Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]2=[O:14].[CH3:19][Sn](C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[CH2:15]([CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][C:9]([F:13])=[C:10]([O:11][CH3:12])[C:2]=2[CH3:19])[C:6]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC1Cc2c(cc(F)c(OC)c2Br)C1=O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCC1Cc2c(cc(F)c(OC)c2C)C1=O
Temperature: 100 °C
Yield: 24.5 %

Procedure:
A mixture of 4-bromo-2-butyl-6-fluoro-5-methoxy-1-indanone (1.86 g, 5.94 mmol), bis(triphenylphosphine)palladium(II) chloride (208 mg, 0.297 mmol), tetramethyltin (0.989 mL, 7.128 mmol), triphenylphosphine (156 mg, 0.594 mmol), lithium chloride (504 mg, 11.88 mmol), and anhydrous N,N-dimethyl-formamide (11.9 mL) was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 100° C. for 22 hours. After cooling to room temperature, the mixture was evaporated under vacuum. The residue in EtOAc (150 mL) was washed with water (4×100 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (2.15 g). The crude product was purified by chromatography on EM silica gel 60 (2.5×29 cm column), eluting with CH2Cl2 (50 mL fore-run followed by 8 mL fractions). Fractions 20-28 were combined and evaporated under vacuum to provide 2-butyl-6-fluoro-5-methoxy-4-methyl-1-indanone (365 mg) as an oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11](Cl)([O:13][C:14](=[O:20])OC(Cl)(Cl)Cl)Cl.[F:22][C:23]1[CH:30]=[C:29]([C:31]2[N:32]=[C:33]([NH:36][C:37](C)([CH3:40])[CH2:38]O)[S:34][CH:35]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>C(Cl)Cl>[CH3:38][C:37]1([CH3:40])[CH2:11][O:13][C:14](=[O:20])[N:36]1[C:33]1[S:34][CH:35]=[C:31]([C:29]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([F:22])[CH:30]=2)[N:32]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)c(F)c2)cs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)c(F)c2)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
N,N-diisopropylethylamine (1.4 mL, 7.9 mmol) and triphosgene (1.2 g, 3.9 mmol) in 20 mL of dry methylene chloride were added to a solution of 2-fluoro-4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (955 mg, 3.3 mmol), prepared in the previous step, in 50 mL of dry methylene chloride at 0° C. The reaction was stirred at 0° C. for 3 h and then allowed to warm to room temperature. The reaction was washed with 1×100 mL of 2N HCl. The aqueous layer was extracted with methylene chloride (2×100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give 1.0 g of a yellow solid. Purification of the solid on silica gel using a stepwise gradient of 5% to 40% ethyl acetate-hexane gave the title compound (450 mg, 43%) as a yellow solid, mp 204-206° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[CH3:13]O>>[CH3:13][O:11][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CO
Product: COC(=O)c1cc2ccccc2[nH]1

Procedure:
50 g Indole-2-carboxylic acid were stirred with 400 ml methanol/10% H2SO4 for 48 hours. The resulting crystals were filtered off and washed with methanol giving 51.3 g product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[N:12]2[C:23](=[O:26])[NH:24][N:25]=[C:11]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].IC.[C:38](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Si:29]([O:28][CH2:27][C:10]1([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[O:15][C:14]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=2[N:12]2[C:23](=[O:26])[N:24]([CH3:38])[N:25]=[C:11]12)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)Oc2ccc([N+](=O)[O-])cc2-n2c1n[nH]c2=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc2n(c1=O)-c1cc([N+](=O)[O-])ccc1OC2(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,4-Bis(((tert-butyldimethylsilyl)oxy)methyl)-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one and iodomethane (0.626 mL) were dissolved in DMF. Cesium carbonate (4.13 g) was added to the solution. The reaction mixture was stirred at room temperature overnight. Water (250 mL) was added to the reaction. The aqueous solution was extracted with EtOAc (2×200 mL). The organic layers were evaporated to give 4,4-bis(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]([S:15]([O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])(=[O:17])=[O:16])=[C:13]=[O:14]>ClCCl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:13](=[O:14])[NH:12][S:15]([O:18][C:19]2[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=2[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])(=[O:17])=[O:16])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: C=CCOC(=O)c1ccccc1OS(=O)(=O)N=C=O
Solvent: ClCCl
Product: C=CCOC(=O)c1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.55 g (0.01 mole) of 2-amino-4,6-dimethoxypyrimidine are dissolved in 100 ml of dichloromethane, and 3.40 g (0.012 mole) of allyl 2-isocyanatosulfonyloxybenzoate, dissolved in 20 ml of dichloromethane, are added at 0° C. The mixture is stirred at room temperature for 18 hours and filtered off with suction, and 2.54 g (58% of theory) of allyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyloxy]-benzoate of melting point 110°-112° C. are obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:36]=[CH:35][C:8]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][C:16]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[O:27])([O:21][Si](C)(C)C)[CH2:17]3)=[CH:7][CH:6]=1.[Cl-].[Na+]>>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:14]3[CH2:20][CH2:19][CH:18]2[CH2:17][C:16]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)=[O:27])([OH:21])[CH2:15]3)=[CH:35][CH:36]=1
Reactant: COc1ccc(OCCCN2C3CCC2CC(O[Si](C)(C)C)(C(=O)c2ccc(F)cc2)C3)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(OCCCN2C3CCC2CC(O)(C(=O)c2ccc(F)cc2)C3)cc1

Procedure:
9 ml. of an aqueous solution containing 0.70 g (0.0174 mol) of sodium hydroxide is added and the solution obtained in Step A, above, stirred for 7 hours. Sodium chloride is added to saturate the aqueous solution followed by 100 ml. of diethyl ether. The solution is agitated, the layers partitioned, and the ethereal solution is dried over anhydrous sodium sulfate. The solution is concentrated in vacuo to afford a yellow oil. After drying on a vacuum pump for 3 hours, the oily solid is recrystallized from 300 ml. of a hot mixture of hexane isomers. The resulting solid is recrystallized from 100 ml. of hot hexanes to afford the title product, {8-[3-(4-methoxyphenoxy)propyl]-3-hydroxy-8-azabicyclo-[3.2.1]oct-3-yl}-4-fluorophenyl methanone; m.p. 100°-101° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:27]=[CH:28]/[C:29]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:30]
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Product: COc1cccc(/C=C/C(=O)Nc2ccn(CCCCC(C)=O)n2)c1OC

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][S:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:3][CH:4]=1)(=[O:11])=[O:10]
Reactant: C1COCCN1
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(Br)cc2)c(OC)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(N3CCOCC3)cc2)c(OC)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of C-(4-bromophenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide (1 g), morpholine (0.3 ml), Pd2(dba)3 (51 mg) and cesium carbonate (1.3 g) in dioxane was stirred at 80° C. for 16 h. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (267 mg) with a molecular weight of 406.5 g/mol (C20H26N2O5S).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]1[C:23]3[C:18](=[C:19]([O:24][CH3:25])[CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH:15]=1)=[CH:11][CH:10]=[C:9]([C:26]([OH:28])=[O:27])[CH:8]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[CH2:31]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:26]([OH:28])=[O:27])[CH:8]=2)[C:13]([C:14]2[C:23]3[C:18](=[C:19]([O:24][CH3:25])[CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH:15]=2)=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: CCCCc1[nH]c2cc(C(=O)O)ccc2c1C1=CCCc2c(OC)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1c(C2=CCCc3c(OC)cccc32)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-butyl-3-(5-methoxy-3,4-dihydro-naphthalen-1-yl)-1H-indole-6-carboxylic acid on Wang resin (100 mg; prepared according to the procedure outlined in Example 9) in dimethylformamide (1.5 mL) was added sodium hydride (60% in mineral oil; 20 mg) and the mixture was stirred at room temperature for 30 min. Benzyl bromide (0.1 mL) was added and the mixture was stirred for 3 h. The mixture was filtered, washed with water (1×1.5 mL), tetrahydrofuran (2×1.5 mL), dichloromethane (2×1.5 mL), and dried. The product was cleaved from the resin by treatment with 1:1 trifluoroacetic acid/dichloromethane for 1 h; 1H NMR (DMSO-d6) δ 0.67 (t, J=7.0 Hz, 3 H), 1.16 (t, J=6.7 Hz, 2 H), 1.34 (t, J=6.7 Hz, 2 H), 2.42 (m, 2 H), 2.55 (m, 2 H), 2.80 (m, 2 H), 3.82 (s, 3 H), 5.59 (s, 2 H), 6.12 (t, 1 H), 6.32 (d, J=7.3 Hz, 1 H), 6.88 (d, J=8.3 Hz, 1 H), 7.00 (m, 3 H), 7.15 (d, J=8.3 Hz, 1 H), 7.30 (m, 3 H), 7.55 (d, J=8.2 Hz, 1 H), 7.94 (s, 1 H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[C:21]([C:28]3[NH:36][C:35]4[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=4[CH:29]=3)[CH:22]=[CH:23][CH:24]=2)[N:19]=1>C1COCC1>[O:37]=[C:31]1[C:30]2[CH:29]=[C:28]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[N:19]=[C:18]([O:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)[CH:27]=[CH:26]4)[NH:36][C:35]=2[CH2:34][CH2:33][NH:32]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(R)-tert-Butyl 3-hydroxypiperidine-1-carboxylate (Astatech Inc, Bristol, Pa.; 406 mg, 2.02 mmol) was added to a suspension of NaH (81 mg, 2.02 mmol) in THF (2.5 mL) and the resulting suspension was stirred at RT for 10 min. 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 75 mg, 0.25 mmol) was added and the resulting suspension was stirred at RT for 5 min, then heated at 70° C. for 5 h. The mixture was cooled to RT and partitioned between EtOAc (60 mL) and saturated aq. NH4Cl (20 mL). The organic layer was separated, sequentially washed with water (20 mL) tand brine (20 mL), then dried over MgSO4, filtered and concentrated in vacuo to give (R)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate as a light yellow solid. The material was used in the next step without further purification. m/z (ESI, +ve ion) 463.1 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([OH:19])=O)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH:32]1[NH2:41])[CH2:38]2>C(Cl)Cl.C(N(CC)CC)C>[CH:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH:32]1[NH:41][C:17]([C:12]13[CH2:11][CH2:10][C:9]([CH2:8][CH2:7][CH2:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])([CH2:14][CH2:13]1)[CH2:16][CH2:15]3)=[O:19])[CH2:38]2
Reactant: CCS(=O)(=O)CCCC12CCC(C(=O)O)(CC1)CC2
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)CCCC12CCC(C(=O)NC3C4CC5CC(C4)CC3C5)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Carboxylic acid 2-8 (0.100 g, 0.348 mmol) was dissolved in 2 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with oxalyl chloride (2 M in methylene chloride, 2 eq., 0.348 mL, 0.696 mmol) and subsequently with 0.050 ml of DMF. The reaction was stirred at room temperature under nitrogen atmosphere for 90 min, then evaporated and placed under vacuum for 20 min. The acid chloride was dissolved in anhydrous methylene chloride (2 mL), and then treated with triethylamine (0.100 ml) and 2-adamantylamine (2 eq., 105 mg). The reaction stirred at ambient temperature for 1 hr. The mixture was diluted with 20 mL of methylene chloride and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The product was purified using a Gilson HPLC with UV detection equipped with a C18 reverse phase column running a gradient of water/acetonitrile (0.1% TFA). The fractions containing product were concentrated to remove some of the acetonitrile and the lyophilized to provide pure product N-2-adamantyl-4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]octane-1-carboxamide (2-9) as a white fluffy amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:5])[CH3:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.ClCCl>[C:18]([O:17][C:13]([CH2:14][CH2:15][C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CCOC(=O)C1(CCC(=O)OC(C)(C)C)CCCCC1=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 2-ethoxycarbonylcyclohexanone (5.0 g, 0.029 mol) and tert-butyl acrylate (4.83 g, 0.037 mol) in tert-butanol (30 ml) was added, in one portion, potassium carbonate (4.0 g, 0.029 mol). The suspension was stirred at room temperature for 22 hours, diluted with dichloromethane (100 ml) and distilled water (100 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (2×100 ml) and the combined dichloromethane extracts dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica by eluting with hexane/ethyl acetate (4:1) to give, after combination and evaporation of appropriate fractions, the title compound as a colorless oil, (7.99 g, 92.3%; 98.92% by GC normalization) (MH+ 299.03, 8.53%). Rf. 0.15 (silica, hexane/ethyl acetate 4:1). 1H-NMR (300 MHz, CDCl3):=1.20 (t, 3H), 1.37 (s, 9H), 1.52-2.46 (m, 12H), 4.08-4.21 (m, 2H) ppm. 13C-NMR (62 MHz, CDCl3):=13.97, 22.38, 27.36, 27.91, 29.52, 30.49, 36.06, 40.85, 59.87, 61.19, 80.10, 171.61, 172.22, 207.39 ppm. Analysis %: Found: C, 64.19; H, 8.80; C16H26O5 requires: C, 64.41; H, 8.78.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[F:10])#[N:2].C([O-])([O-])=O.[Na+].[Na+].[NH2:17][OH:18].Cl>CCO.O>[NH2:7][C:6]1[CH:8]=[CH:9][C:3]([C:1](=[N:17][OH:18])[NH2:2])=[C:4]([F:10])[CH:5]=1
Reactant: NO
Reactant: N#Cc1ccc(N)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc(N)cc1F
Temperature: 60 °C

Procedure:
4-cyano-3-fluoroaniline (10 g, 0.073 mol) dissolved in EtOH (36 ml). Water (7.3 ml) was added followed by Na2CO3 (5.06 g, 0.65 eq) and the temperature of the mixture raised to 60° C. NH2OH.HCl (5.6 g, 1.1 eq) in water (7.3 ml) was added slowly, and the mixture heated at 60° C. overnight. The mixture was cooled to rt, the solid was collected by filtration, washed with, water (7 ml), EtOH (7 ml), ether (20 ml), and dried to give 7.5 g of M16-1.
Reaction SMILES: C(=O)(OC)OC.[C:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:9])C.[O-:17][CH2:18][CH2:19][CH2:20][CH3:21].[O-][CH2:23][CH2:24]CC.C([Sn+2]CCCC)CCC>>[C:7](=[O:9])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:17][C:18]1[CH:24]=[CH:23][CH:21]=[CH:20][CH:19]=1
Reactant: CCCC[O-]
Reactant: CC(=O)Oc1ccccc1
Agent: CCCC[Sn+2]CCCC
Solvent: COC(=O)OC
Product: O=C(Oc1ccccc1)Oc1ccccc1
Reaction time: 1 h

Procedure:
In a stainless steel pressure vessel equipped with a distillation column packed with PRO-PAK protruded 0.16 inch stainless steel packing, air condensor, and receiver, and equipped to maintain pressure from a nitrogen regulator, a quantity of 78 parts dimethyl carbonate, 136 parts phenyl acetate, and 0.5 part dibutyl tin dibutoxide was heated, at 200 psig, to 240° C. for one hour, and then at atmospheric pressure for one hour. A quantity of 89 parts (83% of the theorectical) of diphenyl carbonate was isolated. The pot residue, after removal of the diphenyl carbonate by vacuum distillation, amounting to 3.3 parts, was used as a catalyst in the reaction of 132 parts phenyl acetate and 72 parts dimethyl carbonate. A quantity of 78.1 parts of diphenyl carbonate was recovered, along with 4.4 parts of pot residue for recycle. Analysis indicated less than 1 ppm of tin in the resulting diphenyl carbonate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)C>ClCCl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([C:21]([F:22])([F:24])[F:23])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
To a stirred solution of tert-butyl-4-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (6.8 g, 19.5 mmol) in anhydrous dichloromethane (90 mL) was added TFA (45 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes then the cooling bath was removed and it was allowed to stir at room temperature for 2 hours. Reaction was complete as determined by TLC. Most of TFA was azeotropped with dichloroethane. The residue was then diluted with dichloromethane and washed with saturated Na2CO3 (aq.). Organic layer was dried over MgSO4. Solvent evaporation afforded 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine in 79.9% yield (3.86 g) as light brown oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.78-2.90 (m, 4H) 2.96-3.04 (m, 4H) 7.18-7.25 (m, 1H) 7.29-7.42 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C@H:9]([OH:16])[CH2:10]OS(C)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].[Cl-].[Na+]>COCCOC>[O:16]1[CH2:10][C@@H:9]1[CH2:8][O:7][C:6]1[CH:17]=[CH:18][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CS(=O)(=O)OC[C@@H](O)COc1ccc(C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: N#Cc1ccc(OC[C@H]2CO2)cc1
Yield: 100.6 %

Procedure:
A solution of 2.71 g of (2S)-1-(4-cyanophenoxy)-3-methanesulfonyloxypropan-2-ol in 40 ml of 1,2-dimethoxyethane was stirred with 1.0 g of powdered sodium hydroxide at room temperature for 22 h. 10 ml of saturated sodium chloride solution was added, and the mixture was extracted twice with ether. Washing with 5% sodium hydrogen carbonate, drying over magnesium sulfate, filtration and evaporation gave 1.76 g of crystalline material, m.p. 67.5° C., [α]D20 -14.7° (c=1, acetone)
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+].[Br-].[Na+]>CN(C=O)C>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH2:24][CH:23]([O:26][CH3:27])[O:22][CH3:21])[CH:4]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: COC(CCl)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(OC)OC

Procedure:
A mixture of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (8.06 g, 0.025 mole), chloroacetaldehyde dimethyl acetal (6.23 g; 0.05 mole), potassium carbonate (6.91 g, 0.05 mole) and sodium bromide (2.57 g, 0.025-mole) in 100 ml of dry DMF was stirred at reflux for 8 hours. After four hours at reflux an additional amount of the alkylating agent (6.23 g, 0.05 mole) was added. The mixture was filtered and the DMF was removed under vacuum. The oily residue was redissolved in methylene chloride and washed sequentially with water, aqueous 1.0N NaOH, water and saturated NaCl solution. The solvent was evaporated and the product was further purified by chromatography using a gradient elution of methanol-methylene chloride containing 0.25% of ammonia. The appropriate fractions were combined and evaporated to give a yellow residue. Recrystallization from ethyl acetate-petroleum ether yielded the title compound as a white solid; wt. 5.5 g (59.8%), mp 64°-67°. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ 8.19 (s, 1H); 6.32 (s, 1H); 4.83 (t, 2H); 4.42 (bs, 2H); 4.08 (d, 2H); 3.55 (m, 2H); 3.50 (m, 2H); 2.41 (m, 6H); 1.1 (t, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH:14]=O>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:14][C:10]2[NH:9][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ncc[nH]1
Reactant: Nc1ccc(Cl)cc1
Product: Clc1ccc(NCc2ncc[nH]2)cc1
Yield: 72 %

Procedure:
The title compound was prepared from 4-chloroaniline and 2-imidazole-carboxaldehyde by the same procedure as described in Example 24, part A. The residue was crystallized from ethyl acetate to afford the title compound (1.56 g, 72%) as an off white solid.