Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10](S(C1C(C)=CC=CC=1)(=O)=O)[S:11]([C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])=[O:4].[OH-].[Na+].Cl>O1CCOCC1.CO.O>[C:15]1([CH3:20])[C:14]([S:11]([NH:10][C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([OH:4])=[O:2])(=[O:13])=[O:12])=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1sccc1N(S(=O)(=O)c1ccccc1C)S(=O)(=O)c1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1S(=O)(=O)Nc1ccsc1C(=O)O
Temperature: 85 °C
Yield: 94.3 %

Procedure:
To a stirred mixture of 3-(bis-(Toluene-2-sulfonyl)-amino)-thiophene-2-carboxylic acid methyl ester (2.5 g, 5.35 mmol) in 1,4-dioxane/MeOH/water (3:1:1; 62.5 mL) was added aq. 1 N NaOH solution (16.05 mL, 16.05 mmol, 3.0 eq) and heated at 85° C. for 3.5 h and it was then cooled to rt. To the reaction mixture was added 1.2 N HCl (16.0 mL), extracted with CHCl3 (3×30 mL), washed with brine and dried. Evaporation of the solvent gave 3-(Toluene-2-sulfonylamino)-thiophene-2-carboxylic acid (1.5 g, 99%) as a white solid. 1H NMR (DMSO-d6, 300 MHz) 7.94 (dd, J=7.9 Hz, 1.3 Hz, 1H), 7.76 (d, J=5.5 Hz, 1H), 7.55 (dt, J=7.5 Hz, 1.3 Hz, 1H), 7.42-7.37 (m, 2H), 7.1 (d, J=5.5 Hz, 1H), 2.57 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@H:12]2[C@@H:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+].CO.O>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@@H:12]([N:15]=[N+:16]=[N-:17])[C@H:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2O[C@H]2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Yield: 31.2 %

Procedure:
Heat a mixture of racemic trans-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (0.56 mol, 112 g), sodium azide (1.12 mol, 73.08 g), ammonium chloride (0.56 mol, 30.07 g) and methanol/water (3:1) (1 L) at 65° C. for 16 h. Dilute the reaction mixture with water, extract with dichloromethane, and wash the organic layer with saturated sodium bicarbonate and brine solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify the residue on a silica gel column using 6% ethyl acetate in hexanes as eluent to obtain the title compound (42.3 g, 42%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 1.84 (br s 1H), 1.97-2.01 (m, 1H), 2.74-2.82 (m, 1H), 2.88 (br s, 1H), 3.37-3.40 (m, 1H), 3.50 (br s, 1H), 3.91 (br s, 1H), 4.09 (dd, 1H). ES-MS m/z 143 [M−Boc]+.
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([O:28][CH:29]=[CH2:30])[CH3:27])=[CH:20][CH:19]=2)[CH:11]=1>ClCCl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([O:28][CH:29]3[CH2:1][CH2:30]3)[CH3:27])=[CH:20][CH:19]=2)[CH:11]=1
Reactant: C=COC(C)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Product: CC(COc1ccc(Cc2cc(Br)ccc2Cl)cc1)OC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of diethyl zinc (1.9 mL, 1.0 M in hexane) in dichloromethane (10 mL) at 0° C. under argon was added slowly diiodomethane (0.15 mL) in dichloromethane (2 mL). After stirring for 30 min, 4-bromo-1-chloro-2-(4-(2-(vinyloxy)propoxy)benzyl)benzene (290 mg, 0.76 mmol) in dichloromethane (3 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight, and then quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium bicarbonate and then with brine, and then dried over sodium sulfate. The residue was concentrated and purified by preparative TLC to obtain intermediate DB as an oil (200 mg, yield 66%). 1H NMR (CDCl3, 400 MHz): δ 7.24-7.31 (m, 3H), 7.10-7.12 (m, 2H), 6.87-6.89 (m, 2H), 3.90-4.01 (m, 5H), 3.47-3.48 (m, 1H), 1.31-1.33 (m, 3H), 0.64 (m, 2H), 0.50-0.53 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:20][N:21]([CH3:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:14][C:12]1[S:13][C:9]([C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:8])=[C:10]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:11]=1)=[O:26]
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cccc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
Compound 454 (125 mg, 0.450 mmol) was dissolved in DMF (2 mL), and 3-(dimethylamino)benzoic acid (296 mg, 1.80 mmol), EDC hydrochloride (344 mg, 1.80 mmol) and 1-hydroxybenzotriazole monohydrate (276 mg, 1.80 mmol) were added thereto, followed by stirring at 80° C. for 2 hours. The reaction mixture was poured into water (200 mL), followed by extraction with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1), followed by reslurrying with methanol to afford the entitled Compound 464 (78.5 mg, 41%) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N=[CH:17][N:16](C(N2C=NC=C2)=O)[CH:15]=1.Cl.CNC.CCN(CC)CC>C1COCC1>[CH3:15][N:16]([CH3:17])[C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a stirred solution of 2-(3-nitrophenyl)acetic acid (0.2 g, 1.104 mmol) in THF (6 ml) was added CDI (0.269 g, 1.656 mmol). resulting mixture was heated at 50° C. for 1 hr, cooled to room temperature and then dimethyl amine hydrochloride (0.108 g, 1.325 mmol) and Et3N (0.15 ml, 1.104 mmol) were added sequentially. Resulting reaction mixture was stirred for 24 h at ambient temperature. Solvents were evaporated under vacuum. The residue was purified by flash chromatography to obtain N,N-dimethyl-2-(3-nitrophenyl)acetamide (0.192, 84% yield).
Reaction SMILES: C([CH:3]1[CH2:8][CH2:7][CH2:6][O:5][CH2:4]1)=O.[NH2:9][C:10]1[C:19]([CH3:20])=[C:18]([F:21])[C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1.[CH3:22]C(O)=O.C([BH3-])#N.[Na+]>CO>[F:21][C:18]1[C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=[C:10]([NH:9][CH2:22][CH:4]2[CH2:3][CH2:8][CH2:7][CH2:6][O:5]2)[C:19]=1[CH3:20]
Reactant: CC(=O)O
Reactant: O=CC1CCCOC1
Reactant: Cc1c(N)cc2oc(=O)[nH]c2c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1c(NCC2CCCCO2)cc2oc(=O)[nH]c2c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Formyltetrahydro-2H-pyran (12.9 g, 113 mmol) was added to a solution of 6-amino-4-fluoro-5-methyl-2-benzoxazolone (17.4 g, 96 mmol) in MeOH (600 ml). The mixture was stirred for 1 hour at room temperature. AcOH (1 ml) was added, followed by an addition of sodium cyanoborohydride (8.17 g, 130 mmol). Stirring was continued for 5 hours. The reaction mixture was concentrated in vacuo, and the residue was treated with water. This crude product was recrystallized from EtOH, to give the titled compound.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9])(=[O:5])[C:2]([CH3:4])=[O:3].[Br:12]Br.C(=O)=O>O>[Br:12][CH2:4][C:2](=[O:3])[C:1]([O:6][CH2:7][C:8]([Cl:9])([Cl:10])[Cl:11])=[O:5]
Reactant: BrBr
Reactant: CC(=O)C(=O)OCC(Cl)(Cl)Cl
Agent: O=C=O
Solvent: O
Product: O=C(CBr)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 35.5 %

Procedure:
Trichloroethyl pyruvate (3.7 g, 17 mmole) is heated to 65° and 1.1 ml (17 mmole) of bromine is added dropwise over 1 hour. A stream of carbon dioxide is passed through the reaction mixture during the addition to remove the HBr formed in the reaction. The mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract is dried over MgSO4, evaporated and distilled in vacuum to give 1.8 g of trichloroethyl bromopyruvate, bp 74°-77° (0.01 mm).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OS(C)(=O)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
(S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate (500 mg, 1.7 mmol) was dissolved in DCM (10 ml), and TEA (343 mg, 3.4 mmol) and methanesulfonyl chloride (290 mg, 2.6 mmol) were added. The mixture was stirred at RT for 2 hours, then was washed with HCl 1N (2×). The organic layer was dried over Na2SO4 and evaporated under vacuum to give 570 mg (90%) of the title compound which was employed in the next step without any further purification. MS/ESI+ 374.12 [MH]+.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][CH:10]=2)=O)C.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(=O)(O)[O-].[Na+]>>[N:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:25][C:4]=1[C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][CH:10]=2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]c1=O
Reactant: Nc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]c2ccc(Cl)cc2cc1-c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 6-chloro-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (7-2, 43 mg, 0.17 mmol, 1 equiv) and 1,2-phenylenediamine (37 mg, 0.34 mmol, 2.0 equiv) in polyphosphoric acid (3 mL) was heated at 200° C. for 2.5 h. The hot reaction mixture was poured into ice water (20 mL), and the resulting mixture was allowed to stand until all polyphosphoric acid had dissolved. The acidic suspension was neutralized with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (50 mL). The organic layer were dried over sodium sulfate and concentrated. The residue was suspended in ethyl ether (50 mL) aided by sonication, and the solids were filtered to give 3-(benzoimidazol-2-yl)-6-chloro-quinolin-2-one (7-3) as a yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.66 (br s, 1H), 12.58 (br s, 1H), 9.11 (s, 1H), 8.11 (d, 1H, J=2.2 Hz), 7.73 (m, 1H), 7.66 (m, 1H), 7.65 (dd, 1H, J=8.8, 2.4 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.22 (m, 2H); HRMS (electrospray FT/ICR) calculated for C16H11N3O [M+H]+ 296.0591, found 296.0602.
Reaction SMILES: [Cl:1][C:2](=[CH2:6])[C:3]([O-:5])=[O:4].C([Cl:11])(=O)C=C.ClCl>>[C:3]([O-:5])(=[O:4])[CH:2]=[CH2:6].[Cl:1][CH:2]([CH2:6][Cl:11])[C:3]([O-:5])=[O:4]
Reactant: C=C(Cl)C(=O)[O-]
Reactant: C=CC(=O)Cl
Agent: ClCl
Product: C=CC(=O)[O-]
Product: O=C([O-])C(Cl)CCl

Procedure:
In the case of an α-chloroacrylate monomer, an acrylate is synthesized by the reaction of acrylic acid chloride with an alcohol corresponding to the ester to be prepared or with its alkali salt, and reacted with chlorine gas to obtain an α,β-dichloropropionate, and then an equimolar amount of quinoline or pyridine is added thereto and the mixture is subjected to distillation under reduced pressure or to refluxing, followed by filtration, extraction and separation by column chromatography, to obtain a desired α-chloroacrylate monomer.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1([CH3:29])[CH:24]=[CH:23][CH:22]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:20]=1>>[C:19]1([CH3:29])[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)(=[O:27])=[O:26])[CH:20]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Cc1cccc(S(=O)(=O)N2CCN(c3cccc4nc(N)nc(N)c34)CC2)c1
Yield: 41 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and m-toluenesulfonyl chloride (78.2 mg; 0.41 mmol) to obtain 32.3 mg. (41% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.58 (m, 4H), 7.38 (t, J=8.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 5.92 (br s, 2H), 3.74 (br d, J=11.6 Hz, 2H), 3.44 (m, 1H), 3.1 (br d, J=12 Hz, 2H), 2.85 (m, 2H), 2.53 (m, 4H). ESIMS+399.6 m/z
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11](I)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:9]([N+:16]([O-:18])=[O:17])=[CH:10][C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[F:20])=[C:12]([Cl:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1F
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(-c2ccccc2F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert-butyl ester [CAS-No. 335349-60-5] (30 g, 75.3 mmol) and 2-fluorophenylboronic acid (13.82 g, 98.8 mmol) according to the general procedure D. Obtained as a yellow gum (1.39 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].I[CH3:32].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([CH3:32])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: CI
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (5.0 g) in DMF (50 mL) was added sodium hydride (60%, 576 mg) at 0° C., and the mixture was stirred at 0° C. for 30 min. Iodomethane (978 was added, and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (3.40 g).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:46]1([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:28][N:25]1[CH2:24][CH2:23][CH:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)=[S:57])=[CH:30][CH:29]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:27][CH2:26]1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)ccn3)CC2)CC1
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyridine (153 mg) and (+)-10-camphorsulfonic acid (162 mg) in ethanol (4.0 ml) was added a solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.93 ml) at room temperature, followed by stirring for 3 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (71.8 mg, 33%) as white powder.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[O:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1>O1CCCC1>[CH:8](=[O:7])[C:4]1[O:6][CH:1]=[CH:2][CH:3]=1.[CH:11]([OH:7])([OH:5])[CH2:10][CH2:9][CH3:8]
Reactant: c1ccoc1
Reactant: OCCCCO
Solvent: C1CCOC1
Product: CCCC(O)O
Product: O=Cc1ccco1

Procedure:
Both 1,4-butanediol and tetrahydrofuran are useful as a solvent and raw materials for organic synthesis such as polymeric material. They have been produced through various ways. For example, tetrahydrofuran is produced by (a) catalytic hydrogenation of furan which has been obtained by elimination of carbonyl group from furfural, (b) dehydration cyclization of butanediol obtained by hydrogenation of butynediol which is a reaction product of acetylene and formaldehyde and (c) reaction of 1,4-diacetoxybutanediol and water in the presence of an acid catalyst; and 1,4-butanediol is produced by (d) hydrogenation of butynediol and (e) hydrolysis of 1,4-diacetoxybutane.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])=[N:18][CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])=[N:18][CH:19]=1
Reactant: CON(C)C(=O)C=Cc1ccc(Br)cn1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1ccc(Br)cn1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 56.8 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (17.1 mL, 14.3 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (9.6 mL, 14.3 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(5-bromo-pyridin-2-yl)-N-methoxy-N-methyl-acrylamide (1.3 g, 4.8 mmol, in tetrahydrofuran 12.0 mL) prepared in Step 2 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 0.9 g of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].N1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH2:14]>C(OCC)C>[C:1]([OH:4])(=[O:3])[CH3:2].[C:1]([OH:4])(=[O:3])[CH3:2].[OH:14][CH2:9][C:10]1[C:1]([OH:3])=[CH:2][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: O
Solvent: CCOCC
Product: CC(=O)O
Product: OCc1ccccc1O
Reaction time: 8 h

Procedure:
Acetic anhydride (82.3 g, 0.806 mol) was mixed with pyridine (130 g) and Product A (50 g, 0.403 mol) added slowly with stirring and cooling to prevent the temperature exceeding 50° C. The mixture was allowed to stand overnight at room temperature and then poured into a large excess of cold water. Diethyl ether was added and the reaction product extracted, washed with water, then washed with 1% hydrochloric acid and then again washed with water. The organic layer was dried and the ether removed under vacuum leaving a pale yellow oil.
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2ccc(Cl)cc2CC1C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1N=C(c2ccc(N)c(C)c2)c2ccc(Cl)cc2CC1C
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
3.7 g (10 mmoles) of (±)-3-acetyl-4,5-dihydro-7-chloro-1-(3-methyl-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepine are dissolved in a mixture of 80 cm3 of methanol and 33 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is recrystallized from a 1:2 mixture of ethyl acetate and hexane. Thus, 2.88 g (84%) of the title compound are obtained in the form of yellow ochre solids melting at 200–205° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C@@H:17]2[CH2:21][O:20][C@@H:19]3[C@H](O)[CH2:23][O:24][C@H:18]23)(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>N1C=CC=CC=1>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C@@H:17]2[CH2:21][O:20][C@@H:19]3[C@@H:1]([Br:5])[CH2:23][O:24][C@H:18]23)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Temperature: 65 °C
Yield: 42.7 %

Procedure:
A solution of carbon tetrabromide (18.12 g, 54.63 mmol) in pyridine (100 mL) was added to a solution of monotosylate (50) (14.9 g, 49.66 mmol) and triphenylphosphine (26.1 g, 99.32 mmol) in pyridine (150 mL) over 30 minutes, then the mixture heated at 65° C. for 1.5 hours under an atmosphere of argon. Water (200 mL) was added then the aqueous phase extracted with dichloromethane (5×100 mL). The organic phase was washed with brine (50 mL), then dried (MgSO4), filtered and reduced in vacuo to leave a residue which was azeotroped with toluene (5×50 mL). Flash chromatography over silica, eluting with diethyl ether:heptane mixtures 0:100 to 100:0 gave bromotosylate (46) (7.70 g, 43%) as a white solid. [α]D17 +68.6° (c=0.51, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][CH2:18]O>N1CCCCC1>[NH:1]1[CH:2]=[CH:3][CH:4]=[C:18]1[CH:17]=[N:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Reactant: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N=Cc1ccc[nH]1

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (100 mg) was then suspended in EtOH (3 mL) 2-Pyrrolecarbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-(((1H-pyrrol-2-yl)methylene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.