Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:13]2[CH:12]=[CH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]([C:30]4[CH:31]([C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=5)[C:32]([C:38]([O:40]CCC#N)=[O:39])=[C:33]([CH3:37])[NH:34][C:35]=4[CH3:36])=[O:29])[CH2:20][CH2:19]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl>CO>[CH:14]1[C:10]2[CH:11]=[CH:12][C:13]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[C:18]3[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]([C:30]4[CH:31]([C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=5)[C:32]([C:38]([OH:40])=[O:39])=[C:33]([CH3:37])[NH:34][C:35]=4[CH3:36])=[O:29])[CH2:22][CH2:23]3)[C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)=C(C)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)OCCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)=C(C)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5 ml of methanol and 0.434 ml of 1 N aqueous sodium hydroxide solution were added to 244 mg (0.36 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-cyanoethyl) ester 5-(3-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene) piperidine-1-yl) propan-1-yl) ester and stirred at room temperature for 5 hours. After adding 1 N hydrochloric acid, precipitates were taken by the filtration and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][C@H:11]([C:16]([OH:18])=O)[CH2:10][CH2:9][C:8]=2[N:7]=1)([CH3:5])[CH3:4].[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCOCC1>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:16]([C@@H:11]2[CH2:10][CH2:9][C:8]3[N:7]=[C:6]([C:3]([CH3:5])([CH3:4])[C:2]([F:19])([F:1])[F:20])[CH:15]=[CH:14][C:13]=3[CH2:12]2)=[O:18])=[CH:24][CH:23]=1
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Reactant: Nc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)Nc1ccc(Br)cc1)C2)C(F)(F)F
Temperature: 14 °C

Procedure:
(R)-2-(1,1,1-Trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (30 mg), 4-bromoaniline (17.9 mg), propanephosphonic acid cyclic anhydride (50% wt solution in dichloroethane) (0.093 mL), triethylamine (0.044 mL), and dioxane (2 mL) were combined and heated in a microwave at 14° C. for 20 mins. The solution was evaporated and the residue dissolved in ethyl acetate and extracted with sodium carbonate soln (2×20 ml) and brine (3×20 ml). The organic layer was separated, dried (Na2SO4), filtered and evaporated to give a gum which solidified on standing. Yield 40 mg.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1[CH2:14][CH2:13][NH:12]C1=O.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[C:1]1([N:7]2[CH2:14][CH2:13][NH:12][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1NCCO1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1NCCN1c1ccccc1
Temperature: 195 °C
Yield: 48 %

Procedure:
A mixture of phenyl isocyanate (50 mmoles), 2-oxazolidinone (50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give a yield of 48 percent of the desired product, m.p. 157° C.-159° C.
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2.C([O-])(=O)C.[Na+]>CC(N(C)C)=O>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:24]4[CH:25]=[CH:26][CH:27]=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Brc1cccc2cccnc12
Reactant: C=CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)/C=C/c1cccc3cccnc13)CC2
Yield: 55 %

Procedure:
2-Cyclohexyl-8-ethenesulfonyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (20 mg, 61.5 μmol), 8-bromoquinoline (19 mg, 91.3 μmol), POPd1 (Combiphos, 2.9 mg, 3.1 μmol) and sodium acetate (7.6 mg, 92.6 μmol) in dimethylacetamide (0.6 ml) were mixed in a sealed vessel in a nitrogen atmosphere. This mixture was irradiated in a microwave apparatus (190° C., 40 min). The reaction mixture was cooled, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-cyclohexyl-8-((E)-2-quinolin-8-yl-ethenesulfonyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (15.3 mg, 16%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[C:8]([CH2:14][C:15]([NH2:17])=[O:16])=[CH:7][CH:6]=1.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C(OCC)(=O)C>[CH2:18]([N:20]([CH2:21][CH3:22])[CH2:2][CH2:3][O:4][C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[C:8]([CH2:14][C:15]([NH2:17])=[O:16])=[CH:7][CH:6]=1)[CH3:19]
Reactant: NC(=O)Cc1ccc(OCCBr)c2ccoc12
Reactant: CCNCC
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(CC(N)=O)c2occc12
Yield: 99 %

Procedure:
Combine 2-[4-(2-Bromoethoxy)benzofur-7-yl]acetamide (0.102 g, 0.342 mmol) with neat diethyl amine (3 ml, excess), and heat at 55° C. for 18 hours. Dilute the mixture with ethyl acetate and wash with water and brine. Dry over sodium sulfate, filter, and concentrate to give 0.098 g (99%) of the title compound as a brown solid. Mass spectrum: electrospray (m/z) 264 (M++1).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18])([O-:13])=[O:12].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([S:7]([NH:10][C:17]([C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 1, using benzenesulphonamide (4.7 g, 30 mmol), 3-nitrobenzoic acid (5 g,30 mmol), 4-dimethylamino pyridine (3.66 g, 30 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (5.74 g, 30 mmol), and anhydrous dichloromethane (200 ml). The compound (8.05 g, 88%) was afforded as a colourless solid. mp 188°-190° C. 1H NMR (360 MHz, D6 -DMSO) δ 7.65 (2H, m), 7.72 (1H, m), 7.79 (1H,dd, J=8.0 and 8.0 Hz), 8.02 (2H, m), 8.28 (1H, dd, J=8.0 and 1.5 Hz), 8.45 (1H, dd, J: 8.0 and 1.5 Hz), 8.72 (1H, m).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][C@@:14]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C@H:18]([OH:30])[C@@H:17]2[C@H:15]1[C@H:16]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.O1CCCC1.C(=O)(O)[O-].[Na+]>>[C:6]([O:10][C:11]([NH:13][C@@:14]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C@H:18]([O:30][S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:17]2[C@H:15]1[C@H:16]2[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](OS(C)(=O)=O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Yield: 61.8 %

Procedure:
Methanesulfonyl chloride (0.841 mL, 1.25 g, 10.87 mmol) is added to di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (2.00 g, 3.40 mmol), triethylamine (1.66 mL, 1.20 g, 11.89 mmol), and tetrahydrofuran (33.98 mL, 30.11 g, 417.61 mmol) at 0° C. and stirred. Gradually warm the reaction to room temperature and stir overnight. Dilute the reaction with saturated aqueous sodium bicarbonate then extract with ethyl acetate (3×100 mL). The combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to yield a residue. The residue is purified by flash chromatography using eluting with 5-60% ethyl acetate in hexanes to give the title compound (1.40 g, 2.10 mmol, 62%).
Reaction SMILES: [Cl-].[Li+].[CH2:3]([Sn](CCCC)(CCCC)C=C)[CH2:4]CC.O1CCCC1.FC(F)(F)S(O[C:29]1[CH2:30][C@H:31]2[C@@H:38]([CH:39]=1)[C:33]1([O:37][CH2:36][CH2:35][O:34]1)[CH2:32]2)(=O)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:3]([C:29]1[CH2:30][C@H:31]2[C@@H:38]([CH:39]=1)[C:33]1([O:37][CH2:36][CH2:35][O:34]1)[CH2:32]2)=[CH2:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(OC1=C[C@@H]2[C@H](C1)CC21OCCO1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC1=C[C@@H]2[C@H](C1)CC21OCCO1

Procedure:
Lithium chloride (1.97 g, 46.4 mmol), tetrakis(triphenylphosphine)palladium (0) (0.36 g, 0.31 mmol), and tributyl(vinyl)tin (2.47 mL, 8.50 mmol) were added to a tetrahydrofuran solution (60 mL) of (±)-(1R,5S)-spiro[bicyclo[3.2.0]hept-3-ene-6,2′-[1,3]dioxolan]-3-yl trifluoromethanesulfonate (2.32 g, 7.73 mmol). The mixture was heated to reflux for 2 hours, and water was then added to the reaction solution, followed by extraction with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (990 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.[CH3:13][C:14](OC(C)=O)=[O:15]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:14](=[O:15])[CH3:13])[C:4]=2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1COc2ccc(Br)cc2N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (7A) (2.5 g, 11.7 mmol) was taken up in DCM (100 mL) and treated with TEA (4.07 mL, 29.2 mmol) followed by Ac2O (2.75 mL, 29.2 mmol). 4-DMAP (0.285 g, 2.34 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a gradient of 0 to 50% EtOAc in hexanes to provide 2.62 g 187%) of the desired compound 1-(6-bromo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone (7B).
Reaction SMILES: [S:1](=[O:35])(=[O:34])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9]C(C)(C)[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:24][C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[O:6]1)[NH2:2]>FC(F)(F)C(O)=O.O>[S:1](=[O:35])(=[O:34])([O:3][CH2:4][C@@H:5]1[C@@H:12]([OH:11])[C@@H:8]([OH:9])[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:24][C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[O:6]1)[NH2:2]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 0.17 h
Yield: 67 %

Procedure:
((3aR,4R,6R,6aR)-6-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate (400 mg, 0.80 mmol) was dissolved in a preformed mixture of trifluoroacetic acid (1.8 mL) and water (0.2 mL). The solution was allowed to stand at room temperature for 10 minutes and evaporated to dryness. This was twice evaporated from methanol and the residue was purified by reverse phase HPLC to yield 248 mg (67%) of final compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[C:7]([CH3:16])[C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[OH-].[Na+]>O.CO>[CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[C:7]([CH3:16])[C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1C)SCCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)ccc2c1SCCC2(C)C

Procedure:
62.9 g of methyl 4,4,8-trimethylthiochroman-7-carboxylate were initially charged in 600 ml of a 1:1 mixture of water/methanol, and 15.1 g (0.377 mol) of sodium hydroxide were added. The solution was then heated under reflux for three hours, the organic solvent was removed, 200 ml of water were added and the mixture was made acidic using conc. hydrochloric acid with cooling. The precipitate was filtered off with suction, washed with water and dried.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:24]#[N:25].C(OCC)C.[OH-].[Na+]>CN1CCCC1=O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[C:18]([C:24]#[N:25])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]C#N
Reactant: COc1ccc(Br)cc1[C@H]1CN(Cc2ccccc2)CCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COc1ccc(C#N)cc1[C@H]1CN(Cc2ccccc2)CCO1
Yield: 0.1 %

Procedure:
A solution of (2S)-4-benzyl-2-(5-bromo-2-methoxyphenyl)-morpholine (17.1 g, 47.2 mmol) and copper cyanide (6.35 g, 70.9 mmol) in 1-methyl-2-pyrrolidinone (140 ml) was stirred at 160° C. for 9 hours. Diethyl ether and 1N aqueous sodium hydroxide were added to the reaction mixture, and the solution was passed through Celite column. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (2S)-4-benzyl-2-(5-cyano-2-methoxyphenyl)-morpholine (10.1 mg, 69%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[CH2:19])[C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1>CN(C)C=O>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:16](=[O:18])[CH3:17])[CH2:4][CH2:19]2)=[CH:11][CH:10]=1
Reactant: C[S+](C)C
Reactant: C=C(C(C)=O)c1ccc(C)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C1(c2ccc(C)cc2)CC1
Temperature: 0 °C
Yield: 48.6 %

Procedure:
507 mg of sodium hydride (55% in paraffin oil) is introduced into 20 ml of dimethylformamide under nitrogen at 0° C., and 1.36 g of trimethylsulfonium iodide is added. After 30 minutes at this temperature, 845 mg of ketone 40 is added in drops to 4 ml of dimethylformamide. It is stirred for 1 more hour at 0° C., then quenched with sodium chloride solution, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane, 447 mg of title compound 41 is obtained as a colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([Br:12])[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[Br:12][C:10]1[C:9]2[S:13][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:15][C:8]=2[C:7]([OH:22])=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[N:11]=1
Reactant: CCOC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (191 mg, 0.50 mmole) and glycine (1.33 g, 17.69 mmole) in 0.5 M sodium methoxide/methanol (25.3 ml) was refluxed for 28 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (120 ml) and extracted with dichloromethane (3×100 ml). The remaining aqueous layer was acidified to pH=2 with 1N HCl. The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (137 mg). MS: (+) m/z 408.12, 410.09 (M+1, 79Br/8tBr), (−) m/z 406.08, 408.05 (M−1, 79Br/81Br).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)cc1Cl
Product: O=C(Cl)c1ccc(Br)cc1Cl

Procedure:
Following the procedures described in Example 36: 4-bromo-2-chlorobenzoic acid and oxalyl chloride were reacted to provide 4-bromo-2-chloro-benzoyl chloride, which was reacted with 3-methylamino-but-2-enoic acid methyl ester to provide 2-(4-bromo-2-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester. 2-(4-Bromo-2-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester and hydroxylamine hydrochloride were then reacted to provide 5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester. Following Example 36, Step 4, 5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester was hydrolyzed to 5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid. 5-(4-Bromo-2-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid and (R)-1-(2-chloro-phenyl)-ethanol were then reacted as described in Example 36, Step 5 to provide [5-(4-bromo-2-chloro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.8 %

Procedure:
To a slurry of 2.92 g (22 mmol) 5-hydroxyindole and 12.43 g (90 mmol) K2CO3 in 110 mL acetone was added 2.07 mL (24 mmol) allyl bromide. The reaction was stirred at room temperature over 2 days upon which time TLC indicated that the reaction was not complete. Additional 0.66 mL allyl bromide was added and the reaction was heated to reflux for 1.5 hr and stirred at room temperature over night. The reaction was filtered to remove precipitate and concentrated. The crude product was chromatographed on silica gel using 20–33% EtOAc-hexane to afford 3.128 g (18 mmol) 5-allyloxyindole as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH3:7])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][O:9]CC=C)[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.C(=O)(O)[O-].[Na+]>ClCCl>[O:1]=[C:2]1[N:6]([CH3:7])[C:5]([CH2:8][OH:9])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:21]=1
Reactant: C=CCOCC1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 0.52 g of 4-[2,5-dioxo-3-methyl-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in 40 mL of dichloromethane is added 2 mL of trifluoroborane-dimethylsulfide complex in 10 mL of dichloromethane. The mixture is stirred at rt for 3 hours and poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 70/30 heptane/ethyl acetate mixture to provide the desired product.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.BrC1[S:27][C:28]([CH3:31])=[CH:29][N:30]=1>>[CH3:22][C:14]1([CH3:21])[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:12]([C@H:10]2[CH2:9][C@H:8]([NH:7][C:6]3[S:27][C:28]([CH3:31])=[CH:29][N:30]=3)[CH2:11]2)[C:13]1=[O:23]
Reactant: Cc1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Product: Cc1cnc(N[C@H]2C[C@H](N3C(=O)C(C)(C)c4cccnc43)C2)s1

Procedure:
3,3-Dimethyl-1-(trans-3-((5-methylthiazol-2-yl)amino)cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one was prepared by Method B7 using starting materials 1-(trans-3-aminocyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (intermediate 26, 0.100 g, 0.329 mmol) and 2-bromo-5-methylthiazole (0.0585 g, 0.329 mmol) at 120° C. for 192 h. M+1: 329.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (s, 6 H) 2.23 (d, J=1.17 Hz, 3 H) 2.24-2.33 (m, 2 H) 3.16-3.27 (m, 2 H) 4.23-4.33 (m, 1 H) 5.14 (quin, J=8.41 Hz, 1 H) 6.71 (br. d, J=1.20 Hz, 1 H) 7.08 (dd, J=7.24, 5.28 Hz, 1 H) 7.76 (dd, J=7.24, 1.56 Hz, 1 H) 7.81 (d, J=6.26 Hz, 1 H) 8.21 (dd, J=5.18, 1.66 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:21]([F:28])([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:21]([F:28])([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=2)=[CH:9][CH:10]=1)[CH3:19]
Reactant: CCOC(=O)Cc1ccc(-c2ccnc(Br)c2)cc1
Reactant: CCOC(=O)C(F)(F)Br
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccnc(C(F)(F)C(=O)OCC)c2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a sealed tube were added ethyl 2-(4-(2-bromopyridin-4-yl)phenyl)acetate 203-3 (440 mg, 1.37 mmol), ethyl 2-bromo-2,2-difluoroacetate (1.7 mL, 13.7 mmol), Cu (1.3 g, 20.6 mmol) and DMF (5 mL). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 80° C. for 1 hour. After cooling to room temperature, the mixture was filtered through a layer of Celite and concentrated. The residue was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give ethyl 2-(4-(4-(2-ethoxy-2-oxoethyl)phenyl)pyridin-2-yl)-2,2-difluoroacetate 203-4. MS m/z 364.2 (M+1).