Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8](=O)[NH:7][C:6]([NH2:12])=[N:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>C(N(CC)C1C=CC=CC=1)C>[NH2:12][C:6]1[N:5]=[C:4]2[C:9]([NH:10][C:2]([CH3:1])=[N:3]2)=[C:8]([Cl:15])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2nc(N)[nH]c(=O)c2[nH]1
Solvent: CCN(CC)c1ccccc1
Product: Cc1nc2nc(N)nc(Cl)c2[nH]1

Procedure:
A suspension of 8-methylguanine (Daves et al., J. Am. Chem. Soc., 82, 2633-2640 (1960)) (1.0 g, 6.1mmol) in phosphorous oxychloride (30 mL) and N,N-diethylaniline (1 mL) was refluxed for 3 h. The excess phosphorous oxychloride was evaporated under reduced pressure. The resulting brown oil was dissolved in ice-water and was neutralized with a concentrated aqueous NaOH solution. After evaporation of the solvent, the solid residue was suspended in 70 mL of H2O. Undissolved solid was filtered off, and the filtrate was loaded on a 3×80 cm Sephadex LH-20 column eluted with methanol/water (1:1) at 1 mL/min. Column eluent was continuously monitored at 280 nm and fractions (10 mL) were collected. Evaporation of pooled fractions 50-60 produced 2-amino-6-chloro-8-methylpurine as a crude solid. Crystallization from ethanol/water with charcoal treatment afforded 2-amino-6-chloro-8-methylpurine as a white solid: yield, 0.57 g (51%); mp >265° C. dec.; 1H NMR δ 2.39 (s, 3H, CH3), 6.62 (s, 2H, NH2, exchange with D2O), 12.56 (s, 1H, NH, exchanges with D2O); MS (EI) calcd. m/z for C6H6N535Cl 183.0312, found 183.0309; calcd. m/z for C6H6N537Cl 185.0283, found 185.0286.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:22]([N+:24]([O-:26])=[O:25])[CH3:23])[CH:18]=3)[CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].BrC1C=C2C(=CC=1)C([C:38]([F:41])([F:40])[F:39])=C(O[C@H]1CC[C@H](C(C)(C)C)CC1)C=C2>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:22]([N+:24]([O-:26])=[O:25])[CH3:23])[CH:18]=3)[C:13]=2[C:38]([F:41])([F:40])[F:39])[CH2:7][CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2C(F)(F)F)CC1
Reactant: CC(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Product: CC(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]

Procedure:
2-(trans-4-tert-butylcyclohexyloxy)-6-(1-nitroethyl)-1-(trifluoromethyl)naphthalene was synthesized as per 2-(trans-4-tert-butylcyclohexyloxy)-6-(1-nitroethyl)naphthalene (Example 204) in 35% yield using 6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene as starting material.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1SCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)=O)ccc1SCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 65 h
Yield: 113 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 1-[4-[(3-chloropropyl)-thio]-3-methoxyphenyl]ethanone (3.5 g, 13.6 mmol), K2CO3 (2.3 g, 16.6 mmol), KI (200 mg) and CH3CN (100 ml) was stirred at reflux under nitrogen for 7.5 hours and then was left at ambient temperature for 65 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed twice with water, once with brine and dried over MgSO4. The solvent was removed in vacuo to afford 6.8 g of a light brown oil. The sample was purified by flash chromatography. Concentration of appropriate fractions yielded 3.0 g. Recrystallization from ethanol provided 2.4 g (41%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]ethanone as a beige solid, m.p.=93°-95° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:48]1[CH:49]=[C:50]([C:54](=[O:56])[CH3:55])[CH:51]=[CH:52][CH:53]=1.Cl>C1COCC1.O>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[CH2:15][CH2:14][O:13][C:53]1[CH:52]=[CH:51][C:50]([C:54](=[O:56])[CH3:55])=[CH:49][CH:48]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: CC(=O)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 48 h
Yield: 77.2 %

Procedure:
Diethylazodicarboxylate (20.7 mL, 131.6 mmol) in THF (35 mL) was added dropwise in to a cold (0° C.) solution of 4-(2'-hydroxy-ethyl)-5-methyl-2-phenyloxazole (25.0 g, 123.0 mmol), triphenylphosphine (34.5 g, 131.6 mmol), and 3'-hydroxyacetophenone (18.0 g, 131.6 mmol) and THF (180 mL). The mixture was allowed to come to room temperature and stirred for 48 hours. Then, it was poured into H2O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/EtOAc 5/1) gave a white solid (30.5 g, 77% yield, m.p. 70°-71° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH2:44][CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH2:44][CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(CC)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (240 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K20) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (339 mg, 79%).
Reaction SMILES: [N:1](=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])[OH:2].[H-].[Na+].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>O1CCCC1.C(OCC)C>[CH3:13][N:14]([CH3:18])[C:15]([O:2][N:1]=[C:3]1[S:7][C:6]([CH3:9])([CH3:8])[N:5]=[C:4]1[CH3:10])=[O:16]
Reactant: CN(C)C(=O)Cl
Reactant: CC1=NC(C)(C)SC1=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=NC(C)(C)SC1=NOC(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.0 g (0.019 mol) of 5-oxo-2,2,4-trimethyl-3-thiazoline oxime are added portionwise to a suspension of 0.9 g of sodium hydride in 20 ml of tetrahydrofuran. The sodium hydride was liberated shortly before its use from a 55% suspension in oil by two-fold extraction with a small amount of absolute pentane. After completion of the hydrogen evolution, the mixture is stirred at room temperature for an additional 1 hour. 2.05 g (0.019 mol) of dimethylcarbamoyl chloride are added dropwise, and the reaction mixture is stirred at room temperature for 16 hours. The residue is then taken up in diethyl ether, and the organic phase is washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is subsequently distilled off, and the residue is recrystallized from diethyl ether/n-hexane to yield 5-oxo-2,2,4-trimethyl-3-thiazoline O-(dimethylcarbamoyl) oxime, m.p. 92°-95° C.
Reaction SMILES: Br[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[OH:4].[I-].[Na+].[N-:18]=[N+:19]=[N-:20].[Na+].CS(C)=O>O>[N:18]([CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[OH:4])=[N+:19]=[N-:20]
Reactant: CS(=O)(=O)Nc1ccc([C@H](O)CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)Nc1ccc([C@@H](O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 37 %

Procedure:
A mixture of N-{4-[(1S)-2-bromo-1-hydroxyethyl]phenyl}methanesulfonamide (which was obtained in Example 112) (1.73 g, 5.9 mmol), sodium iodide (0.88g, 5.9 mmol), sodium azide (1.53 g, 23.6 mmol), and methyl sulfoxide (15 mL) was stirred at ambient temperature for 7 days, poured into water and extracted with ethyl acetate. The organic extracts were washed with water, and dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/chloroform/isopropylalcohol 5/4.5/0.5) gave an off-white solid (0.56 g, 70% yield); MS (ES) m/z: 256 (M)+; 1H NMR (400 MHz, DMSO-d6) δ 2.94 (s, 3H), 3.30 (m, 2H), 4.74 (m, 1H), 5.75 (d, 1H), 7.17 (d, 2H), 7.32 (d, 2H), 9.67 (s, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7](=[O:25])[CH:8]([OH:24])[CH2:9][NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([F:21])[CH:20]=1)[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]2.C(N(CC)CC)C>ClCCl>[CH3:5][O:6][C:7]([C@@H:8]1[O:24][C:1](=[O:2])[N:10]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([F:21])[CH:20]=2)[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]3)[CH2:9]1)=[O:25]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)C(O)CNc1cc(F)c2c(c1)CCC(=O)N2C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)CCC(=O)N3C)C(=O)O1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
Phosgene (20% solution in toluene, 4.07 ml, 7.69 mmol) is added dropwise at 0° C. to 3-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)-2-hydroxypropionic acid methyl ester (Step 4, 1.81 g, 6.41 mmol) and triethylamine (2.23 ml, 16.0 mmol) in dichloromethane (25 ml). The mixture is allowed to warm to room temperature and stirred for an additional hour. The reaction is washed with 2N aqueous hydrochloric acid and saline, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography (50% ethyl acetate/hexane) to give the title compound as a white solid (1.71 g, 83%); MS (m/z): [M+H]+=323.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1>C(O)C>[Cl:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:26]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Clc1cc(N2CCC3(CC2)OCCO3)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (9.02 g) and diisopropylethylamine (9.77 g) in ethanol (30 ml) was added 4,6-dichloropyrimidine (9.88 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was diluted with dichloromethane (150 ml). The mixture was washed with 0.3N sodium hydroxide solution and saturated brine, dried and concentrated, and the residue was crystallized from diethylether to give colorless crystals of 8-(6-chloropyrimidine-4-yl)-1,4-dioxa-8-azaspiro[4,5]decane (15.84 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)/[CH:10]=[CH:11]/[C@@H:12]2[C@@H:24]3[C@@H:15]([O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23]3)[CH2:14][C@H:13]2[O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:40]([NH2:42])[CH3:41].Cl>O1CCCC1.O>[CH2:40]([NH:42][C:17](=[O:25])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][C@H:24]1[C@@H:15]([OH:16])[CH2:14][C@@H:13]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C@@H:12]1/[CH:11]=[CH:10]/[C@@H:9]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:41]
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Reactant: CCN
Agent: Cl
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2ccccc2)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Temperature: 40 °C
Yield: 73.8 %

Procedure:
A solution of (6Z,8aR,9R,10R,11aS)-4,5,8,8a,9,10,11,11a-octahydro-9-((S,E)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-1-enyl)-10-(tetrahydro-2H-pyran-2-yloxy)cyclopenta[b]oxecin-2(3H)-one (3.0 g, 5.57 mmol) in 15 mL tetrahydrofuran (THF) was treated with 2 M ethylamine (31 ml) in THF. This mixture was stirred and heated at 40° C. over 18 hours under an atmosphere of nitrogen. The mixture was diluted with 50 mL water and the pH was adjusted to 6 with 1N HCl. The layers were separated and the aqueous layer was extracted with 20 mL ethyl acetate twice. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. Then, the crude product was purified by column chromatography providing 2.4 g of the title compound (73.8% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Cl:7][S:8](O)(=[O:10])=[O:9]>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:8]([Cl:7])(=[O:10])=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccsc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccsc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
A 49-g (0.5 mol) sample of 3-methylthiophene was added in small portions to a cooled solution (-20° C) of 128 g (1 mol) chlorosulfonic acid in 250 cc chloroform. After the addition was completed, the reaction mixture was allowed to warm to about 25° C and then heated at reflux for 30 minutes. The reaction mixture was then diluted with ice water and neutralized with aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and evaporated to give 30 g of 3-methyl-2-thienylsulfonyl chloride.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][C:3]1=[CH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1>CO.CC(N(C)C)=O.[Pd]>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH:3]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:4]1
Reactant: COC(=O)c1ccc(C=C2COc3ccccc3C2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(CC2COc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
Pd/C 10% was added to a suspension of 260 (200 mg, 0.68 mmol) in MeOH (40 ml) and DMA (10 ml) which was previously purged under vacuum. The reaction mixture was stirred during 4 h at room temperature. After evaporation of the MeOH, water was added to the oily residue and the precipitate obtained was filtered. The crude residue was then purified by flash chromatography on silica gel (5-8% AcOEt/Hex) to afford the title compound 263 (114 mg, 59%) as a white solid. LRMS: 282.1 (Calc.); 283.0 (found).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21](=O)[CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[NH2:37][NH2:38].CC(O)=O>CCO>[Cl:1][C:2]1[C:3]([C:21](=[N:37][NH2:38])[CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cnc21
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC(=NN)c2c(Cl)cnc3[nH]ccc23)CC1
Yield: 44.2 %

Procedure:
To a suspension of tert-butyl 4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxoethyl)piperidine-1-carboxylate (1.00 g, 1.87 mmol) in EtOH (6.4 mL) were added anhydrous hydrazine (2.94 mL, 94.0 mmol) and AcOH (0.536 mL, 9.36 mmol). The reaction mixture was stirred at reflux for about 16 h. The solvent was removed under reduced pressure and the crude material was taken up in DCM and dried over anhydrous MgSO4. The solvent was removed and DCM (3 mL) was added. The solid was removed by filtration and the filtrate was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford tert-butyl 4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydrazonoethyl)piperidine-1-carboxylate (0.324 g, 44%) as a white solid consisting of a 1/1 mixture of E/Z isomers: LC/MS (Table 1, Method r) Rt=1.46 and 1.53 min; MS m/z: 392/394 and 392/394 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.ClC1SC2C=CC=C(Cl)C=2N=1.[OH-].[Na+].O.[CH2:26]([OH:30])[CH:27]([CH3:29])[CH3:28]>>[CH2:26]([O:30][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CO
Reactant: Clc1cccc2sc(Br)nc12
Agent: Clc1nc2c(Cl)cccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)COc1nc2c(Cl)cccc2s1
Yield: 96.8 %

Procedure:
A mixture (11.30 g, 0.05 mole) of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole and 94% sodium hydroxide (2.34 g, 0.055 mole) in isobutanol (100 c.c.) was heated under reflux for 1 hour. Water was added and the alcohol was distilled azeotropically together with water. The resulting oily substance was extracted with chloroform, and the chloroform layer was washed with water. The solvent was then removed under reduced pressure to obtain 11.70 g of 2-isobutoxy-4-chlorobenzothiazole as a yellow viscous liquid. Yield 96.8%, purity 97.2%, b.p. 103.5°-105° C./0.15 mmHg.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:8]3[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:7]=3[N:6]2[CH:26]=1.C(=O)([O-])[OH:28].[Na+]>O1CCOCC1.O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:8]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:7]=2[N:6]2[CH:26]=[C:3]([CH2:2][OH:28])[N:4]=[C:5]2[CH2:11][N:10]=1
Reactant: O=C([O-])O
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nc(CCl)cn1-2
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nc(CO)cn1-2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 54.4 %

Procedure:
A solution of 2.7 g of 2-chloromethyl-6-(2-chlorophenyl)-8-nitro-4H-imidazo [1,2-a][1,4]benzodiazepine in 30 ml of dioxan was treated with a solution of 0.74 g of sodium hydrogen carbonate in 10 ml of water and the mixture was stirred at 80° C. for 2.5 h. The mixture was filtered and the filtrate was made neutral with aqueous 3N hydrochloric acid. The filtrate was evaporated in a vacuum and the residue was taken up in chloroform and water. The chloroform phase was washed with water, dried over sodium sulphate and evaporated in a vacuum. The residue was crystallized in 30 ml of ethyl acetate and diethyl ether and filtered. The crystals were dissolved in dichloromethane and chromatographed over 75 g of silica gel. With dichloromethane/ ethanol 99:1, 98:2 and 97:3 there were eluted small amounts of different impurities, with dichloromethane/ethanol 95:5 there was eluted 6-(2-chlorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol. After recrystallization from ethyl acetate there were obtained 1.4 g of pure 6-(2-chlorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 173-174° C. which was converted into the methane-sulphonate (m.p. 211-212° C.).
Reaction SMILES: OO.[CH3:3][C:4]1([CH3:23])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH:11]=2)[C:6](=[O:22])[CH2:5]1.C([O-])([O-])=[O:25].[K+].[K+].CS(C)=O>O>[CH3:3][C:4]1([CH3:23])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]([NH2:19])=[O:25])=[CH:16][N:15]=3)[CH:11]=2)[C:6](=[O:22])[CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(=O)c2ccc(Oc3ccc(C#N)cn3)cc21
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CC(=O)c2ccc(Oc3ccc(C(N)=O)cn3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 188.3 %

Procedure:
Add 30% aqueous H2O2 (3.15 ml) to a suspension of 6-(3,3-Dimethyl-1-oxo-indan-5-yloxy)-nicotinonitrile (877 mg, 3.15 mmol), K2CO3 (218 mg, 1.57 mmol) and DMSO (10 ml) stirring under nitrogen at ambient temperature. After four hours, dilute the reaction mixture with water (100 ml) and extract with EtOAc (2×). Wash the extract with water and brine, dry (MgSO4) and concentrate on rotary evaporator to yield 876 mg of the title compound as an off-white solid. Mass spectrum (ion spray): m/z=297 (M+1); 1HNMR (CDCl3): 8.62 (s, 1H), 8.24 (d, 1H), 7.75 (d, 1H), 7.24 (s, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 5.91 (broad, 2H), 2.63 (s, 2H), 1.43 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][O:12][CH2:11][C:10](=S)[NH:9]1.CO.[NH3:22]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][O:12][CH2:11][C:10]([NH2:22])=[N:9]1
Reactant: N
Reactant: Fc1ccccc1C1(C(F)(F)F)CCOCC(=S)N1
Solvent: CO
Product: NC1=NC(c2ccccc2F)(C(F)(F)F)CCOC1
Temperature: 25 °C

Procedure:
5-(2-Fluoro-phenyl)-5-trifluoromethyl-[1,4]oxazepane-3-thione (1.25 g, 4.26 mmol) was dissolved in NH3 solution 7 mol/L in methanol (27 mL, 128 mmol). The sealed reaction vessel was stirred over night at rt. The reaction mixture was evaporated, dissolved in TBME and extracted with 1N HCl. The layers were separated, washed with water and TBME. The aqueous layers were combined, basified by addition of solid K2CO3 and extracted with dichloromethane four times. The combined CH2Cl2 layers were dried over MgSO4.H2O and evaporated to give 1.12 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:19]Br.C1(C)C=CC=CC=1>C(O)(=O)C>[Br:19][C:11]1[C:12]([C:13]#[N:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[C:15]([F:18])([F:16])[F:17]
Reactant: BrBr
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen purge, a suspension or 2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile(1.6 g7 0.005 mol) in acetic acid (25 mL) is heated, all the material dissolving to a clear solution at about 60° C. A solution of bromine (0.8 mL; 0.015 mol) in acetic acid (10 mL) is added dropwise over 15 minutes to the refluxing solution. The solution is refluxed 6 hours then allowed to stir 18 hours at room temperature. The HPLC of the reaction mixture shows about 80% conversion to product. The mixture is heated back to reflux and more bromine (0.5 mL; 0.01 mol) in acetic acid (5 mL) is added dropwise. After refluxing another 3 hours, the aliquot shows >95% conversion to product. The reaction is cooled, and solvent removed under reduced pressure on a rotary evaporator to obtain a dark grey solid. Toluene is added to the mixture and removed under reduced pressure, but the odor of acetic acid still remains. The entire material is dissolved in hot toluene (75 mL) to a turbid solution which is treated with DARCO filter and filtered. The light pink solution deposits a white solid upon cooling to ambient. After cooling in the freezer, the solid is collected by filtration, washed with hexanes, and dried on the filter. Further drying in a vacuum oven at 45° C. provides the product (1.2 g; app. 60% theoretical); mp 247°-250° C.