Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[C:6](=[O:21])[NH:7][C:8]3[N:9]([N:11]=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=2)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:41][N:42]1[C:46]([CH2:47]O)=[N:45][CH:44]=[N:43]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([C:5]2[C:6]([O:21][CH2:47][C:46]3[N:42]([CH3:41])[N:43]=[CH:44][N:45]=3)=[N:7][C:8]3[N:9]([N:11]=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1C1CCC1
Reactant: Cn1ncnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncnc1COc1nc2c(-c3ccccc3F)nnn2cc1C1CCC1
Yield: 68.1 %

Procedure:
6-Cyclobutyl-3-(2-fluorophenyl)-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (33 mg, 0.12 mmol), triphenylphosphine (76 mg, 0.29 mmol) and (2-methyl-2H-1,2,4-triazol-3-yl)methanol (37 mg, 0.29 mmol) were dissolved in dry tetrahydrofuran (1.5 ml) with stirring. Diethyl azodicarboxylate (46μl, 0.29 mmol) was added and the reaction stirred at room temperature for 16 hours before purification by preparative thin layer chromatography to afford 6-cyclobutyl-3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[1,5-α]pyrimidine (31 mg, 70%) as a white crystalline solid, m.p. 181-184° C.; δH (400 MHz, d6-DMSO) 1.77-1.85 (1H, m, CH(CH2)3), 1.96-2.06 (1H, m, CH(CH2)3), 2.19-2.30 (4H, m, CH(CH2)3), 308 (1H, quintet, J=8.6 Hz, CH(CH2)3), 3.88 (3H, s, NMe, 5.65 (2H, s, OCH2), 7.34-7.38 (2H, m, ArH), 7.41-7.48 (1H, m, ArH), 7.94 (1H, s, triazole CH), 7.97 (1H, t, J=7.2 Hz, ArH), 9.25 (1H, s, pyrimidine CH); m/z (ES+) 380 (M+H+).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12]O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].P(Br)(Br)[Br:15]>>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][Br:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: BrP(Br)Br
Reactant: CCCC[C@H]1CC[C@H](CCO)CC1
Product: CCCC[C@H]1CC[C@H](CCBr)CC1
Temperature: 25 °C
Yield: 144.4 %

Procedure:
31 g (0.17 mol) of 2-(trans-4'-butylcyclohexyl)ethanol was given dropwise addition of 23 g (0.09 mol) of PBr3 while stirring at room temperature, after which it was stirred for 1 hour on a 70° C. hot water bath. The reactant was cooled to room temperature, poured into ice water to decompose the excess PBr3, the oily layer was taken off, and the water layer was extracted with chloroform and combined with the oily layer and washed with water. The chloroform was removed, and the remaining oily substance was distilled under reduced pressure (b. p. 99° C./2 mmHg) to obtain 32 g (0.13 mol) of 2-(trans-4'-butylcyclohexyl)-1-bromoethane.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.Cl.[CH3:24][C:25]1[CH:26]=[C:27]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[NH2:28]>C(O)C.CO>[CH3:24][C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=3)[N:3]=2)[CH:29]=[C:30]([CH3:32])[CH:31]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1cc(C)cc(Nc2nc(Nc3ccc(P(C)(C)=O)cc3)ncc2C(F)(F)F)c1
Yield: 65 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 10 L of Hydrochloric acid in Methanol (2M) and 3,5-Dimethyl aniline (14 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (32 mg, 65% yield.) MS/ES+: m/z=435
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>C(Cl)Cl.[OH-].[Na+]>[C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])(=[O:11])=[O:10])(=[O:11])=[O:10]
Reactant: NCCCCN
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)NCCCCNS(=O)(=O)c2c(C)cc(C)cc2C)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
2-Mesitylenesulfonyl chloride (54.40 g, 0.249 mol) in CH2Cl2 (300 ml) was added to 1,4-diaminobutane (11.34 g, 0.129 mol) in 1 N NaOH (300 ml) at 0° C., and the biphasic mixture was stirred for 24 hours at room temperature. Organic solvent was evaporated and 2.4 N HCl (250 ml) was added to the combined portions. Solid was filtered, washed with water (250 ml) and recrystallized from aqueous ethanol to give 50.46 g (90%) of (1) as needles: mp 156.5-157.5° C.; NMR (CDCl3/TMS) δ1.36-1.60 (m, 4H), 2.27 (s, 6H), 2.57 (s, 12H), 2.69-2.96 (m, 4H), 4.65 (t, 2H, J=6), 6.89 (s, 4H). Anal. calcd. for C22H32N2O4S2: C, 58.38, H, 7.13, N, 6.19. Found: C, 58.31, H, 7.19, N, 6.14.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:10][C:11]1[C:12]([CH2:24][CH:25]([CH3:27])[CH3:26])=[N+:13]([O-:23])[C:14]([O:21][CH3:22])=[C:15]([C:17](OC)=[O:18])[N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(OCC)C.O>[CH2:3]([O:10][C:11]1[C:12]([CH2:24][CH:25]([CH3:27])[CH3:26])=[N+:13]([O-:23])[C:14]([O:21][CH3:22])=[C:15]([CH2:17][OH:18])[N:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1OC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1c(CO)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Yield: 30.5 %

Procedure:
2.4 Milligrams of lithium borohydride was added to 1 ml of a solution of 12.5 mg of 3-benzyloxy-2-isobutyl-6-methoxy-5-methoxycarbonylpyrazine 1-oxide dissolved in anhydrous diethyl ether. The mixture was refluxed for 6 hours in an argon gas stream with stirring, then 0.2 ml of 1N hydrochloric acid was added to the reaction mixture with ice cooling, and the mixture was diluted with water. The reaction mixture was extracted with ethyl acetate and the extract was washed with an aqueous solution saturated with NaCl solution and dried over magnesium sulfate, and the solvent was removed by evaporation. The residue was purified by a thin layer chromatography (developing solvent: dichloromethane/methanol=40/1) to obtain 3.5 mg of 3-benzyloxy-5-hydroxymethyl-6-methoxy-2-isobutylpyrazine 1-oxide (Compound B-24) as colorless needle-like crystals having a melting point of 68.0°-69.2° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C[Mg]Br.Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[CH:5][NH:6]2
Reactant: ClCc1cccnc1
Reactant: Brc1cccc2[nH]ccc12
Agent: C[Mg]Br
Solvent: ClCCl
Product: Brc1cccc2[nH]cc(Cc3cccnc3)c12
Yield: 31.4 %

Procedure:
Treatment of 4-bromo-1H-indole (J.Org.Chem., 48 2066(1983)) (16.95 g) with methyl magnesium bromide (34.6 ml of 3M solution in ether) followed by a dichloromethane solution of 3-(chloromethyl)pyridine (prepared from 17.02 g of 3-(chloromethyl)pyridine hydrochloride) according to the method of Preparation 6 gave the title compound (7.80 g), m.p. 173°-174° C. Found: C,58.90; H,3.88; N,9.80. C,14 H11BrN2 requires: C,58.55; H,3.86; N,9.76%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@H:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.CC([O-])(C)C.[K+].F[C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=1>CN1CCOCC1>[F:25][C:24]([F:27])([F:26])[C:23]1[C:18]([O:10][C@@H:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)[CH3:9])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@@H](O)c1ccnc(N)n1
Reactant: Fc1ncccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCOCC1
Product: C[C@@H](Oc1ncccc1C(F)(F)F)c1ccnc(N)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of (R)-1-(2-aminopyrimidin-4-yl)ethanol (6a) (250 mg) in dry N-methylmorpholine (4 mL) at ambient temperature was added potassium 2-methylpropan-2-olate (222 mg) and the solution was left to stir for 30 min then 2-fluoro-3-(trifluoromethyl)pyridine (282 mg) was added the mixture was stirred for 10 min at ambient temperature and then heated to 100° C. with microwave irradiation for 2 minutes then cooled and quenched into water (50 mL). The precipitated solid was filtered and washed with water and air dried under a slight vacuum. The semi-dried material was taken up in methylene chloride and dried over magnesium sulfate to which activated charcoal was added then filtered through a bed of dicalite and evaporated to give the title compound (359 mg), MS (ES): m/z 285 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]3[NH:9][CH:10]([C:16]4[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=4)[CH2:11][C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH3:25].O1CCOCC1>O>[OH:15][C:12]1[CH:11]=[C:10]([C:16]2[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=2)[N:9]=[C:8]2[C:7]3[C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=[CH:5][C:6]=3[O:14][C:13]=12
Reactant: COc1ccc2oc3c(c2c1Cl)NC(c1csc(C(C)C)n1)CC3=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2oc3c(O)cc(-c4csc(C(C)C)n4)nc3c2c1Cl
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of 10B (10.3 g, 27.33 mmol, crude) and FeCl3.6H2O (33.04 g, 164.0 mmol, 6 eq) was added to 1,4-dioxane (300 mL) The mixture was refluxed for 16 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (300 mL), extracted with ethyl acetate and concentrated to give a crude product 10C (8.75 g), which was used for the next step directly.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:36])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:30]1[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:36])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1-c1cccc(C2=Nc3ccc(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M14) (280 mg, 0.545 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pink solid (163 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.[H][H]>[Ni].O1CCCC1>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Agent: [Ni]
Solvent: C1CCOC1
Product: CN(C)c1ccc(N)cn1
Yield: 99.5 %

Procedure:
A mixture of Example 175A (5.27 g, 31.5 mmol) and Raney Nickel (5.27 g, 90 mmol) in tetrahydrofuran (60 mL) was subjected to an atmosphere (30 psi) of hydrogen gas for 2 hours at ambient temperature. Mixture was filtered and concentrated to afford 4.3 g (100%) of the title compound. MS (ESI) m/z 138 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:30])[C:15]([C:28]#[N:29])=[CH:16][N:17]3[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:12][C:11]=2[N+:31]([O-])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C1COCC1.C(O)C.[Pd]>[NH2:31][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[CH:16]=[C:15]([C:28]#[N:29])[C:14]2=[O:30]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(NCCN3CCOCC3)cc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc(N)c(NCCN3CCOCC3)cc21
Yield: 110.3 %

Procedure:
A suspension of 916.4 mg (1.93 mmol) of 7-{[2-(4-morpholinyl)ethyl]amino}-6-nitro-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile in 52 mL of THF and 19 mL of ethanol is hydrogenated in a Parr apparatus at 40 psi for 6 hours in the presence of 183.3 mg of 10% palladium-on-carbon. The catalyst is removed by filtration and the solvent is evaporated in vacuo to give 944.0 mg of 6-amino-7-{[2-(4-morpholinyl)ethyl]amino}-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile as a deep yellow solid which is used directly in the next step.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:13]([OH:35])[CH2:14][N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]1[C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:12]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C@H:13]([OH:35])[CH2:14][N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]1[C:28]([NH:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29]
Reactant: CC(C)(C)NC(=O)C1c2[nH]c3ccccc3c2CCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)C1c2[nH]c3ccccc3c2CCN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 104.7 %

Procedure:
A solution of 150 mg of 2-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide (isomer A) in 5 ml of ethanol was hydrogenated under a pressure of 3.4 atmospheres over 10% palladium-on-charcoal at 20° C. for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 120 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide (isomer A); MS: m/e 435 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[CH:15]([OH:17])[CH3:16].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:19](=[O:21])[O:17][CH:15]([CH3:16])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)ccc1N
Solvent: C1CCOC1
Product: CC1OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.17 h
Yield: 283.1 %

Procedure:
A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanol (0.03 g, 0.13 mmol) and triphosgene (0.01 g, 0.04 mmol) in dry THF (3 mL) was stirred under a blanket of nitrogen for 10 minutes. The solvent was removed to give 6-(3-chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one as a white solid (0.031 g, 91%): mp 155-156° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.72 (m, 1H), 7.62 (m, 2H), 7.56 (m, 1H), 7.47 (t, 1H, J=8.00 Hz), 7.39 (d, 1H, J=8.0 Hz), 6.98 (d, 1H, J=8.0 Hz), 5.50 (q, 1H, J=6.82 Hz), 1.6 (d, 3H, J=6.82 Hz); MS (APCI) m/z 274 ([M+H]+, 100%)
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:34][C:35]1[S:39][C:38]([S:40](Cl)(=[O:42])=[O:41])=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:13][N:12]([S:40]([C:38]2[S:39][C:35]([Br:34])=[CH:36][CH:37]=2)(=[O:42])=[O:41])[CH2:11][CH2:10][N:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CC(O)(c1ccc(N2CCNC[C@@H]2Cc2ccccc2)cc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(Br)s3)C[C@@H]2Cc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
The 2-(4-((2S)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (147 mg, 0.404 mmol) was dissolved in CH2Cl2 (10 mL) was cooled to 0° C. To this solution was added triethylamine (124 μL, 0.889 mmol) followed by 5-bromothiophene-2-sulfonyl chloride (127 mg, 0.485 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was allowed to slowly warm to room temperature and stirred for 2 h. The mixture was concentrated and absorbed onto silica gel. The crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(4-((2S)-2-benzyl-4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (105 mg).
Reaction SMILES: Cl[C:2](=[CH:5][S:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:3]#[N:4].O1CCCC1.O.[OH-].[Na+]>[Na+].[Cl-]>[N:8]1[CH:9]=[CH:10][CH:11]=[N:12][C:7]=1[S:6][C:5]#[C:2][C:3]#[N:4]
Reactant: N#CC(Cl)=CSc1ncccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#CC#CSc1ncccn1
Reaction time: 1 h
Yield: 44.3 %

Procedure:
Into a 250 ml reaction flask is added 2-chloro-3-(2-pyrimidyl)thio-2-propenenitrile (1.5 g, 0.007 moles), tetrahydrofuran (35 ml) and water (35 ml). The mixture is stirred at zero degree Celsius until the solid is completely dissolved and then aqueous sodium hydroxide solution (7.5 ml 1N NaOH, 0.0075 moles, diluted with 50 ml water) is added slowly with stirring at such a rate so as to maintain the reaction pH below 11. The resultant reddish brown solution is stirred at zero degree Celsius for three hours followed by one hour at room temperature and then diluted with 50 ml of saturated aqueous NaCl solution. The product is extracted twice with 100 ml portions of dichloromethane. The combined dichloromethane extract is dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated under vacuum to give 0.5 g of pale yellow solid (yield 40 percent, purity 90 percent by GC/MS) which is characterized by GC/MS and 1H NMR.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1.C(OP([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Reaction time: 15 h
Yield: 91.5 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carbaldehyde (1.50 g), ethyl diethylphosphonoacetate (0.87 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.17 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give ethyl (2E)-3-{3-[(4-([2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazol-4-yl)-2-propenoate as colorless crystals (1.60 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[O:15])=[CH:8][CH:7]=1)=O.C(=O)([O-])[O-].[K+].[K+].CO>O>[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)N1CCN(c2ccc(C(=O)CCc3ccc(NC(=O)C(F)(F)F)cc3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)N1CCN(c2ccc(C(=O)CCc3ccc(N)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.1 %

Procedure:
A mixture of 2,2,2-trifluoro-N-(4-{3-[4-(4-methanesulfonylpiperazin-1-yl)-phenyl]-3-oxopropyl}phenyl)acetamide (0.43 g, 0.88 mmol), and a solution of potassium carbonate (0.61 g, 4.39 mmol) in water (10 mL), and methanol (20 mL) was warmed on a steam bath, then stirred at room temperature for about 12 hours. The reaction mixture was concentrated to one-third volume, diluted with cold water, and extracted with dichloromethane. The organic extract was washed with water, brine, dried, and concentrated in vacuo. Purification by silica gel chromatography, eluting with 2% methanol in dichloromethane gave the title compound as a white solid (0.28 g, 82%), m. p.166.5-170.0° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[C:23]([Cl:24])=[C:22]([CH2:25][CH3:26])[N:21]=[CH:20][N:19]=1>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[C:23]([Cl:24])=[C:22]([CH2:25][CH3:26])[N:21]=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ncnc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.4 g (10 mmol) of sodium hydride (80% dispersion in oil) was added to a solution of 2.0 g (10 mmol) of 1-(tert-butoxycarbonylpiperidin-4-ol and 1.8 g (10 mmol) of 4,5-dichloro-6-ethylpyrimidine in 25 ml of tetrahydrofuran, and the mixture was stirred for 2 hours at room temperature for 1 hour at reflux. After cooling, the mixture was concentrated, the residue was taken up in water/toluene, and the organic phase was dried and concentrated. For purification, the product was chromatographed on silica gel (petroleum ether/ethyl acetate 7:3). This gave 2.5 g (73.5% of theory) of a yellow oil.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([C:11]([NH2:13])=[O:12])([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.[Br:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][CH:20]2[C:25]([CH3:27])([CH3:26])[O:24][C:23](OC)=[N:22][S:21]2(=[O:31])=[O:30])=[C:17]([F:34])[CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][C@@H:20]2[C:25]([CH3:27])([CH3:26])[O:24][C:23]([NH:1][C:2]34[CH2:9][CH:8]5[CH2:10][C:4]([C:11]([NH2:13])=[O:12])([CH2:5][CH:6]3[CH2:7]5)[CH2:3]4)=[N:22][S:21]2(=[O:31])=[O:30])=[C:17]([F:34])[CH:16]=1
Reactant: NC(=O)C12CC3CC(C1)C(N)(C3)C2
Reactant: COC1=NS(=O)(=O)C(Cc2ccc(Br)cc2F)C(C)(C)O1
Solvent: ClCCl
Product: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1Cc1ccc(Br)cc1F
Temperature: 35 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
3a-Aminohexahydro-2,5-methanopentalene-2-carboxamide (58 mg) and 5-(4-bromo-2-fluorobenzyl)-2-methoxy-6,6-dimethyl-5,6-dihydro-[1,4,3]oxathiazine 4,4-dioxide (110 mg) were dissolved in methylene chloride and stirred at 35° C. for 16 h. In the course of this, the solvent was evaporated. Purification was effected by preparative HPLC. This gave the product (84 mg) with a molecular weight of 528.5 g/mol (C22H27BrFN3O4S), MS (ESI): (M+H+) 529.5 g/mol.