Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNN.Cl[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11](C=O)[CH2:10][C:9](=CO)[C:8]2=O.C(O)(=O)C>CO>[N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=CN1CC(=CO)C(=O)c2cc(Cl)ccc21
Agent: CNN
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc2ncccc2c1
Reaction time: 1.5 h
Yield: 116 %

Procedure:
Methylhydrazine (52.5 g) was dropwise to a mixture of 6-chloro-1-formyl-3-hydroxymethylene-4-oxo-1,2,3,4-tetrahydroquinoline (276 g) and acetic acid (13 ml) in methanol (2.76 liters) at 10° C. to 12° C. over a period of 10 minutes. After being stirred for 1.5 hours at the same temperature, the resulting precipitate was collected by filtration, washed with methanol and dried to give 8-chloro-4,5-dihydro-5-formyl-1-methyl-1H-pyrazolo 4,3-c]quinoline (174 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.[Cl-].[Na+]>O1CCCC1>[CH3:8][S:9]([O:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC(O)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCC(OS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
13.3 ml of triethylamine and subsequently 7.4 ml of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 10 g of 4-hydroxy-1-methylpiperidine dissolved in 100 ml of dry tetrahydrofuran. The mixture was then stirred at 0° to 5° C. for 2 hours and then at room temperature for 1.5 hours, after which it was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, to afford 12.74 g of the title compound as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([CH3:28])([C:9]1[CH:14]=[CH:13][C:12]([Sn](CCCC)(CCCC)CCCC)=[CH:11][CH:10]=1)[CH3:8])(=[O:3])[CH3:2].Br[C:30]1[N:31]=[C:32]([N:40]2[CH2:45][CH2:44][N:43]([CH2:46][CH3:47])[CH2:42][CH2:41]2)[C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:46]([N:43]1[CH2:42][CH2:41][N:40]([C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:39]=[C:30]([C:12]3[CH:11]=[CH:10][C:9]([C:7]([CH3:8])([CH3:28])[CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=3)[N:31]=2)[CH2:45][CH2:44]1)[CH3:47]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(C)(C)CCOC(C)=O)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(C(C)(C)CCOC(C)=O)cc3)cc3ccccc23)CC1
Yield: 86.2 %

Procedure:
3-Methyl-3-(4-tributylstannylphenyl)butyl acetate (4.05 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.10 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.16 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.32 g) of 1-(4-ethylpiperazin-1-yl)-3-[4-(3-acetoxy-1,1-dimethylpropyl)phenyl]isoquinoline as a brown viscous oil and the starting material-The resulting mixture (1.32 g) was then dissolved in methanol (30 ml), to which was then added a 5N aqueous solution of sodium hydroxide (3.00 ml), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated, and water was added to the resulting residue and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 0.74 g of the free compound of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:13]1([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:14]=1>O1CCCC1>[C:1]([NH:5][S:23]([C:13]1[CH:14]=[C:15]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A solution of 1.46 grams (20 mmole) of t-butylamine and 2.02 grams (20 mmole) of triethylamine in tetrahydrofuran was added dropwise to a solution of 5.5 grams (20 mmole) of 1,3-benzenedisulfonyl chloride in tetrahydrofuran. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo. The residue was purified on silica gel eluting with methylene chloride to give 3.86 grams of the titled compound as an oil.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[N+:11]([C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[N:14][CH:15]=[N:16][CH:17]=2)[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Reactant: OB(O)c1cncnc1
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
Product: O=[N+]([O-])c1cc(-c2cncnc2)c2occc2c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 898.3 %

Procedure:
Pd(PPh3)4 (240 mg, 209 mmol) was added to 7-iodo-5-nitro-1-benzofurane (1.00 g, 3.45 mmol) in DME (11 mL) and the resulting mixture was stirred for 10 min. The color went from dark red to mustard yellow. Pyrimidine-5-boronic acid (0.24 g, 0.21 mmol) and 1 M Na2CO3 (5 mL) were added and the reaction mixture was refluxed at 100° C. for 2.5 h. The mixture was concentrated in vacuo and the residue was dissolved in 1 M HCl (50 mL) and washed with diethyl ether (50 mL). The aqueous layer was made basic (pH 8), by addition of K2CO3, and extracted with chloroform (3×). The combined organic layers were dried with K2CO3, filtered and concentrated to afford 0.455 g (55%) of a yellow solid. HPLC 100%, RT: 1.870 min (System A; 10-97% over 3 min). 1H NMR (270 MHz, CDCl3) δ ppm 7.06 (d, J=2.47 Hz, 1H) 7.90 (d, J=2.23 Hz, 1H) 8.45 (d, J=2.23 Hz, 1H) 8.63 (d, J=2.23 Hz, 1H) 9.28-9.31 (m, 3H). LC-MS 242 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([OH:52])[CH2:46]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:65]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=1[S:74](Cl)(=[O:76])=[O:75])([O-:67])=[O:66]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][S:74]([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][C:68]=3[N+:65]([O-:67])=[O:66])(=[O:75])=[O:76])[CH2:46]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 17-ethyl-20-fluoro-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in dry methylene chloride (20 ml) is added diisopropylethylamine (150 μl) followed by 2-nitrobenzenesulonyl chloride (60 mg), then 4-dimethylaminopyridine (27 mg). The solution is stirred at room temperature under nitrogen atmosphere for 4 h, then quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent is removed in vacuo. Chromatography on silica gel gives the title compounds.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:24][CH:23]=1.[C:1]([O:4][CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Reaction time: 2 h
Yield: 125.9 %

Procedure:
Using the method outlined in German Offenlegungschrift No. 2,103,014, 20.4 g of 3-acetoxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid was dissolved in 60 ml of dry pyridine, with heating and then 6 ml of acetic anhydride was added to the cooled solution. The mixture solidified on standing for 2 hours. It was then diluted with 50 ml of pyridine and the solid filtered and washed with 150 ml of ethyl acetate. The product was recrystallized from 150 ml of ethyl acetate and 20 ml of alcohol to yield 15.4 g of 3-acetoxymethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid pyridine salt, mp 150°-151° d.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 144 h

Procedure:
13.5 g of N-methyl-hydrazine carboxylic acid tert-butyl ester was dissolved in 90 mL of chloroform, added with 90 mL of 1N sodium hydroxide aqueous solution and 28 mL of benzyl chloroformate, and stirred at room temperature for 6 days. Adding water, extracting with chloroform, and the resultant organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, followed by purification by silica gel column chromatography (ethyl acetate:hexane=1:4), to afford 17.7 g of the title compound as a colorless oil.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+].O>C(Cl)(Cl)Cl>[CH2:26]([NH:33][CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Reactant: NCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: c1ccc(CNCC2CCn3c(nc4ccccc43)S2)cc1
Yield: 31.3 %

Procedure:
To a solution of 1.12 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in chloroform (20 ml) was added with 0.41 g of benzylamine and a catalytic amount of sodium hydride, and refluxed for 11 hours. The reaction mixture was cooled and then condensed under reduced pressure. Theresidue was added with water, extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.29 g (Yield: 31%) of theintended product, m.p. 155°-156° C.; IR νmaxKBr cm-1 : 3260, 3100-2800, 1600, 1420; Anal. Calcd. for C18H19N3S: C, 69.87; H, 6.19; N, 13.58; S, 10.36; Found: C, 70.00; H, 6.21; N, 13.69; S, 10.10.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([F:11])[CH2:8][NH:7]1.Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2.C(N(C(C)C)C(C)C)C>C(O)CCC>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([F:11])[CH2:8][N:7]1[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][NH:21]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: F[C@@H]1CN[C@@H](COc2ccccc2Cl)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: F[C@H]1C[C@H](COc2ccccc2Cl)N(c2ncnc3[nH]cnc23)C1

Procedure:
7.8 780 mg of (2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidine and 525 mg of 6-chloropurine are irradiated at 120° C. in the microwave for 6 h together with 1.2 ml of N-ethyldiisoproylamine and 40 ml of 1-butanol, during which a pressure of 10 bar arises. After conventional aqueous work-up, the residue obtained is crystallised from ether, giving 350 mg of 6-[(2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidin-1-yl]-9H-purine (“A7”) as beige crystals; Rt.: 1.790 min; [M+H]+348.2; m.p. 143-144°;
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8](=[O:34])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]2[C:18](=[O:33])[O:19][C:20]3[CH:21]=[N:22][C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][C:26]([O:31][CH3:32])=[CH:25][CH:24]=4)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].C(OCC)(=O)C>CO>[C:3]([O:7][C:8](=[O:34])[NH:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([CH2:16][CH:17]([CH2:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=3)[N:22]=[CH:21][C:20]=2[OH:19])[CH2:18][OH:33])[CH2:14][CH2:15]1)([CH3:4])([CH3:6])[CH3:5]
Reactant: COc1ccc2ncc3oc(=O)c(C[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)cc3c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(O)c(CC(CO)C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (86 mg, 2.28 mmol, 10.0 eq) is added at 0° C. to a stirred suspension of [trans-4-(6-methoxy-2-oxo-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (100 mg, 0.23 mmol, 1.0 eq) in methanol (10 mL). After 8 hours stirring at room temperature, the reaction mixture is quenched with ammonium chloride aqueous solution (10 mL), methanol is removed and the resulting residue is extracted with ethyl acetate (3×20 mL) and brine (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 2:1, v/v) to afford {trans-4-[3-hydroxy-2-(3-hydroxy-6-methoxy-quinolin-4-ylmethyl)-propyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (60 mg, 59% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH3:24])[CH:20]([NH:25][CH3:26])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH3:24])[CH:20]([N:25]([CH3:26])[C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: CNC1CN(Cc2ccccc2)CCC1C
Solvent: CCN(CC)CC
Product: CC1CCN(Cc2ccccc2)CC1N(C)c1ncnc2[nH]ccc12
Temperature: 100 °C
Yield: 48.7 %

Procedure:
A solution of 4-chloropyrrolo[2,3-d]pyrimidine (2.4 grams, 15.9 mmol), prepared by the method of Davoll, J. Am. Chem. Soc., 82, 131 (1960), which is incorporated by reference in its entirety, and the product from Method A (1.7 grams, 7.95 mmol) dissolved in 2 equivalents of triethylamine was heated in a sealed tube at 100° C. for 3 days. Following cooling to room temperature and concentration under reduced pressure, the residue was purified by flash chromatography (silica; 3% methanol in dichloromethane) affording 1.3 grams (50%) of the title compound as a colorless oil. LRMS: 336.1 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[C:7]([O:19][CH:20]2[CH2:23][CH2:22][CH2:21]2)=[C:8]2[C:13](=[C:14]([F:17])[C:15]=1[F:16])[NH:12][C@@H:11]([CH3:18])[CH2:10][CH2:9]2>ClCCl.N1C=CC=CC=1>[Br:5][C:6]1[C:7]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23]2)=[C:8]2[C:13](=[C:14]([F:17])[C:15]=1[F:16])[N:12]([C:1](=[O:3])[CH3:2])[C@@H:11]([CH3:18])[CH2:10][CH2:9]2
Reactant: CC(=O)Cl
Reactant: C[C@H]1CCc2c(c(F)c(F)c(Br)c2OC2CCC2)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2c(F)c(F)c(Br)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Yield: 105.3 %

Procedure:
Acetyl chloride (0.21 mL, 3.02 mmol) was added dropwise to a 0° C. solution of (S)-6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.0 g, 3.02 mmol) in dichloromethane (20 mL) and pyridine (0.6 mL), and the resulting solution was allowed to stir and warm to room temperature overnight. The reaction mixture was diluted with dichloromethane (40 mL), washed with 1 N hydrochloric acid (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-1-(6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (1.19 g, 99%) as yellow oil. MS (ESI, pos. ion) m/z 374, 376 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]([C:13]([F:16])([F:15])[F:14])=O.[CH3:18][NH:19][NH2:20]>C(O)(=O)C.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:19]([CH3:18])[N:20]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cc(F)ccc1F
Reactant: CNN
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cn1nc(-c2cc(F)ccc2F)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
34.5 g of 1-(2,5-difluorophenyl)-3-(trifluoromethyl)-propane-1,3-dione was dissolved in 250 ml of acetic acid and 9.5 mL of methylhydrazine slowly added. The mixture was heated at 100° C. for 5 minutes then cooled and diluted with ether. The ether solution was washed with water and potassium carbonate solution, then dried with magnesium sulfate, filtered and concentrated. The residue was chromatographed to give 9.5 g of 3-(2,5-difluorophenyl)-1-methyl-5-(trifluoro-methyl)-1H-pyrazole.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ccc(NC(=O)c3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), benzoyl chloride (47.1 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (111 mg, yield 89%).
Reaction SMILES: O1CCOCC1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH:18]3[CH:16]([O:17]3)[CH2:15]2)=[CH:10][CH:9]=1.[N-:20]=[N+]=[N-].[Na+].[Cl-].[Na+]>C(OCC)(=O)C>[NH2:20][C@@H:18]1[CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)[CH2:15][C@H:16]1[OH:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(N2CC3OC3C2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N[C@@H]1CN(c2ccc(F)cc2)C[C@H]1O
Temperature: 100 °C
Reaction time: 7 h
Yield: 74.3 %

Procedure:
To a 1,4-dioxane (3 mL) solution of 3-(4-fluorophenyl)-6-oxa-3-azabicyclo[3.1.0]hexane (75 mg), an aqueous (1 mL) solution of sodium azide (82 mg) was added, and the reaction solution was agitated at 100° C. for 7 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and a saturated sodium chloride solution were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 10% Palladium carbon (48% water content, 10 mg) was added to an ethanol (5 mL) solution of the residue, and the reaction solution was agitated at room temperature under a hydrogen current for 3 hours. 61 mg of the title compound was obtained by carrying out celite filtration of the reaction solution, and condensing the filtrate under reduced pressure. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].C(Cl)(Cl)Cl>C(N(CC)CC)C>[C:1]1([S:7][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: C=CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCSc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of 12.12 g (0.11 mol) of thiophenol, 10.01 g (0.10 mol) ethyl acrylate, 20 mL of HCCl3 at 0° C. in a 100-mL, round-bottom flask, 0.50 mL of triethylamine was added under N2. The ice bath was removed after the addition of triethylamine and the solution was allowed to stir at room temperature for 3 hours. The resulting solution was idluted with 150 mL of ether and washed with 10% NaOH, H2O, and saturated NaCl solution. The mixture was dried (Na2SO4, overnight) and the solvents were removed. Vacuum distillation gave 19.36 g (92.1%) of ethyl 3-(phenylthio)propionate as a clear, colorless liquid: bp 112°-115° C./0.2 mm [literature reports 117° C./2.5 mm; see K. Iwai, H. Kosugi, A. Miyazaki, and Huda, Synthetic Communications, 6, 357 (1976)]; IR (neat) 1740 cm-1 (C=O); 1H NMR (DCCl3) δ1.14 [t, 3H, CO2CH2CH3 ], 2.54 [t, 2H, CH2CO2CH2CH3 ], 3.10 [t, 2H, ArSCH2 ], 4.06 [q, 2H, CO2CH2CH3 ], 7.13-7.32 [m, 5H, ArH]; 13C NMR (DCCl3) ppm 13.6 [CO2CH2CH3 ], 28.3 [ArSCH2 ], 33.8 [CH2CO2CH2CH3 ], 60.0 [CO2CH2CH3 ], 125.8, 128.4, 129.3, 134.8, 170.9 [C=O]. Both hydrogen and carbon-13 NMR spectra shifts were measured from tetramethylsilane (TMS) standard on a Varian XL-300 spectrometer confirming the correct hydrogen distribution and carbon atom assignments. ##STR11##
Reaction SMILES: [CH3:1][NH2:2].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]1[C:12](Cl)=[O:13]>C1COCC1>[CH3:1][NH:2][C:12]([C:4]1[S:3][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=1)=[O:13]
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred solution of 2.0 M methylamine in THF (60 mL) and THF (60 mL) was added dropwise at 0° C. a solution of benzothiophene-2-carbonyl chloride (10.8 g, 55 mmole) in THF (50 mL) over 15 minutes. After the addition the reaction was allowed to warm to RT then was concentrated under vacuum. Trituration with a cold solution of 4:1 H2O/methanol (50 mL), filtration, and drying under vacuum gave the title compound (10.35 g, 98%) as a white solid: MS (ES) m/e 191.9 (M+H)+.