Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[C:42]1(=[O:52])[O:47][C:45](=[O:46])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12>ClCCCl>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:42]([C:43]5[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=5[C:45]([OH:47])=[O:46])=[O:52])[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II (25.3 mg, 0.05 mmol) in 1,2-dichloroethane (3 mL) was added triethyl amine (14 μL, 0.1 mmol) and phthalic anhydride (7.4 mg, 0.05 mmol). The resulting mixture was stirred at ambient temperature for 4 hours. After evaporation of the solvents, the residue was purified by flash chromatography on silical gel, eluting with a gradient of 10-30% methanol in ethyl acetate to afford 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid as amorphous solid (29 mg, quant.). 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J=6.6 Hz, 1H), 7.53-7.50 (m, 1H), 7.48-7.36 (m, 7H), 7.25-7.21 (m, 1H), 7.17-7.09 (m, 3H), 4.61-4.54 (m, 1H), 3.26 (br, 4H), 3.95 (br, 1H), 3.09 (br, 1H), 2.46 (s, 3H), 2.42-2.32 (m, 3H), 2.24-2.06 (m, 1H), 2.00-1.86 (m, 5H), 1.86-1.76 (m, 5H), 1.61 (d, J=7.7 Hz, 2H). HRMS m/z (M+H)+ calcd 577.3179; obsd 577.3176.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:19])[NH:10][N:11]([CH:16]([CH3:18])[CH3:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O:23][CH2:24][C@H:25]1[O:30][C@H:29](Br)[C@H:28]([O:32]C(C)=O)[C@@H:27]([O:36]C(C)=O)[C@@H:26]1[O:40]C(C)=O)=O.[OH-].[Na+]>ClCCl>[CH2:1]([C:8]1[C:9]([O:19][C@@H:29]2[O:30][C@H:25]([CH2:24][OH:23])[C@@H:26]([OH:40])[C@H:27]([OH:36])[C@H:28]2[OH:32])=[N:10][N:11]([CH:16]([CH3:18])[CH3:17])[C:12]=1[CH:13]([CH3:14])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C(C)C
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)c1c(Cc2ccccc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a suspension of 4-benzyl-1,5-diisopropyl-1,2-dihydro-3H-pyrazole-3-one (0.078 g), acetobromo-α-D-glucose (0.62 g) and benzyl(n-tributyl)ammonium bromide (0.054 g) in dichloromethane (4 mL) was added a sodium hydroxide aqueous solution (5 mol/L, 0.6 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi purified 4-benzyl-1,5-diisopropyl-3-(2,3,4,6-tetraacetyl-β-D-glucopyranosyloxy)-1H-pyrazole was dissolved in methanol (3 mL), and sodium methoxide (28% methanol solution, 0.58 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours. The solvent of the reaction mixture was removed under reduced pressure, and the residue was acidified by adding 10% citric acid aqueous solution. The mixture was purified by solid phase extraction on ODS (washing solvent: water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) gave the title compound (0.11 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:25]S(C2C=CC(C)=CC=2)(=O)=O)=[N:10][N:11]2[C:16]=1[C:15]([CH3:17])=[N:14][N:13]=[C:12]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].[CH3:36][N:37]1[C:41]([CH2:42]O)=[N:40][CH:39]=[N:38]1.[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:25][CH2:42][C:41]2[N:37]([CH3:36])[N:38]=[CH:39][N:40]=2)=[N:10][N:11]2[C:16]=1[C:15]([CH3:17])=[N:14][N:13]=[C:12]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]
Reactant: Cn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2-c2ccccc2F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(-c2ccccc2F)n2nc(OCc3ncnn3C)c(-c3ccccc3F)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To toluene-4-sulfonic acid 3,7-bis(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (200 mg, 0.407 mmol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (57.5 mg, 0.0509 mmol; prepared as described in EP-A-170073) in DMF (5 ml) was added sodium hydride (23.7 mg of a 60% dispersion in mineral oil; 0.593 mmol) and the mixture was stirred at room temperature for 30 min. Water (50 ml) was added, then the solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel eluting with 0 to 100% ethyl acetate in dichloromethane. 3,7-Bis(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under isohexane (75 mg). 1H NMR (400 MHz, CDCl3) δ 2.52 (3H, s), 3.73 (3H, s), 5.44 (1H, d, J=13 Hz), 5.49 (1H, d, J=13 Hz), 7.18-7.31 (3H, m), 7.36-7.46 (3H, m), 7.63 (1H, m), 7.78 (1H, m), 7.82 (1H, s); MS (ES+) m/e 434 [MH]+. Anal. Found C, 61.03; H, 4.08; N, 21.95%. C22H17F2N7O.0.1 C6H14 requires C, 61.41; H, 4.20; N, 22.18%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21]C1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:22]1[CH2:23][CH2:24][N:19]([CH:16]([CH3:17])[CH3:18])[CH2:21]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)C3)ccc2[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a cold (0° C.) mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (10 g, 1.0 eq.), 1-isopropyl-piperidin-4-ol (intermediate 1, step 1, 7.32 g, 1.05 eq.) and triphenylphosphine (15.3 g, 1.2 eq.) in tetrahydrofuran (280 ml) was slowly added a solution of diisopropylazodicarboxylate (11.8 g, 1.2 eq.) in tetrahydrofuran (20 mL). The mixture was stirred 30 min at 0° C. and overnight at room temperature, was concentrated in vacuo, dissolved in methyltertiobutylether (310 mL), washed with sodium hydroxide aqueous solution (0.5N), brine, dried over Na2SO4, filtered and evaporated. The residue was purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 7.0 g (43%) of the desired product as white solid. MS (m/e): 331.5 (MH+, 100%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:8])=[N:6][CH:7]=1.Br[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: Sc1ccc(Br)cn1
Reactant: BrC1CCCC1
Solvent: CS(C)=O
Product: Brc1ccc(SC2CCCC2)nc1
Reaction time: 0.08 h
Yield: 78.8 %

Procedure:
5-bromopyridine-2-thiol (0.5 g, 3.44 mmol) was dissolved in anhydrous DMSO (10 mL). CS2CO3 (2.23 g, 6.89 mmol) was added and stirred for 5 minutes followed by addition of bromocyclopentane (0.73 mL, 6.89 mmol). The reaction mixture was stirred for 30 min. at room temperature. The reaction mixture was poured on ice cold water (25 mL) and extracted with MTBE (2×25 mL) washed with water and brine dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product which was purified by column chromatography over silica gel using 2-5% ethyl acetate in hexanes as eluent to provide 5-bromo-2-cyclopentylsulfanyl-pyridine (0.7 g).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH2:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18][NH:17][CH2:16]1.[C:26]([OH:31])(=[O:30])[C:27]([OH:29])=[O:28].CO>C(OCC)(=O)C>[C:26]([OH:31])(=[O:30])[C:27]([OH:29])=[O:28].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:17]3[CH2:16][CH2:15][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCc2ccccc2CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 73% overall yield. FDMS m/e=336 (M+ of free base). α[D]589 =-14.17 (c=0.61, methanol).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH3:19].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:20][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH3:19])(=[O:24])=[O:23]
Reactant: CCC#CCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC#CCCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (4.3 ml) was added to a solution of 9-dodecyn-1-ol (5.1 g, 28 mmol) in 50 ml CH2Cl2, and the mixture was then added dropwise at 0° C. to a solution of methanesulfonyl chloride (2,2 ml, 28 mmol) in 10 ml CH2Cl2. The mixture was stirred another 4 hours at room temperature, then cooled to 0°-5° C. The solution was washed with cold 5% aqueous sodium bicarbonate, cold 1N HCl, cold water, then saturated brine. The extract was dried over Na2SO4 and filtered and evaporated. The solvent was evaporated to leave crude 1-(9-dodecynyl) methanesulfonate.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[CH:15])[CH:5]=[CH:4][C:3]1=2.Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21

Procedure:
A mixture of 4 g (19 millimoles) of (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethyne, 2.8 g (12.5 millimoles) of 4-bromobenzonitrile, 50 mg of palladium (II) acetate, 100 mg of triphenylphosphine and 25 ml of degased anhydrous triethylamine was refluxed for 4 hours under nitrogen. Thereafter, solid material was filtered off and the filtrate was evaporated down.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[CH:9][C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:19]([O:16][C:15]1[CH:17]=[CH:18][C:10]([CH:9]=[O:8])=[CH:11][C:12]=1[O:13][CH3:14])(=[O:21])[CH3:20]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Triethylamine (2.8 liters, 20.1 moles) was added dropwise to a solution of vanillin (2.00 kg., 13.15 moles) and acetic anhydride (2.6 liters, 27.5 moles) in methylene chloride (11.3 liters) maintaining temperature below 25° C. After adding 4-dimethylaminopyridine (20 g.) the solution was stirred at room temperature for 30 minutes. The reaction mixture was washed twice with water, followed by 20% (w/w) hydrochloric acid and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to 8 liters. Hexane (15 liters) was added slowly while removing remaining methylene chloride. After cooling, 2.45 kg. (96% yield) product was filtered off. Recrystallization of a small sample from anhydrous ether gave the acetate as fine yellow needles, M.P. 76°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:25]([C:27]#[N:28])[K]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([S:18]([NH:19][C:27]([NH2:28])=[O:25])(=[O:20])=[O:21])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1sc(S(N)(=O)=O)cc1C
Reactant: N#CO[K]
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)NCCc1sc(S(=O)(=O)NC(N)=O)cc1C

Procedure:
311 mg (0.8 mmol) of 2-[2-(5-chloro-2-methoxybenzoyl-amino)ethyl]-3-methyl-5-sulfamoylthiophene were treated with 448 mg of KOCN and 0.6 ml of triethylamine, and the mixture was then heated to reflux for 4 h. The cooled solution was filtered and evaporated to dryness. The residue was stirred with 40 ml of H2O, 25 ml of triethylamine and 25 ml of ethyl acetate. The organic phase was extracted 3 times with water/1% triethylamine. The combined aqueous phases were acidified with 2N hydrochloric acid. The precipitate formed was stirred for 3 hours in an ice bath and filtered off with suction.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCc1ccc(C(F)(F)F)cc1)C1CCNCC1
Yield: 94.4 %

Procedure:
A mixture of tert-butyl N-(1-benzylpiperidin-4-yl)-N-[2-(4-trifluoromethylphenyl)ethyl]carbamate (0.437 g, 0.944 mmol) prepared in Reference Example 120 and 20% palladium hydroxide/carbon (100 mg) in ethanol (20 ml) was stirred at room temperature under an atmospheric pressure of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford tert-butyl N-(piperidin-4-yl)-N-[2-(4-trifluoromethylphenyl)ethyl]carbamate (0.332 g, yield 94%) as a colorless oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]([C:12]1([C:23]([OH:25])=[O:24])[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCOCC1>[O:2]=[C:1]1[O:24][C:23](=[O:25])[C:12]2([CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]2)[N:5]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)N1CCC(Nc2ccccc2)(C(=O)O)CC1
Solvent: C1COCCO1
Product: CCOC(=O)N1CCC2(CC1)C(=O)OC(=O)N2c1ccccc1
Reaction time: 0.5 h

Procedure:
Phosgene gas is introduced through a stirring mixture of 29.2 parts of 4-anilino-1-(ethoxycarbonyl)isonipecotic acid in 240 parts of dioxane: exothermic reaction (temperature rises to 45° C.). Stirring is continued for 30 minutes at 45° C. The mixture is heated to reflux and phosgene gas is gently introduced for 2 h. 30. Then nitrogen gas is introduced for 30 minutes. The reaction mixture is evaporated in a boiling water-bath for 30 minutes. The solid residue is triturated in ether, yielding ethyl 2,4-dioxo-1-phenyl-3-oxa-1,8-diazaspiro[4,5]decane-8-carboxylate; mp. 210.7° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1C(=O)N([I:27])C(=O)C1>CC#N>[I:27][C:17]1[N:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)=[CH:12][C:13]2=[N:19][CH:18]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CS(=O)(=O)c1ccc(-c2ccn3ccnc3c2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2ccn3c(I)cnc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Treat a solution of 7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine (101 g, 371.3 mmol, 1 eq) in 2000 mL of CH3CN at 0° C. with NIS (83.5 g, 371.3 mmol, 1 eq). Allow the mixture to stir at room temperature for 1 hour. Remove the solvent and the dissolve the residue in 5000 mL of CH2Cl2, wash with 10% NaOH solution, NaHSO3 sat., water and aqueous saturated sodium chloride. Dry over MgSO4 and evaporate. Triturate the solid obtained with hexanes, filter and dry in vacuo to afford 110 g of the title compound as a yellow solid. (Yield: 75%). MS (ES), m/z 399 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH:7][N:6]=1)(=[O:3])[CH3:2].[Br:14]Br.O>C(O)(=O)C>[C:10]([C:8]1[NH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:9]=1[Br:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: BrBr
Reactant: CC(=O)Nc1cc(C(C)(C)C)[nH]n1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1n[nH]c(C(C)(C)C)c1Br
Temperature: 60 °C
Yield: 80 %

Procedure:
4.5 g (0.025 mole) of 3-acetylamino-5-t-butylpyrazole prepared in Example 3 was dissolved in 20 ml of acetic acid, and 4.0 g of bromine was added dropwise thereto while stirring. The reaction solution was heated at 60° C. for one hour and then cooled. 50 ml of water was added to the resulting solution and allowed to stand, whereby crystals were precipitated. The crystals were collected by filtration, washed with water and then dried to obtain 5.2 g of 5-t-butyl-4-bromo-3-acetylaminopyrazole. This product was recrystallized from methanol and found to have a melting point of 234° to 235° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:30]([O-])([N+]([O-])=O)=[O:31]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:30]=[O:31])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 81.9 %

Procedure:
3.5 g of 1-(2-chloroethyl)-3-n-pentyl-3-D-glucopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 3.1 g of 1-(2-chloroethyl)-1-nitroso-3-n-pentyl-3-D-glucopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][C:14](=[O:16])[CH3:15])[CH2:10][C@H:9]1[C:17](=[O:35])[N:18]([CH2:20][C:21](=[O:34])[N:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[CH3:23])[CH3:19])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:33][O:32][C:30](=[O:31])[C:27]1[CH:28]=[CH:29][C:24]([N:22]([C:21](=[O:34])[CH2:20][N:18]([C:17]([C@@H:9]2[CH2:10][C@@H:11]([S:13][C:14](=[O:16])[CH3:15])[CH2:12][NH:8]2)=[O:35])[CH3:19])[CH3:23])=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)CN(C)C(=O)[C@@H]2C[C@@H](SC(C)=O)CN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(N(C)C(=O)CN(C)C(=O)[C@@H]2C[C@@H](SC(C)=O)CN2)cc1
Yield: 116.2 %

Procedure:
2.92 g (5.7 mmol) (2S,4R)-4-Acetylsulfanyl-2-[[[(4-methoxycarbonyl-phenyl)-methyl-carbamoyl]-methyl]-methyl-carbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester in 60 ml CH2Cl2 were treated with 15 ml TFA at 0° C. until no starting material could be detected. The solution was concentrated, dissolved in toluene and evaporated 3 times yielding 2.7 g (93%) (2S,4R)-4-[[[(4-Acetylsulfanyl-pyrrolidine-2-carbonyl)-methyl-amino]-acetyl]-methyl-amino]-benzoic acid methyl ester.trifluoro-acetate salt as brown foam, MS 408 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:5]=[C:4]([O:12][CH2:13][CH3:14])[N:3]=1.[Na].[CH3:16][OH:17]>>[CH3:16][O:17][C:2]1[CH:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:5]=[C:4]([O:12][CH2:13][CH3:14])[N:3]=1
Reactant: CO
Reactant: CCOc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Agent: [Na]
Product: CCOc1cc(C(Cl)(Cl)Cl)cc(OC)n1
Temperature: 62 °C
Reaction time: 8 h

Procedure:
To a solution of 54.99 grams (0.20 mole) of 2-chloro-6-ethoxy-4-(trichloromethyl)pyridine dissolved in 100 ml of methanol at 60° C. was rapidly added a solution of 6.90 grams (0.3 mole) of sodium metal dissolved in 150 ml of methanol. The mixture was heated to reflux for ~1 hour and then stirred at 62° C. overnight and thereafter refluxed for 8 hours followed by stirring at 62° C. overnight and then refluxed for 1 hour. A solution of 3.45 grams of sodium metal dissolved in 75 ml of methanol was added and the mixture brought back to reflux. The mixture was thereafter cooled and covered and allowed to sit ~64 hours (over a weekend). The methanol was removed by evaporation and the residue diluted with water and extracted with methylene chloride. The extract was washed with water, dried with sodium sulfate and the methylene chloride removed by evaporation. The desired 2-methoxy-6-ethoxy-4-(trichloromethyl)pyridine product was recovered by crystallization of the residue from methanol followed by recrystallization from ethanol. The product was recovered in a yield of 8.5 grams and melted at 36°-38° C. Upon analysis, the product was found to have carbon, hydrogen, nitrogen and chlorine contents of 39.49, 3.54, 5.17 and 39.82 percent, respectively, as compared with the theoretical contents of 39.95, 3.72, 5.17 and 39.31 percent, respectively, as calculated for the above-named compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[CH:8]=2)[CH:3]=[CH:2]1.Cl.Br[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>>[N:22]1[CH:23]=[CH:24][C:19]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]4[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=4)[CH:8]=3)[CH:3]=[CH:2]2)=[CH:20][CH:21]=1
Reactant: Oc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: Brc1ccncc1
Agent: Cl
Product: Oc1ccc(-c2ccc3ccn(-c4ccncc4)c3c2)cc1

Procedure:
The target compound was prepared as in Example 1 using 4-(1H-indol-6-yl)phenol (200 mg, 0.96 mmol) and 4-bromopyridine hydrochloride (205 mg, 1.06 mmol).
Reaction SMILES: [C:1]1([SH:7]2(=[O:19])[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][C:12]1[SH:7](=[O:19])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:8][CH:9]=[N:10][C:11]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: BrBr
Reactant: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=CN1
Solvent: ClC(Cl)Cl
Product: O=[SH]1(c2ccccc2)NC=NC(c2ccccc2)=C1Br
Reaction time: 0.5 h
Yield: 160.3 %

Procedure:
To a solution of 4.5 g (16 mmole) of 1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide of Example 1 in 225 ml of chloroform was added over 20 minutes a solution of 2.8 g, (7.5 mmole) of bromine in 25 ml of chloroform. After the addition was complete, the mixture was stirred for 30 minutes before reducing to an oil which was subjected to flash chromatography (SiO2, petrol:chloroform 1:1) to obtain 4.2 g of (73%) 6-bromo-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide melting at 135°-136° C. after crystallization from ethyl acetate/ether.