Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:14][CH2:13][C:8]3[N:9]([CH3:12])[N:10]=[CH:11][C:7]=3[C:4]=2[NH:5][N:6]=1.[H-].[Na+].I[CH3:18].[ClH:19]>CN(C)C=O.C(OCC)C>[ClH:19].[CH3:18][N:5]1[C:4]2[C:7]3[CH:11]=[N:10][N:9]([CH3:12])[C:8]=3[CH2:13][CH2:14][C:3]=2[C:2]([CH3:1])=[N:6]1
Reactant: CI
Reactant: Cc1n[nH]c2c1CCc1c-2cnn1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1nn(C)c2c1CCc1c-2cnn1C
Temperature: 0 °C
Yield: 20 %

Procedure:
A solution of 14.5 g of 1,4,5,6-tetrahydro-3,6-dimethylbenzo[1,2-c:3,4-c']dipyrazole in 50 ml of dimethylformamide was added to an ice-cold stirred suspension of 2.4 g of sodium hydride in 50 ml of dimethylformamide. The reaction was stirred at 0° C. for 20 minutes and then a solution of 6.3 ml of iodomethane in 15 ml of dimethylformamide was added dropwise. The mixture was allowed to come to room temperature and stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane and water. The aqueous layer was extracted exhaustively with dichloromethane and the combined dichloromethane extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographed (7.5% 2-propanol in dichloromethane) to give crude product. This crude mixture was dissolved in ethyl ether and acidified with ethereal hydrogen chloride. The cream color precipitate which formed was recrystallized from 2-butanol to give 1,4,5,6- tetrahydro-1,3,6-trimethylbenzo[1,2-c:3,4-c']dipyrazole monohydrochloride as light-yellow granules (20% yield) melting at about 252°-254° C.
Reaction SMILES: [O-:1]CC.[Na+].[CH2:5]([O:7][C:8]([C:10]1[C:15](=[O:16])[N:14](CC2C=CC=C(F)C=2)[C:13]2[CH:25]=[CH:26][S:27][C:12]=2[C:11]=1N1CCNCC1)=[O:9])[CH3:6]>C(O)C>[CH2:5]([O:7][C:8]([C:10]1[C:15](=[O:16])[NH:14][C:13]2[C:25]([C:11]=1[OH:1])=[CH:26][S:27][CH:12]=2)=[O:9])[CH3:6]
Reactant: CC[O-]
Reactant: CCOC(=O)c1c(N2CCNCC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cscc2[nH]c1=O
Yield: 56.9 %

Procedure:
Sodium ethoxide (4.75 g, 66.34 mmol) was added to a solution of 4-(2-ethoxycarbonyl-acetylamino)-thiophene-3-carboxylic acid methyl ester (19) (8.57 g, 31.59 mmol) in anhydrous ethanol and refluxed overnight. The solution was cooled and excess solvent was distilled off The residue was dissolved in water and acidified by cold diluted HCl solution. The solids formed were filtered, washed by water and dried under vacuum at room temperature to get 4.3 g (57%) of 7-hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester as white solid. MP 193° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.27 (t, J=7.2 Hz, 3H), 4.28 (q, J=7.2 Hz, 2H), 6.83 (d, J=3.2 Hz, 1H), 8.24 (d, J=3.6 Hz, 1H), 11.10 (s, 1H), 12.90 (s, 1H) ppm; MS m/z=240 amu (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([OH:12])[CH2:10][OH:11].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([O:11][CH2:10][CH2:9][OH:12])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1cc(Cl)ncn1
Reaction time: 2 h

Procedure:
To a mixture of 4,6-dichloropyrimidine (5.0 g), ethylene glycol (100 ml) and tetrahydrofuran (100 ml) is added sodium hydride (60% dispersion, 1.34 g) under ice-cooling, and the mixture is stirred at the same temperature for two hours, and evaporated under reduced pressure to remove the solvent. The residue is extracted with ethyl acetate, and the extract is dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=5:1~2:1) to give 2-(6-chloropyrimidin-4-yloxy)ethanol (5.67 g) as an oily product.
Reaction SMILES: COS([O-])(=O)=O.[CH3:7][C:8]1[N:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]2[C:20]=1[CH2:21][N+](C)(C)C.[CH3:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1>C(O)C>[CH3:7][C:8]1[N:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]2[C:20]=1[CH2:21][C:27]1([CH3:26])[N:31]=[CH:30][CH:29]=[N:28]1
Reactant: Cc1ncc[nH]1
Reactant: Cc1nc2c3ccccc3ccn2c1C[N+](C)(C)C
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Product: Cc1nc2c3ccccc3ccn2c1CC1(C)N=CC=N1
Reaction time: 4 h
Yield: 37.5 %

Procedure:
A mixture of 2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline methylsulfate (3 g) and 2-methylimidazole (1.6 g) in ethanol (50 ml) was refluxed with stirring for 4 hours and evaporated in vacuo. To the residue was added water and the resulting precipitates were collected by filtration, dried and recrystallized from ethyl acetate to give 2-methyl-3-(2-methyl-1-imidazolylmethyl)imidazo[2,1-a]isoquinoline (0.85 g).
Reaction SMILES: CN1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)=[N:5][CH2:4][C:3]1=[O:23].[CH2:24]([O:26]C(=O)OCC)[CH3:25].[H-].[Na+]>>[CH2:24]([O:26][C:3]([C:4]1[NH:5][C:6]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)=[C:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:23])[CH3:25]
Reactant: CCOC(=O)OCC
Reactant: CN1C(=O)CN=C(c2cccc(C(F)(F)F)c2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1[nH]c(-c2cccc(C(F)(F)F)c2)c2ccccc12

Procedure:
According to the procedure described in Example 1, 1,3-dihydro-1-methyl-5-(α, α, α-trifluoro-m-tolyl)-2H-1,4-benzodiazepin-2-one is reacted with diethylcarbonate in the presence of sodium hydride, and there is obtained 3-(α, α, α-trifluoro-m-tolyl)-isoindole-1-carboxylic acid ethyl ester, having a melting point of 155°-157° C. Recrystallization from ethanol does not increase the melting point.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>O1CCCC1.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cccc(S(=O)(=O)CCO)c1
Yield: 100 %

Procedure:
2-(3-Nitrophenylsulfonyl)ethanol (10 g; 43 mmol) was dissolved in 200 ml tetrahydrofuran and 200 mL ethanol, 3 g Pd/C (10%) was added and the mixture treated with hydrogen gas. The solvents were removed to obtain 8.8 g (43 mmol, 100% yield) of the desired compound as colourless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:33][CH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41]>ClCCl>[OH:43][C:36]1[C:35]([CH2:34][NH:33][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[O:13])=[C:40]([CH3:41])[CH:39]=[C:38]([CH3:42])[N:37]=1
Reactant: Cc1[nH]c2ccccc2c1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)[nH]c3ccccc23)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 51.5 %

Procedure:
To a solution of 2-methyl-1H-indole-3-carboxylic acid (3.3 g, 18.85 mmol), 1-hydroxybenzotriozole (4.69 g, 37.7 mmol, 2 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.24 g, 37.7 mmol, 2 eq), triethylamine (20.0 mL) in dichloromethane (100 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (5.77 g, 37.7 mmol, 2 eq). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=10:2) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide as a white solid (3.00 g, 9.7 mmol, 51%). LRMS (M+H+) m/z: calcd 309.36. found 310. HPLC Purity (214 nm): >95%. 1H NMR (300 MHz, d6-DMSO): δ 11.61 (s, 1H), 11.43 (s, 1H) 7.74 (d, J=5.1 Hz, 1H), 7.58-7.54 (m, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.04 (t, J=6 Hz, 3H), 5.89 (s, 1H), 4.32 (d, J=4.5 Hz, 2H), 2.57 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=2[C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:56][C:57]1[CH:68]=[CH:67][C:60]2[NH:61][C:62]([C@@H:64]([NH2:66])[CH3:65])=[N:63][C:59]=2[CH:58]=1>CN1C(=O)CCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:66][C@H:64]([C:62]3[NH:61][C:60]4[CH:67]=[CH:68][C:57]([Cl:56])=[CH:58][C:59]=4[N:63]=3)[CH3:65])=[O:20])=[CH:16][C:15]=2[C:23]([F:26])([F:24])[F:25])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 4-(4-N-Boc-piperazin-1-yl)-3-trifluoromethyl-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in NMP and subsequent purification by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=50:50).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]O)=[CH:23][N:24]=2)[CH:3]=1.[Br-:27].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(=O)([O-])O.[Na+]>ClCCl>[Br:27][CH2:25][C:22]1[O:21][C:20]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]3[C:5]=2[CH:6]=[N:7][N:8]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:24][CH:23]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CO)o3)cc(Cl)cc21
Reactant: [Br-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CBr)o3)cc(Cl)cc21
Temperature: 3 °C
Reaction time: 0.17 h

Procedure:
(2-(6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methanol (1.0 eq., 1 wt, 34.0 g) and triphenylphosphine dibromide (1.3 eq., 1.32 wt, 45.0 g) are stirred in dichloromethane (15 vols, 510 ml) at 20 (±3° C.) under a nitrogen atmosphere for 1 hr. The reaction is then checked by HPLC for completion. Once complete methanol (0.8 vols, 27.2 ml) is added to the reaction, with vigorous stirring 8% w/w sodium hydrogen carbonate solution (10 vols, 340 ml) is added drop wise over 15 minutes (check aqueous pH>7). The mixture is heated to 30° C. (±3° C.) and stirred together for 10 minutes, then separated, the aqueous is back extracted with dichloromethane (5 vols, 170 ml) and the combined dichloromethane layers are washed with water (5 vols, 170 ml). The dichloromethane solution is then evaporated under reduced pressure to a volume of approximately 4 vols. To the solution is added methanol (15 vols, 510 ml) and the solution evaporated under reduced pressure at 260 mbar, 20° C. to remove the remaining dichloromethane down to ˜15 vols. The suspension is then stirred at 20° C. for at least 6 hrs. The solid is filtered, washed with methanol (2×1 vols, 2×34 ml), sucked dry for 20 minutes, then dried under high vacuum at 30° C. (±3° C.) to constant probe temperature to afford 5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole as a beige solid.
Reaction SMILES: N1C=CC=NC=1.Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:9]=1[N+:25]([O-:27])=[O:26].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:8]2[C:9]([N+:25]([O-:27])=[O:26])=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[N:11]=[CH:12][N:13]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1cncnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
General Procedure for the Addition of Amine to pyrimidine: (6-Chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (132 mg, 0.4 mmole), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.4 mmole, 1 eq) and K2CO3 (0.4 mmole, 1 eq) were dissolved in DMF, and the mixture was stirred at 60° C. for 1 hour. Final product was precipitated out with water to provide Compound B1 as a yellow solid (152 mg, 77%). 1H NMR (400 MHz CDCl3) δ (ppm): 10.8 (s, 1H), 9.18 (d, 1H), 8.17 (s, 1H), 7.90 (d, 2H), 7.85 (d, 2H), 4.39-4.32 (m, 1H), 4.02 (m, 2H), 3.01 (s, 3H), 2.95-2.90 (m, 2H), 2.00 (m, 2H), 1.57-1.50 (m, 2H), 1.46 (s, 9H). Exact mass calculated for C21H28N6O6S 492.18, LCMS (ESI) m/z 493.4 (M+H+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:18]>C(#N)C.C1COCC1.[Ag-]=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:18])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Reactant: CI
Agent: O=[Ag-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N=[N+]=[N-]
Temperature: 25 °C

Procedure:
24.1 A solution of 1.0 g (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.2) in 15 ml acetonitrile and 3 ml THF was treated with 3.0 g silver(I) oxide and and 2.7 ml iodomethane. The reaction mixture was stirred over night at r.t., then again treated with 3.0 g silver(I) oxide and 2.7 ml iodomethane. The reaction was agitated over night at r.t., then filtrated. The filtrate was concentrated. The crude product was purified by chromatography (silica gel; cyclohexane/EtOAc 2:1) to give 1.0 g (3S,4S)-3-azido-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester as light yellow oil. MS 243.4 ([M+H]+)
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[OH:19]>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Cl:1][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[OH:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2ccccc2c1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: Oc1ccc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a cooled (0-5° C.) solution of N-chlorosuccinimide (1.4 g, 10.4 mmol) in 100 mL of CH2Cl2, ZrCl4 (0.122 g, 5% mol) was added followed by 1.5 g (10.4 mmol) of naphthalen-2-ol. The mixture was stirred for 18 h at room temperature until the complete disappearance of the starting material as judged by TLC and GC analysis. The mixture was quenched with saturated NH4Cl aqueous solution (30 mL) and transferred to a separatory funnel. The two phases were separated and the organic one was washed with water (3×10 mL), dried over Na2SO4 and evaporated under vacuum to give yellow oil. The crude was purified by flash cromatography (petroleum ether/ethyl acetate 85:15) to afford 1-chloronaphtalen-2-ol (1.4 gr, 78% yield), as white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[Cl:22][CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][Cl:22])[CH:25]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.8 %

Procedure:
Triethylamine (1.93 mL; 13.78 mmol) was added at 0° C. to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.3 g; 5.51 mmol) and 3-(chloromethyl)benzoyl chloride (1.13 g; 5.79 mmol) in dichloromethane (75 mL). The mixture was stirred for 20 minutes at room temperature and was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to furnish 1.45 g (76%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCCc2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 52 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 1-bromo-3-phenylpropane (167 μL). The reaction mixture is allowed to stir at room temperature for 72 h. The reaction mixture is poured into water (25 mL) and extracted with EtOAc (2×25 mL). The organic layer is dried (Na2SO4) and concentrated. The resulting crude solid is purified by recrystallization from ethanol to afford 277 mg (52%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[CH:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:19]=[CH:18]3)([OH:14])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]1[C:31]#[N:32].[O-:33][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[C:31]([C:5]1[N:4]([CH2:3][C:2]([OH:33])=[O:1])[CH:8]=[C:7]([C:9]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:19]=[CH:18]3)([OH:14])[C:10]([F:12])([F:13])[F:11])[CH:6]=1)#[N:32]
Reactant: N#Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cn1CC=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cn1CC(=O)O
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a solution of 1-(2-oxoethyl)-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyrrole-2-carbonitrile (208 mg, 0.47 mmol, 1 equiv.) in 12 mL of 3:1 acetone-water was added KMnO4 (78 mg, 0.49 mmol, 1.1 equiv.). After 18 hours, the mixture was filtered through CELITE® filter aid and the filter cake washed with acetone. The filtrate was evaporated and the aqueous was diluted with water and EtOAc. The mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to provide 197 mg (91%) of (2-cyano-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}pyrrol-1-yl)acetic acid which was used without further purification.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:8])[C:5]([OH:7])=O.[Br:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].N1C=CC=CC=1>C(Cl)Cl>[Br:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:5](=[O:7])[C:4]([O:3][CH3:2])=[O:8])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(OCCCBr)c1
Reactant: COC(=O)C(=O)O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc(OCCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.5 ml of oxalic acid monomethyl ester chloride in 10 ml of methylene chloride is added dropwise to a solution of 3.5 g of 3-(3-bromopropoxy)-aniline and 1.3 ml of pyridine in 40 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for 2 hours, the mixture is poured onto water and extracted with methylene chloride. The combined extracts are evaporated and the residue is chromatographed on silica gel with methylene chloride/ethyl acetate (10:1). The eluate is evaporated and the residue is crystallised from ether/hexane. Methyl N-[3-(3-bromopropoxy)-phenyl]-oxamate of melting point 90°-91° is obtained.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][N:6]=1)=[O:3].[OH-].[Na+].N1C=CC=CC=1.C([O:25][C:26]1C(=[CH:31][CH:32]=[CH:33][CH:34]=1)C(Cl)=O)(=O)C>Cl.C(#N)C>[NH2:13][S:10]([C:8]1[S:9][C:5]([NH:4][C:2](=[O:3])[C:1]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[OH:25])=[N:6][N:7]=1)(=[O:12])=[O:11]
Reactant: CC(=O)Nc1nnc(S(N)(=O)=O)s1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: c1ccncc1
Product: NS(=O)(=O)c1nnc(NC(=O)c2ccccc2O)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetazolamide (50 g) was stirred and heated at reflux in 500 ml 3N hydrochloric acid for half an hour. The cooled solution was made basic with 50% sodium hydroxide. The precipitated white solid 5-amino-1,3,4-thiadiazole-2-sulfonamide was collected (Compound 1, 28 g). It was dried further at 70° C. in a vacuum oven overnight. To a mixture of Compound 1 (4.5 g, 0.025 mole) and pyridine (2.42 ml, 0.03 mole) in 70 ml acetonitrile was added acetylsalicyloyl chloride (98%, 5 g, 0.025 mole). The reaction mixture warmed and became a clear solution. Solid deposits occurred slowly after stirring at room temperature for 1/2 hour. After two hours the solvent was evaporated; the residue was triturated with isopropyl alcohol/water for two hours and then filtered, rinsed in succession with isopropyl alcohol/water, isopropyl alcohol/isopropyl ether, 2×isopropyl ether. From the combined mother liquor and rinsings, a second crop was collected. Both the first and second crops were combined and dissolved in 50 ml N-methyl-2-pyrrolidone. The solution was filtered and the filtrate was treated with 15 ml 3N hydrochloric acid at 70° C. for half an hour. Upon dilution with 200 ml water, a white solid precipitated. The solid was collected, rinsed with water, and dried in a vacuum over at 80° C. overnight to 4.4 g of title compound, mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH3:29][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:29])=[O:25])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1

Procedure:
4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzoic acid from Step A (32 mg, 0.077 mmol) was dissolved in MeOH (0.5 mL) and DCM (0.5 mL). Trimethylsilyl diazomethane (2.0 M in ether) was slowly added at 0° C. until a yellow color persisted. The volatiles were evaporated to give methyl 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzoate which was used without further purification. LCMS: m/z 421.1 (M+H)+.