Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][CH:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:24](=O)[NH:23][CH:22]=[N:21][C:20]1=2)(=[O:3])[CH3:2].CN(C=O)C.C(Cl)[Cl:35]>>[Cl:35][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[C:25]=1[N:26]=[CH:27][N:19]2[C@@H:6]1[O:7][C@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:5]1[O:4][C:1](=[O:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(=O)OC[C@H]1OC(n2cnc3c(=O)[nH]cnc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 55 °C

Procedure:
Crude compound 2 (130 mg) was dissolved in dry CH2Cl2 (10 mL) and heated to 55° C. Dry DMF (1 mL) followed by a 2 M solution of SOCK in CH3Cl2 (2.43 mL, 0.57 mmol) were added dropwise over a period of 45 minutes. The reaction mixture was gently refluxed for an additional 75 minutes. The reaction mixture was cooled to room temperature and diluted with CH2Cl2. The organic layer was washed with saturated NaHCO3 solution (2×50 mL), brine (50 mL) and dried (anhydrous sodium sulfate). The organic phase was concentrated in vacuo and purified by preparative TLC (5% MeOH/CHCl3) to obtain pure 3 (50 mg, 26% from 1): UV (MeOH)λmax 263.0 nm, 212.5 nm.
Reaction SMILES: O=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:4]=O.O.[NH2:19][NH2:20]>CCO>[C:12]1([C:2]2[C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][NH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC(C(=O)c1ccccc1)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1ccc(-c2c[nH]nc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
3-Oxo-2,3-diphenylpropanal (5.00 g, 22.3 mmol) was dissolved in EtOH (40 mL). Hydrazine monohydrate (2.0 mL, 38.7 mmol) was added slowly via syringe. The reaction was stirred at room temperature for an hour. The solvent was evaporated and the residue was purified by silica gel column chromatography to yield the title compound as a light purple solid (2.75 g). LCMS m/z=221.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.99-7.57 (m, 10H), 7.66-8.09 (bs, 1H), 13.15 (bs, 1H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>CO.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:3][CH:2]=1
Reactant: C(=Cc1ccco1)c1ccncc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1coc(CCc2ccncc2)c1
Yield: 30.8 %

Procedure:
A solution of 1-(pyridin-4-yl)-2-(furan-2-yl)ethene (8 g, 46.8 mmol) in methanol (200 ml) was treated with ammonium formate (14.7 g, 234.0 mmol). 10% Palladium on charcoal catalyst (400 mg, 5% (w/w)) was added and the mixture was stirred at reflux for five hours. The catalyst was filtered off and the solvent evaporated. The residue was partitioned between dichloromethane and water. The organic layer was separated, dried (MgSO4) and evaporated to give a beige oil. This material was chromatographed on silica gel with a gradient of ethyl acetate in hexane (50%-100%) as eluant to afford the title compound as a colourless oil (2.5 g, 31%); δH (DMSO-d6) 2.94-3.06 (4H, m, 2×CH2), 6.06-6.12 (1H, m, furanyl H), 6.32-6.38 (1H, m, furanyl H), 7.20-7.28 (2H, m, pyridinyl H), 7.50-7.56 (1H, m, furanyl H), and 8.40-8.50 (2H, m, pyridinyl H).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Br:11]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:11][C:7]1[CH:6]=[CH:5][C:4]([O:8][CH3:9])=[CH:3][C:2]=1[CH:1]=[O:10]
Reactant: COc1cccc(C=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
To a solution of m-anisaldehyde (55.4 g, 0.41 mol) in DMF (400 mL) was added a solution of N-bromosuccinimide (124.0 g, 0.69 mol) dropwise at room temperature. After the addition, the reaction solution was stirred at room temperature for 12 h, then poured into a mixture of ice and water and stirred for 10 min. The precipitate was collected by filtration and dissolved in ethyl acetate. The resulting solution was washed with water (2×) and brine, dried over sodium sulfate and concentrated in vacuo to give Compound 19 (76.4 g, 87%) as an off-white solid: 1H NMR (CDCl3, 500 MHz) δ 10.32 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.42 (d, J=3.5 Hz, 1H), 7.04 (dd, J=9.0, 3.0 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:16][CH2:17]OS(C)(=O)=O)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:29]([O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:30].C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([N:11]1[CH2:15][CH2:14][C:13]([CH2:16][CH2:17][N:47]2[CH2:46][CH2:45][CH:44]([NH:43][C:35]3[N:34]([CH2:33][CH2:32][O:31][CH2:29][CH3:30])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:49][CH2:48]2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)CCN(C(=O)OCc2ccccc2)C1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)OCc4ccccc4)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-carbobenzyloxy-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (10.2 g, 25.3 mmol), (1.34 g, 2.5 mmol), (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (30.4 mmol), and N,N-diisopropylethylamine (18 mL, 101 mmol) in acetonitrile (300 mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel to give 1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:26](N(C)C1C=NC=CC=1C1C=CC=CC=1C)=[O:27])(=[O:22])=[O:21].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:18][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[C:26](=[O:27])[C:25]1[CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:24]=1
Reactant: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: Fc1ccccc1-c1ccncc1NCC(F)F
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(C(=O)N(CC(F)F)c2cnccc2-c2ccccc2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(2,2-difluoroethyl)-4-(2-fluorophenyl)pyridin-3-amine (112 mg, 444 μmol) in CH2Cl2 (3 mL) was added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (119 mg, 444 μmol, example 114, intermediate) and 2-bromo-1-ethylpyridinium tetrafluoroborate (146 mg, 533 μmol) and N,N-diisopropylethylamine (115 mg, 155 μL, 888 μmol). The reaction mixture was stirred at room temperature for 24 hours and then concentrated under vacuum. The residue was dissolved in 30 mL 1M aqueous HCl and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL 1M aqueous HCl and 30 mL 10% aqueous NaHCO3 solution and 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Yellow solid (84 mg, 38%). MS (ESI): m/z=503.085 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[C@H:6]2[CH2:11][C@@H:8]([CH2:9][CH:10]=1)[C:7]2([CH3:13])[CH3:12].C12BC(CCC1)CCC2.[O:23]1CCC[CH2:24]1>>[CH3:1][O:2][CH2:3][CH2:4][C@H:5]1[C@H:10]([CH:24]=[O:23])[CH2:9][C@@H:8]2[CH2:11][C@H:6]1[C:7]2([CH3:13])[CH3:12]
Reactant: COCCC1=CC[C@@H]2C[C@H]1C2(C)C
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: COCC[C@H]1[C@H](C=O)C[C@@H]2C[C@H]1C2(C)C
Temperature: -35 °C
Reaction time: 1.5 h

Procedure:
To a solution of (1S,5R)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene (940 mg) in tetrahydrofuran (5 mL) was added dropwise 9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 10.43 mL). The reaction mixture was heated to reflux overnight, then cooled to −35° C. and then placed under a CO atmosphere (1 atm). LiAl(OtBu)3H (1M in tetrahydrofuran, 5.21 mL) was added dropwise over 30 minutes. Following the addition, the reaction mixture was stirred for 1.5 hours under CO (1 atm), during which time the reaction temperature was increased to 0° C. The mixture was warmed to room temperature and stirred for 45 minutes, then the system was flushed with argon and a buffer solution (5.28 g NaH2PO4 and 6.86 g K2HPO4 in 20 mL water) was added. The flask was chilled in a −10° C. cooling bath and the reaction was quenched by dropwise addition of 30% aqueous H2O; solution (2.2 mL), then warmed to room temperature and stirred for 15 minutes. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (3×75 mL). The organic phase was then washed with 10% Na2S2O3 (3×50 mL) and brine (50 mL), then dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]2[S:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:7]2=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:11]2[S:10][C:8]3=[N:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=[C:7]3[CH:12]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: CC(C)c1ccc2cc(C(=O)O)sc2n1
Product: CC(C)c1ccc2cc(C(=O)Nc3ccc(OCC(C)(C)C)c(C#N)c3)sc2n1
Yield: 16.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 6-isopropylthieno[2,3-b]pyridine-2-carboxylic acid (2 g) and 5-amino-2-neopentyloxybenzonitrile (1.9 g), the title compound (0.6 g) was obtained. melting point: 244-245° C.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:27]=[O:28]>>[CH2:1]([S:8]([NH:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:27]([NH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Br:19])=[O:28])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccccc1NS(=O)(=O)Cc1ccccc1
Product: O=C(Nc1ccccc1Br)Nc1ccccc1NS(=O)(=O)Cc1ccccc1
Yield: 23.9 %

Procedure:
The urea was synthesized from 2-(benzylsulfonylamino)aniline(1 mmol) and 2-bromophenylisocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.11 g, 23%). EI-MS m/z 460 (M+H)+.
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.[CH2:9]([C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])[CH3:10].C([Li])CCC.C(I)C>C1COCC1.C1CCCCC1.O>[CH:9]([C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[C:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])=[O:14])([CH2:3][CH3:4])[CH3:10]
Reactant: CN(C)CCN(C)C
Reactant: CCc1ccccc1C(=O)N(CC)CC
Agent: [Li]CCCC
Solvent: O
Solvent: CCI
Solvent: C1CCCCC1
Product: CCC(C)c1ccccc1C(=O)N(CC)CC
Temperature: -78 °C
Yield: 40.9 %

Procedure:
To a solution of 4.74 mL (0.031 mol) of tetramethylethylenediamine in 300 mL of THF (passed through alumina prior to use) was added 5.8 g (0.03 mol) of 2-ethyl-N,N-diethyl-benzamide. The solution was cooled to -78° C. and treated with 34.9 mL (0.031 mol) of a 0.9M solution of butyl lithium in cyclohexane. When addition was completed, the mixture was stirred for twenty minutes and then treated with a solution of 3.2 mL (0.04 mol) of ethyliodide while maintaining the temperature at -78° C. The temperature was then allowed to rise to ambient temperature and the mixture was stirred for about sixteen hours and then poured into water. The resulting oil was separated and chromatographed on silica gel, eluting with 10% ethyl acetate/hexane to give 2.86 g (43%) of 2-sec-butyl-N,N-diethylbenzamide as yellow oil.
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([Cl:21])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:16]1[N:15]=[C:14]([N:9]2[C@@H:8]([C@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]2=[O:13])[CH:19]=[C:18]([Cl:20])[N:17]=1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a round bottom flask containing (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (1 g, 2.99 mmol) was added DCM (7.5 mL) followed by the addition of TFA (7.5 mL). The resulting homogenous reaction mixture allowed to stir 1 hr at room temperature. The volatiles were then removed. Residue dissolved in DCM and neutralized with a saturated solution of NaHCO3. The phases were partioned, the aqueous phase extracted with DCM. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a white foam of (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (737 mg, 2.65 mmol, 89% yield). 1H NMR (400 MHz, CDCl3) δ 1.19 (d, J=6.46 Hz, 3H) 4.47 (dd, J=9.37, 8.53 Hz, 1H) 4.55 (quin, J=5.69 Hz, 1H) 4.63 (dd, J=9.49, 2.79 Hz, 1H) 4.89 (ddd, J=8.19, 4.96, 2.79 Hz, 1H) 8.24 (s, 1H). LCMS m/z 278.0 (M+H)+, Rt 0.66 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.[Cl-].[NH4+]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: BrCCOC1CCCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 33.9 %

Procedure:
To a mixture of sodium hydride (60% w/w dispersion in mineral oil) (19.24 g) and anhydrous tetrahydrofuran (450 ml) at 0° C. under a nitrogen atmosphere was added a solution of 3,4-dichlorophenylacetonitrile (89.5 g) in anhydrous tetrahydrofuran (450 ml), dropwise over 40 minutes. After a further 30 minutes, a solution of 2-(2-bromoethoxy)tetrahydropyran (100 g) in anhydrous tetrahydrofuran (100 ml) was added. The mixture was allowed to warm to room temperature and then stirred for 14 hours. 30% w/w Aqueous ammonium chloride solution (500 ml) was added and the mixture extracted with diethyl ether (2×400 ml). The organic extracts were combined, washed with water (2×400 ml), dried over anhydrous magnesium sulphate and the solvent removed under reduced pressure. The residue was chromatographed on silica gel eluting with a solvent gradient of 1:9 changing to 1:1, by volume, diethyl ether:hexane to give 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)-butanenitrile (51 g) as an oil and as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[C:8]([NH:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:45]=[O:46])C>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][CH:20]=[C:7]2[C:6]=1[CH:45]([OH:46])[N:10]([C:11]([CH3:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:8]2=[O:9]
Reactant: CN(C)C=O
Reactant: COCOc1cccc(C(=O)NC(C)(C)c2ccccc2)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1cccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 96.2 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (8.07 g, 27.0 mmol) was dissolved in THF (320 mL), and the solution was treated with TMEDA (13.0 mL, 85.4 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 87.1 mL, 86.3 mmol) and DMF (4.60 mL, 59.3 mmol), followed by purification by slurry using hexane to obtain 4-methoxymethoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (8.50 g, yield 96%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:37])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[C:21]([CH3:36])[CH:20]=2)[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][CH:7]=1)#[N:2].Cl.C(N(CC)CC)C.[N-:46]=[N+:47]=[N-:48].[Na+].Cl>C1(C)C=CC=CC=1.O>[CH3:36][C:21]1[CH:20]=[C:19]([O:18][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([C:5]([NH:4][CH2:3][C:1]3[NH:48][N:47]=[N:46][N:2]=3)=[O:37])=[CH:11][CH:10]=2)[CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:24]=[C:23]([CH3:25])[C:22]=1[C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=1
Reactant: Cc1cc(OC(CC(C)(C)C)c2ccc(C(=O)NCC#N)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(OC(CC(C)(C)C)c2ccc(C(=O)NCc3nnn[nH]3)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
N-Cyanomethyl-4-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-benzamide (160 mg, 0.32 mmol) is dissolved in toluene (20 mL). Triethylamine hydrochloride (132 mg, 0.96 mmol) is added followed by sodium azide (62 mg, 0.96 mmol) and then the reaction is refluxed for 24 h. The mixture is allowed to cool to room temperature, poured into water and adjusted to pH=3 with aqueous HCl. The product is extracted into ethyl acetate, dried, and concentrated to give 145 mg (82%) of the titled compound. MS (ES): 552.2 [M+1]+, 550.2 [M−1]−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)([O-])=O.Cl.O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: CN1CCC(c2n[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CN1CCC(c2n[nH]c3ccc(N)cc23)CC1
Reaction time: 24 h
Yield: 103 %

Procedure:
A mixture of 5-nitro-3-(1-methylpiperidin-4-yl)-1H-indazole (287 mg, 1.1 mmol), 5N aqueous hydrochloric acid (0.5 mL), water (5ml), and methanol (15 mL) was warmed to give a homogeneous solution. Palladium (86 mg, 5% on carbon) was added to the solution and the resulting mixture was stirred under an atmosphere of hydrogen gas for 24 hours. The palladium catalyst was filtered and the filtrate was concentrated in vacuo. The residue was slurried in methylene chloride and 5N aqueous sodium hydroxide then extracted with chloroform/isopropanol (3:1). The organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 261 mg of a light brown foam. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 223 mg (87.8%) of a brown oil. The product was crystallized as the dihydrochloride salt. EA calculated for C13H20Cl2N4: C, 51.49; H, 6.65; N, 18.48. Found: C, 51.44; H, 6.76; N, 18.47.
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[C:19]([C:5]2[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: OBO
Product: O=Cc1cccc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
6-(3-(trifluoromethyl)phenyl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and (3-(trifluoromethyl)phenyl)boronic acid (115 mg, 135.1 mg theoretical, 85.1%). LC-MS m/z 252.2 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][S:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C>[Cl:13][C:10]1[NH:9][C:8]2[C:7]([S:6][CH2:5][C:4](=[O:3])[N:14]=2)=[CH:12][N:11]=1
Reactant: CCOC(=O)CSc1cnc(Cl)nc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: O=C1CSC2=CN=C(Cl)NC2=N1
Temperature: 70 °C

Procedure:
A suspension of ethyl[(4-amino-2-chloro-5-pyrimidinyl)thio]acetate (0.786 g, 3.17 mmol) in ethanol (50 ml) was heated to 70° C. Cesium carbonate (1.034 g, 3.17 mmol) was added and the solution was heated for a further 5 minutes. A white solid precipitated out of solution almost immediately. The solution was concentrated under reduced pressure. The residue was dissolved in water and brought to pH=5 with 1N HCl. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a light yellow solid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[Br-:6].[K+:7].[Br:8]Br>O>[Br-:6].[K+:7].[Br:6][C:2]([Br:8])([C:1]#[N:5])[C:3]#[N:4]
Reactant: BrBr
Reactant: N#CCC#N
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: N#CC(Br)(Br)C#N
Reaction time: 2 h
Yield: 329.5 %

Procedure:
A mixture of 99 g of malononitrile and 75 g of potassium bromide in 900 ml of water was cooled to 5°-10° and, while maintaining the temperature at 5°-10°, 488 g of bromine was added slowly during 2.75 hours. After addition was completed, the mixture was stirred for 2 hours at 5°-10°, and filtered. The collected solid was washed with 150 ml of ice-water and air-dried on the filter to give 356 g of the complex which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C1([O:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])C=CC=CC=1.Cl>C1COCC1.C(OCC)(=O)C.O>[CH3:29][O:28][C:21]1[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=1[C:19]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:18]
Reactant: O=C1CCc2sccc21
Reactant: COc1ccc(C(=O)Oc2ccccc2)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)C2Cc3sccc3C2=O)c(OC)c1
Temperature: 100 °C
Yield: 47 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL of THF was treated with NaH (60 percent, 1.45 g, 12.4 mmol). After the addition of 2,4-Dimethoxy-benzoic acid phenyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(2,4-Dimethoxy-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.0 g, 6.6 mmol) as brown solid in 47% yield.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.Cl[CH2:14][C:15]([OH:17])=[O:16].Cl>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][C:15]([OH:17])=[O:16])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: O=C(O)CCl
Reactant: COc1cc(Cl)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Cl)ccc1OCC(=O)O
Temperature: 95 °C
Reaction time: 3 h
Yield: 120 %

Procedure:
To a solution of sodium hydroxide (6.6 g, 160 mmol) in water (45 mL) was added 4-chloro-2-methoxy-phenol (2.0 mL, 16 mmol) and chloroacetic acid (7.7 g, 81 mmol). The resulting mixture was heated to 95° C. and stirred for three hours. The reaction was allowed to cool to ambient temperature and slowly acidified with concentrated hydrochloric acid (10 mL) until the mixture became a solution and then extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (4.16 g).