90 (s, 3H), 3.78 (s, 3H), 3.96 (s, 2H), 7.01 (dt, J=1, J=7.5 Hz, 1H), 7.11 (br d, J=8 Hz, 1H), 7.28 (dt, J=1.5, J=8.5 Hz, 1H), 7.50 (dd, J=1.5 Hz, J=7.5 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.5 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.62 (d, J=2.5 Hz, 1H). MS: m/z 388 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CO.C1(OC)C=CC=CC=1>[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([OH:14])=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a suspension of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (48 g) in methanol (250 ml) and anisole (70 ml) was added p-toluenesulfonic acid (85 g), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was poured into 10% aqueous sodium carbonate (600 ml) and ethyl acetate (700 ml), followed by adjusting to pH 7.5 with 20% aqueous sodium carbonate. The separated aqueous solution was washed with ethyl acetate (500 ml) and then adjusted to pH 2.5 with conc. hydrochloric acid, followed by stirring under ice-cooling for an hour. The precipitated crystals were collected by filtration and washed with acetone to obtain 7-amino-3-vinyl-3-cephem-4-carboxylic acid (15.4 g), mp 200° to 230° C. (dec.).
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1ncc(C#N)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ncc(C#N)c(Cl)n1

Procedure:
A stirred solution of 4-hydroxy-2-(methylthio)pyrimidine-5-carbonitrile (British patent GB901749) (1.00 g, 5.98 mmol) in POCl3 (5 mL) was heated to reflux for 2 h. The reaction mixture was concentrated in vacuo and the residue quenched with ice (100 g). The solution was then basified to pH 8 with sat. aq NaHCO3 and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate layers were washed with water (20 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([N+:21]([O-])=O)[C:14]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3]>CO.O1CCCC1.[C].[Pd]>[NH2:21][C:13]1[C:14]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N2CCCCC2)c(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(N2CCCCC2)c(S(C)(=O)=O)c1
Yield: 95.5 %

Procedure:
10% Palladium-carbon (1.5 g) was added to a mixture of methyl 3-methylsulfonyl-5-nitro-4-piperidinobenzoate (5.6 g) in a mixture of methanol (50 ml) and tetrahydrofuran (50 ml) and the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with a mixture of diisopropyl ether and n-hexane to give methyl 5-amino-3-methylsulfonyl-4-piperidinobenzoate (4.88 g).
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([NH2:11])=[O:10])[C:5]=1[N+:12]([O-])=O)([CH3:3])[CH3:2]>[Pd].C(O)C>[NH2:12][C:5]1[C:6]([C:9]([NH2:11])=[O:10])=[N:7][NH:8][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1[nH]nc(C(N)=O)c1N
Yield: 102.4 %

Procedure:
5-Isopropyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (3 g, 15.1 mmol) and 10% palladium on carbon (500 mg) in ethanol (30 ml) were stirred under hydrogen (50 psi) at room temperature for 18 hours. The reaction mixture was filtered and the solid was washed with methanol (50 ml), dichloromethane (50 ml), ethanol (50 ml) and ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane methanol (9:1, by volume) to give 4-amino-5-isopropyl-1H-pyrazol-3-carboxylic acid amide (2.6 g) as an off-white solid. 1H NMR (400 MHz, DMSO-D6): δ=12.20-12.30 (1H, brs), 7.02-7.14 (1H, brs), 6.85-6.95 (1H, brs), 4.30-4.46 (2H, brs), 2.90-3.00 (1H, m), 1.15-1.21 (6H, d) ppm. LRMS (electrospray): m/z [M−H]+ 167, [2M−H]+ 335. Anal. Found C, 49.86; H, 7.21; N, 33.07. C7H12N4O requires C, 49.99; H, 7.19; N, 33.31%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH:9]1([C:12]#[N:13])[CH2:11][CH2:10]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Cl)cn1
Reactant: N#CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(Cl)cn2)CC1
Temperature: 22 °C
Reaction time: 0.75 h
Yield: 30.9 %

Procedure:
To a solution of 5-chloro-2-fluoropyridine (2 g, 1.53 ml, 15.2 mmol, Eq: 1.00) and cyclopropanecarbonitrile (1.02 g, 1.15 ml, 15.2 mmol, Eq: 1.00) in toluene (20.0 ml) was added dropwise over 5 min. KHMDS 0.5 M in toluene (30.4 ml, 15.2 mmol, Eq: 1.00) at 0° C. The solution turned brown. After 45 min, the reaction mixture was allowed to warm up to 22° C. and stirred for 2.5 h. Saturated aqueous NH4Cl solution (50 ml) was then added and the aqueous phase was extracted with AcOEt (3×60 ml). The combined organic phases were dried over Na2SO4, filtered and concertrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 20% EtOAc in heptane) to yield the title compound as a white solid (840 mg; 31%). m/z=179.0373 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][O:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH2:24][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=2)[CH2:23][CH2:22][CH2:21][O:20]1)=[O:6]
Reactant: Cc1ncc(C2(CN)CCCO2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCCO2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and (2-(2-methylpyrimidin-5-yl)tetrahydrofuran-2-yl)methanamine. LCMS (MH+): m/z=366.0, tR (minutes, Method E)=0.52
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:19]([C@:22]1([CH2:65][O:66][CH2:67][CH2:68][Si:69]([CH3:72])([CH3:71])[CH3:70])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:24]([C@@H:42]([CH2:62][CH3:63])[CH2:43][O:44][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:23]1=[O:64])[CH:20]=[CH2:21]>C1COCC1.CCOC(C)=O>[CH2:19]([C@@:22]1([CH2:65][O:66][CH2:67][CH2:68][Si:69]([CH3:72])([CH3:71])[CH3:70])[CH2:27][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C@@H:25]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[N:24]([C@@H:42]([CH2:62][CH3:63])[CH2:43][OH:44])[C:23]1=[O:64])[CH:20]=[CH2:21]
Reactant: C=CC[C@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O

Procedure:
A 1M solution of TBAF in THF (2.15 mL, 2.15 mmol) was added to a solution of (3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one (Example 414, Step A; 860 mg, 1.074 mmol) in THF. The reaction was heated to reflux for 3 hours. After cooling, it was diluted with EtOAc and washed with HCl (1N in water). The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated to give the crude material as a glass which was purified by chromatography on silica eluting with 20% EtOAc in hexane, to provide the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([NH2:13])([CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[O:14]([CH2:21][CH2:22][CH2:23]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:25].CO>C(#N)C>[ClH:25].[O:14]([CH2:21][CH2:22][CH2:23][NH:13][C:2]([CH3:1])([CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: BrCCCOc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 62 h

Procedure:
To a stirred suspension of 50% KF-Celite (0.35 g, 3 mmol) in anhydrous acetonitrile (10 mL) was added 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.27 g, 1.5 mmol) and 3-phenoxypropyl bromide (0.484 g, 2.25 mmol). The reaction mixture was refluxed under nitrogen for 6 hours, followed by stirring at room temperature for 62 hours. The mixture was filtered and the filtrate, was evaporated. The hydrochloride was prepared by dissolving the residue in HCl/methanol. The resulting solution was concentrated and dried on a lyophilizer. The residue was redissolved in dry methanol and diluted with diethyl ether, which caused precipitation of 210 mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.) 298 (M−15, 2), 193 (15), 192 (100), 120 (13), 107 (5), 98 (9), 77 (8), 72 (7), 71 (8), 70 (6), 41 (4).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:4][CH2:3]1.O.[OH-].[Li+]>>[CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]\[C:21]([OH:23])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)/C=C/c1cccc([Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3cc([Se]c4cccc(/C=C\C(=O)O)c4)ccc32)cc1

Procedure:
In a manner similar to that of Example 1g, by reacting 0.088 g (0.18 mmol) of ethyl (E)-3-[3-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanyl)phenyl]acrylate with 0.09 g (2.14 mmol) of lithium hydroxide hydrate, a yellow solid is obtained (0.06 g; yield=73%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([OH:12])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:30]3[C@H:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([N:28]1[CH2:27][C@H:26]2[C@H:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:12]
Reactant: CC(C(=O)O)c1ccccc1N(C)C
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1N(C)C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
N,N'-Carbonyldiimidazole (0.85 g) is added to a solution of (RS)-2-[2-dimethylaminophenyl]propionic acid (1 g) in dichloromethane (30 cc) cooled to 5° C. and the mixture is then stirred for 30 minutes at this temperature. A solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.7 g) and triethylamine (1.4 cc) in dichloromethane (30 cc) is added. The reaction mixture is stirred at 20° C. for 16 hours, washed with water (2×100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 3 cm, height 50 cm), eluting under a nitrogen pressure of 0.5 bar with ethyl acetate and collecting 125 cc fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR,7aR)-2-[(RS)-2-(2 -dimethylaminophenyl)propionyl]-7,7-diphenyl-4-perhydroisoindolone (1.4 g) in the form of a white meringue.