Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C:12](=[O:28])[NH:13][C:14]1[C:18]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[N:17][O:16][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:36]([O:43][C:44](=[O:56])[NH:45][C:46]1[CH:51]=[CH:50][C:49]([C:52](=[O:55])[CH2:53]Br)=[CH:48][CH:47]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:36]([O:43][C:44](=[O:56])[NH:45][C:46]1[CH:47]=[CH:48][C:49]([C:52](=[O:55])[CH2:53][N:20]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=[C:19]2[C:18]2[C:14]([NH:13][C:12](=[O:28])[CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:29])=[N:15][O:16][N:17]=2)=[CH:50][CH:51]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C(Nc1ccc(C(=O)CBr)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
To a stirred solution of 0.4 g of {[4-(1H-benzoimidazol-2-yl)-furazan-3-ylcarbamoyl]-methyl}-carbamic acid benzyl ester (0.97 mmol, 1 eq.) in 6 mL of N,N′-dimethylformamide are added 0.2 g of potassium carbonate (1.4 mmol; 1.45 eq.) at room temperature followed by the addition of 0.41 g of [4-(2-bromo-acetyl)-phenyl]-carbamic acid benzyl ester (CAS 157014-41-0) (1.16 mmol; 1.2 eq.). The reaction mixture is stirred for 2 h at room temperature and is then diluted with 20 mL of ethyl acetate. The solution is washed with water (2×10 mL) and brine (2×10 mL), dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is then dissolved in hot ethyl acetate (2 mL) and the solution is placed in an ice-bath. After 0.5 h, the resulting suspension is filtered and the solid is washed with cold ethyl acetate (1 mL) to afford 0.2 g of the desired product as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:16]=[CH:15][C:13]3[N:14]=[C:10]([NH:9][C:5]4[CH:4]=[C:3]([CH2:2][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[CH:8]=[CH:7][N:6]=4)[S:11][C:12]=3[CH:18]=2)=[CH:20][CH:21]=1
Reactant: C1CCNC1
Reactant: ClCc1ccnc(Nc2nc3ccc(-c4ccncc4)cc3s2)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(-c2ccc3nc(Nc4cc(CN5CCCC5)ccn4)sc3c2)ccn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A solution of N-(4-(chloromethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine (80 mg, 0.23 mmol, 1 eq.) in 1 mL dioxane was treated with 15 mg of pyrrolidine and 20 mg DIEA. The reaction mixture was stirred at 140° C. under microwave condition for 1 h. After cooling to rt, the mixture was concentrated in vacuo. The residue was washed with EtOH to afford 6-(pyridin-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 102 without further purification (67 mg). 1HNMR (CD3OD, 400 MHz) δ 8.83 (d, 2H), 8.60 (m, 1H), 8.54 (m, 1H), 8.46 (m, 2H), 8.10 (m, 1H), 7.92 (d, 1H), 7.52 (s, 1H), 3.37 (d, 1H), 4.53 (s, 2H), 3.62 (br s, 2H), 3.25 (m, 2H overlapping with signal from CD3OD), 2.22 (m, 2H), 2.09 (m, 2H). MS (ES-API): MH+=388.1. HPLC tR=2.16 min.
Reaction SMILES: [CH3:1][Si:2]([CH3:53])([CH3:52])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[CH:9]=1.[Br:54]N1C(=O)CCC1=O>CC#N.ClCCl>[CH3:51][Si:48]([CH3:50])([CH3:49])[CH2:47][CH2:46][O:45][CH2:44][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:52])[CH3:53])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH:31]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:34]([CH2:33][CH2:32]3)[CH2:35]2)[C:9]=1[Br:54]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 2.3 mmol) in CH3CN (10 mL) and dichloromethane (10 mL) was added N-bromosuccinimide (0.45 g, 2.5 mmol) portionwise and the resulting mixture was stirred at room temperature for 0.5 h, at which time LC/MS confirmed full conversion of starting material to product. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) gave tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)=[O:9])=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([NH:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38])=[O:14])=[O:9])=[CH:18][CH:19]=1
Reactant: CC(C)[C@H](N)CO
Reactant: Cc1ccc(COC(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: Cc1ccc(COC(=O)N2CCC[C@H]2C(=O)N[C@H](CO)C(C)C)cc1

Procedure:
The subject compound was prepared from 3.9 g (14.8 mmol) p-methylbenzyloxycarbonyl-L-proline, 2.0 g (14.6 mmol) isobutyl chloroformate, 1.5 g (14.8 mmol) N-methylmorpholine, and 1.5 g (14.5 mmol) L-valinol, using a procedure described in Example 1. The product, N-(p-methylbenzyloxycarbonyl)-L-prolyl-L-valinol, obtained after recrystallization from ethyl acetate/ n-hexane, melted at 122°-123.5°, α25D -61.9° (C=1.00 g/100 mL in acetone).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C:21]3([NH:25][C@@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH:22]3I)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C>CO.[Pd]>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)[C@H]1CC(I)C2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reaction time: 8 h

Procedure:
To a solution of methyl(2R,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-4-iodo-1,8-diazaspiro[4.5]decane-2-carboxylate (860 mg, 1.179 mmol) in methanol (20 ml), triethylamine (0.822 ml, 5.89 mmol) was added followed by palladium on carbon 10% (172 mg, 0.162 mmol). Resulting mixture was hydrogenated at atmospheric pressure of H2 at room temperature overnight.
Reaction SMILES: [NH3:1].[CH:2]1([C:5]2[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7](C(Cl)(Cl)Cl)[N:6]=2)[CH2:4][CH2:3]1>O1CCCC1>[NH2:1][C:7]1[N:6]=[C:5]([CH:2]2[CH2:4][CH2:3]2)[N:10]=[C:9]([O:11][CH3:12])[N:8]=1
Reactant: COc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1
Reactant: N
Solvent: C1CCOC1
Product: COc1nc(N)nc(C2CC2)n1
Temperature: 80 °C

Procedure:
5 ml of concentrated aqueous ammonia are added to a solution of 1 g of 2-cyclopropyl-4-methoxy-6-trichloromethyl-1,3,5-triazine in 3 ml of tetrahydrofuran; the whole is placed into a bomb tube and heated at 80° C. for 30 minutes. The mixture is cooled and then filtered; the filter residue is dissolved in 30 ml of methylene chloride, and the solution is dried over magnesium sulfate, and concentrated by evaporation. The residue crystallises to leave 0.4 g of white crystals, m.p. 157°-158° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=4[CH3:29])[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43]>CN(C=O)C>[CH3:29][C:23]1[CH:24]=[C:25]([NH:28][C:42]([C:38]2[O:37][CH:41]=[CH:40][CH:39]=2)=[O:43])[CH:26]=[CH:27][C:22]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][CH:11]=2)[CH:17]=1
Reactant: Cc1cc(N)ccc1-c1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2)c1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2ccco2)ccc1-c1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2)c1
Reaction time: 18 h

Procedure:
A solution of 4′-amino-2′-methyl-biphenyl-3-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (40 mg) and triethylamine (0.4 ml) in dry DMF (3 ml) was treated with furan-2-carbonyl chloride (0.015 ml) and the mixture stirred at 20 C for 18 h. The mixture was then partitioned between water and dichloromethane. The dried extract was then evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 400:8:1 gave a colourless foam (46 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-nitro-4-tert-butylphenol (2 g) and N,N-dimethylethanolamine (1.3 g) and PPh2 (4 g) in THF (50 ml) was added DEAD (2.6 ml). The reaction was stirred at RT for 1 h, diluted with EtOAc (50 ml) and washed with 1 N HCl twice. The aqueous layer was basified with NaHCO3, extracted with EtOAc twice and washed with H2O and brine. The organic layer was dried over Na2SO4 and evaporated to give {2-[4-(tert-butyl)-2-nitrophenoxy]-ethyl}dimethylamine, was used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([O:30][CH3:31])=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:39])C(=O)C1.O>CN(C)C=O>[Br:39][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[N:18]([C:17]1[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=1)=[CH:14][C:13]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][CH:11]=3)[CH2:19][CH2:20][CH2:21]2
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccccc43)nc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(Br)ccc43)nc2c1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (300 mg, 0.73 mmol) in N,N-dimethylformamide (20 ml) was added NBS (193 mg, 1.08 mmol) under an inert atmosphere of nitrogen. The resulting solution was stirred for 1.5 h at −10° C. Then water (150 ml) was added and the reaction was extracted with ethyl acetate (3×50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel chromatography eluting with 1%-2% ethyl acetate in petroleum ether to afford methyl 3-(6-bromo-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (200 mg, 56%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][C@@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([C@@H:9]3[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@H:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]=2[CH:18]=1
Reactant: CC(=O)OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Reaction time: 4 h

Procedure:
(1R, 2S, 3S, 5S)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (1.00 g, 1.92 mmole) was refluxed in ethanol (10 mL) with isopropylamine (1.6 mL, Fluka) under nitrogen for 24 hours. A second portion of isopropylamine (0.80 mL) was added and reflux continued for an additional 4 hours. Volatiles were evaporated, the residue was redissolved in ethanol, 1 N sodium hydroxide (1.90 mL) was added, and volatiles were reevaporated. The residue was chromatographed on a silica gel column. Title compound was eluted with 10% methanol-ethyl acetate as a colorless glass. Concentration of an ethanol solution gave title compound as a off-white solid foam (360 mg, 46%). Such a sample was solidified by trituration with 95% water-5% methanol to give title compound as white powder (96%), m.p. 137-138° C.; 1H-NMR(DMSO-d6)δ 7.60 and 7.39 (both s, 2, aromatic CH), 6.64 (d, J=7.4 Hz, 1, NH), 5.14 (t, J=4.3 Hz, 1, OH), 4.81 (d, J=7.3 Hz, 1, OH), 4.70 (d, J=3.5 Hz, 1, OH), 4.70-4.50 (m, 1, NCH), 4.50-4.30 (m, 1, OCH), 4.10-4.00 (m, 1, NCH of cyclopropylamino), 3.9-3.75 (m, 1, OCH), 3.70-3.50 (m, 2, OCH2), 2.20-1.80 (m, 3, CH2 and CH of cyclopentane), 1.24 (d, J=6.6 Hz, 6, 2 CH3); mass spectrum (CI): 374(M+1); [α 20 589-3.72°, [α]20 578-2.60°, [α]20 546-2.23°, [α]20 436-9.67°, [α]20 365-51.7 ° (c=0.269, methanol). [See Examples 16-18 and 20]
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH:11]([CH2:13][C:14](O)=[O:15])[CH3:12].C(N(CC)CC)C>CS(C)=O>[CH3:12][N:11]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:14](=[O:15])[CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CNCC(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccccc21

Procedure:
5.2 g of o-fluoro-nitrobenzene, 3.2 g of sarcosine and 5.2 ml triethylamine was stirred in 25 ml DMSO at 70° C. for 4 days. The mixture was then evaporated in vacuo and the residue was partitioned between water and methylene chloride. The organic phase was evaporated in vacuo. The residue was dissolved in 100 ml 96% ethanol and was hydrogenated at normal pressure using 0.5 g Pd/C. After completion of hydrogen uptake, the mixture was filtered and evaporated in vacuo. The residue was washed with water with disodium carbonate, ether and water. Yield of title compound: 1.3 g M.p. 132° C.
Reaction SMILES: [C:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(N(CC)CC)C>[C:23]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(c1ccccc1)c1ccccc1O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(c1ccccc1)c1ccccc1OC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Cumylphenyl benzoate is prepared in accordance with the following procedure: one mole of cumylphenol was dissolved in 600 ml of benzene containing 1.2 moles of triethylamine in a 2-liter stirred glass reactor equipped with external heating and cooling devices. The reaction mass was cooled to and maintained at 15°-20° C. during the addition of 1.1 moles of benzoyl chloride over a period of 1.5 hours. After completion of addition, the resulting slurry was heated to and maintained at 40°-45° C. for 1 hour, and thereafter cooled to ambient temperature and filtered. The filter cake was washed with 200 ml of toluene and the combined washings and filtrate distilled to give 214.9 g (68 mole %) of a pale yellow oil having a boiling point at 0.5 mm Hg of 261°-265° C., a specific gravity at 55° C. of 1.082, and a viscosity at 55° C. of 215 cps. On standing, the oil solidified to form a white solid having a melting point of 43°-46.5° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[O:13]([CH2:21][CH2:22]O)[Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:22][CH2:21][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: CC(C)(C)Oc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 8 h
Yield: 87 %

Procedure:
4-Tert-butoxyphenol (1 g, 6.02 mmole), 2-(t-butyldimethylsiloxy)ethanol (1.38 g, 7.83 mmole), and PPh3 (2.05 g, 7.82 mmole) were combined in toluene (30 mL) at RT. To this was added DIAD (1.52 mL, 7.82 mmole) slowly at RT. After stirring overnight the mixture was concentrated. Flash column chromatography (Biotage-SNAP-50 g SiO2, 0-10% EtOAc/hexanes) gave the title compound (1.7 g, 87%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 6.90 (d, J=8.8 Hz, 2 H); 6.80 (d, J=8.8 Hz, 2 H); 4.03-3.92 (m, 4 H); 1.30 (s, 9 H); 0.91 (s, 9 H); 0.10 (s, 6H).
Reaction SMILES: C(O[C:4](=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:6]=1)C.[CH2:32]([CH2:34][NH2:35])[OH:33].C([O-])([O-])=O.[K+].[K+]>CCO>[OH:33][CH2:32][CH2:34][NH:35][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:6]=1
Reactant: CCOC(=O)c1cccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(NCCO)c1cccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
3-[3-(3-Pyrazol-1-yl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-benzoic acid ethyl ester (Ex. 1.10) (1 eq, 0.098 mmol, 40 mg) and ethanol amine (10 eq, 0.98 mmol, 0.06 ml) are dissolved in EtOH (2 ml) and K2CO3 (1.5 eq, 0.147 mmol, 20.3 mg) is added. The reaction mixture is stirred for 5 h at 55° C. The solvent is removed in vacuo and the reaction is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-(2-hydroxy-ethyl)-3-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-a]-pyridin-7-yl]-benzamide as a white solid; [M+H]+=424
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH3:36][N:37]([CH3:43])[S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39]>>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:42][CH2:41][S:38]([N:37]([CH3:43])[CH3:36])(=[O:40])=[O:39])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: C=CS(=O)(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCS(=O)(=O)N(C)C)CC3)cc1OCC2

Procedure:
2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt was reacted with N,N-dimethylethenesulfonamide to give 249 as a white solid. 1H NMR δ (ppm) (DMSO-d6): 8.28 (1 H, d, J=8.29 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.01 (1 H, dd, J=8.37, 1.77 Hz), 6.85 (1 H, d, J=1.72 Hz), 5.88-5.80 (1 H, m), 4.48-4.42 (4 H, m), 3.23-3.15 (2 H, m), 2.95 (2 H, d, J=11.09 Hz), 2.74 (6 H, s), 2.68-2.60 (2 H, m), 2.09-1.98 (2 H, m), 1.73 (2 H, d, J=12.61 Hz), 1.64-1.55 (2 H, m), 1.43 (6 H, d, J=6.61 Hz). 1 Proton obscured by solvent peak. LCMS: RT=2.90 M+H+=513
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:25]([O-])([O-:27])=[O:26].[NH4+]>C(Cl)Cl>[N+:25]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][C:1]2=[O:11])=[CH:6][CH:7]=1)([O-:27])=[O:26]
Reactant: O=C1CCCc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 41.2 %

Procedure:
14.62 g of 1-tetralone in 45 ml of methylene chloride were treated with 29.3 ml of trifluoroacetic anhydride and 8.40 g of ammonium nitrate while cooling with ice/NaCl. After 18 hours the mixture was poured cautiously into an ice/conc. NaOH solution and extracted with diethyl ether. The organic phase was washed in succession with soda solution and NaCl solution, dried and evaporated. Flash chromatography on silica gel (hexane/ethyl acetate=9/2) followed by recrystallization from hexane/ethyl acetate (1/1) yielded 7.87 g of 7-nitro-1-tetralone as brownish crystals of m.p. 104°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[Cl:34])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccccc2Cl)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 91.1 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (403 mg) was reacted with 2-chlorophenol (390.2 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-(2-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (390.2 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=2)[N:11]=[N:10]1.Cl[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].[Cl-].[NH4+]>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:18][CH:19]=2)[N:11]=[N:10]1
Reactant: CC(C)OC(=O)Cl
Reactant: Fc1ccccc1-n1cc(C2=CCNCC2)nn1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CC(C)OC(=O)N1CC=C(c2cn(-c3ccccc3F)nn2)CC1
Reaction time: 1 h

Procedure:
4-[1-(2-Fluorophenyl)-1H-[1,2,3]-triazol-4-yl]-1,2,3,6-tetrahydropyridine hydrochloride (22.7 mg) prepared in the above 1) was dissolved in 0.5 ml of pyridine and 0.06 ml of isopropyl chloroformate was added thereto followed by stirring for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution and the product was extracted with ethyl acetate, dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting residue was separated and purified by a thin-layer chromatography (ethyl acetate/hexane=1/1) to give 4.9 mg of the title compound as a white solid.