Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:17]([CH3:19])[CH3:18])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:8])=[O:4].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C@H:34]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[CH2:33][CH2:32][C@H:31]2[C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:39][C:38]1[CH:37]=[CH:36][C:35]([C@@H:34]2[CH2:33][CH2:32][C@@H:31]([C:42]3[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=3)[N:30]2[C:27]2[CH:26]=[CH:25][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:29][CH:28]=2)=[CH:41][CH:40]=1)=[O:16])=[O:8])[CH:17]([CH3:19])[CH3:18])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Reactant: CC(C)(C)c1ccc(N2[C@H](c3ccc(N)cc3)CC[C@H]2c2ccc(N)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc([C@@H]2CC[C@@H](c3ccc(N)cc3)N2c2ccc(C(C)(C)C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a solution of the product from Example 37B (17.7 mg, 0.065 mmol) and the product from Example 37E (50 mg, 0.130 mmol) in anhydrous DMSO (1.3 mL) was added HATU (27.1 mg, 0.071 mmol) and Hunig's Base (0.015 mL, 0.084 mmol). The resulting mixture was stirred at rt for 30 min, and was then partitioned between H2O (5 mL) and EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4. The drying agent was filtered off, and solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% MeOH in CH2Cl2 to give the title compound (20 mg, 24%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.88 (d, J=6.72 Hz, 3 H), 0.93 (d, J=6.72 Hz, 3 H), 1.11 (s, 9 H), 1.52-1.66 (m, 2 H), 1.79-2.06 (m, 4 H), 2.06-2.20 (m, 1 H), 2.34-2.47 (m, 2 H), 3.52 (s, 3 H), 3.56-3.67 (m, 1 H), 3.74-3.87 (m, 1 H), 4.02 (t, J=8.51 Hz, 1 H), 4.42 (dd, J=8.08, 4.83 Hz, 1 H), 4.83-4.94 (m, 2 H), 5.02 (d, J=7.16 Hz, 0.5 H), 5.08 (d, J=7.59 Hz, 0.5 H), 6.18 (d, J=8.78 Hz, 2 H), 6.48 (d, J=8.35 Hz, 2 H), 6.84 (d, J=8.35 Hz, 2 H), 6.93 (d, J=8.89 Hz, 2 H), 7.11 (d, J=8.57 Hz, 2 H), 7.31 (d, J=8.35 Hz, 1 H), 7.48 (d, J=8.57 Hz, 2 H), 9.97 (s, 1 H); MS (ESI) m/z 640.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH:7](O)[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[CH3:23].[CH3:24][NH:25][CH3:26]>C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH:7]([N:25]([CH3:26])[CH3:24])[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[CH3:23]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(O)C(C)(C)O2
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(N(C)C)C(C)(C)O2
Yield: 89 %

Procedure:
Using tert-butyl (7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 236 and dimethylamine, the title compound was synthesized in the same manner as in Example 297. Yield: 89%. Melting point: 111-112° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH:22]([CH3:27])[C:23](=O)[CH2:24][OH:25]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][OH:25])[CH:22]([Cl:21])[CH3:27])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CC(Cl)C(=O)CO
Reactant: NNC1=Nc2ccc(F)cc2C(c2ccccc2)=NC1
Solvent: C1CCOC1
Product: CC(Cl)C(CO)=NNC1=Nc2ccc(F)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-fluoro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 3-chloro-1-hydroxy-2-butanone under nitrogen to give 7-fluoro-2-[[2-chloro-1-(hydroxymethyl)propylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH2:1]([S:5][C:6]1[NH:11][C:10](=O)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:15])=O>>[CH2:1]([S:5][C:6]1[N:11]=[C:10]([Cl:15])[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCSc1nccc(=O)[nH]1
Product: CCCCSc1nccc(Cl)n1
Temperature: 25 °C

Procedure:
A mixture of 2-butylsulfanyl-3H-pyrimidin-4-one (3.0 g) and phosphorus oxychloride (15 mL) was heated at reflux for 3 h; it was then cooled to RT and evaporated under reduced pressure. The residue was poured into an ice-water mixture, and the resulting mixture was extracted with DCM. The combined organic extracts were washed with a diluted aqueous solution of NaHCO3, dried over Na2SO4, filtered and evaporated under reduced pressure to give 1.2 g of 2-butylsulfanyl-4-chloro-pyrimidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:9]=1
Reactant: C1CNCCN1
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: c1cncc(N2CCNCC2)c1
Temperature: 120 °C
Yield: 86 %

Procedure:
A 200 ml Kjeldahl flask equipped with a cooling condenser and a thermometer was charged with a solution of 22 g of piperazine in 20 ml of o-xylene, a solution of 6.72 g of 3-bromopyridine in 20 ml of o-xylene and a solution of 5.66 g of NaOBut in 20 ml of o-xylene, and further with a solution of 48 mg of palladium acetate in 15 ml of o-xylene (the ratio of palladium atom/heterocyclic aromatic halide=0.5% by mole). The flask was flushed with nitrogen for about 20 minutes while the content was stirred, and 0.2 ml of tri-tert.-butylphosphine was added. Then the mixture was heated to 120° C., and maintained at that temperature for 3 hours with stirring. After completion of the reaction, the same treatment as employed in Example 1 was conducted to give colorless oily 1-(3-pyridyl)piperazine. The yield was 86% by mole.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[CH3:25][C:26]([NH2:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]>>[CH3:25][C:26]([NH:34][C:22]([C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)=[CH:4][CH2:5]3)=[O:23])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]
Reactant: CC(C)(N)c1ccccc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(C)(C)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 70 %

Procedure:
The title compound was prepared in a yield of 70% in a similar manner to that described in Example 37 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 1-methyl-1-phenylethylamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][C@H:11]([OH:14])[CH2:12][OH:13].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:13][CH2:12][C@@H:11]([OH:14])[CH2:10][C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H](O)Cc1cc2ccccc2[nH]1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)Cc2cc3ccccc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
To a solution of (S)-3-indol-2-yl-propane-1,2-diol (S)-1 (15 g, 78.5 mmol) in dry pyridine (120 mL) was added p-toluenesulfonyl chloride (15.5 g, 81.3 mmol) at 0° C. After stirring for 5 hours at 0° C., the solution was poured into cold hydrochloric acid (100 mL, 6N) and extracted with ether (3×60 mL). The combined extracts were washed with hydrochloric acid (6N, 2×30 mL) followed by brine (2×80 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by flash chromatography to give 24.5 g (90.4%) of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1>C(#N)C>[CH2:2]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:3][CH2:4][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)CCCBr
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CC(=O)CCCn1ccnc1

Procedure:
5-Bromo-2-pentanone (1.65 g.) and imidazole (3.5 g.) in 15 ml. acetonitrile were stirred at 60° C. for 48 hours and the solvent removed. The residue was chromatographed on silica gel, eluting with 10% methanol in dichloromethane to give 1-(n-pentan-4-onyl)imidazole. This material in 40 ml. methanol was reduced with sodium borohydride in a similar manner to that described in Preparation 2A to give 1-(4-hydroxy-n-pentyl)imidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:10])[NH:7][N:8]=1)([O-:3])=[O:2].[C:12](=O)(O)[O-].[Na+]>CO.S(=O)(=O)(O)O>[CH3:12][O:10][C:9]([C:6]1[NH:7][N:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:11]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Temperature: 25 °C

Procedure:
A solution of 5-Nitro-2H-pyrazole-3-carboxylic acid (5 gm, 32 mmol) in 100 ml of 2% sulfuric acid methanol was refluxed for 20 hours. The mixture was cooled to room temperature and added to saturated sodium bicarbonate. The mixture was extracted with ethyl acetate three times to obtain 3.59 gm of title product after drying over magnesium sulfate, filtering and evaporating to dryness. ESI M+1=171.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.[CH3:20][N:21]1[C:26](=[O:27])[C:25]2[CH2:28][NH:29][CH2:30][CH2:31][C:24]=2[NH:23][C:22]1=[O:32]>CN(C)C=O>[CH3:20][N:21]1[C:26](=[O:27])[C:25]2[CH2:28][N:29]([CH2:11][CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH2:30][CH2:31][C:24]=2[NH:23][C:22]1=[O:32]
Reactant: ClCCOC1CCCCO1
Reactant: Cn1c(=O)[nH]c2c(c1=O)CNCC2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)[nH]c2c(c1=O)CN(CCOC1CCCCO1)CC2
Temperature: 70 °C
Yield: 26.9 %

Procedure:
40 g of ethyldiisopropylamine and 52.5 g of 2-(2-chloroethoxy)tetrahydropyran (96% pure according to GC) were added to 54.5 g of 3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione in 1.5 l of dimethylformamide, with stirring, and the mixture was heated for 30 h at 70° C. It was concentrated under vacuum, the residue was worked up by extraction with dichloromethane and water and the combined dichloromethane phases were dried and concentrated to give 25 g of 3-methyl-6-[2-(tetrahydropyran-2-yloxy) ethyl]-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione, which was purified by bulb-tube distillation at a bath temperature of 80° C. and 0.1 mbar and by column chromatography on aluminum oxide (activity grade III) and elution with dichloromethane/ethanol (volume ratio 95:5).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[C:29]1(O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[F:28][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]([O:27][C:37]4[C:38]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:34]=[CH:35][CH:36]=4)=[O:26])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=C(O)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Product: O=C(Oc1cccc2ccccc12)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1

Procedure:
2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-1, 7.00 g) is reacted analogously to Example I-811 with 1-naphthol (3.12 g). This gives, after chromatographic purification, 1-naphthyl-2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (4.0 g, 44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:11](=[O:25])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29][C:30]1[CH:34]=[C:33]([CH3:35])[O:32][N:31]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13]3)[C:11](=[O:25])[N:10]([CH2:29][C:30]3[CH:34]=[C:33]([CH3:35])[O:32][N:31]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(CBr)no1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCC2c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CN2CC(c3ccc(F)cc3)C3(CCCN(C(=O)OC(C)(C)C)C3)C2=O)no1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Tert-butyl 4-(4-fluorophenyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (200 mg; 0.574 mmol) was solubilised in DMF (5 ml) and cooled to 0° C. 60% Sodium hydride dispersion in mineral oil (46 mg, 1.148 mmol) was added and the mixture stirred at 0° C. for 45 minutes. 3-(Bromomethyl)-5-methylisoxazole (101 mg; 0.574 mmol) was solubilised in DMF (0.7 ml) and added. The reaction was stirred at 0° C. for 30 minutes then warmed to RT for 3 hr. The mixture was quenched with water and extracted with EtOAc. The organics were combined and washed with brine and dried over magnesium sulphate, filtered and concentrated in vacuo. The resultant oil was purified by chromatography on silica eluting with 50-100% TBME in iso-hexane to yield tert-butyl 4-(4-fluorophenyl)-2-((5-methylisoxazol-3-yl)methyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate.
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH2:27][CH3:28])[C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:40][CH2:41][CH:42](CO)[OH:43]>>[CH2:1]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH2:27][CH3:28])[C:23]([O:25][CH2:26][CH:42]([OH:43])[CH2:41][OH:40])=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(CC)C(=O)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCC=CCCCNc1ccc(C(CC)C(=O)OCC(O)CO)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-(4-tetradecenylamino)phenylbutyrate, 280 mg. of glycerol, and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield the product as a white solid.
Reaction SMILES: [Li+].[OH-].[CH2:3]([N:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([O:18]C)=[O:17])[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C1COCC1.CO>[CH2:3]([N:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[C:11]1=[O:20])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1nccn(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nccn(Cc2ccccc2)c1=O
Reaction time: 4 h
Yield: 81.6 %

Procedure:
LiOH (0.82 mL, 0.82 mmol, 1.0 M) was added to a solution of methyl 4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylate (0.10 g, 0.41 mmol) in a mixture of THF-MeOH (3:1 ratio, 6 mL) at room temperature. After stirring for 4 hours, 1 N HCl (0.9 mL) was added. The reaction mixture was extracted with EtOAc, dried over MgSO4, and concentrated to give the desired product (0.077 g, 82%). 1H NMR (400 MHz, CD3OD) δ 8.0 (d, 1H), 7.68 (d, 1H), 7.36-7.42 (m, 5H), 5.29 (s, 2H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39]([CH3:42])(=[O:41])=[O:40]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[C:10]([F:11])[C:5]3=[N:4][CH:3]=2)=[CH:19][C:18]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39]([CH3:42])(=[O:41])=[O:40]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccc(F)cc3S(C)(=O)=O)c2)OC1(C)C
Reactant: Fc1c(C(F)(F)F)ccn2c(Br)cnc12
Product: CS(=O)(=O)c1cc(F)ccc1-c1cc(-c2cnc3c(F)c(C(F)(F)F)ccn23)ccc1F
Yield: 42 %

Procedure:
3-Bromo-8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridine was coupled to 2-(2,4′-difluoro-2′-methanesulfonylbiphenyl-5-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 1 to give 3-(2,4′-difluoro-2′-methanesulfonylbiphenyl-5-yl)-8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridine as a white solid (147 mg, 42%): δH (400 MHz, CDCl3) 2.91 (3H, s), 6.99 (1H, dd, J 7 and 6), 7.35-7.47 (3H, m), 7.61-7.65 (2H, m), 7.85 (1H, s), 7.98-8.01 (1H, m), 8.48 (11H, d, J 7); m/z (ES+) 471 [MH+].
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:27][C:28]1[CH:29]=[C:30]([OH:35])[CH:31]=[CH:32][C:33]=1[F:34].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:35][C:30]2[CH:31]=[CH:32][C:33]([F:34])=[C:28]([F:27])[CH:29]=2)[N:11]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To an oven-dried round bottom flask was added toluene (1 mL), the product of Example 112 (0.050 g; 0.122 mmol), and 3,4-difluorophenol (0.016 g; 0.122 mmol), and cesium carbonate (0.044 g; 0.134 mmol). The reaction mixture was heated at 100° C. and stirred for 4 hours. The reaction mixture was allowed to cool to room temperature, then it was partitioned between ethyl acetate and 2N aq. NaOH solution. The organic portion was separated and washed with more 2N aq. NaOH solution (2×), brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-10% ethyl acetate:hexane) to afford the desired product: m/e=504 (M+1) Rt=4.61 min on LCMS.
Reaction SMILES: [F:1][C:2]([F:19])([C:5]([F:18])([F:17])[CH2:6][O:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:3]=O.FC(F)(C1C=CC=CC=1)/C=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[F:1][C:2]([F:19])([C:5]([F:18])([F:17])[CH2:6][O:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[CH:3]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=CC(F)(F)C(F)(F)COC/C=C/c1ccccc1
Reactant: CCOC(=O)/C=C/C(F)(F)c1ccccc1
Product: CCOC(=O)/C=C/C(F)(F)C(F)(F)COC/C=C/c1ccccc1
Yield: 70 %

Procedure:
Obtained from Intermediate 38 (1.37 g, 4.96 mmol) by the procedure described in Intermediate 20. Purification by column chromatography with silica gel using n-hexane/ethyl acetate (15:1) as eluent gave the title compound (1.2 g, 70%) as oil.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:23][C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42]Br)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42][N:29]1[CH2:28][CH2:27][CH:26]([C:24](=[O:25])[NH:23][C:10]2[CH:11]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=3)[CH:13]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][CH:32]=3)[CH:9]=2)[CH2:31][CH2:30]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: N#Cc1ccc(Oc2cc(NC(=O)C3CCNCC3)cc(Oc3ccc(C#N)cc3)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Product: CC(C)(C)OC(=O)NCCN1CCC(C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 37.8 %

Procedure:
Following the procedure of Example 11(e) 4-[3,5-bis-(4-cyano-phenoxy)-phenyl-carbamoyl]-piperidine (0.8 g, 1.82 mmol) and (2-bromo-ethyl)-carbamic acid tert-butyl ester (0.49 g, 2.19 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.4 (9H, s), 1.42 (4H, m), 2.31 (3H, m), 1.8 (2H, t), 2.81 (2H, m), 3.15 (1H, m), 3.7 (1H, m), 6.76 (1H, s), 7.26 (6H, m), 7.86 (4H, d).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:14]([N:16]=[C:17](SC)[S:18][CH3:19])#[N:15]>C(O)C>[C:14]([NH:16][C:17](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1)[S:18][CH3:19])#[N:15]
Reactant: COc1cccnc1CSCCN
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: COc1cccnc1CSCCN=C(NC#N)SC
Reaction time: 8 h

Procedure:
A solution of 2-[2-aminoethylthiomethyl]-3methoxypyridine (2.1g in ethanol (15 ml) was added over one hour to a stirred solution of dimethyl N-cyanodithioimidocarbonate (1.5 g) in ethanol (15 ml). The mixture was allowed to stand overnight and nitrogen was bubbled through for one hour. The crystalline precipitate was recrystallised from ethanol/ether to yield N-cyano-N'-[2-((3-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea (2.2 g), m.p. 102°-103°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:18]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(C(F)(F)F)c1
Reaction time: 18 h
Yield: 80.8 %

Procedure:
A mixture of 100 g (0.618 mole) of α,α,α-trifluoro-m-cresol, 106 g (0.632 mole) of ethyl bromoacetate, 87.5 g (0.632 mole) of potassium carbonate, and 1500 ml of acetone is stirred at reflux for 4 hours, and at room temperature for 18 hours. The mixture is filtered, evaporated under vacuum on a rotorary evaporator at 45° C and at 85° C (0.1 mm) to remove excess ethyl bromoacetate. The reaction mixture is taken up in 500 ml of ether, washed three times with 100 ml each of 0.1M potassium carbonate, once with 100 ml of water, 100 ml of 0.01M hydrochloric acid, and 100 ml of water. It is then dried with magnesium sulfate, filtered and evaporated, giving 142 g of the crude product. This is fractionally distilled at 73°-75° C (0.1 mm) to give 124 g of the purified subject product as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:5][S:6][CH2:7][C:8]([OH:10])=[O:9].C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:5][S:6]([CH2:7][C:8]([OH:10])=[O:9])=[O:24]
Reactant: COc1ccc(CSCC(=O)O)cc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CS(=O)CC(=O)O)cc1O
Temperature: -5 °C
Reaction time: 6 h

Procedure:
To a cooled (−5° C.) solution of 2-((3-hydroxy-4-methoxybenzyl)sulfanyl)acetic acid (2.9 g) in anhydrous DCM (15 mL) is added MCPBA (20 mmol, 50% concentration basis, Lancaster). The reaction mixture is stirred at −5° C. for 6 hours. The precipitated 3-chlorobenzoic acid is removed by filtration. The filtrate is washed with water, dried over magnesium sulfate and concentrated. After removal of the solvent, the product 2-((3-hydroxy-4-methoxy-benzyl)sulfinyl)acetic acid is purified either by crystallization or by silica gel chromatography.