Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:3]1.[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:5]=[N:6][N:2]([CH3:1])[N:3]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(-c2nnn(C)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Product: Cn1nnc(-c2ccc(CBr)cc2)n1

Procedure:
In a first step as depicted in Scheme 2, an appropriately substituted phenyl derivative, for example, the known compound 2-methyl-5-(4-methylphenyl)-1,2,3,4-tetrazole, is brominated with, for example N-bromosuccinimide and light, to afford the corresponding 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetrazole (A1). Intermediate (A1) is then reacted under basic conditions with an appropriately substituted cyclic amine derivative, for example, the known compound 4-piperidone hydrochloride monohydrate, to afford the corresponding 1-{[4-(2-methyl-1,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidin-4-one (B1). Intermediate (B1) is then reacted under acidic conditions with, for example sodium cyanide, to afford the corresponding nitrile compound, 4-hydroxy-1-{[4-(2-methyl(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carbonitrile (C1). Intermediate (C1) is esterified under acidic conditions with, for example ethanol, to afford the corresponding ethyl 4-hydroxy-1-{[4-(2-methyl-(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carboxylate (D1). The Grignard of an appropriately substituted halophenyl derivative, for example 4-trifluoromethoxybromobenzene, is reacted with intermediate (D1) to provide compounds of formula I-B, wherein X and Y are, for example hydroxyl. Example 2, set forth below, provides detailed methods to how compounds of formula I (-B) shown in Scheme 2 were prepared.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([NH:21][S:22]([CH2:25][CH2:26][NH2:27])(=[O:24])=[O:23])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([NH:21][S:22]([CH2:25][CH2:26][NH:27][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])(=[O:24])=[O:23])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CC(NS(=O)(=O)CCN)C1
Product: CC(C)(C)OC(=O)N1CC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)C1

Procedure:
3-{2-[(5-Chloro-thiophene-2-carbonyl)-amino]-ethanesulfonylamino}-azetidine-1-carboxylic acid tert-butyl ester was prepared by an analogous procedure as described in example 5 iii) starting from 240 mg (1.3 equiv.) 5-chloro-thiophene-2-carboxylic acid and 308 mg (1.1 mmol) 3-(2-amino-ethanesulfonylamino)-azetidine-1-carboxylic acid tert-butyl ester. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 3-{2-[(5-chloro-thiophene-2-carbonyl)-amino]-ethanesulfonylamino}-azetidine-1-carboxylic acid tert-butyl ester. The title compound was obtained in form of a colorless amorphous material.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:16][C:11]2=[CH:12][N:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1)=[O:7])[CH3:4].[CH3:17]I.[NH4+].[Cl-]>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:16]([CH3:17])[C:11]2=[CH:12][N:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1cc2ccncc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccncc2n1C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
NaH (60% dispersion in mineral oil, 51 mg, 1.26 mmol) was added to a solution of 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (200 mg, 1.05 mmol) in anhydrous DMF (10 mL) at 0° C. The mixture was stirred for 1 h, before being treated with MeI (79 μL, 1.26 mmol) and allowed to warm to 20° C. After 16 h, saturated aqueous NH4Cl (10 mL) was added, then the suspension was stirred vigorously for 1 h. The mixture was partitioned between H2O (10 mL) and EtOAc (30 mL), then the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated, then the residue was purified by flash chromatography (IH-EtOAc, 1:1) to provide 1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester: δH (CDCl3): 1.45 (t, 3H), 4.20 (s, 3H), 4.42 (q, 2H), 7.25 (s, 1H), 7.58 (d, 1H), 8.36 (d, 1H), 8.95 (s, 1H). A solution of this ester (36 mg, 180 μmol) in EtOH (3 mL) was treated with 2 M NaOH (270 μL, 540 μmol), then the mixture was stirred at 60° C. for 4 h. On cooling to ambient temperature, the mixture was treated dropwise with dilute AcOH to adjust the pH to 4. The resulting suspension was allowed to stand at ambient temperature for 7 d, then the precipitated solid was collected, washed with H2O, and dried to furnish the title compound: δH(CD3OD): 4.23 (s, 3H), 7.20 (s, 1H), 8.01 (d, 1H), 8.17 (d, 1H), 9.12 (s, 1H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:43][O:44][C:45]1[CH:53]=[C:49]([C:50](O)=[O:51])[C:48]([OH:54])=[CH:47][CH:46]=1>ClCCl.O>[OH:54][C:48]1[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:53][C:49]=1[C:50]([NH:11][CH2:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:13][CH:12]=1)=[O:51]
Reactant: COc1ccc(O)c(C(=O)O)c1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(O)c(C(=O)NCCc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
4-nitrophenethylamine hydrochloride (1.81 g; 8.9 mmol), triethylamine (2.8 ml; 20 mmol), hydroxybenzotriazole (1.45 g; 10.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (3.75 g; 19.62 mmol) are added to a solution of 1.5 g (8.9 mmol) of 5-methoxy-salicylic acid in dichloromethane (80 ml). The reaction medium is agitated overnight at 25° C. The mixture is diluted with 40 ml of water and agitated for ten minutes, then the product is extracted with dichloromethane. The organic solution is dried over sodium sulphate, filtered and concentrated under vacuum and the evaporation residue is purified on a silica column (eluent=ethyl acetate/heptane; 50/50) in order to produce a white solid which is obtained with a yield of 64%. Melting point: 200° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=[C:16]([CH3:26])[C:15]=2[C:27](OCC)=[O:28])=[CH:10][CH:9]=1>CCOCC>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=[C:16]([CH3:26])[C:15]=2[CH2:27][OH:28])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CO
Reaction time: 0.83 h
Yield: 66 %

Procedure:
A slurry of LiAlH4 (305 mg, 8.04 mmol) in dry Et2O (30 ml) at 0° C. treated with a solution of 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid, ethyl ester (1.587 gm, 4.73 mmol) in Et2O (4 ml). After 50 minutes, the reaction was quenched and diluted with H2O and the solution was adjusted to neutral pH with 10% HCl. EtOAc was added to dissolve suspended product into the Et2O layer and the mixture was subsequently extracted three times with EtOAc. The combined organic layers were washed with H2O and brine, then dried (Na2SO4), filtered and stripped to give a yellow solid. Recrystallization of the solid from hot hexane/acetone afforded 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinemethanol (916 mg) as a white solid. An additional 283 mg of 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinemethanol was obtained by evaporation of the mother liquor followed by recrystallization of the residue from hot hexane/EtOAc, giving a total of 1.199 gm (86%) product.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[CH:29]=[N:30][NH:31][C:25]=2[CH:24]=1.CNCCNC.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[CH:29]=[N:30][N:31]([C:2]3[N:7]=[C:6]([N:8]4[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]4)[CH:5]=[N:4][CH:3]=3)[C:25]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)n2)CC1
Reactant: Clc1cc2[nH]ncc2cn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(-n3ncc4cnc(Cl)cc43)n2)CC1
Temperature: 100 °C
Yield: 73.8 %

Procedure:
To a mixture of tert-butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate (0.45 g, 1.26 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (192 mg, 1.26 mmol) in dioxane (10 mL) was added CuI (19 mg, 0.1 mmol), N1,N2-dimethylethane-1,2-diamine (6.3 mmol, 0.55 g), K2CO3(3.78 mmol, 0.53 g). The reaction mixture was heated at 100° C., which was monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure. The crude material was purified by silica gel chromatography using petroleum ether/ethyl acetate (5% to 50%) as eluting solvents to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate as yellow solid (0.4 g, 74%). MS (ESI) m/z: δ 430 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[F:18][Sb-:19]([F:24])([F:23])([F:22])([F:21])[F:20].[Na+]>CO>[F:18][Sb-:19]([F:24])([F:23])([F:22])([F:21])[F:20].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N+:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[CH:5][CH:4]=1
Reactant: Clc1ccccn1
Reactant: COc1ccc(CCl)cc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C[n+]2ccccc2Cl)cc1

Procedure:
4,698 g (0.03 mol) of 4-methoxybenzyl chloride and 10.22 g (0.09 mol) of 2-chloropyridine were reacted in 40 ml of methanol at 40° C. for 3 days. After the reaction, the solvent was evaporate in vacuo and ether-water was added to the residue to extract unreacted reactants in the etherial layer. To the aqueous layer containing the pyridinium chloride was added 7.764 g (0.03 mol) of sodium hexafluoroantimonate. The resulting crystals were suction filtered, washed and dried to give the title compound melting at 122°-124° C.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8](OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.O1CCOCC1.[F:22][CH:23]1C(=O)[CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[C:1]([CH:3]=[C:4]1[CH2:5][N:6]([C@H:8]2[CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][C@H:23]2[F:22])[CH2:7]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](N2CC(=CC#N)C2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.3 %

Procedure:
To a solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (3.0 g, 15 mmol) in tetrahydrofuran (8 mL) was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (10 mL, 40 mmol). After being stirred at room temperature for two hours, the solution was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL). To it were added tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (3.392 g, 15.62 mmol) and triethylamine (3.126 g, 30.89 mmol). After being stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (8.184 g, 38.61 mmol) was added. The mixture was stirred at room temperature overnight and diluted with aqueous NaHCO3 and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification with combi-flash (20-100% EtOAc in hexanes) afforded 0.5 g (66% yield) of the desired product. LC/MS found: 240.1 (M−56)+.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\C(C2C=CC3C=CSC=3C=2)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:43][C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([F:53])[CH:52]=1)[C:47]([OH:49])=O>>[Cl:43][C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([F:53])[CH:52]=1)[C:47](/[N:31]=[C:14]1/[N:13]([C@H:10]2[CH2:9][CH2:8][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:2])[CH3:3])[CH2:12][CH2:11]2)[C:21]2[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:18]=[CH:17][C:16]=2[NH:15]/1)=[O:49]
Reactant: O=C(O)c1cc(F)cc(Cl)c1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cc(F)cc(Cl)c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 38.5 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 3-chloro-5-fluorobenzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-3-chloro-5-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (38.5% yield). MS m/z=585.4 [M+H], calc 585.11 for C30H38ClFN6O3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][CH2:12][C@H:13]([CH2:22][OH:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:24]OC(C1C2OC[C@H](CO)N(C3C=CC(CC)=CN=3)C=2C=CC=1)=O.[H-].[Na+].CI>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][CH2:12][C@H:13]([CH2:22][O:23][CH3:24])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1OC[C@H](CO)N2c1ccc(C)cn1
Reactant: CCc1ccc(N2c3cccc(C(=O)OC)c3OC[C@@H]2CO)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@H]1COc2c(C(=O)OC)cccc2N1c1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
3.0 g (9.5 mmol) of (S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-carboxylic acid methyl ester (compound 22) obtained in (34-6) were dissolved in 50 mL of THF. The solution was cooled to 0° C. and 1.1 g (28.6 mmol) of NaH was added slowly. The solution was stirred at 0° C. for 10 min and then at room temperature for 5 min. The solution was re-cooled to 0° C. and 120 uL (19.1 mmol) of MeI was added slowly. The mixture was placed at the same temperature for 1-2 hr and stirred while heating to room temperature. When the reaction terminated, the reaction mixture was neutralized by slow addition of 1N HCl solution, and dissolved in ethyl acetate and washed with distilled water and saturated sodium chloride solution, followed by drying over magnesium sulfate and concentration under reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate/hexane=1/2) to obtain the title compound (2.7 g, yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2S(C2C=CC=CC=2)(=O)=O)=[C:5]2[CH:21]([CH3:26])[NH:22][CH2:23][CH2:24][O:25][C:4]=12.[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:21]([CH3:26])[NH:22][CH2:23][CH2:24][O:25][C:4]=12
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c2c1OCCNC2C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2[nH]ccc2c2c1OCCNC2C
Temperature: 80 °C
Yield: 96.9 %

Procedure:
To 6-methoxy-1-methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Example 87, 0.12 g, 0.32 mmol) dissolved in EtOH (20 mL), 2 M NaOH (5 mL, 10 mmol) was added and the reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was cooled and extracted with DCM (50 mL). The organic layer was collected, dried (MgSO4) and evaporated to afford the title compound (72 mg). MS m/z 233 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:17])[CH2:6][CH:7]=O)=[O:4].Cl.[NH2:19][OH:20].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][CH2:2][C:3]([N:5]([C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:17])[CH2:6][CH:7]=[N:19][OH:20])=[O:4]
Reactant: CCc1cccc(C)c1N(CC=O)C(=O)CCl
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCc1cccc(C)c1N(CC=NO)C(=O)CCl
Yield: 51.2 %

Procedure:
A solution of 5 g (0.2 mol) alpha-(N-chloroacetyl-2-methyl-6-ethylphenylamino)acetaldehyde, 3.3 g (0.04 mol) hydroxylamine hydrochloride and 3.4 g (0.04 mol) sodium bicarbonate in 50 ml ethanol was heated at 40° C. for 40 minutes. The reaction mixture was filtered, evaporated under reduced pressure, diluted with ethyl ether, filtered again and evaporated under reduced pressure to give 5.5 g of a yellow oil which crystallized to a solid on standing. The crude solid was recrystallized from ethyl ether/hexane to give 3.2 g of the product as a white solid, m.p. 113°-115° C. The product is tabulated in Table I as Compound No. 11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:22])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Solvent: c1ccncc1
Product: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1

Procedure:
A solution of (0.025 mole) of 1,3-dihydro-7-chloro-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one in about 500 ml. of pyridine is treated with 5.55 g. (0.025 mole) of phosphorus pentasulfide and heated under reflux in a nitrogen atmosphere for 2 hours. The pyridine is removed in vacuo and the thus-produced residue is poured onto crushed ice. The aqueous phase is extracted with methylene chloride and then discarded. The extract is washed successively with three 200-ml. portions of water and 100 ml. of brine, and dried over anhydrous sodium sulfate. Removal of the solvent gives a solid which is recrystallized from ethanol-water, to give crude material which, after recrystallization from ethanolwater, gives pure 1,3-dihydro-7-chloro-5-(2-chlorophenyl)-2H-1,4-benzodiazepine-2-thione, melting point 251°-253° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[F:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCCCCl)c1cccc(F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using 5-chloro-1-(3-fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.CC(C)([O-])C.[K+].CN(C=O)C>C(OCC)(=O)C>[N:31]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)(=[O:23])=[O:24])=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3F)nccc2c1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3-n3ccnc3)nccc2c1
Temperature: 150 °C

Procedure:
A microwave vial was charged with 1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.090 g, 0.198 mmol), imidazole (0.054 g, 0.794 mmol), and potassium tert-butoxide (0.111 g, 0.992 mmol). DMF (0.992 ml) was added and the reaction was heated in a microwave reactor at 150° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, then acidified with concentrated HCl solution and extracted twice with ethyl acetate. The aqueous layer was passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The ammonia/methanol filtrate was combined with the previously isolated organic layers. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 10% MeOH:DCM) to afford 1-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.90 (br. s., 1H), 8.66 (d, J=5.7 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 8.13 (d, J=5.4 Hz, 1H), 8.08 (s, 1H), 8.03 (dd, J=1.2, 8.1 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.79-7.73 (m, 1H), 7.70-7.63 (m, 1H), 7.48 (t, J=1.0 Hz, 1H), 7.26 (d, J=4.6 Hz, 1H), 6.89-6.81 (m, 2H), 6.62 (t, J=1.1 Hz, 1H). m/z (ESI) 502.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20]C)=[O:19])[CH:8]=[C:7]2Cl)(=[O:3])[CH3:2].[CH2:23]([NH2:25])[CH3:24].O>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[NH:25][CH2:23][CH3:24])(=[O:3])[CH3:2]
Reactant: CCN
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Solvent: O
Solvent: CCO
Product: CCCc1c(O)c(C(C)=O)cc2c(NCC)cc(C(=O)O)nc12

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propylquinoline-2-carboxylate (8.9 g; 27.7258 mmole) and ethylamine in ethanol (33% w/w; 24 ml) was heated at 100° C. under pressure (autoclaved) for 28 hours. The mixture was cooled, treated with water and concentrated, followed by extraction with chloroform. The organic extract was washed with water, dried and evaporated to give a red solid (8.1 g; 81%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])[CH:2]1[O:4][CH2:3]1.[C:16](=[S:18])=[S:17]>O1CCCC1.[Br-].[Li+]>[CH3:11][O:10][Si:9]([O:12][CH3:13])([O:14][CH3:15])[CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]1[O:4][C:16](=[S:18])[S:17][CH2:3]1
Reactant: S=C=S
Reactant: CO[Si](CCCOCC1CO1)(OC)OC
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CO[Si](CCCOCC1CSC(=S)O1)(OC)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.2 %

Procedure:
To a solution of (3-glycidoxypropyl)trimethoxy-silane (X=methoxy; 75.6 g, 320 mmol) and lithium bromide (1.38 g, 16.0 mmol) in tetrahydrofuran (250 ml), a solution of carbon disulfide (29.2 g, 384 mmol) in tetrahydrofuran (150 ml) was added dropwise at 0° C., and the mixture was stirred at 25° C. After 12 h, the volatiles were removed under reduced pressure, and the residue was dissolved in diethylether (500 ml), washed with saturated distilled water (200 ml) three times. The ether layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was distilled under vacuum to give 5-(3-trimethoxysilylpropyloxymethyl)-1,3-oxathiolane-2-thione (1a) as a yellow oil (51.2 g, 164 mmol, 51%).