Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.P([N:34]=[N+:35]=[N-:36])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.ClC1C(Cl)=CC=CC=1C=CC1C=CN=CC=1>C1COCC1>[N:34]([CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OC(Cc1ccncc1)c1cccc(Cl)c1Cl
Agent: Clc1cccc(C=Cc2ccncc2)c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(Cc1ccncc1)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
1-(2,3-dichlorophenyl)-2-(pyridin-4-yl)ethanol (7) (6.20 g, 23.2 mmol) in THF (100 mL) was added diphenyl phosphorazidate (6.00 mL, 27.8 mmol), and DBU (4.20 mL, 23.1 mmol) at 0° C. The mixture was stirred at room temperature overnight. The mixture was heated at 50° C. for 1.5 hour. The solvents were evaporated under reduced pressure. The residue was diluted with water, and extracted with ethyl acetate (3×). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. Silica gel was added to the filtrate, and the solvents were evaporated under reduce pressure. Purification by chromatography on silica gel (60% hexane, 40% ethyl acetate) gave a 4:1 mixture of products: 4-(2-azido-2-(2,3-dichlorophenyl)ethyl)pyridine (8) (4 parts, 3.82 g, 10.6 mmol, 46% yield), and 4-(2,3-dichlorostyryl)pyridine (9) (1 part).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.N1C2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:16])=[CH:12][CH:13]=2)[CH:8]=C1.CI.[H-].[Na+]>O>[CH3:1][N:2]1[C:5]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:24])[F:25])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:3]1
Reactant: CC(CCCCOC(=O)c1ccc2[nH]ccc2c1)=C(F)F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(CCCCOC(=O)c1ccc2c(ccn2C)c1)=C(F)F
Reaction time: 1 h
Yield: 86 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.40 g (1.4 mmol) of 6,6-difluoro-5-methyl-5-hexenyl 1H-indole-5-carboxylate and 0.40 g (2.8 mmol) of methyl iodide, followed by the addition of 0.07 g (1.7 mmol) of sodium hydride at room temperature and stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 0.36 g (yield: 86%) of 6,6-difluoro-5-methyl-5-hexenyl 1-methyl-1H-indole-5-carboxylate.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[CH:21]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]1.[F:31][C:32]1([F:39])[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1>C1COCC1>[F:31][C:32]1([F:39])[CH2:37][CH2:36][C:35]([C:21]2([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]2)([OH:38])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: O=C1CCC(F)(F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(C2(O)CCC(F)(F)CC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
A solution of LDA prepared from diisopropylamine (304 mg, 3.00 mmol) and butyllithium (1.20 mL, 3.00 mmol) in THF was added to a cold (−78° C.) solution of tert-butyl cyclopropanecarboxylate (427 mg, 3.00 mmol) in THF (2 mL), and the mixture was stirred at −78° C. for 1 h. A solution of 4,4-difluorocyclohexanone (268 mg, 2 mmol) in THF (0.5 mL) was added dropwise and the mixture was stirred at −78° C. for 2 h and allowed to warm to rt overnight. The crude product was purified by silica gel FCC (DCM) to afford tert-butyl 1-(4,4-difluoro-1-hydroxycyclohexyl)cyclopropanecarboxylate as a clear oil (0.273 g). 1H NMR (500 MHz, CDCl3) δ ppm 2.12-2.30 (2H, m), 1.79-1.96 (4H, m), 1.48-1.53 (2H, m), 1.41-1.47 (9H, m), 1.21-1.34 (1H, m), 1.11-1.17 (2H, m), 0.90-0.97 (2H, m).
Reaction SMILES: CN1CCOCC1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2([C:21]([OH:23])=O)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1.Cl.Cl.[F:26][C:27]1[C:32]2[C:33](=[O:40])[O:34][C:35]3([CH2:39][CH2:38][NH:37][CH2:36]3)[C:31]=2[CH:30]=[CH:29][N:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN(C)C=O>>[F:26][C:27]1[C:32]2[C:33](=[O:40])[O:34][C:35]3([CH2:39][CH2:38][N:37]([C:21]([C:18]4([C:11]5[C:12]6[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=6)[N:8]=[CH:9][CH:10]=5)[CH2:19][CH2:20]4)=[O:23])[CH2:36]3)[C:31]=2[CH:30]=[CH:29][N:28]=1
Reactant: O=C(O)C1(c2ccnc3ccccc23)CC1
Reactant: O=C1OC2(CCNC2)c2ccnc(F)c21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1OC2(CCN(C(=O)C3(c4ccnc5ccccc45)CC3)C2)c2ccnc(F)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl in dioxane (4.0 M, 1 mL) was added to tert-butyl 4-fluoro-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidine]-1′-carboxylate (25.8 mg, 0.0000837 mol). The reaction mixture was stirred at room temperature for 30 minutes before the volatiles was removed to afford the free amine (hydrochloric acid salt), which was subsequently used in the coupling reaction. 4-Methylmorpholine (50 μL, 0.0004 mol) was added to a mixture of 1-quinolin-4-ylcyclopropanecarboxylic acid (17.8 mg, 0.0000837 mol), 4-fluoro-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride (23.5 mg, 0.0000837 mol), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (45.7 mg, 0.0000879 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol). The reaction mixture was stirred at room temperature for 2 hours. The crude product was purified by prep-LCMS. LC/MS: 402.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[O:29]1[CH2:32][CH:31]([NH2:33])[CH2:30]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([NH:33][CH:31]2[CH2:32][O:29][CH2:30]2)=[O:26])[CH:4]=[N:3]1
Reactant: NC1COC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)NC2COC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 20 h
Yield: 38.2 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), oxetan-3-amine hydrochloride (60.5 mg, 552 μmol), diisopropylethylamine (241 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 20 hours at reflux under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried. The residue (94 mg white solid) is triturated with ethyl acetate, filtered and the filtrate is evaporated affording 1-methyl-N4-(oxetan-3-yl)-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (44 mg, 38.2%) as a white solid. mp.: >250° C. MS: m/z=418.3 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1([CH:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([OH:39])[CH:37]=3)[CH2:32][CH2:31][N:30]2[CH3:42])[CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1([CH:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([O:39][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:37]=3)[CH2:32][CH2:31][N:30]2[CH3:42])[CH2:28][CH2:27]1
Reactant: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)Oc1cc2c(cc1OC)CCN(C)C2C1(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hexadecanoyl chloride (0.83 g) in dichloromethane (5 ml) was added dropwise to a stirring solution of 1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (1.04 g, prepared from the (+)-enantiomer of the hydrobromide salt, prepared in a similar manner to that described in Example 77), triethylamine (0.91 g) and dichloromethane (20 ml). The mixture was stirred at ambient temperature for 2 hours, then washed with dilute sodium hydroxide solution, water and brine. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The resulting oil was dissolved in petroleum ether (b.p. 60°-80° C.) and washed repeatedly with water. The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to yield (+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hexadecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinoline (1.45 g) which had a specific optical rotation αD of +21.18°.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[S:9]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:14]([C:13]1[S:9][C:10]2[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=2[CH:12]=1)(=[O:15])=[O:16]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of o-phenylenediamine (5 mmol) in DCM (25 mL) and pyridine (5 mL) at 0° C., benzo[b]thiophene-2-sulfonyl chloride (5.5 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (25 mL). The organic phase was washed with water (2×25 mL) and 25 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 1.2 g of benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide. Tr 0.94 min, MS: 305.7 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 6.40 (t, 1H), 6.60 (d, 1H), 6.78 (d, 1H), 6.89 (t, 1H), 7.45 (t, 1H), 7.50 (t, 1H), 7.80 (s, 1H), 7.90 (d, 1H), 8.80 (d, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[O:5][CH:6]([CH3:10])[C:7](O)=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[O:5][CH:6]([C:7]1[S:18][C:17]([NH2:19])=[N:16][N:15]=1)[CH3:10]
Reactant: CC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(Oc1cc(Cl)cc(Cl)c1)c1nnc(N)s1
Temperature: 90 °C

Procedure:
A 100 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser, was charged with 9.4 grams (0.040 mole) of 2-(3,5-dichlorophenoxy)propanoic acid, (3.6 grams, 0.040 mole) of thiosemicarbazide and 30 milliliters of dioxane. The slurry was heated to 90° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (6.7 grams, 0.044 mole) was slowly added (for 22 minutes) while maintaining the temperature within 85°-90° C. The resulting mixture was refluxed for 60 minutes. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), fifty (50) milliliters of water was added and 50 percent solution of NaOH was also added until the pH of the solution was 10; an oil formed. The oil was extracted with diethylether, dried over MgSO4, filtered, and topped in a roto-vac at 70° C. to yield 7.9 grams of a pale yellow oil of 5-[1-(3,5-dichlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazol.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(O)C.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:3]=1)=[O:15]
Reactant: C1CCNCC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCCCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 120 °C

Procedure:
To a 10 mL reaction vial containing stir bar were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.060 g, 0.160 mmol), ethanol (1.5 mL), and then piperidine (0.318 mL, 3.21 mmol) via syringe at once. The contents were capped, placed into a heat block, and heated at 120° C. for 18 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL), adjusted to pH 6-7, and stirred for 15 min. The contents were filtered and washed with water. The product was dried in vacuum oven at 50° C. for 5 hr. The product was obtained as 57 mg (82%). LCMS E-S (M+H)=422.8. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (d, J=6.82 Hz, 6H), 1.53-1.67 (m, 6H), 2.12 (s, 3H), 2.20 (s, 3H), 3.61-3.73 (m, 4H), 4.34 (d, J=5.05 Hz, 2H), 4.91-5.04 (m, 1H), 5.89 (s, 1H), 7.10 (s, 1H), 7.97 (s, 1H), 8.65 (t, J=4.93 Hz, 1H), 11.51 (br. s., 1H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([CH:17]2[CH2:19][CH2:18]2)=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.[NH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[NH2:21].NN>C(O)C.CCCCCCC.Cl>[CH:17]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]3[C:6]=2[C:4](=[O:5])[N:20]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=2)[N:21]=3)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C2CC2)nc2ccccc2c1Cl
Reactant: NNc1ccc(C(=O)O)cc1
Agent: Cl
Agent: NN
Solvent: CCCCCCC
Solvent: CCO
Product: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Yield: 80.2 %

Procedure:
4-Chloro-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester (1.15 g, 0.0041 mols) and 4-hydrazino-benzoic acid (1.0 g, 0.0068 mols) were stirred in ethanol (30 ml) at reflux for 16 h. The bright yellow suspension was diluted with heptane, filtered, washed with cold t-butylmethyl ether and left to dry under suction to yield crude solid containing hydrazine. This solid was suspended in 1 M HCl, filtered, washed with water and then dried in vacuo to yield 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (1.135 g, 80%) as a yellow solid, LCMS m/z 346.20 [M+H]+ @ RT 1.05 min: 96% purity. δH (400 MHz, (CD3)2SO) 11.4 (1H, s), 8.43 (2H, d, J 8.1), 8.21 (1H, dd, J1 1.2, J2 8.1), 8.07 (2H, d, J 8.1), 7.92 (1H, d, J 8.1), 7.67 (1H, t, J 6.6), 7.52 (1H, t, J 6.5), 3.43 (1H, m), 1.59 (2H, m), 1.43 (2H, m). Step 4 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]-quinolin-2-yl)-benzoyl chloride
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[NH2:14][C@@H:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CO>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:14][C@@H:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17]([O:19][CH3:20])=[O:18])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)C[C@@H](N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C[C@@H](Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccccc1

Procedure:
To a solution of 2,4-dinitrochlorobenzene (5.1 g, 25 mmol) in methanol (60 mL) was added methyl (3R)-3-amino-3-phenylpropanoate (3.75 g, 21 mmol, prepared according to Davies et. al., Tetrahedron Asymm., 1991, 183) and triethylamine (2.9 mL, 21 mmol). The mixture was brought to reflux, heating in total for 5 hours, and was then cooled and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5), to afford the title compound, [LCMS (Method C, Mobile Phase I) RT=3.22 mins, MH+ 346].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:34])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>N1C=CC=CC=1>[C:32]([C:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[S:3][C:4]=3[C:10]=2[N+:11]([O-:13])=[O:12])[CH:16]=1)=[O:34])([CH3:30])[CH3:31])#[N:33]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])c2)c1
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3[N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
To a solution of N-{3-[(2-amino-7-nitro-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (3.0 g, 6.33 mmol) in pyridine (30 mL) was added cyclopropanecarbonyl chloride (1.15 ml, 12.7 mmol) at 4° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL)/tetrahydrofuran (30 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (2.71 g, 79%) as a yellow powder.
Reaction SMILES: [OH:1][CH:2]([C:4]1[NH:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3]>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[C:2]([C:4]1[NH:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)(=[O:1])[CH3:3]
Reactant: COc1cccc2nc(C(C)O)[nH]c12
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc2nc(C(C)=O)[nH]c12
Yield: 64.9 %

Procedure:
A solution of 2-(1-hydroxyethyl)-4-methoxybenzimidazole (2.18 g) in acetic acid (8.5 ml) was heated at 100° C. and treated with a solution of chromium trioxide (0.85 g) in water (3 ml). After 10 minutes the reaction was poured into water (110 ml), the precipitate was removed by filtration through a plug of Celite and the product extracted with dichloromethane (3×100 ml). The combined organic layers were dried over magnesium sulphate, filtered, and evaporated in vacuo and to yield the desired product as a light-brown solid (1.4 g).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>C(Cl)(Cl)Cl>[CH:1]1([NH:7][C:10](=[O:11])[CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[Br:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)C(Br)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCCCC1)C(Br)c1ccccc1
Yield: 41.3 %

Procedure:
To a mixture of cyclohexylamine (10.9 g), triethylemine (11.1 g) and chloroform (200 ml), α-bromophenylacetyl chloride (23.3 g) was added dropwise over 10 minutes under cooling with ice and stirring, and the mixture was refluxed for 10 hours. After cooling by allowing to stand, the reaction mixture was washed with 0.5N hydrochloric acid (100 ml), with 0.5N aqueous solution of sodium hydroxide (100 ml) and with saturated saline solution (100 ml), and then concentrated. The residue was recrystallized from ethyl acetate-ethanol to obtain 12.2 g of title compound as colorless crystals. The mother liquor from recrystallization was concentrated and the residue was purified by means of column chromatography (developing solvent, chloroform:ethanol=20 : 1) to obtain 13.0 g of additional. title compound as colorless crystals (overall yield 85.4%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.C[Si]([N:26]=[N+:27]=[N-:28])(C)C.C([Sn](=O)CCCC)CCC>O1CCOCC1>[CH3:1][C:2]1([CH3:21])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]4[NH:28][N:27]=[N:26][N:17]=4)[CH:14]=3)=[CH:12][C:3]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: C1COCCO1
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc21
Yield: 25.6 %

Procedure:
A mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d][1,3]oxazin-6-yl)benzonitrile (0.77 g, 2.8 mmol), trimethylsilyl azide (0.68 g, 5.6 mmol), and dibutyl tin oxide (0.071 g, 0.28 mmol) in dioxane (20 mL) was heated at reflux under a blanket of nitrogen. Upon completion of the reaction, the dioxane was removed, the organics taken up in ethyl acetate (100 mL), and washed with NaHCO3 (100 mL). The aqueous layer was acidified with 1 N aqueous HCl and extracted with ethyl acetate (100 mL). The organic layer was dried over MgSO4, and concentrated. Crystallization from ether (20 mL) gave 4,4-dimethyl-6-[3-(1H-tetrazol-5-yl)-phenyl]-1,4-dihydrobenzo[d][1,3]-oxazin-2-one as a light yellow solid (0.23 g, 26%): mp 238-240° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 8.3 (bs, 1H), 8.02 (d, 1H, J=7.66 Hz), 7.9 (d, 1H, J=7.91 Hz), 7.72-7.65 (m, 3H), 7.03 (d, 1H, J=8.75 Hz), 1.70 (s, 6H); MS (ESI) m/z 320 ([M−H]−, 100%); Anal. Calc. For C17H15N5O2: C, 63.54; H, 4.71; N, 21.79. Found: C, 62.16; H, 4.67; N, 21.31.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][OH:33]>C(O)CCC>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][O:33][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CN(C)CCOc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 120 °C
Yield: 74 %

Procedure:
A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline, (100, 0.293), triethylamine (123 μL, 0.879 mmol), N,N-dimethylethanolamine (959 μL, 0.586 mmol) in n-butanol (3.0 mL) was heated in the microwave at 120° C. for 20 minutes, then concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 25S column eluting with chloroform/7 N ammonia in methanol (0.1-5%) to afford the title compound (75 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[NH:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=[C:19]1[NH:13][C:14](=[O:15])[NH:16][C:17]1=[O:18]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: O=C1CNC(=O)N1
Solvent: NCCO
Solvent: O
Product: COc1ccc(OC)c(C=C2NC(=O)NC2=O)c1

Procedure:
A mixture of 2,5-dimethoxybenzaldehyde (2.504 g.) and hydantoin (1.507 g., 1 molar ratio) in water (15 ml) was heated to 70°. To this 2 layer liquid was added monoethanolamine (1.38 g., 1.5 molar ratio). The mixture was heated 4 hours at 90°-92° (bath temperature) with magnetic stirring. The title compound was isolated in the usual manner and obtained as a yellow solid (3.288 g.), m.p. 250°-252°. Crystallization from dioxane (96% recovery) gave m.p. 251°-252°.