Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19].[OH-:20].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([NH2:19])=[O:20]
Reactant: N#Cc1ccc(-c2ncccc2C(F)(F)F)nc1N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Cool concentrated sulfuric acid (120 mL) in an ice bath under nitrogen atmosphere. Add in portions 6-amino-3′-trifluoromethyl[2,2′]bipyridinyl-5-carbonitrile (19.8 g) over a period of 15 minutes. Stir at room temperature 48 hours. Pour the reaction mixture over ice, adjust the pH to 10 using 10 N aqueous NaOH, filter the solid, wash the solid with water and dry under vacuum to give 6-amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carboxylic acid amide as a light pink solid.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][C@H:2]1[C@@H:6]([CH:19]([F:21])[F:20])[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)C(C)=[O:25].C(=O)([O-])[O-].[Na+].[Na+].OOS([O-])=O.[K+]>C(#N)C.O.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+]>[C@H:3]12[O:25][C@H:4]1[CH2:5][O:1][C@@H:2]2[C@@H:6]([CH:19]([F:20])[F:21])[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)C(F)(F)F
Reactant: O=C(NC[C@H](C(F)F)[C@@H]1C=CCO1)OCc1ccccc1
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Solvent: O
Solvent: CC#N
Product: O=C(NC[C@H](C(F)F)[C@H]1OC[C@@H]2O[C@H]12)OCc1ccccc1
Reaction time: 0.42 h
Yield: 123.8 %

Procedure:
To a solution of alkene (104b) (147 mg, 0.49 mmol) in acetonitrile (3.6 mL) and aqueous Na2.EDTA (0.04 mmol solution, 3.6 mL) at 0° C. was added 1,1,1-trifluoroacetone (0.53 mL, 5.9 mmol). To this solution was added in portions a mixture of sodium carbonate (0.352 g, 4.2 mmol) and OXONE® (0.942 g, 1.53 mmol) over a period of 1 hour. The mixture was stirred for 25 minutes then diluted with water (25 mL) and the product extracted into dichloromethane (3×25 mL). The combined organic layers were washed consecutively with water (150 mL), aqueous sodium hydrogen sulphite solution (5%, 25 mL) and brine (25 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a colourless oil (0.19 g), used without further purification. HPLC-MS 314.1 [M+H]+, 336.1 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]#[N:18])=[CH:12][C:3]=1[C:4]([O:6]CCCCC)=O.[CH3:19][NH2:20].C[O-].[Na+]>>[NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]#[N:18])=[CH:12][C:3]=1[C:4]([NH:20][CH3:19])=[O:6]
Reactant: CN
Reactant: CCCCCOC(=O)c1cc(C#N)cc(C)c1N
Agent: C[O-]
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Yield: 68.6 %

Procedure:
The above-described method (Example 3) was repeated to stir pentyl 2-amino-5-cyano-3-methylbenzoate (1.50 g, mmol) with methylamine (10.8 g, mmol, 40% in methanol) and sodium methoxide (441 mg, 0.12 mmol, 30% in methanol) at room temperature for 18 hours. The entire reaction batch was vacuum distilled and stirred with diisopropyl ether. 2-Amino-5-cyano-N,3-dimethylbenzamide (0.79 g, 70.6% of theory, 96.4 area % LC) was obtained as a brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[NH:9][C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>O1CCCC1.O>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:10]2[NH:9][C:8]3[CH:21]=[CH:22][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)=[N:13]1
Reactant: COC(=O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Yield: 99.4 %

Procedure:
A stirred solution of 3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole [84.5 mg, Example 235(ac)] and sodium hydroxide (74 mg) in tetrahydrofuran (4 mL) and water (2 mL) was heated at 75° C. overnight. The reaction mixture was evaporated and the oily residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH 6 and extracted with ethyl acetate. The organic layers was dried over magnesium sulfate and then evaporated to give [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid (80 mg) as an oil. MS: 279.14 (M+H)+. HPLC (METHOD H): RT=2.81 minutes.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([O:40][CH3:41])=[O:39])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]([N:25]([CH3:33])[CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=O)[CH2:18][C:17]4[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([O:40][CH3:41])=[O:39])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:25]([CH3:33])[CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH2:18][C:17]4[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CC(=O)N(C)Cc1cccnc1)Cc1ccccc1-3
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)Cc1cccnc1)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 14-cyclohexyl-6-{2-[methyl(pyridin-3-ylmethyl)amino]-2-oxoethyl}-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate in THF (0.05 M), BH3.Me2S (20 eq, 2 M solution in THF) was added. The solution was stirred overnight at RT. The solution was carefully quenched by adding 1.25 N HCl in MeOH until effervescence subsided. Then the volatiles were driven off by boiling the mixture to dryness. The crude residue was used directly in the next step; MS (ES+) m/z 537 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]([CH3:38])[C:33](=[O:39])[CH:32]=[C:31]3[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([OH:27])[C:9]2[N:10]=[C:11]([Si](CC)(CC)CC)[N:12]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:13]=2)=[CH:4][CH:3]=1>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]([CH3:38])[C:33](=[O:39])[CH:32]=[C:31]3[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([OH:27])[C:9]2[N:10]=[CH:11][N:12]([S:14]([N:17]([CH3:18])[CH3:19])(=[O:15])=[O:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)c1nc(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2ccccc2)cc(=O)n3C)cn1S(=O)(=O)N(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(C)S(=O)(=O)n1cnc(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2ccccc2)cc(=O)n3C)c1
Temperature: 110 °C
Yield: 11.2 %

Procedure:
Butyllithium (30.1 ml) was added slowly at −78° C. to a solution of N,N-dimethyl-1H-imidazol-1-sulfonamide (8,4 g) in tetrahydrofuran (150 ml) and the mixture was stirred at −78° C. for 15 minutes. Chlorotriethylsilane (8.1 ml) was added and the mixture was stirred till the temperature reached 20° C. The mixture was cooled till −78° C., butyllithium (30.1 ml) was added, the mixture was stirred at −78° C. for 1 hour and allowed to reach −15° C. The mixture was cooled again till −78° C., a solution of 6-(4-chlorobenzoyl)-1-methyl-4-phenyl-2(1 H)-quinolinone (15 g) in tetrahydrofuran (30 ml) was added and the mixture was stirred till the temperature reached 20° C. The mixture was hydrolized and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The product was used without further purification, yielding 26 g (100%) of (±)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-2-(triethylsilyl)-1H-imidazole-1-sulfonamide (intern. 3-a). A mixture of intermediate (3-a) (26 g) in sulfuric acid (2.5 ml) and water (250 ml) was stirred and heated at 110° C. for 2 hours. The mixture was poured into ice, basified with NH4 and extracted with DCM. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 99/1/0.2). The pure fractions were collected and evaporated, yielding 2.4 g (11%) of (±)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-1H-imidazole 1-sulfonamide (interm. 3-b).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH2:19]([N:22]=[C:23]=[O:24])[CH2:20][CH3:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:19]([NH:22][C:23]([NH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1)=[O:24])[CH2:20][CH3:21]
Reactant: CCCN=C=O
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1nn(Cc2ccccc2)cc1C(=O)OCC
Yield: 48 %

Procedure:
Sodium (1.9 g) was dissolved in anhydrous ethanol (100 ml) to prepare a solution of sodium ethoxide. To this, were added 3-amino-4-ethoxycarbonylpyrazole (12.4 g) and benzyl chloride (10 g), and the resulted mixture was refluxed for 1 h. After filtration of the hot mixture, the filtrate was concentrated to quarter volume, and cooled to crystallize. The crude product was recrystallized from an ether-water mixture to give 3-amino-1-benzyl-4-ethoxycarbonylpyrazole (10.7 g, yield 44%). To a solution of 3-amino-1-benzyl-4-ethoxycarbonylpyrazole (0.2 g) in dried toluene (30 ml), were added propyl isocyanate (0.307 ml) and triethylamine (0.11 ml), and the mixture was refluxed in a sealed tube for 8 h. The reaction mixture was evaporated under reduced pressure followed by silica-gel column chromatography (toluene : ethyl acetate=20:1) to give the title compound (0.129 g, yield 48%). 1H-NMR (CDCl3) δ ppm: 0.92 (3H, t, J=7Hz, CH2CH2CH3 ), 1.32 (3H, t, J=7Hz, COOCH2CH3 ), 1.57 (2H, 6th, CH2CH2CH3), 4.28 (2H, q, J=7Hz, COOCH2CH3), 5.14 (2H, s, CH2 --Ph), 7.25 (5H, m, CH2 --Ph), 7.91 (2H, brs, NH), 8.00 (1H, s, C5-H)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:42](O)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31](/[C:41](=[CH:45]\[CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:42]([NH:52][C:53]2[S:54][CH:55]=[CH:56][N:57]=2)=[O:43])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1Cl
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
A solution of triphenylphosphine (290 mg, 1.1 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (195 mg, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid (192 mg, 0.55 mmol) in methylene chloride (3 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (166 mg, 1.66 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (40 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 7/3 to 2/3 hexanes/ethyl acetate) afforded (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide (86 mg, 36%) as an amorphous solid: EI-HRMS m/e calcd for C20H21ClN6OS (M+) 428.1186, found 428.1189.
Reaction SMILES: [CH:1]1([N:4]([CH:31]2[CH2:33][CH2:32]2)[C:5]([C:7]2[N:28]([CH2:29][CH3:30])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:25](O)=[O:26])=[CH:23][N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:34]1([NH:37][C:25]([C:22]2[S:21][C:20]([NH:19][C:12]3[N:11]=[C:10]4[N:28]([CH2:29][CH3:30])[C:7]([C:5](=[O:6])[N:4]([CH:1]5[CH2:3][CH2:2]5)[CH:31]5[CH2:32][CH2:33]5)=[CH:8][C:9]4=[C:14]4[N:15]([CH3:18])[CH:16]=[N:17][C:13]=34)=[N:24][CH:23]=2)=[O:26])[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)O)s3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)NC4CC4)s3)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a mixture of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylic acid (example 20A, 13.97 mg, 0.030 mmol) in DMF (300 μL) was added cyclopropylamine (4.16 μL, 0.060 mmol), HATU (14.83 mg, 0.039 mmol), and Hünig's Base (15.72 μL, 0.090 mmol). The reaction mixture was stirred at rt 1 h and concentrated in vacuo: The residue was taken up in MeOH and purified by preparative HPLC. N-Cyclopropyl-2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxamide (3 mg, 19.82% yield) was isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[OH-].[K+].[F:14][C:15]([F:19])=[C:16]([F:18])[F:17]>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:16]([F:18])([F:17])[CH:15]([F:19])[F:14]
Reactant: FC(F)=C(F)F
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
20 Grams of 2-chloro-4-nitrophenol was dissolved in 200 ml of N,N-dimethylformamide, and 3.4 g of potassium hydroxide was added thereto. Tetrafluoroethylene was blown into the resulting solution at an inner temperature of 50° C., after which stirring was continued for 50 minutes at an inner temperature of 50° C. Thereafter, 3.5 g of potassium hydroxide was added to the stirred solution and the resulting solution was further stirred for 6 hours at an inner temperature of 100° C. The reaction solution was poured into ice water and extracted with ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue obtained wa subjected to column chromatography on silica gel with chloroform as an eluent to obtain 12.55 g of 3-chloro-4-(1',1',2',2'-tetrafluoroethoxy)nitrobenzene. 1H-NMR (CDCl3): δ(ppm) 8.37(1H, d, J=3 Hz), 8.20(1H, dd, J=9, 3 Hz), 7.57(1H, d, J=9 Hz), 6.07(1H, tt, J=53, 3 Hz)
Reaction SMILES: [CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.CO[CH:33](OC)[CH2:34][NH2:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)CCC.S(=O)(=O)(O)O>[CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[N:6]3[CH:33]=[CH:34][N:35]=[C:7]3[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)NC(=S)CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Reactant: COC(CN)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: Cc1cc2c(cc1C)-n1ccnc1C=C(c1ccc(-n3c(C)nc4cnccc43)cc1)N2
Temperature: 100 °C

Procedure:
A mixture of 2,3-dihydro-7,8-dimethyl-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-thione (575 mg. 1.4 mmol), aminoacetaldehyde dimethyl acetal (294 mg, 2.8 mmol), and p-toluenesulphonic acid (14 mg) in n-butanol (7 ml) was heated at reflux for 8 hours under nitrogen. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (eluting with ethyl acetate/methanol=6:1). The intermediate thus obtained was dissolved in concentrated sulphuric acid (5 ml) and heated at 100° C. for 20 minutes. The mixture was cooled and poured onto ice, and then neutralised with saturated aqueous sodium bicarbonate. The product was extracted into dichloromethane (2×150 ml), and the combined extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (eluting with ethyl acetate:methanol=6:1) gave the title compound as a buff solid, (180 mg, 31%), m.p. 193°-195° C. after dissolution in methanol and precipitation with acetone.
Reaction SMILES: [OH2:1].Br.[CH2:3]([O:10][C@@H:11]1[C@@H:16]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[O:15][CH:14]=[CH:13][C@H:12]1[O:22][C:23](=[O:25])[CH3:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:26].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:3]([O:10][C@H:11]([C@@H:16]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[OH:15])[C@H:12]([O:22][C:23](=[O:25])[CH3:24])[C@@H:13]([OH:26])[CH:14]=[O:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OCc1ccccc1
Reactant: O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC[C@@H](O)[C@@H](OCc1ccccc1)[C@H](OC(C)=O)[C@@H](O)C=O
Temperature: 25 °C

Procedure:
48% Hydrobromic acid water solution (0.5 mL) was added to a mixture of 4-O-benzyl-3,6-di-O-acetyl-D-glucal (5 mmol) in tetrahydrofuran (50 mL), and obtained solution was stirred in room temperature. After reaction was completed (TLC) the reaction mixture was poured into the 10% water solution of sodium bicarbonate (125 mL), and water solution was extracted with ethyl acetate (3×30 mL). Combined organic extracts were washed with water and dried over sodium sulfate. Drying agent and solvents were removed and product was purified by column chromatography (SilicaGel 60 Merck), using hexanes:ethyl acetate as eluents.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[F:35][C:36]1[CH:58]=[CH:57][C:39]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[N:50]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:38][CH:37]=1.C(N(CC)CC)C.ClCCl.CO>C(#N)C.ClCCl>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][C:39]4[CH:57]=[CH:58][C:36]([F:35])=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: Fc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)cc1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (1.51 g, 3.2 mmol), 4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (1.78 g, 3.07 mmol), and triethylamine (2 mL, 14.35 mmol) in acetonitrile (40 mL). Heat to reflux. After 22 hours, cool to ambient temperature and dilute with dichloromethane, and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrated ammonium hydroxide 95/5/0.05 to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[OH:17][N:16]=[C:7]([C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: Cc1ncoc1C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ncoc1C(=NO)c1ccccc1
Temperature: 50 °C
Yield: 40.1 %

Procedure:
To a stirred solution of (4-methyl-1,3-oxazol-5-yl)(phenyl)methanone (1.34 g, 7.15 mmol) in pyridine (40 mL), was added hydroxylamine hydrochloride (1.24 g, 17.9 mmol) and the reaction mixture was heated at 50° C. for 15 h. The reaction mixture was concentrated in vacuo. Water (60 mL) was added and the mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude material on silica gel afforded N-hydroxy-1-(4-methyl-1,3-oxazol-5-yl)-1-phenylmethanimine (0.58 g, 39%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:48]=[CH:49][CH:50]=1)[O:31][C:32]1[CH:44]=[CH:43][C:35]2[N:36]=[C:37]([NH:39][C:40](=[O:42])[CH3:41])[S:38][C:34]=2[C:33]=1[N+:45]([O-:47])=[O:46]>O1CCCC1.C(OCC)(=O)C>[C:40]([NH:39][C:37]1[S:38][C:34]2[C:33]([N+:45]([O-:47])=[O:46])=[C:32]([O:31][C:30]3[CH:29]=[C:28]([NH:27][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=4[Cl:1])[CH:50]=[CH:49][CH:48]=3)[CH:44]=[CH:43][C:35]=2[N:36]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c([N+](=O)[O-])c2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (360 mg, 1.60 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (172 μL, 2.00 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2.5 mL). N-[6-(3-Aminophenoxy)-7-nitro-1,3-benzothiazol-2-yl]acetamide (460 mg, 1.34 mmol) was added to the solution, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was successively purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and basic silica gel column chromatography (ethyl acetate/n-hexane=70/30→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from 2-butanone/n-hexane to give the title compound (300 mg, 41%) as a white powder.