Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.Br[CH2:24][C:25]#[C:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)C.CN(C)C=O>[CH2:24]([N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1)[C:25]#[C:26][CH3:27]
Reactant: CC#CCBr
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC#CCN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of the 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30 mg, 0.1 mmol) produced in Example (8b), 1-bromo-2-butyne (16.1 mg, 0.12 mmol), potassium carbonate (20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 4 hours and 20 minutes at an external temperature of 80° C. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with diethyl ether. The separated organic layer was washed with water, and then the solvent was distilled off by nitrogen stream. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-but-2-ynyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([S:39]([N:38]([CH3:43])[CH3:37])(=[O:41])=[O:40])[CH2:28][CH:29]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Fc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5ncc(F)cn5)CC4)sc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
To a solution of 2-((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (20 mg, 0.049 mmol) and triethylamine (0.014 mL, 0.097 mmol) in CH2Cl2 (0.7 mL) at 0° C. was added dimethylsulfamoyl chloride (17.4 mg, 0.122 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt for 3 h. The reaction mixture was quenched with sat. aq. NaHCO3 (1 mL) and extracted with CH2Cl2 (3×1 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 40% EtOAc) to afford 4-(2-((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)benzo[d]thiazol-6-yl)-N,N-dimethyl-5,6-dihydropyridine-1(2H)-sulfonamide (15 mg, 0.027 mmol, 57% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 2H), 7.64 (d, J=1.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.40 (dd, J=8.5, 1.9 Hz, 1H), 6.07 (dt, J=3.2, 1.8 Hz, 1H), 5.45 (tt, J=7.7, 3.7 Hz, 1H), 4.17 (ddd, J=13.4, 7.2, 3.9 Hz, 2H), 3.98-3.92 (m, 2H), 3.70 (ddd, J=13.4, 8.3, 3.6 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 2.86 (s, 6H), 2.69-2.61 (m, 2H), 2.21-2.12 (m, 2H), 2.00-1.88 (m, 2H). LCMS (m/z)=519 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:26][CH2:27][CH2:28][OH:29])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12][CH3:13])=[CH:8][C:7]1([OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>ClCCl>[OH:1][CH:2]([CH2:26][CH2:27][CH2:28][OH:29])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12]([CH3:13])=[O:38])=[CH:8][C:7]1([OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)C1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Reaction time: 3 h
Yield: 38 %

Procedure:
To a solution of 71 mg of 5-[(E)-4,7-dihydroxy-2-heptenylidene]-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 91 dissolved in 2 ml of dichloromethane was added a solution of 45 mg of 3-chloroperbenzoic acid in 2 ml of dichloromethane, and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogencarbonate was added. The mixture was extracted twice with ethyl acetate, and the organic layers were combined, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to give 27 mg (yield 38%) of low polarity isomer and 25 mg (yield 35%) of high polarity isomer of 5-[(E)-4,7-dihydroxyheptenylidene]-4-hydroxy-2-methylsulfinyl-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH2:19])=[CH:13][CH:12]=1.O>C(O)(=O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])=[CH:13][CH:12]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)/C(Cl)=C(/Cl)C(O)=NCCc1ccc(F)cc1
Temperature: 20 °C
Yield: 52.3 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 14.0 g (0.1 mol) of 2-(4-fluorophenyl)-ethylamine are stirred in 100 ml of glacial acetic acid at 120° C. for 4 hours. The mixture is cooled to 20° C. and 10 ml of water are added. A colorless precipitate separates out, and is filtered off with suction and dried. 16 g of dichloromaleic acid N-[2-(4-fluorophenyl)-ethyl]-imide of melting point 137°-138° C. are obtained. A further 5.1 g of imide can be isolated by stirring the mother liquor with water. The total yield is 73% of theory.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:5]1[CH:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:8]=[CH:7][N:6]=1
Reactant: Oc1cc(C(F)(F)F)ncn1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Cl)ncn1

Procedure:
6-Trifluoromethyl-pyrimidin-4-ol ([1546-78-7], 5 g) was refluxed in phosphorus oxychloride (17 mL) for 2 hours. The reaction mixture was carefully concentrated in vacuo and the residue was distilled (Kugelrohr) under reduced pressure (bp=30-55° C.@10 mbar) to yield the title compound ([37552-81-1], 1.4 g). MS (EI): 182.0 (M).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:24](=[O:29])[NH:25][CH2:26][C:27]=2[N:28]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:41].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:37])[N:7]([C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:24](=[O:29])[N:25]([CH3:41])[CH2:26][C:27]=2[N:28]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3c2ccc(Cl)cc2)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CN(C)C(=O)N3c2ccc(Cl)cc2)c(OC)c1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of [1-(4-chloro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (Example 21, low RF compound from Step 1) (120 mg, 0.23 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 14 mg, 0.34 mmol, 1.5 equiv) and the reaction mixture was stirred for 1 h. Iodomethane (30 μL, 0.46 mmol, 2 equiv) was added and stirring was continued overnight. Water was added and the product was extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and the solvent evaporated. The crude material was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-100%) to afford [1-(4-chloro-phenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (49 mg). MS: [M+H]+=539.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:14]=[C:15]([OH:21])[CH:16]=[C:17]([F:20])[C:18]=1[F:19]>>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:21][C:15]2[CH:14]=[C:13]([F:12])[C:18]([F:19])=[C:17]([F:20])[CH:16]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cc(F)c(F)c(F)c1
Product: N#Cc1cc(C=O)ccc1Oc1cc(F)c(F)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile (200 mg, 1.341 mmol) and 3,4,5-trifluorophenol.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1C(O)=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].ClC1C=C(C=CC=1Cl)CN1CCNCC1>C(Cl)Cl>[C:16]([O:15][C:13]([N:20]1[CH2:27][CH2:26][CH2:25][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Clc1ccc(CN2CCNCC2)cc1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.03 g, 7 mmol) was added to a solution of N-BOC-D-Proline (1.51 g, 7 mmol) in methylene chloride (12 ml) and the reaction mixture was stirred at room temperature. After 0.5 h, 3,4-dichlorobenzylpiperazine (1.32 g, 5.4 mmol) [prepared as described in Example 1] was added and the stirring was continued for 16 h. The reaction mixture was then quenched with water, basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and concentrated. Flash chromatography with 30% acetone in dichloromethane as the eluant gave 2(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]}-N-(tert-butoxycarbonyl)pyrrolidine (1.2 g) as an oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>C1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:5]([O:4][CH2:2][CH3:3])=[O:11])=[S:28])=[CH:22][C:21]=1[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]
Reactant: CC(C)OC(=O)c1cc(N=C=S)ccc1Cl
Reactant: CCOC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1CCCN1C(=S)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
1.8 g (0.01 mol) of proline ethyl ester hydrochloride and 1.0 g of triethylamine were added dropwise to 30 ml of benzene and 2.6 g (0.01 mol) of 4-chloro-3-isopropoxycarbonylphenyl isothiocyanate were added thereto. The mixture was stirred at room temperature for an hour, washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by means of silica gel column chromatography to give 2.5 g (yield 63%) of the desired product as a yellow glassy substance.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([OH:29])[CH2:14][CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[N:19][C:18]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[N:26][C:17]2=3)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:18]2[N:19]=[CH:20][C:21](=[O:22])[N:16]([CH2:15][CH2:14][C@H:13]3[CH2:12][O:29]3)[C:17]=2[N:26]=1
Reactant: COc1ccc2ncc(=O)n(CC[C@H](O)COS(=O)(=O)c3ccc(C)cc3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc2ncc(=O)n(CC[C@H]3CO3)c2n1
Reaction time: 17 h
Yield: 62.2 %

Procedure:
In methanol (15 ml) was dissolved (2S)-2-hydroxy-4-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)butyl 4-methylbenzenesulfonate (227 mg, 0.540 mmol), and potassium carbonate (90 mg, 0.648 mmol) was then added to the solution at room temperature. The obtained mixture was stirred for 17 hours. Thereafter, the solvent was removed from the reaction solution under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 83 mg (62%) of the above-captioned compound in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:21])[C:5]2[N:6]([C:8]([CH2:17][C:18](O)=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.B.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:21])[C:5]2[N:6]([C:8]([CH2:17][CH2:18][OH:19])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1cc(Cl)cn2c(CC(=O)O)c(-c3ccccc3)nc12
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(Cl)cn2c(CCO)c(-c3ccccc3)nc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
(6-Chloro-8-methyl-2-phenyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid 43a (239 mg, 0.80 mmol) was suspended in anhydrous THF (3 mL) and cooled to 0° C. A borane solution (BH3.THF) (1.0 M in THF, 2.4 mL, 2.4 mmol) was added, and the resulting opaque solution was stirred at a temperature ranging from about 0° C. to about room temperature over 4 h. All material was in solution after about 1 h. 2 M HCl (5 mL) was added slowly, and the resulting solution was allowed to stir at room temperature for 1 h, then washed with CH2Cl2 (3×20 mL). The organic washes were combined and washed with brine (1×20 mL), then dried (Na2SO4), filtered and concentrated to give the title compound (209 mg, 92%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=1.1 Hz, 1H), 7.55-7.53 (m, 2H), 7.35-7.33 (m, 2H), 6.79 (s, 1H), 3.82 (t, J=5.87 Hz, 2H), 2.99 (at, 2H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.1, 142.9, 128.7, 128.5, 127.9, 127.3, 124.8, 120.2, 120.1, 61.8, 27.8, 16.9. Mass spectrum (m/e) 286 (M+).
Reaction SMILES: N12CCCN=C1CCCCC2.[SH:12][C:13]1[S:14][CH2:15][CH2:16][N:17]=1.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH2:29])(=[O:28])=[O:27]>C(#N)C.O>[S:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][S:12][C:13]1[S:14][CH2:15][CH2:16][N:17]=1)(=[O:27])(=[O:28])[NH2:29]
Reactant: NS(=O)(=O)c1ccccc1CCl
Reactant: SC1=NCCS1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccccc1CSC1=NCCS1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
With cooling, 7.9 g of 97% 1,8-diazabicyclo[5.4.0]undec-7-ene are added to a suspension of 6.2 g of 97% 4,5-dihydro-2-mercaptothiazole in 50 ml of acetonitrile. To the yellow solution so obtained are added 10.3 g of 2-chloromethylbenzenesulfonamide and the reaction mixture is stirred for 1 hour at 20°-25° C. The reaction solution is then diluted with about 1 liter of water. The precipitate is isolated by filtration and dried, affording 11.9 g (76% of theory) of 4,5-dihydro-2-(2-sulfamoylphenylmethylthio)thiazole of m.p. 123°-125° C.
Reaction SMILES: Br[C:2]1[O:3][C:4]([CH3:7])=[N:5][N:6]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[Cl:60][C:61]1[CH:62]=[C:63]([CH:65]=[C:66]([Cl:68])[CH:67]=1)[NH2:64]>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].C1(C)C=CC=CC=1>[Cl:60][C:61]1[CH:62]=[C:63]([NH:64][C:2]2[O:3][C:4]([CH3:7])=[N:5][N:6]=2)[CH:65]=[C:66]([Cl:68])[CH:67]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: Cc1nnc(Br)o1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nnc(Nc2cc(Cl)cc(Cl)c2)o1
Temperature: 140 °C

Procedure:
In a 5 mL microwave tube, 2-bromo-5-methyl-1,3,4-oxadiazole (200 mg, 1.23 mmol, Eq: 0.05), Tris(dibenzylideneacetone)dipalladium(0) (56.2 mg, 61.4 μmol, Eq: 0.05) and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (38.2 mg, 61.4 μmol, Eq: 0.05) were combined with toluene (10.0 ml) to give a brown suspension. Sodium tert-butoxide (236 mg, 2.45 mmol, Eq: 2.00) and 3,5-dichloroaniline (199 mg, 1.23 mmol, Eq: 1.00) were added. The solution was degassed with argon for 5 min, heated to 140° C. for 30 min under microwave.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.CCCCCCC.C(C1C=CC=CC=1)C.[C:31]([O:35][C:36](=[O:50])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]#[C:46][CH2:47][OH:48])[C:40]=1[CH3:49])([CH3:34])([CH3:33])[CH3:32].[C:51]1([N:57]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:58](Cl)=[O:59])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.[Cl-].[NH4+]>O1CCCC1>[C:31]([O:35][C:36](=[O:50])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]#[C:46][CH2:47][O:48][C:58](=[O:59])[N:57]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:40]=1[CH3:49])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(C#CCO)cccc1OCC(=O)OC(C)(C)C
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1c(C#CCOC(=O)N(c2ccccc2)c2ccccc2)cccc1OCC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 34.8 %

Procedure:
2.0 M Lithium diisopropylamide in toluene/heptane/ethylbenzene (0.77 mL, 1.54 mmol) was added to a stirred solution of [3-(3-hydroxyprop-1-ynyl)-2-methylphenoxy]acetic acid tert-butyl ester (370 mg, 1.34 mmol) in tetrahydrofuran (4 mL) at −78° C. under an argon atmosphere. The mixture was stirred for 10 minutes and solid diphenylcarbamyl chloride (310 mg, 1.34 mmol) was added. The mixture was allowed to reach 0-5° C. and stirred for 16 hours. Saturated ammonium chloride was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate, gave [3-(3-diphenylcarbamoyloxyprop-1-ynyl)-2-methylphenoxy]acetic acid tert-butyl ester as a colorless oil (220 mg, 35%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37]([C:42](Cl)=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1>C(Cl)Cl>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:42]([C:37]4[C:36]([C:33]5[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:45])[F:46])=[CH:31][CH:32]=5)=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:43])=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
A mixture of 4-[4-(phenylmethyl)-1-piperazinyl]-benzenamine (0.3 mol) and triethylamine (0.36 mol) in DCM (1500 ml) was stirred at room temperature for 15 minutes. 4′-(Trifluoromethyl)-[1,1′-biphenyl]-2-carbonyl chloride (0.36 mol) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 3 hours and then washed twice with water, then washed with a saturated NaCl solution. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE (800 ml). The precipitate was filtered off, washed twice with DIPE and dried in vacuo at 50° C., yielding 140.2 g of N-[4-[4-(phenylmethyl)-1-piperazinyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 1, mp. 180° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].[CH2:23]=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][OH:24])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=1[F:15])=[O:8]
Reactant: C=O
Reactant: O=C(c1cc(Cl)ccc1-n1ccnc1)c1c(F)cccc1F
Product: O=C(c1cc(Cl)ccc1-n1ccnc1CO)c1c(F)cccc1F

Procedure:
In the manner given in Example 1, 5-chloro-2',6'-difluoro-2-(imidazol-1-yl)benzophenone is heated in a bomb to 150° C. with 37% aqueous formaldehyde solution to give 5-chloro-2',6'-difluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].O.[CH3:11][S:12](=O)(SC)=O>C(O)C.[Cl-].[Na+]>[CH3:11][S:12][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CSS(C)(=O)=O
Reactant: O=C(O)CCCCCS
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSSCCCCCC(=O)O
Yield: 73.6 %

Procedure:
To an ice/water bath cooled flask containing a solution of 6-mercaptohexanoic acid (500.0 mg, 3.37 mmol) de ionized water (2 mL) was added a solution of S-Methyl methanethiosulfonate (468 mg, 3.71 mmol) in ethanol (1 mL). After 16 hr the reaction was diluted with saturated sodium chloride (400 mL) and extracted with ethyl ether (3×150 mL). The combined extracts were washed with saturated NaCl (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The product was purified by silica chromatography eluting with ethyl acetate/hexanes/acetic acid (40:58:2). Product containing fractions were combined and concentrated in vacuo to give 482 mg (73% yield) of the desired product. MS calcd (M+Na)+, 217.3; found, 217.3
Reaction SMILES: [C:1]([C:8]1[NH:9][CH:10]=[CH:11]N=1)([C:3]1NC=CN=1)=O.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].N1CCCCC1>C(OCC)(=O)C>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:9]2[CH2:8][CH2:1][CH2:3][CH2:11][CH2:10]2)=[O:20])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)N1CCCCC1
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
A 5-L flask was charged with ethyl acetate (2.3 L) and carbonyl diimidazole (500.0 g, 2.48 mol) to which 4-chloro-3-nitrobenzoic acid (402.5 g, 2.48 mol) was added in portions over 1 hour. The solution was stirred for an additional 1.5 hours. Piperidine (222.2 g, 2.60 mol) was added dropwise over 2 hours and the resulting solution was stirred for an additional 4 hours. The reaction mixture was washed sequentially, twice with 6N HCl solution (600 mL), twice with saturated NaHCO3 (250 mL), and finally with saturated NaCl (250 mL). The organic solution was dried over anhydrous Na2SO4 and filtered, and the solvent was removed in vacuo to yield 646 g (97%) of 4-chloro-3-nitrobenzoyl-piperidine as a yellow crystalline solid with m.p. =76—78 ° C. IR: 1633, 1535, and 1440 cm31 1. 1H NMR (500 MHz, CDCl3): δ 7.92 (1H, d, J 1.5 Hz), 7.60 (1H, d, J=8.1 Hz), 7.56 (1H, dd, J═8.1 and 1.5 Hz), 3.70 (2H, br s), 3.35 (2H, br s), 1.70 (4H, br s), and 1.56 ppm (2H, br s).