Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[CH2:13]([Sn:17]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])Cl)[CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH3:1][O:2][C:3]1[S:4][C:5]([Sn:17]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][N:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(OC)s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 22.8 %

Procedure:
To a stirred solution of 2-methoxythiazole (5 g, 43.4 mmol) in tetrahydrofuran (THF) (50 mL) was added n-BuLi (35.3 mL, 56.4 mmol) and the contents stirred at −78° C. After 15 min, tributylchlorostannane (14.13 mL, 52.1 mmol) was added and the mixture stirred with warming to room temperature over a 3 h period. The reaction mixture was quenched with water (20 mL) and the contents extracted with ether (25 mL). The organic layer was separated and dried over anhydrous sodium sulphate, filtered, and the filtrate concentrated in vacuo to afford the crude product (6 g). The crude product was purified by silica gel column chromatography (eluent: 2% EtOAc/Hexane) to afford 2-methoxy-5-(tributylstannyl)thiazole (4 g, 22%) as yellow liquid. 1H NMR (400 MHz, CDCl3-d3) δ ppm 0.90-0.98 (m, 9H), 1.05-1.15 (m, 6H), 1.30-1.40 (m, 6H), 1.50-1.65 (m, 6H), 4.04 (s, 3H), 7.03 (s, 1H). LCMS (ES) [M+H]+ 405.99.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-:13].[Na+].[Na+].O.[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(=O)C>[N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[NH:4][C:3]=1[C:2]([OH:13])=[O:1]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1nc2ccccc2[nH]1

Procedure:
The 2-hydroxymethylbenzimidazole from Part A (4 gms.) was refluxed in a small amount of saturated sodium carbonate solution with addition of sufficient boiling water to dissolve it. A hot, dilute solution of 6.67 gms. of potassium permanganate then was added slowly with stirring. Upon completion of the addition, the resulting suspension was refluxed for 30 minutes. The resulting hot liquid was separated by filtration from manganese dioxide which had formed. The filtrate then was cooled and rendered acidic (pH 5.0) by addition of acetic acid. The resulting yellow precipitate was filtered, dried, and recrystallized from hot water to obtain 1.98 gms. of the title compound as fine yellow needles.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][N:21]=2)[CH2:16][C:15]1=[O:23]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[C:16]1[C:17]2[C:22](=[N:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:15]1=[O:23])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1C(C)C
Reactant: O=C1Cc2cccnc2N1
Product: COc1ccc(C=C2C(=O)Nc3ncccc32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 7-aza-2-oxindole to give 0.25 g of 3-(3-isopropyl-4-methoxy-benzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]([F:49])([C:38](=[O:48])[NH:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:3]([OH:37])[CH:4]([NH:8][C:9](=[O:36])[CH2:10][N:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:14]=[C:13]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)=[O:25])[C:12]1=[O:35])[CH:5]([CH3:7])[CH3:6].Cl>>[F:49][C:2]([F:1])([C:38](=[O:48])[NH:39][CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:3](=[O:37])[CH:4]([NH:8][C:9](=[O:36])[CH2:10][N:11]1[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][CH:14]=[C:13]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)=[O:25])[C:12]1=[O:35])[CH:5]([CH3:6])[CH3:7]
Reactant: Cc1cccc(COC(=O)Nc2ccc(-c3ccccc3)n(CC(=O)NC(C(C)C)C(O)C(F)(F)C(=O)NCCc3ccccc3)c2=O)n1
Agent: Cl
Product: Cc1cccc(COC(=O)Nc2ccc(-c3ccccc3)n(CC(=O)NC(C(=O)C(F)(F)C(=O)NCCc3ccccc3)C(C)C)c2=O)n1

Procedure:
N-[3,3-Difluoro-2-hydroxy-1-isopropyl-3-(N-phenethylcarbamoyl)propyl]-2-[3-(6-methylpyrid-2-ylmethoxycarbonylamino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]acetamide was oxidized using a procedure similar to that described in Example 1.i., but omitting the hydrochloric acid wash. The crude material was purified by chromatography, with methanol:chloroform (1:99) as the eluent. The resulting material was triturated with diethyl ether and petroleum ether to give a solid which was triturated with petroleum ether to yield the title compound; TLC: Rf =0.31, chloroform:methanol (30:1); 300 MHz NMR: 9.20 (t,1), 8.68 (s,1), 8.50 (d,1), 7.91 (d,1), 7.71 (t,1), 7.48-7.11 (m,14), 6.22 (d,1), 5.18 (s,2), 4.83-4.75 (m,1), 4.50 (broad s,2), 2.76 (t,2), 2.27-2.12 (m,1), 8.48 (d,3), 7.36 (d,3); MS: m/z=674(M+1). Analysis for C37H37F2N5O6 : Calculated: C, 64.18; H, 5.54; N, 10.40; Found: C, 64.21; H, 5.72; N, 10.10.
Reaction SMILES: Br[CH2:2][C:3]([C:5]12[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]2=[O:18])=O.[CH:19]([NH2:21])=O.[NH3:22]>C(Cl)Cl.O>[NH:22]1[CH:2]=[C:3]([C:5]23[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]3=[O:18])[N:21]=[CH:19]1
Reactant: N
Reactant: NC=O
Reactant: O=C(CBr)C12CCCCC1c1ccccc1C2=O
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2C2CCCCC12c1c[nH]cn1
Temperature: 135 °C
Reaction time: 4 h

Procedure:
9a-(2-Bromoacetyl)-1,2,3,4,4a,9a-hexahydrofluoren-9-one (6.6 g) was mixed with formamide (22 ml) and the mixture was heated at 135° C. for 30 minutes. Ammonia gas was led into the reaction mixture and the stirring was continued at 135° C. for further 4 hours. After cooling to the ambient temperature the mixture was diluted with CH2Cl2 (30 ml) and water (30 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2 (30 ml). The combined organic phases were mixed with water (60 ml) and the pH was adjusted to 1 with concentrated HCl solution. The layers were separated and the aqueous phase was washed with CH2Cl2 (30 ml). The aqueous phase was mixed with CH2Cl2 (60 ml) and the pH was adjusted to 11.5-13.5 with 48% NaOH solution. The phases were separated and the aqueous phase was extracted with CH2Cl2 (20 ml). The combined organic phases were washed with water (50 ml), dried over Na2SO4 and evaporated. The yield was 2.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][Cl:14])[CH:7]=1
Reactant: COc1ccc(Cl)cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Cl)cc1CCl
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a solution of (5-chloro-2-methoxy-phenyl)-methanol (17.1 g, 99.1 mmol) in methylene chloride (100 mL) was added thionyl chloride (14.5 mL, 198 mmol). The reaction was stirred at reflux for 3 hours, cooled to room temperature and concentrated in vacuo. The crude product was dissolved in methylene chloride and washed with saturated aqueous sodium hydrogen carbonate then dried over magnesium sulfate. Concentration in vacuo gave 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4 g). To a solution of 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4 g, 96.4 mmol) in acetonitrile (100 mL) was added potassium cyanide (12.5 g, 193 mmol) and 18-crown-6 (2.54 g, 9.64 mmol). The reaction was stirred 12 hours at ambient temperature, diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by passing it through a pad of silica gel, eluting with methylene chloride to give the title compound (17.2 g).
Reaction SMILES: C1N(CCS(O)(=O)=O)CC[O:3]C1.[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16].O=C(CCC([O-])=O)C([O-])=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:3][C@H:19]1[CH2:20][NH:13][C@H:14]([C:15]([OH:17])=[O:16])[CH2:18]1
Reactant: O=S(=O)(O)CCN1CCOCC1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])CCC(=O)C(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 0.5 h

Procedure:
The enzyme reaction with purified L-proline-4-hydroxylase obtained in Example 5 was carried out. The reaction mixture was composed of 200 mM MES buffer (pH 6.5), 20 mM L-proline, 20 MM 2-ketoglutarate, 5 mM L-ascorbic acid, 2 mM ferrous sulfates and 90 U of purified enzyme preparation in total volume of 50 μl. The reaction was carried out at 35° C. for 30 min. As a result of the reaction, 12.9 mM (1.7 g/1) of trans-4-hydroxyl-proline was produced in the reaction mixture.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=[O:36].C(OCC)(OCC)OCC.O1CCC[C@@H]1CN>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([CH2:1][C@H:2]4[CH2:3][CH2:4][CH2:5][O:36]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NC[C@H]1CCCO1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1C[C@H]1CCCO1
Yield: 72.4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), (R)-(tetrahydrofuran-2-yl)methanamine (0.102 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 97.3 mg (0.31 mmol, 72.4% yield) of the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].N1C=CC=CC=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][N:15]=1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([C:13]([F:24])([F:23])[F:12])=[N:15][CH:16]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of N,O-dimethylhydroxylamine hydrochloride (9.47 g, 97.1 mmol) and pyridine (18.6 mL, 230 mmol) in CH2Cl2 (100 mL) was added a solution of 6-(trifluoromethyl)nicotinoyl chloride (18.50 g, 88.28 mmol) in CH2Cl2 (250 mL) over 3-5 min. The reaction mixture was stirred at rt overnight, and then carefully quenched with 150 mL of saturated aq. NaHCO3 solution and stirred for about 1 hr. The mixture was diluted with CH2Cl2 (50 mL) and the organic phase was separated and washed with aq. NaHCO3 solution (100 mL) and brine (50 mL), dried (Na2SO4), filtered, and evaporated. The residue was redissolved in toluene (about 50 mL) and evaporated again to azeotrope the pyridine off. This was repeated with toluene (about 50 mL). The product was isolated as a colorless oil (with a small amount of crystalline material) (19.1 g, 92%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[N:22]=[C:21]([C:4]2=[CH:3][CH:2]=1)[N:20]=[C:19]1[C:23]2[C:28]([C:17](=[N:18]1)[N:16]=[C:15]1[C:29]4[C:34]([C:13](=[N:14]1)[N:12]=[C:11]1[C:35]5[C:40]([C:9](=[N:10]1)[N:8]=3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][CH:26]=[CH:25][CH:24]=2.[Cu:41].[Na].[Cl:43][S:44]([OH:47])(=O)=[O:45].S(Cl)([Cl:50])=O>>[CH:38]1[CH:39]=[C:40]2[C:9]3[N:10]=[C:11]([C:35]2=[CH:36][CH:37]=1)[N:12]=[C:13]1[C:34]2[C:29]([C:15](=[N:14]1)[N:16]=[C:17]1[C:28]4[C:23]([C:19](=[N:18]1)[N:20]=[C:21]1[C:4]5[C:5]([C:7](=[N:22]1)[N:8]=3)=[CH:6][CH:1]=[CH:2][CH:3]=5)=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:30][CH:31]=[CH:32][CH:33]=2.[Cu:41].[S:44]([Cl:43])([Cl:50])(=[O:47])=[O:45]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)Cl
Agent: [Cu]
Agent: [Na]
Agent: c1ccc2c(c1)C1=NC2=NC2=NC(=NC3=NC(=NC4=NC(=N1)c1ccccc14)c1ccccc13)c1ccccc12
Product: O=S(=O)(Cl)Cl

Procedure:
Next, copper phthalocyanine (tri- or tetra-) sulfonic acid (tri- or tetra-) sodium salt was gradually fed to chlorosulfonic acid followed by dropping of thionyl chloride to perform reaction. The reaction liquid was cooled and the deposited crystal was filtered to obtain a wet cake of desired copper phthalocyanine (tri- or tetra-) sulfonyl chloride, which was then stirred and suspended followed by addition of aqueous ammonia, and a compound represented by the following chemical formula (γ) to perform reaction. Then, water and sodium chloride were added to the reaction liquid to deposit crystal. The deposited crystal was filtered, washed with an aqueous sodium chloride solution, filtered/washed again, followed by drying to obtain the color material represented by the chemical formula (3).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A mixture of sodium carbonate (0.903 g), tetrakis(triphenylphosphine)palladium(0) (0.246 g), 4-(trifluoromethoxy)phenylboronic acid (1.14 g) and 3-bromopyridin-2-amine (0.737 g) in 1,2-dimethoxyethane (50 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.069 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:4][CH2:3]1.O.NN>C(O)C.C(Cl)Cl>[NH2:9][O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CN1CCC(ON)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 25.4 %

Procedure:
To a solution of 2-[(1-methylpiperidin-4-yl)oxy]-1H-isoindole-1,3(2H)-dione 49 (1.18 g, 4.53 mmol) in a mixture of ethanol (3 mL) and DCM (18 mL) was added hydrazine hydrate (0.268 g, 4.53 mmol). The reaction mixture was stirred at room temperature for 4.5 h. Precipitate was filtered off. The filtrate was evaporated and sonicated in ethyl acetate (20 mL). Solid was filtered off and filtrate was evaporated to give the residue which was subjected to chromatography to give 50 (0.15 g, 25%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.CCCCCC>CO.C(Cl)Cl>[NH2:1][C:2]1[N+:7]([O-:32])=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)n1
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)[n+]1[O-]

Procedure:
20.6 g of methyl 2-amino-6-[(p-tolylsulphonyl)oxy]-4-pyrimidinecarbamate are suspended in 120 ml of methanol and 720 ml of methylene chloride. While stirring there are added thereto at room temperature 20.5 g of m-chloroperbenzoic acid and after 6 hours a further 16.3 g of m-chloroperbenzoic acid. The mixture is stirred overnight and subsequently treated with 1.5 l of hexane, whereby a precipitate separates. The precipitate is filtered off under suction and dried, there being obtained crude methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate-3-oxide of melting point 139°-142°.
Reaction SMILES: [CH3:1][S:2](Cl)(=O)=O.[Cl:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:26]O)[CH:22]=3)[N:17]([CH3:28])[CH:16]=2)=[O:14])=[CH:9][CH:8]=1.[N:31]1[C:36](C)=CC(C)=[CH:33][C:32]=1C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:26][N:31]4[CH2:36][CH2:1][S:2][CH2:33][CH2:32]4)[CH:22]=3)[N:17]([CH3:28])[CH:16]=2)=[O:14])=[CH:9][CH:8]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Reactant: Cc1cc(C)nc(C)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCSCC3)ccc21
Reaction time: 2 h
Yield: 74 %

Procedure:
Methanesulfonyl chloride (0.193 mL) is added to a solution of N-(4-chloro-benzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (357 mg) from Example No. 2, DMAP (20 mg), and 2,4,6-collidine (0.33 mL) in anhydrous DMF (20 mL). The mixture is stirred at room temperate for 2 h, and poured into water (60 mL). The resulting percipitate is filtered, washed with water (20 mL), and recrystallized from acetonitrile to afford 0.328 g (74%) of the title compound as a white solid.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5](Cl)[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C.[OH2:28]>>[NH2:2][C:3]1[N:4]([CH2:17][CH2:18][CH2:19][CH3:20])[C:5](=[O:28])[C:6]([C:14]#[N:15])=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:8]=1
Reactant: CCCCNc1cc(N)[n+](CCCC)c(Cl)c1C#N
Reactant: O
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CCCCNc1cc(N)n(CCCC)c(=O)c1C#N
Yield: 75 %

Procedure:
3.2 gms (.01 mole) of 2-amino-1-n-butyl-4-n-butylamino-6-chloro-5-cyano-pyridinium chloride (compound 6 - Table 1) was dissolved in hot water, 4.0 gms (0.04 mole) of triethylamine added and the solution refluxed on a boiling water bath. After 2 hours 2.0 gms (75% yield) of 2-amino-1-n-butyl-4-n-butylamino-5-cyano-pyridine-6-one (compound 87 - Table 6) had precipitated and was filtered off. (MPt 177° - 179°C).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:15])[O:9][N:8]=1.FC(F)(F)C(O)=O.O.[OH-].[Na+]>ClCCl>[NH:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:14](=[O:15])[CH2:13][CH2:12][C:10]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:11]=2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)CCc2nc(-c3ccccn3)no2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CCc1nc(-c2ccccn2)no1)NC1CCNCC1
Yield: 63.3 %

Procedure:
tert-Butyl 4-({3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoyl}amino)-1-piperidinecarboxylate (0.40 g) was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (3 ml) was added. After 2 hours water, 2N sodium hydroxide and dichloromethane were added and the phases were separated. The organic phase was dried, filtered and evaporated to give the subtitle compound (0.19 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].CCOC(C)=O.O>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([F:14])=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trimethyl phosphonoacetate (182 mg, 1.00 mmol) in THF (1.70 mL) was added dropwise (caution—vigorous reaction!) to sodium hydride (60% in oil) (60 mg, 1.50 mmol) in THF (1.70 mL) under an atmosphere of nitrogen at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and then 4-fluoro-3-nitrobenzaldehyde (169 mg, 1.00 mmol) in THF (0.50 mL) was added. After 1 hour, EtOAc/water was added and the organic layer washed with more water, dried (Na2SO4), and the solvent concentrated in vacuo. The crude product was purified by column chromatography eluting with 33% EtOAc in heptane to give the title compound. Yield: 160 mg, 71%; LC-MS 41.31 min; HPLC Purity: >75%; MS (ES+) m/z not detectable (M+H)
Reaction SMILES: [CH3:1][C:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:27][N:15]4[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.Cl.C(N(C(C)C)CC)(C)C.[F:38][C:39]([F:51])([F:50])[C:40]1[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1>O1CCOCC1.C(Cl)Cl>[CH3:1][C:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:27][N:15]4[CH2:16][CH2:17][N:18]([S:46]([C:42]5[CH:43]=[CH:44][CH:45]=[C:40]([C:39]([F:38])([F:50])[F:51])[CH:41]=5)(=[O:48])=[O:47])[CH2:19][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:3][CH2:4]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](Oc3cnc(C4(C)CC4)cn3)C[C@H]2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(c2cnc(O[C@@H]3C[C@H]4CN(S(=O)(=O)c5cccc(C(F)(F)F)c5)CCN4C3)cn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 206A (28 mg, 0.075 mmol) in 1,4-dioxane (1 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 2.0 mmol). The resulting mixture was stirred at room temperature for 90 minutes, and the mixture was then concentrated and dried in vacuo. To the resulting colorless solid was added CH2Cl2 (0.75 mL), diisopropylethylamine (0.065 mL, 0.375 mmol) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (22.02 mg, 0.090 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was partitioned between water and CH2Cl2, and the organic layer was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-40% ethyl acetate in hexanes. The title compound was obtained as a colorless solid (10 mg, 28%). 1H NMR (300 MHz, CDCl3) δ ppm 0.72-0.81 (m, 2H), 1.07-1.17 (m, 2H), 1.48 (s, 3H), 1.72-1.88 (m, 1H), 1.92-2.05 (m, 1H), 2.12 (t, J=10.51 Hz, 1H), 2.33 (dd, J=9.92, 5.16 Hz, 1H), 2.38-2.63 (m, 3H), 2.94-3.07 (m, 1H), 3.65 (dd, J=10.31, 6.74 Hz, 1H), 3.72-3.82 (m, 1H), 3.86-3.98 (m, 1H), 5.23-5.35 (m, 1H), 7.70 (t, J=7.93 Hz, 1H), 7.87 (d, J=7.93 Hz, 1H), 7.96 (d, J=7.93 Hz, 1H), 8.00 (d, J=1.19 Hz, 1H), 8.01-8.04 (m, 1H), 8.05 (d, J=1.19 Hz, 1H); MS (ESI) m/z 483 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2Br)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH2:23][NH2:24]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]3[C:20]([CH3:21])=[N:19][N:18]=[C:17]3[NH:24][N:23]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: Cc1nnc(Br)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NN2

Procedure:
U.S. patent application Ser. No. 391,647, filed Aug. 27, 1973, now U.S. Pat. No. 3,891,666, describes a process for reacting a mixture of 5-chloro-2-(3-bromo-5-methyl-4H-1,2,4-triazol-4-yl)benzophenone with hydrazine or its mineral acid salt and a base in a lower alkanol, e.g., ethanol at 70°-120° C. to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,3,4]benzotriazepine, indicating that hydrazine reacts with halogen on the triazole ring of triazolylbenzophenone compounds.