Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:28]1[CH2:29][CH:30]=[C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH2:26][CH2:27]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C1=C(c2ccccn2)CCNC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H](N1CC=C(c2ccccn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 49.6 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (2.21 g, 8.8 mmol) and 1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (7.47 g, 46.6 mmol) were dissolved in acetonitrile (100 ml), and lithium perchlorate trihydrate (7.48 g, 46.6 mmol) was added thereto and refluxed for 48 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 1.90 g of the intended substance (yield 49.6%).
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1.[C:14]([O:18][C:19](=O)[O:20]C(C)(C)C)([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1>[C:14]([O:18][C:19]([NH:3][CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]([OH:13])=[O:12])[CH2:9][CH2:10]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reaction time: 20 h

Procedure:
63.6 ml of an N aqueous NaOH solution and 1.28 g of MgO are introduced, at 0° C., into 50 ml of dioxane containing 5 g of trans-4-(aminomethyl)cyclohexylcarboxylic acid, followed, slowly, by 6.94 g of di(t-butyl)carbonate in solution in 20 ml of dioxane. After 20 hours at room temperature, the mixture is filtered, the solvent is removed and the residue is taken up in 100 ml of H2O and the aqueous phase is washed with (C2H5)2O before acidifying it up to pH 2 by addition of KHSO)4 ; it is then extracted in CH3COOC2H5 to yield 7.3 g of trans-N-(t-butoxycarbonyl)-4-(aminomethyl)cyclohexylcarboxylic acid which melts at 125° C.
Reaction SMILES: [ClH:1].Cl.Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:15][C@@H:14]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH2:30])[CH2:19][CH2:18]3)[CH2:13][O:12]2)=[CH:7][CH:6]=1.[O-:31][C:32]#N.[K+]>C(O)C>[ClH:1].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:15][C@@H:14]([CH2:16][N:17]3[CH2:18][CH2:19][CH:20]([N:23]4[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[NH:30][C:32]4=[O:31])[CH2:21][CH2:22]3)[CH2:13][O:12]2)=[CH:7][CH:6]=1
Reactant: N#C[O-]
Reactant: Nc1ccccc1NC1CCN(C[C@H]2CO[C@@H](c3ccc(F)cc3)C2)CC1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1C1CCN(C[C@H]2CO[C@@H](c3ccc(F)cc3)C2)CC1
Reaction time: 8 h

Procedure:
A mixture of 9.56 g of 1-[cis-2-(4-fluorophenyl)-tetrahydro-4-furylmethyl]-4-(2-aminoanilino)piperidine trihydrochloride and 2.0 g of potassium cyanate in 100 ml of ethanol is heated under reflux with stirring for 8 hours. The ethanol is then distilled off under reduced pressure, and 10 ml of 10% aqueous sodium hydroxide solution and 50 ml of water are added to the residue and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in a small amount of ethanol, and ethanolic hydrochloric acid is added thereto. The crystals precipitated are collected by filtration and recrystallized from ethanol-water to give 1-[1-(cis-2-(4-fluorophenyl)-tetrahydro-4-furylmethyl)-4-piperidyl]benzimidazolin-2-one hydrochloride, melting at 276° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([C:10]3(O)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:6]=2[CH:24]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([C:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=3)[C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2csc3ccc(Cl)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2scc(C3=CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.2 %

Procedure:
To a solution of 0.32 gm (0.86 mMol) 5-chloro-3-(4-hydroxy-1-(tert-butoxycarbonyl)piperidin-4-yl)benzothiophene in 3.0 mL dichloromethane were added 2.0 mL trifluoroacetic acid. The reaction mixture was stirred for 4 hours at room temperature and was then concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with chloroform containing 5% methanol. Fractions shown to contain product were combined and then concentrated under reduced pressure to give 0.14 gm (64%) of 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)benzothiophene as a foam. This material was dissolved in diethyl ether and the solution was saturated with hydrogen chloride. The resulting solution was concentrated under reduced pressure to give the title compound as an orange solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:24]=[C:23]([Cl:25])[C:22]([O:26]CC3C=CC=CC=3)=[CH:21][C:20]=2[O:34]CC2C=CC=CC=2)[O:8][N:7]=1)=[O:5])[CH3:2].B(Cl)(Cl)Cl>ClCCl>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:24]=[C:23]([Cl:25])[C:22]([OH:26])=[CH:21][C:20]=2[OH:34])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(OC)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(Cl)c(O)cc2O)c1-c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-bath cooled solution of 5-(2,4-Bis-benzyloxy-5-chlorophenyl)-4-(4-methoxy-phenyl)-isoxazole-3-carboxylic acid ethylamide (0.213 mg, 0.374 mmol) in dichloromethane (5 mL) under a nitrogen atmosphere was added a 1.0M solution of Boron trichloride in dichloromethane (1.12 mL; 1.12 mmol). The reaction mixture was stirred at 0° C. for 15 minutes then at ambient temperature for 35 minutes. The reaction mixture was re-cooled to 0° C. and quenched by the addition of saturated aqueous sodium hydrogen carbonate solution (5 mL). After stirring for 5 minutes the dichloromethane was removed in vacuo and the residue was partitioned between ethyl acetate (30 mL) and water (30 mL). The phases were separated and the organic phase was washed with water (30 mL), saturated aqueous sodium chloride solution (30 mL) then dried over sodium sulphate. The mixture was filtered and the filtrate solvents were removed in vacuo to afford a foam-like colourless solid which was purified by adsorption onto silica gel then flash chromatography on silica gel (10 g IST) eluting with 50% ethyl acetate in hexane. This affords 5-(5-chloro-2,4-dihydroxyphenyl)-4-(4-methoxy-phenyl)-isoxazole-3-carboxylic acid ethylamide as a colourless solid (0.097 g; 67%). LCMS: [M+H]+ 391, 389 (37Cl; 35Cl). 1H NMR (400 MHz, d6-DMSO) □ 1.08 (t, 3H), 3.22 (m, 2H), 3.73 (s, 3H), 6.59 (s 1H), 6.87 (d, 1H), 7.13-7.17 (m, 3H), 8.88 (brt, 1H), 10.09 (s, 1H), 10.62 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][C@@H:11]2[N:12]([CH3:23])[C:13]3[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[C@H:10]2[CH:9]1Br)=O)(C)(C)C.[CH3:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=1[NH2:30]>>[CH3:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=1[NH:30][C:16]1[CH:15]=[C:14]([C:19]([F:21])([F:22])[F:20])[C:13]2[N:12]([CH3:23])[C@H:11]3[CH2:24][CH2:25][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1
Reactant: CN1c2c(cccc2C(F)(F)F)[C@H]2C(Br)N(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: Cc1cccc(C)c1N
Product: Cc1cccc(C)c1Nc1cc2c(c(C(F)(F)F)c1)N(C)[C@H]1CCNC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a yellow solid (18 mg, 50%) from (4aS,9bR)-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 41 mg, 0.095 mmol) and 2,6-dimethylaniline (39 mg, 0.30 mmol). 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.87–1.98 (m, 2H), 2.20 (s, 6H), 2.30–2.70 (m, 3H), 2.78–3.20 (m, 6H), 3.33–3.45 (m, 1H), 5.07 (s, 1H), 6.46 (d, J=2.2 Hz, 1H), 6.59 (d, J=2.2 Hz, 1H), 7.00–7.18 (m, 3H).
Reaction SMILES: [CH3:1][NH2:2].Cl.[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:6][CH:5]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][NH:2][S:12]([CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=1)(=[O:14])=[O:13]
Reactant: CN
Reactant: O=S(=O)(Cl)CCc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)CCc1ccncc1
Temperature: 25 °C

Procedure:
To 50 ml of a 40% solution of methylamine in methanol was added 3.0 g of 2-(pyridin-4-yl)ethanesulfonyl chloride hydrochloride as such (i.e., as a solid). After stirring for a while at room temperature, a solution of 2.1 g of sodium hydrogencarbonate in 15 ml of water was carefully added thereto. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 1.3 g of the title compound as brownish white scaly crystals.
Reaction SMILES: [NH:1]1C=CN=[CH:2]1.[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N:21]=[N:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[N+:32]([O-:34])=[O:33])[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:8])[CH3:7]>>[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N:21]=[N:22][C:23]1[C:24]([N+:32]([O-:34])=[O:33])=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][C:28]=1[C:2]#[N:1])[N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])(=[O:8])[CH3:7]
Reactant: c1c[nH]cn1
Reactant: CCN(CC)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1

Procedure:
A stirred mixture of 3-acetylamino-4-(2'-bromo-4',6'-dinitro phenylazo)-N,N-diethylaniline (4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.8 parts), imidazole (1.35 parts), and nitrobenzene (100 parts) was heated to 85° C. for 71/2 hours when thin layer chromatography showed reaction to be effectively complete. Isolation of the product by the method of Example 9 gave 3-acetylamino-4-(2'-cyano-4',6'-dinitrophneylazo)-N,N-diethylaniline (infra red spectrum identical with that of authenic material). When this experiment was repeated using 3.6 parts of imidazole in place of 1.8 parts a considerable amount of 3-acetylamino-4-(2',4'-dinitrophenylazo)-N,N-diethylaniline was produced in addition to the desired 3-acetylamino-4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([CH3:10])[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:12]([CH2:14][C:15]([NH2:17])=[O:16])#[N:13].N1CCCCC1>C(O)C>[C:12]([C:14]1[C:15](=[O:16])[NH:17][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([CH3:10])[CH2:9]2)#[N:13]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C1CC(C)CCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(C)CC2

Procedure:
To the total amount of the crude 2-acetyl-4methylcyclohexanone prepared in (1), 35 ml of ethanol, 3.36 g of cyanoacetamide and a small amount of piperidine were added and the obtained reaction mixture was heated under reflux for four hours. The crystals thus precipitated were filtered and recrystallized from a mixture of methanol and water to give 4.22 g of 4-cyano-1,7-dimethyl-2,3,5,6,7,8hexahydro-3-oxoisoquinoline. m.p. >290° C. NMRδTMSCF3COOH : 1.23 (3H, d), 2.60 (3H, s) and 1.8-3.3 (7H,m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ccccc1I
Product: Clc1ccccc1N1CCc2ccccc21

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-chloro-2-iodobenzene: ESMS m/e: 227.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3](I)=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[N+:13]([C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18])([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.[Cu]>[N+:13]([C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:3]1[C:2]([CH3:1])=[C:10]([CH3:11])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])([O-:15])=[O:14]
Reactant: Cc1ccc(C(=O)O)c(I)c1C
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)O)c(Nc2ccccc2[N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
10 g of 3,4-dimethyl-2-iodobenzoic acid, 6 g of 2-nitroaniline, 250 mg of powdery copper and 25 g of potassium carbonate were added to N,N-dimethylformamide and heated under reflux while stirring for 2 hr. Then the reaction mixture was cooled to room temperature and diluted with water. After adjusting the pH value thereof to pH 4 with conc. hydrochloric acid, it was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 2.5 g of the title compound.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O.[CH:19](O)(C)C>[Pd]>[CH3:3][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15]
Reactant: CC(C)O
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Product: Cc1c(C(=O)OC(C)C)[nH]c2ccccc12
Yield: 25 %

Procedure:
Sodium borohydride (0.23 g) was added to a stirred solution of ethyl 3-formylindole-2-carboxylate (0.2 g) and 10% palladium on carbon (0.11 g) in isopropanol (45 ml). The solution was heated at reflux for 4 hours, cooled and filtered through Celite. The solution was partitioned between ethyl acetate and water. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-10% ethyl acetate as eluent to give the desired end product as a white solid (0.05 g, 25%); NMR δ (CD3SOCD3) 1.3 (d, 6H), 2.5 (s, 3H), 5.2 (m, 1H), 7.0 (m, 1H), 7.2 (m, 1H), 7.4 (m, 1H), 7.6 (d, 1H), 11.3 (bs, 1H).
Reaction SMILES: [NH3:1].[F:2][C:3]([F:32])([F:31])[C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26](OCC)=[O:27])=[O:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.O1CCCC1>CO>[F:2][C:3]([F:31])([F:32])[C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]([NH2:1])=[O:27])=[O:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1
Reaction time: 22 h

Procedure:
5.90 ml (41.40 mmol) of a solution of ammonia (7N) in methanol are added to a solution of 0.30 g (0.69 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{6-[3-(trifluoromethyl)phenyl]-3-pyridyl}-1-piperazinecarboxylate, obtained in step 7.5. of Example 7, in 6 ml of a 1/1 mixture of methanol and tetrahydrofuran. Stirring is continued at room temperature for 22 hours. After concentrating under reduced pressure, the residue obtained is purified by chromatography on silica gel, eluting with a 96/4 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether. 0.19 g of pure product is obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH:27]=[O:28])[CH2:23][C:22]1=[O:29])=[O:6])[CH:2]=[CH2:3].O>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH:27]=[O:28])[CH2:23][C:22]1=[O:29])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CN1CCN(C=O)CC1=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CN1CCN(C=O)CC1=O
Yield: 132.5 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-(4-formyl-2-oxopiperazin-1-yl) methylpyrrolidine (11.74 g) in tetrahydrofuran (100 ml) was added n-tetrabutylammonium fluoride under ice cooing with stirring, and the mixture was stirred at the same temperature for 1 hour. Water was added to the mixture, and the mixture was evaporated in vacuo. Ethanol was added to the residue, and the mixture was stirred at 60° C. for 20 minutes. The mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of chloroform and methanol (9:1 v/v) to give (2S,4R)-1-allyloxycarbonyl-2-(4-formyl-2-oxo-piperazin-1-yl) methyl-4-hydroxypyrrolidine (11.38 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[OH-].[K+].Cl[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]1.O>CS(C)=O>[CH3:16][C:13]1([CH3:17])[O:12][C@@H:11]([CH2:10][N:1]2[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]2)[CH2:15][O:14]1
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: Nc1cc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)OC[C@H](Cn2ccc(N)n2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1H-pyrazol-3-amine in DMSO (15 mL) was added potassium hydroxide (3.18 g) at room temperature. After stirring at room temperature for 30 minutes, to the reaction mixture was added a solution of (R)-(+)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane (3.0 g) in DMSO (10 mL), followed by stirring at room temperature for 3 days. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained crude product was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1-1:3) to obtain 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-amine (1.0 g) as a pale violet oily substance.
Reaction SMILES: C([Mg]Br)C.[CH:5]1([C:8]#[CH:9])[CH2:7][CH2:6]1.[N:10]([C:13]1[S:14][C:15]2[CH2:16][CH2:17][O:18][C:19]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:20]=3[C:21]=2[N:22]=1)=[N+:11]=[N-:12]>C1COCC1>[Br:27][C:25]1[CH:24]=[CH:23][C:20]2[C:21]3[N:22]=[C:13]([N:10]4[C:8]([CH:5]5[CH2:7][CH2:6]5)=[CH:9][N:12]=[N:11]4)[S:14][C:15]=3[CH2:16][CH2:17][O:18][C:19]=2[CH:26]=1
Reactant: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: C#CC1CC1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCCc1sc(-n3nncc3C3CC3)nc1-2
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a 1M solution of ethylmagnesium bromide in THF (1.3 mL, 1.3 mmol) under a nitrogen atmosphere, was added dropwise cyclopropylethyne (70% in toluene, 0.154 mL, 1.3 mmol). The reaction mixture was heated at 50° C. for 15 mins then allowed to cool down to RT. A solution of 2-azido-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (425 mg, 1.3 mmol) in THF (1.5 mL) was then added dropwise. The reaction mixture was stirred at RT for 2 h, quenched with aqueous saturated ammonium chloride and diluted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was triturated with 20% ethyl acetate/cyclohexane and filtered to afford the title compound as a pale yellow solid (373 mg, 64%). LCMS 110142391 (Method B): RT=4.40 min, [M+H]+=390. 1H NMR (DMSO-d6): 8.20 (1H, d, J=8.6 Hz), 7.71 (1H, d, J=0.7 Hz), 7.36 (1H, dd, J=8.6, 2.1 Hz), 7.30 (1H, d, J=2.1 Hz), 4.40 (2H, t, J=5.0 Hz), 3.41 (2H, t, J=5.0 Hz), 2.70-2.63 (1H, m), 1.21-1.15 (2H, m), 0.91-0.86 (2H, m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([OH:26])=O)=[CH:22][N:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.Cl.C([N:41]=C=NCCCN(C)C)C.CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([NH2:41])=[O:26])=[CH:22][N:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.4 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carboxylic acid (0.17 g), 1-hydroxybenzotriazole ammonia complex (0.08 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carboxamide as colorless crystals (0.15 g, yield 88%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 175-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:23]Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[Cl:23])=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Reactant: ClCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(-n2ncc(Cl)c2-c2ccc(Cl)cc2)cc1
Yield: 78 %

Procedure:
4-[5-(4-Chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide from Step 2 (3.0 g, 9 mmol) was dissolved in 50 mL of acetic acid, and 9 mL of 1M chlorine in acetic acid was added dropwise. The mixture was stirred for 16 hours when sat. aq. sodium bicarbonate solution was slowly added until the mixture was neutral to pH paper. The mixture was extracted with ethyl acetate (3×50 mL), combined and washed with sat. aq. sodium bicarbonate and with brine, dried over magnesium sulfate, filtered, and concentrated. The resultant product was recrystallized from isopropanol to yield 2.6 g (78%) of a white solid: mp 168°-171° C. (dec); 1H NMR (DMSO-D6/300 MHz) 8.08 (s, 1H), 7.83 (d, J=8.7Hz, 2H), 7.55 (d, J=8.7Hz, 2H), 7.46 (brs, 2H), 7.44 (d, J=8.7Hz, 2H), 7.35 (d, J=8.7Hz, 2H). Anal. Calc'd for C15H11N3SO2Cl2: C, 48.93; H, 3.01; N, 11.41. Found: C, 49.01; H, 2.97; N, 11.41.