Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Sn](Cl)(Cl)(Cl)Cl.[C:23](Cl)(=[O:25])[CH3:24].O>C(Cl)Cl>[C:23]([C:8]1[C:7]([O:9][CH3:10])=[CH:6][C:5]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
To a solution of N-(3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (31.8 g, 130 mmol) in anhydrous methylene chloride (450 mL), cooled in an ice bath, is added a solution of tin (IV) chloride (29.9 mL, 260 mmol dissolved in 30 mL anhydrous methylene chloride) dropwise over 10 minutes. Acetyl chloride (9.1 mL, 130 mmol) is added slowly, maintaining the temperature of the reaction below 5° C. After stirring 3 hours at room temperature, the reaction is cooled in an ice bath. Water (300 mL) is added, maintaining the temperature of the reaction below 25° C., and the reaction is stirred at room temperature for 18 hours. The reaction mixture is extracted with methylene chloride, and the organic layer is separated, washed with water, dried, filtered and evaporated under reduced pressure. The residue is purified by silica gel column chromatography eluting with 20% to 30% hexanes/ethyl acetate to yield N-(4-acetyl-3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (4.8 g, 13%) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:25]=[CH:24][C:14]([CH2:15][NH:16]C(=O)OC(C)(C)C)=[CH:13][C:12]=2[O:26][CH3:27])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[F:28][CH:2]([F:1])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:25]=[CH:24][C:14]([CH2:15][NH2:16])=[CH:13][C:12]=2[O:26][CH3:27])=[CH:5][CH:4]=1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCc1ccc(C(F)F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CN)ccc1OCc1ccc(C(F)F)nc1
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a stirred solution of tert-butyl 4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzylcarbamate (7.32 g, 18.56 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (15 mL, 194.70 mmol). After 2 h, the reaction mixture was concentrated, and the residue was dissolved in water (75 mL). The acidic solution was extracted with diethyl ether (50 mL). The aqueous phase was retained and made basic with concentrated ammonium hydroxide solution (50 mL). The basic aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 4.54 g (83%) of (4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1.[H-].[Na+].[CH3:18]I.Cl>O1CCCC1>[CH3:18][O:1][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1
Reactant: OCc1coc(SCCC(F)=C(F)F)n1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1coc(SCCC(F)=C(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
A solution of 2.7 g of 4-hydroxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole in 50 ml of tetrahydrofuran (dehydrated) was added dropwise to a suspension of 0.5 g NaH (purity about 60%) in 20 ml of tetrahydrofuran (dehydrated) at 0° C. After stirring the mixture at room temperature for 1 hour, a solution of 2.0 g of methyl iodide in 20 ml of tetrahydrofuran (dehydrated) was added at 0° C. and further stirred at room temperature for 1 hour. The reaction mixture was poured into a mixed solution of 200 g ice and 2N hydrochloric acid. After extraction with 100 ml of dichloromethane, the solution was washed with water and dried with anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (eluent: dichloromethane) to obtain 1.5 g of 4-methoxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 52.5%). n20D=1.4710.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH:4]1[S:8][CH2:7][CH2:6][S:5]1)[CH3:3].[CH3:17][O:18]C(Cl)Cl.O>ClCl.C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:2]([CH:4]2[S:5][CH2:6][CH2:7][S:8]2)([CH3:1])[CH3:3])=[CH:10][C:11]=1[CH:17]=[O:18]
Reactant: COc1ccc(C(C)(C)C2SCCS2)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: ClCl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(C)(C)C2SCCS2)cc1C=O
Temperature: -60 °C
Reaction time: 0.05 h
Yield: 30.5 %

Procedure:
To a stirred solution of Compound 80 (0.254 g, 1 mmol) in dry CH2 Cl2 (5 ml) was added a solution of TiCl4 in CH2Cl2 (1M, 3 ml) with cooling (-60° C.). After 3 min., to this was added dichloromethyl methyl ether (0.46 g, 4 mmol) dropwise. The reaction mixture was stirred at same temperature for 1 hr. The mixture was poured into water and stirred at room temperature for 15 min. The organic layer was separated and the aqueous layer was extracted with Et2O (50 ml×2). The combined solution was washed with brine, dried (MgSO4) and concentrated in vacuo to give crude product. The crude product was purified by a column chromatography to give Compound 81 (86 mg) as an oil
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=[O:5].[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH2:18][CH:17]1[CH2:26][NH2:27].C(N(CC)CC)C.O>CN(C)C=O>[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH2:18][CH:17]1[CH2:26][NH:27][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=[O:5]
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(CCCl)Nc1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCNCC1COc2ccccc2O1)Nc1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
To a solution of 10 g of N-(3-chloropropionyl)-3,4-methylenedioxyaniline in 50 ml of dimethylformamide are added 8.7 g of 1,4-benzodioxan-2-ylmethylamine and 8.9 g of triethylamine and the mixture is stirred for 20 hours at 50° C. After completion of the reaction, water is added and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is dissolved in ethyl acetate and 20% hydrogen chloride in ethyl acetate is added. The resulting crystals are collected by filtration and recrystallized from ethanol to give 13.7 g (77%) of N-[3-{(1,4-benzodioxan-2-ylmethyl)amino}propionyl]-3,4-methylenedioxyaniline.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(O[C@H]2CCCN(Cc3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O[C@H]2CCCNC2)cc1
Yield: 87.5 %

Procedure:
A mixture of 1-benzyl-(3S)-3-(4-nitrophenoxy)piperidine (6.5 g) and 1.2 g of 10% Pd/C in methanol (30 mL) was subjected to hydrogenation (50 psi). When the reaction was completed, the reaction mixture was filtered. The filtrate was concentrated in vacuo, giving a yellow solid. Recrystallization in CH2Cl2/hexane afforded (3S)-3-(4-aminophenoxy)piperidine (3.5 g, 88% yield) as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH:4]([S:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:3]1.[C:15]1([CH2:21][CH2:22][CH:23]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:21][CH2:22][CH2:23][N:2]2[CH2:6][CH2:5][CH:4]([S:7][C:8]3[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=3)[CH2:3]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CCCc1ccccc1
Reactant: Oc1cccc(SC2CCNC2)c1
Agent: Cl
Product: Oc1cccc(SC2CCN(CCCc3ccccc3)C2)c1

Procedure:
The title compound, MS: m/e=314.3 (M+H+) was prepared from (RS)-3-(pyrrolidin-3-yl-sulfanyl)-phenol hydrochloride and 3-phenylpropionaldehyde.
Reaction SMILES: [CH3:1]O.[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:13])[CH:5]=1.Cl>O1CCOCC1>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:1])=[O:9])=[C:6]([Cl:13])[CH:5]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Br)cc1Cl

Procedure:
To a methanol solution (25 ml) of 4-bromo-2-chlorobenzoic acid (5.0 g) was added hydrochloric acid/a 1,4-dioxane solution (4 N, 25 ml), followed by heating at reflux for 90 minutes. The reaction solution was brought back to room temperature, and concentrated under reduced pressure. Dichloromethane and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the solution was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford methyl 4-bromo-2-chlorobenzoate (5.3 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])#[N:26].N1CCCCC1>C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:13][C:10]=1/[CH:11]=[C:27](\[C:25]#[N:26])/[C:28]([O:30][CH3:31])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)/C(C#N)=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2,4-dibenzyloxybenzaldehyde (1 g), methyl cyanoacetate (0.27 mL), piperidine (0.1 mL) and ethanol (30 mL) is stirred at ambient temperature for 20 minutes and the solvent is removed under reduced pressure. The residue is recrystallized from ethanol to give methyl (E)-3-(2,4-dibenzyloxyphenyl)-2-cyanoacrylate as a yellow solid (400 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Temperature: 75 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
1-Chloro-4-fluoro-2-methyl-5-nitrobenzene (D22) (1.5 mmol, 284 mg) in dimethylformamide (5 mL) was treated under argon at room temperature with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 194 mg, 1 eq) then stirred at 75° C. overnight. The mixture was concentrated under reduced pressure, treated with 10% Na2CO3 aqueous solution and extracted twice with ether. Organics were combined, dried on MgSO4 and concentrated under reduced pressure to give the title compound as a clean orange solid (1.46 mmol, 539 mg, 97% yield). M−H=368.16.
Reaction SMILES: [CH:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])([CH2:3][CH3:4])[CH3:2].C(C1CCCC([Cl:22])C1=O)(C)(C)C>>[CH:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([Cl:22])[C:6]1=[O:11])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)C1CCCCC1=O
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Product: CCC(C)C1CCCC(Cl)C1=O

Procedure:
The chlorination of 2-sec-butylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32]1([C:38]2([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:41]3[CH2:42][CH2:43][C:38]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:50])[CH3:49])([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:39][CH2:40]3)=[O:22])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(NC(=O)OC(C)(C)C)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 87 %

Procedure:
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq., 201 mg, 0.53 mmol), triethylamine (3 eq, 0.22 mL, 0.157 mmol), tert-butyl N-(4-phenyl piperidin-4-yl)carbamate (1 eq, 146 mg, 0.53 mmol), and Benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1 eq, 233 mg, 0.53 mmol) was stirred in tetrahydrofuran (10 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure tert-butyl N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)carbamate (295 mg, 87%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.37 (br. s., 9H) 2.11 (dd, J=12.67, 4.00 Hz, 2H) 2.21 (s, 3H) 2.24-2.34 (m, 1H) 2.34-2.56 (m, 1H) 3.26 (t, J=12.01 Hz, 1H) 3.56 (t, J=12.39 Hz, 1H) 4.32 (d, J=13.75 Hz, 1H) 4.64 (d, J=13.56 Hz, 1H) 4.96 (br. s., 1H) 7.08 (d, J=8.38 Hz, 2H) 7.13-7.49 (m, 10H).
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH:23]([CH3:25])[CH3:24])[C:16]=2[F:26])=[CH:11][C:10]1=[O:27])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[F:26][C:16]1[C:17]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:28])=[O:2])[C:10](=[O:27])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2c(F)ccc(OC(C)C)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2c(F)ccc(OC(C)C)c2F)=CC1=O
Temperature: 20 °C
Yield: 86.1 %

Procedure:
To a solution containing (S)-2-[4-(2,6-difluoro-3-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (3.10 g, 0.008 mol) in tetrahydrofuran (35 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 35 mL, 0.018 mol). The mixture was stirred at 20° C. for 2H, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2,6-difluoro-3-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (2.64 g, 88%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:21]([CH3:22])=[N:20][N:19]([CH3:23])[C:10]=2[N:11]=[C:12]([NH:15][CH2:16][C:17]#[CH:18])[CH2:13][N:14]=1.S(=O)(=O)(O)O.N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:21]([CH3:22])=[N:20][N:19]([CH3:23])[C:10]=2[N:11]2[C:17]([CH3:18])=[CH:16][N:15]=[C:12]2[CH2:13][N:14]=1
Reactant: C#CCNC1=Nc2c(c(C)nn2C)C(c2ccccc2Cl)=NC1
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1nn(C)c2c1C(c1ccccc1Cl)=NCc1ncc(C)n1-2
Reaction time: 16 h

Procedure:
With stirring, 1.4 g. of 4-(2-chlorophenyl)-1,6-dihydro-1,3-dimethyl-7-(2-propynylamino)pyrazolo[3,4-e][1,4]-diazepine is dissolved in a solution of 1 mg. of mercuric oxide in 5 ml. of concentrated sulfuric acid at 50° C. The solution is allowed to stand for 16 hours at room temperature (20°-30° C.), then is poured over crushed ice and basified with excess concentrated aqueous ammonia. The mixture is extracted repeatedly with dichloromethane. The extracts are combined, dried and evaporated at reduced pressure to give a residue of 4-(2-chlorophenyl)-1,6-dihydro-1,3,9-trimethylimidazo-[1,2-a]pyrazolo[4,3-f][1,4]diazepine; m.p. 189-190° C. (dec.) after sublimation at 130° C. and 0.1 mm. Hg.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]2=3)[CH2:4][CH2:3]1.B(F)(F)F.[CH3:30][CH2:31]OCC>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:19]([O:21][CH2:30][CH3:31])=[O:20])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CCOCC
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccc(C(=O)O)cc32)CC1
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)C(=C1CCN(C)CC1)c1ccccc1C=C2

Procedure:
Racemic 5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylic acid (0.03 mole) and an equal molar amount of boron trifluoride etherate in 60 ml of absolute ethanol was refluxed overnight. The solution was evaporated to dryness and the residue was partitioned between ether and a saturated aqueous solution of sodium bicarbonate. The ether was separated and dried over MgSO4. The resulting ethyl ester, crystallized from acetonitrile, had m.p. 102°-103° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([N+]([O-])=O)=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[CH3:20].[N+:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[C-:22].C1CCN2C(=NCCC2)CC1.O>C1COCC1.CC(=O)OCC>[CH2:27]([O:26][C:24]([C:23]1[NH:21][CH:22]=[C:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[CH3:20])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:25])[CH3:28]
Reactant: Cc1c(F)cccc1CC(=Cc1ccccc1)[N+](=O)[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc(Cc2cccc(F)c2C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
The compound of step 3 (21.45 g, 79.07 mmol) and ethyl isocyanoacetate (10.37 ml, 94.88 mmol) were dissolved in 225 ml of anhydrous THF under a nitrogen atmosphere at 5° C. and DBU (14.16 ml, 94.88 mmol) was added dropwise. The solution was stirred at room temperature for 18 h. Then 200 ml of water and 200 ml of EA were added. The organic phase was washed with 1 N hydrochloric acid (200 ml) and brine (150 ml), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 90:10, then 85:15) to give 16.68 g of the title compound as a yellow solid melting at 120-122° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[C@H:7](O)[CH3:8].S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH:7]([C:6]1[S:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:3][C:2]=1[CH3:1])[CH3:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@@H](C)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Cl
Reaction time: 0.5 h

Procedure:
To a solution of [rac]-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol (200 mg, 0.7 mmol; PCT Int. Appl. (2002), WO 02/062774 A1) in dichloromethane (2 ml) was added thionyl chloride (0.1 ml, 1.4 mmol) at −10° C. The cooling bath was removed after 10 min and stirring was continued for 30 min. The solvent was removed under reduced pressure and the residue dried under vacuo to give 220 mg (0.7 mmol, quant.) of the title compound as yellow solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.Cl[C:9]1[N:14]=[C:13]2[NH:15][N:16]=[CH:17][C:12]2=[CH:11][N:10]=1.Cl>C(O)(C)C>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:9]2[N:14]=[C:13]3[NH:15][N:16]=[CH:17][C:12]3=[CH:11][N:10]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(N)cn1
Reactant: Clc1ncc2cn[nH]c2n1
Agent: Cl
Solvent: CC(C)O
Product: Cn1cc(Nc2ncc3cn[nH]c3n2)cn1
Temperature: 140 °C

Procedure:
A suspension of 1-methyl-1H-pyrazol-4-amine (173 mg, 1.29 mmol), 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 1.29 mmol) and HCl (25 μL, 4M in dioxane) in isopropanol (2 mL) was heated in the microwave at 140° C. for 1 h. After cooling to rt, the mixture was filtered and the resulting solid washed with cold isopropanol and diethyl ether to give N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([C:33]3[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:30]=[CH:31][CH:32]=2)O1>CN(C)C(=O)C.O.C(=O)([O-])O.[Na+].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>[N:4]1[CH:3]=[C:2]([C:31]2[CH:30]=[C:29]([C:33]3[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:28]=[CH:27][CH:32]=2)[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]=12
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: Brc1cnc2cnccn12
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: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1-c1cccc(-c2cnc3cnccn23)c1
Temperature: 80 °C
Yield: 37 %

Procedure:
A mixture of 3-bromoimidazo[1,2-α]pyrazine (150 mg, 0.76 mmol), potassium phosphate (321 mg, 1.51 mmol) and 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (3 ml of a 0.5M solution in N,N-dimethylacetamide) were degassed with N2 for 15 min. Tetrakis(triphenylphosphine)palladium(0) (44 mg, 0.04 mmol) was added and the mixture heated at 80° C. for 18 h. The reaction was allowed to cool to room temperature, diluted with water (20 ml) and saturated sodium hydrogencarbonate solution (20 ml) then extracted with ethyl acetate (2×75 ml). The combined organic fractions were washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to give a black oil. The oil was purified by silica gel chromatography eluting with dichloromethane and 1% 0.88 ammonia on a gradient of methanol (1-2%). The solid obtained was triturated with diethyl ether which gave 3′-(imidazo[1,2-α]pyrazin-3-yl)biphenyl-2-carbonitrile (83 mg, 37%) as a white powder: δH (400 MHz, CDCl3) 7.52 (1H, td, J 8 and 1), 7.58 (1H, dd, J 8 and 1), 7.61-7.74 (4H, m), 7.80-7.85 (2H, m), 7.94-7.97 (2H, m), 8.55 (1H, d), 9.18 (1H, s).