Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)=[O:6])([CH3:4])[CH3:3].C[Si](C)(C)[C:18]([F:21])([F:20])[F:19]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Si-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:4][C:2]([S:5]([NH:7][CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)[C:18]([F:21])([F:20])[F:19])=[O:6])([CH3:1])[CH3:3]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cccc(/C=N/S(=O)C(C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[Si-](F)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(C(NS(=O)C(C)(C)C)C(F)(F)F)n1
Temperature: -78 °C

Procedure:
A solution of 2-methyl-N-[(1E)-(6-methylpyridin-2-yl)methylene]propane-2-sulfinamide (0.33 g, 1.48 mmol) in THF (6 mL) was added to a dry flask containing TBAT (0.88 g, 1.63 mmol) and the solution was cooled to −78° C. under a nitrogen atmosphere. To this was added trimethyl(trifluoromethyl)silane (0.26 mL, 1.78 mmol) and the reaction was warmed to −20° C. for 2 hours. The reaction was quenched with ammonium chloride solution and partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (5-40% ethyl acetate/hexane) gave 2-methyl-N-[2,2,2-trifluoro-1-(6-methylpyridin-2-yl)ethyl]propane-2-sulfinamide. LC-MS EIMS: m/z 295.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CC(C)=O>[CH2:19]([N:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1)[CH:18]=[CH2:17]
Reactant: C1CCC2NCCCC2C1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN1CCCC2CCCCC21
Temperature: 5 °C
Yield: 74.6 %

Procedure:
To a 500 mL 3-necked round-bottomed flask, was added 24.0 g of decahydroquinoline dissolved in 150 mL acetone. To this mixture was added 29.7 g of powdered anhydrous potassium carbonate. The reaction mixture was cooled to 5° C. with an ice bath. While stirring, 20.8 g of allyl bromide in 50 mL acetone was added slowly to the reaction mixture. After addition was complete, the reaction mixture was allowed to stir at room temperature for 24 hours. The reaction mixture was filtered, and the solvent was removed from the filtrate under reduced pressure using a rotary evaporator yielding 23.0 g of N-allyl decahydroquinoline as a viscous liquid. To a 500 mL 3-necked round-bottomed flask was added 22.0 g of N-allyl decahydroquinoline dissolved in 100 mL diethyl ether. After cooling to 5° C. with an ice bath, 15.5 g of allyl bromide in 20 mL diethyl ether was added slowly. After completion of addition of allyl bromide, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid residue thus formed was collected by filtration and was washed with diethyl ether (2×500 mL). The washed solid was recrystalled from acetonitrile. After removal of acetonitrile by filtration, the residue was dried under vacuum yielding 24.0 g of N,N-diallyl decahydroquinolinium bromide as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.Br[C@H:19]([CH3:41])[C:20]([N:22]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH2:24][C@H:23]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:21]>C(#N)C>[CH2:6]([O:5][C:3]([C@@H:2]([NH:1][C@@H:19]([CH3:41])[C:20]([N:22]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH2:24][C@H:23]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:21])[CH2:8][CH2:9][CH3:10])=[O:4])[CH3:7]
Reactant: CCC[C@H](N)C(=O)OCC
Reactant: C[C@@H](Br)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC[C@H](N[C@@H](C)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)OCc1ccccc1)C(=O)OCC

Procedure:
Introduce 123 g of ethyl (2S)-2-aminopentanoate, 160 ml of triethylamine and 160 ml of acetonitrile into a reactor, and then bring the mixture to 60° C., slowly add the solution obtained in Step A and reflux for 4 hours. After returning to ambient temperature, wash the mixture with water and with a dilute acetic acid solution, and then evaporate off the solvents to yield benzyl (2S)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:24][N:23]=[C:22](CC(C)(C)C([O-])=O)[CH:21]=4)=[CH:16][CH:15]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[OH:33]>CO.[OH-].[K+]>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:24][N:23]=[C:22]([OH:33])[CH:21]=4)=[CH:16][CH:15]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: CC(C)(Cc1cc(-c2ccc(OCc3cc(-c4ccccc4)on3)cc2)on1)C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: Oc1cc(-c2ccc(OCc3cc(-c4ccccc4)on3)cc2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(4-((5-phenylisoxazol-3-yl)methoxy)phenyl)isoxazol-3-ylpivalate (21 mg) in methanol (2 ml), 0.4 ml of 5M potassium hydroxide methanol solution was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was neutralized, then extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified through reversed phase medium pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid). The solvent of the resultant fraction was distilled off under reduced pressure to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH2:4]>>[OH:3][CH2:1][C@@H:2]([C@H:1]([C@@H:2]([C@@H:1]([CH2:2][OH:4])[OH:3])[OH:4])[OH:3])[OH:4]
Reactant: O
Reactant: CCO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
A solution is formed of the ethanol, water and sorbitol ingredients. The Pluronic F-108 is added, followed by potassium bicarbonate/zinc oxide and other ingredients in the listed order with high speed stirring.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([NH:26][C:27]2[N:32]=[C:31]([C:33]3[CH:34]=[N:35][N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=34)[CH:30]=[CH:29][N:28]=2)=[CH:20][C:19]=1[NH2:42].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)[C:19]([NH2:42])=[CH:20][C:21]=1[NH:26][C:27]1[N:32]=[C:31]([C:33]2[CH:34]=[N:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=23)[CH:30]=[CH:29][N:28]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Br)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
1,1 Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.7 mg, 0.03 mmol) was added to a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 137, 215 mg, 0.52 mmol), and K3PO4 (220 mg, 1.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior to use). The mixture was then heated at 100° C. for 1 h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc and this solution was washed three times with water, then with brine. The solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (160 mg, 72%) as a tan solid after trituration with diethyl ether; 1H NMR: 1.79-1.87 (2H, m), 1.96-2.03 (2H, m), 2.29 (3H, s), 2.34-2.40 (2H, m), 2.58 (2H, t), 2.98-3.02 (2H, m), 3.15 (2H, t), 3.75 (3H, s), 4.12 (2H, t), 4.32 (2H, br s), 5.67-5.71 (1H, m), 6.60 (1H, s), 7.01 (1H, d), 7.58 (1H, s), 7.69 (1H, s), 8.09 (1H, s), 8.32 (1H, d); m/z: ES+ MH+ 432.72.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C:13]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1[CH:22]=CC2N(O)N=[N:27][C:25]=2[CH:26]=1.N1CCCC1.CCN(CC)CC>C(Cl)Cl>[CH3:19][C:13]1([CH3:20])[C@H:14]([C:16]([N:27]2[CH2:22][CH2:21][CH2:26][CH2:25]2)=[O:18])[CH2:15][C@@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Product: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.5 %

Procedure:
To a stirred solution of (1R,3S)-3-(benzyloxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (Intermediate 1-Step 3, 0.650 g, 2.346 mmol) in DCM (5 ml) EDCI (0.674 g, 3.519 mmol) and HOBt (0.475 g, 3.519 mmol) were added at about 0° C., after 10 minutes pyrrolidine (0.40 ml, 4.692 mmol) and Et3N (0.65 ml, 4.692 mmol) were added drop wise and the reaction mixture was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude purified by silica gel column (100-200 mesh, elution 20% EtOAC in hexane) to afford the title compound as an off white solid. Wt: 0.600 g; Yield: 77.5%; 1H NMR (300 MHz, CDCl3): δ 7.40-7.28 (m, 5H), 5.18-4.99 (m, 3H), 3.97-3.87 (m, 1H), 3.77-3.67 (m, 1H), 3.49-3.28 (m, 3H), 2.83 (t, 1H, J=8.4 Hz), 2.47-2.20 (m, 2H), 3.65-3.41 (m, 6H), 1.35 (s, 3H), 0.87 (s, 3H); Mass: [M+1]+ 331 (20%), [M+Na]+ 353 (100%); IR (KBr, cm−1): 3304, 3035, 2954, 1716, 1618, 1529, 1497, 1439, 1387, 1368, 1311, 1253, 1222, 1159, 1041, 912, 753.
Reaction SMILES: [CH2:1]([O:7][C:8]([NH:10][C@@H:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([CH:76]=[CH2:77])=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([C@@:65]3([O:74][CH3:75])[CH2:69][NH:68][C@H:67]([C:70]([O:72][CH3:73])=[O:71])[CH2:66]3)=[CH:61][CH:60]=2)[CH:58]=1>C(Cl)Cl>[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([CH:76]=[CH2:77])=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([C@@:65]3([O:74][CH3:75])[CH2:69][N:68]([C:12](=[O:14])[C@@H:11]([NH:10][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])=[O:9])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:67]([C:70]([O:72][CH3:73])=[O:71])[CH2:66]3)=[CH:61][CH:60]=2)[CH:58]=1
Reactant: C=CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1ccc(Cl)cc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3cc(Cl)ccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
(S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (186 mg, 0.723 mmol), DIEA (0.303 mL, 1.735 mmol) and HATU (242 mg, 0.636 mmol) were added to a solution of (2S,4R)-methyl 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (215 mg, 0.578 mmol) in DCM (7 mL). The reaction was stirred at r.t. overnight. The reaction was evaporated and purified on the Biotage (10-50% EtOAc:Hex) to give (2S,4R)-methyl 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-1-((S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxypyrrolidine-2-carboxylate (13 mg, 0.201 mmol, 35% yield) as a colorless oil. LCMS: rt=2.58 min. [M+H]+=612; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][C:34]([CH2:39][OH:40])([CH2:37][OH:38])[CH2:35][OH:36].CCCCCC>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][C:34]([CH2:39][OH:40])([CH2:37][OH:38])[CH2:35][OH:36])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: NC(CO)(CO)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NC(CO)(CO)CO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 22 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (4:1) and treated with 2-amino-2-[hydroxymethyl]-1,3-propandiol as for example 34. After the standard workup, trituration with hexane gave 4-(2-fluoro-4-iodoanilino)-N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (22%) as a yellow/cream solid; m.p. (EtOAc/Hexane) 100-105° C. (glue-liquid). 1H NMR [400 MHz, (CD3)2SO] δ 9.62 (br s, 1H), 8.15 (s, 1H), 7.73 (dd, J=10.2, 1.7 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.32 (s, 1H), 7.26 (t, J=8.5 Hz, 1H), 5.54 (s, 1H), 4.59 (t, J=5.7 Hz, 3H), 3.68 (d, J=5.7 Hz, 6H), 3.37 (s, 3H). HPLC 78.1% (254 nm). HRMS (FAB+) cald for C17H20FIN3O5 492.043 (M+), found 492.0425.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1([CH3:17])[CH2:14][C:13](=O)[O:12][C:11]1=[O:16]>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:12])[CH2:14][C:10]([CH3:17])([CH3:9])[C:11]2=[O:16])=[N:6][CH:7]=1
Reactant: Nc1ccc(I)cn1
Reactant: CC1(C)CC(=O)OC1=O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)N(c2ccc(I)cn2)C1=O
Temperature: 150 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
5-iodopyridin-2-amine (1 g, 4.55 mmol) was dissolved in DMF (5 ml) and 3,3-dimethyldihydrofuran-2,5-dione (1.28 g, 10.0 mmol, 2.2 equiv.) was added at room temperature. The mixture was stirred for 3 hr at 150° C. The reaction mixture was evaporated to dryness and loaded directly to a silica gel column. The crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(5-iodopyridin-2-yl)-3,3-dimethylpyrrolidine-2,5-dione (1.3 g, 3.94 mmol, 86.6% yield) was obtained as a yellow solid, MS: m/e=331.0 (M+H+).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[OH:11]S(O)(=O)=O>>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH2:8])=[O:11])=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(CBr)cc1
Product: NC(=O)c1ccc(CBr)cc1

Procedure:
Stirred the solution of 4-(bromomethyl)benzonitrile (1.5 g) in cocn.H2SO4 at 100° C. for 3-4 h. After completion of the reaction, the reaction mass was quenched in ice and filtered to afford 0.900 of desired product. 1H NMR (400 MHz, DMSO d6): δ 4.71 (s, 2H), 7.26 (br s, 1H), 7.49 (d, J=7.8 Hz, 2H), 7.82 (d, J=7.8 Hz, 2H), 7.89 (br s, 1H); MS (m/z): 214.36 (M+H)+.
Reaction SMILES: C(OC([C@@H:6]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:8]([CH2:9][C@H:10](C(OCC)=O)[C@@H:11]3[C@@H:28]2[CH2:27][C@H:26]([OH:33])[C@@:25]2([CH3:34])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:24])[CH2:17][CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])[CH2:7]1)=O)C.[OH-:40].[Na+].[OH2:42].Cl>O.C(O)C>[OH:40][C@@H:6]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:8]([CH2:9][C@H:10]([OH:42])[C@@H:11]3[C@@H:28]2[CH2:27][C@H:26]([OH:33])[C@@:25]2([CH3:34])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:24])[CH2:17][CH:18]([CH3:23])[C:19]([OH:21])=[O:20])[CH2:7]1
Reactant: O
Reactant: CCOC(=O)[C@@H]1CC[C@@]2(C)[C@@H](C1)C[C@H](C(=O)OCC)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CC(C)C(=O)OC)CC[C@@H]12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C)C(=O)O

Procedure:
The solution of 3α,7β-diethoxycarbonyl-12α-hydroxy-23-methyl-5β-cholan-24-oic acid, methyl ester (0.6 g; 0.0011 mol) in 20 ml of a water/ethanol mixture (40/60) and 3 g of NaOH was refluxed for 12 hours, then treated with 80 ml of water, acidified with concentrated HCl and extracted with 4×40 ml of CHCl3. The organic solution was washed with NaCl-saturated water and dried on MgSO4. By chromatography on silica gel, under N2 -pressure (eluent: CHCl3), 340 mg of the title compound were obtained. M.p. 151°-153° C. The structure of the compound is fully confirmed by the analytical and spectral data.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[SH2:7]>>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[S:7][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: S
Reactant: Clc1cccs1
Product: c1csc(Sc2cccs2)c1
Temperature: 560 °C

Procedure:
Through a 570-mm long silica tube, 26 mm in diameter, heated to a temperature of 560° C, for 90 minutes are passed 40.0 g (0.34 mole) of 2-chlorothiophene and hydrogen sulphide at a rate of 5.2 litres per hour. The molar ratio of 2-chlorothiophene to hydrogen sulphide is 1:1. The condensate is distilled to give 16 g (48.2 percent by weight) of di(2-thienyl) sulphide boiling at 133°-140° C (5 mm Hg), nD20 = 1.6603, and 6.5 g of the starting 2-chlorothiophene (conversion 84 percent by weight).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].[F:10][C:11]([F:35])([F:34])[CH2:12][O:13][C:14]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][C:15]=1[C:16](OCC(F)(F)F)=[O:17]>>[F:10][C:11]([F:34])([F:35])[CH2:12][O:13][C:14]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][C:15]=1[C:16]([NH:9][CH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH2:1][CH3:2])=[O:17]
Reactant: O=C(OCC(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
Using the synthetic method illustrated in Example 23, 1-ethyl-2-aminomethyl pyrrolidine and 2,2,2-trifluoroethyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate are reacted to provide a white solid, 2,5-bis(2,2,2-trifluoroethoxy)-N-[(1-ethyl-2-pyrrolidyl)methyl]benzamide, m.p. 78° -80° C.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][S:25][CH2:24][CH2:23]2)=[N:11][CH:10]=1.[OH:39]OS([O-])=O.[K+]>CO>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][S:25](=[O:39])[CH2:24][CH2:23]2)=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(N2CCSCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1-c1cc(N2CCS(=O)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 159.9 %

Procedure:
To a solution of 1.24 g (2.24 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-thiomorpholin-4-yl-4-o-tolyl-nicotinamide (Example 50) in 25 ml methanol were added 689 mg (1.12 mmol) Oxone® at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. Quenching with 5 ml 40% aqueous sodium hydrogen sulfite solution was followed by addition of 6 ml 1N sodium hydroxide solution to adjust the pH to 7-8. The mixture was diluted with 50 ml water and extracted with 3 150-ml portions of dichloromethane. The combined extracts were dried with sodium sulfate and concentrated to give 1.20 g of crude product. Flash chromatography afforded 1.02 g (79.9%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C@H:11]3[CH2:13][C@H:8]([CH2:9][CH2:10]3)[C:7]=2[C:6]([OH:14])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:21]([O:14][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[C@@H:8]1[CH2:13][C@H:11]2[CH2:10][CH2:9]1)[CH:22]=[CH2:23]
Reactant: COc1ccc(O)c2c1[C@@H]1CC[C@H]2C1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(OC)c2c1[C@H]1CC[C@@H]2C1
Yield: 89.1 %

Procedure:
Treatment of (1R*,4S*)-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-ol (14.61 g, 0.077 mol) with potassium carbonate (31.84 g, 0.23 mol) and allyl bromide (10.68 g, 0.088 mol) generally according to the procedure described for Intermediate 1 provided 15.8 g (89%) of (1R*,4S*)-5-(allyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalene as a colorless oil. Anal. calcd. for C15H18O2.0.3H2O: C, 76.44; H, 7.95. Found: C, 76.43; H, 7.79.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([F:30])=[C:26]([I:29])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[ClH:18].[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:19]3[C:28]4[C:23](=[CH:24][C:25]([F:30])=[C:26]([I:29])[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc2ncnc(Cl)c2cc1I
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Product: Cl
Product: Fc1cc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2cc1I

Procedure:
Prepared according to Procedure A from 1-benzyl-1H-indazol-5-ylamine and 4-chloro-6-iodo-7-fluoroquinazoline. δ H (400 MHz, DMSO-d6): 11.55 (s, 1H), 9.41 (d, 1H), 8.8 (s, 1H), 8.18 (s, 1H), 8.05 (d, 1H), 7.78 (d, 1H), 7.69 (d, 1H), 7.61 (m, 1H), 7.29 (m, 2H), 7.23 (m, 3H), 5.67 (s, 2H). ESI-MS m/z 496 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[N:6][S:5][N:4]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1>>[S:5]1[N:6]=[CH:7][C:3]([CH2:2][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=2)=[N:4]1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: BrCc1cnsn1
Product: CC(=O)Cc1ccc(OCc2cnsn2)cc1

Procedure:
Prepared from 3-bromomethyl-1,2,5-thiadiazole and 4-hydroxyphenylacetone by the method of Example 1.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[N:28]([CH3:29])[N:27]=[CH:26][C:25]=1[C:30]#[N:31]>ClCCl.CN(C)C=O>[C:30]([C:25]1[CH:26]=[N:27][N:28]([CH3:29])[C:24]=1[NH:23][C:12]([C:11]1[C:5]2[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=2[C:8]([O:15][CH3:16])=[CH:9][CH:10]=1)=[O:14])#[N:31]
Reactant: CCc1nc2c(OC)ccc(C(=O)O)c2s1
Reactant: Cn1ncc(C#N)c1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nc2c(OC)ccc(C(=O)Nc3c(C#N)cnn3C)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a suspension of 2-ethyl-4-methoxybenzothiazole-7-carboxylic acid (0.1 g) in dichloromethane (10 ml) was added oxalyl chloride (1.0 ml) and dimethylformamide (1 drop). The reaction was stirred at room temperature for 16 hrs, and then the solvent was removed in vacuo to yield a brown solid residue. 5-Amino-1-methyl-1H-pyrazole-4-carbonitrile (0.1 g) was taken up in dichloromethane (10 ml) and sodium hexamethyldisilylamine (1.0M in tetrahydrofuran, 0.84 ml) was added. After 5 minutes the acid chloride was added and the reaction stirred at room temperature for 16 hrs. The solvent was removed in vacuo and the product purified by flash chromatography (eluent 50% ethyl acetatethexane-75% ethyl acetate/hexane) to yield the title compound as an off-white solid (0.088 g). TLC Rf 0.13 (50% ethyl acetate/hexane); Mpt 190-191° C.
Reaction SMILES: [N:1]1([CH2:4][C@@H:5]([OH:15])[CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.[BrH:16]>CC(C)=O>[BrH:16].[Br:16][CH2:3][CH2:2][NH:1][CH2:4][C@@H:5]([OH:15])[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1nccn1C[C@H](O)CN1CC1
Agent: Br
Solvent: CC(C)=O
Product: O=[N+]([O-])c1nccn1C[C@H](O)CNCCBr

Procedure:
In another alternate procedure, treatment of (R)-(-)-α-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol, synthesized as described in Example 2 (e), with aqueous hydrogen bromide in acetone, as described in The Journal of Medicinal Chemistry, 33, 2608 (1990), gives the product, mp 149°-150.5° C. (decomposition), 99.3% optically pure by chiral HPLC.