Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].S([O-])([O-])(=O)=O.[NH4+].[NH4+].C[Si](C)(C)N[Si](C)(C)C.[C:28]([O:31][CH2:32][CH:33]([O:39][CH2:40]OC(=O)C)[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:30])[CH3:29]>>[C:36]([O:35][CH2:34][CH:33]([O:39][CH2:40][N:6]1[CH:7]=[N:8][C:9]2[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]1=2)[CH2:32][O:31][C:28](=[O:30])[CH3:29])(=[O:38])[CH3:37]
Reactant: CC(=O)OCOC(COC(C)=O)COC(C)=O
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: CC(=O)OCC(COC(C)=O)OCn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 0.5 h

Procedure:
A mixture of 50.0 g (0.33 mole) of guanine, 33 g of ammonium sulfate, and 2.2 l of hexamethyldisilazane was stirred at reflux under N2 for 3 days, during which time all of the solid dissolved. The solvent was then removed by distillation under reduced pressure. To the very viscous, orange residual oil was added under N2 84 g (0.34 mole) of acetoxymethyl 1,3-diacetoxy-2-propyl ether, which formed in second liquid phase at the bottom of the flask. The flask was fitted with a distillation adapter, and the mixture was heated under low vacuum in an oil bath at approximately 135°. After an induction period lasting several minutes, boiling began and soon became quite vigorous. Distillation of trimethylsilyl acetate (along with any residual hexamethyldisilazane) proceeded rapidly at first but slowed after 30 minutes. After 2 hours the mixture was added to 1.3 l of 90% EtOH. The mixture was heated to boiling and maintained there until the separated gummy material was transformed to a tractable solid. The solid (8.2 g, consisting almost exclusively of guanine) was removed by filtration while hot. The filtrate was allowed to stand overnight, resulting in separation of an orange-brown gum. The supernatant was decanted away from the gum, filtered, and then concentrated to small volume. The solid which separated on concentration was collected on a filter and washed with H2O, then with some EtOH, to give 15.4 g of cream-colored crystals. By NMR, this material was solely the -alkylated isomer, although TLC indicated partial side chain deactylation. The material was suitable for deprotection without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][C:11]([CH3:14])([O-:13])[CH3:12].[K+]>O1CCCC1.C(OCC)(=O)C>[C:11]([O:13][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1)([CH3:14])([CH3:12])[CH3:10]
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(I)cc(Cl)n1

Procedure:
To a solution of 2,6 dichloro-4-iodo pyridine (1 g, 3.65 mmol) in 15 mL tetrahydrofuran was added 1M potassium tert-butoxide (4.02 mL, 4.02 mmol) and the solution heated at reflux for 2 hours. The mixture was diluted with ethyl acetate, washed with water and brine and dried over magnesium sulfate, filtered and concentrated. The crude material was used without further purification. MS (DCI) m/e 312.0 (M+H)+.
Reaction SMILES: [Na+].[C:2]1([NH:8][S:9](=[O:12])(=O)[O-:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:14].C1(C(F)(F)F)C=CC=CC=1>>[C:2]1([NH:8][S:9]([Cl:14])(=[O:12])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])Nc1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: FC(F)(F)c1ccccc1
Product: O=S(=O)(Cl)Nc1ccccc1
Temperature: 70 °C

Procedure:
Phenyl sulfamic acid sodium salt (1.0 g), prepared by the method of Audrieth L. F et al, J. Org. Chem. 1944, 9, 89-101, and PCl5, 1.16 g were combined in the absence of solvent. After the exotherm subsided the contents were heated for a further 16 h at 70° C. Benzotrifluoride (5 mL) was added and the contents heated for a further 2 h, cooled, filtered and concentrated to give 182 mg of phenylsulfamoyl chloride. Compound 5 (Y═H) as its hydrochloride salt (20 mg, 0.085 mmol) was dissolved in 1 mL of dry CH2Cl2, and phenylsulfamoyl chloride (34 mg) in 0.5 mL of CH2Cl2 was added in portions followed by triethylamine (50 μL, 36 mg) in 0.5 mL of CH2Cl2. After stirring at ambient temperature for 16 h the reaction was quenched with saturated NaHCO3, separated, washed with water and brine, dried and purified by flash column chromatography (2% EtOAc in CH2Cl2) to give 20 mg of the title compound. LC-MS RT=3.56 min. (M−H)− 395.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[CH2:14][C@:13]4([CH:19]5[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]5)[CH2:15]4)[O:12][C:9]3=[N:10][CH:11]=2)=[CH:2]1.[Br:22]Br>CN(C=O)C.C(Cl)(Cl)Cl>[Br:22][C:2]1[O:1][CH:5]=[CH:4][C:3]=1[C:6]1[CH:7]=[C:8]2[CH2:14][C@:13]3([CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[O:12][C:9]2=[N:10][CH:11]=1
Reactant: BrBr
Reactant: c1cc(-c2cnc3c(c2)C[C@@]2(CN4CCC2CC4)O3)co1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Brc1occc1-c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
(2′R)-5′-(Furan-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (102 mg, 0.37 mmol), was stirred with bromine (65 mg, 0.41 mmol) in DMF (3 ml) at room temperature for 1 h. Vaccum was applied, and the mixture was stirred for a further 30 min. The reaction mixture was diluted with chloroform, and washed with aqueous sodium hydroxide, then the organic layer was dried, filtered and evaporated. The compound was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound (28 mg) as a pale solid; m/z 361, 363 (MH+).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:12][CH2:11][N:10]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])C>C(O)C.O>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:8]3([C:6]([OH:7])=[O:5])[CH2:12][CH2:11][N:10]([C:13](=[O:21])[C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[CH2:9]3)=[CH:29][CH:28]=2)=[CH:31][CH:32]=1)#[N:37]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccc(F)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-c2ccc(OCC3(C(=O)O)CCN(C(=O)c4ccc(F)cc4)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
Lithium hydroxide (16 mg, 0.67 mmol) was added to a stirred solution of 3-(4′-cyano-biphenyl-4-yloxymethyl)-1-(4-fluoro-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 29) (105 mg, 0.22 mmol) in ethanol (1 mL) and water (1 mL). The resulting mixture was stirred at RT for 5 hours. The mixture was concentrated under reduced pressure to remove ethanol and the residue was partitioned between ethyl acetate (5 mL) and 2M HCl aqueous solution (5 mL). The organic layer was washed with brine (5 mL), dried over magnesium sulphate and concentrated under reduced pressure to afford a white solid. This was recrystallised from isopropyl alcohol (2.5 mL) to afford the title compound as a white solid (76 mg, 77%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:17])[C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.[ClH:20].N([O-])=O.[Na+]>C(#N)C.O>[Cl:20][C:2]1[S:3][C:4]2[C:9]([N:10]([C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])[CH3:17])=[N:8][C:7]([S:18][S:18][C:7]3[N:8]=[C:9]([N:10]([C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])[CH3:17])[C:4]4[S:3][C:2]([Cl:20])=[N:19][C:5]=4[N:6]=3)=[N:6][C:5]=2[N:19]=1
Reactant: Cl
Reactant: CCC[C@H](CO)N(C)c1nc(S)nc2nc(N)sc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC[C@H](CO)N(C)c1nc(SSc2nc(N(C)[C@@H](CO)CCC)c3sc(Cl)nc3n2)nc2nc(Cl)sc12
Reaction time: 72 h
Yield: 75 %

Procedure:
(2R)-2-[(2-Amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)(methyl)amino]pentan-1-ol (1.0 g, 3.34 mmol) was dissolved in acetonitrile (25 ml) and concentrated hydrochloric acid (40 mL). Sodium nitrite (461 mg, 6.67 mmol) was dissolved in water (2 mL) and added at 0° C. The reaction mixture was kept at 0° C. for three days. The reaction mixture was poured onto ice and the precipitated product was collected by filtration and washed with water. Drying in vacuo gave the title compound 800 mg (75% yield).
Reaction SMILES: [CH2:1]=O.[CH:3]1[C:15]2[CH:14]([CH2:16][O:17][C:18]([NH:20][C@@H:21]([CH2:25][O:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[C:22]([OH:24])=[O:23])=[O:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:23]=[C:22]1[O:24][CH2:1][N:20]([C:18]([O:17][CH2:16][CH:14]2[C:15]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:19])[C@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1
Reactant: C=O
Reactant: Cc1cccc(OC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(OC[C@H]2C(=O)OCN2C(=O)OCC2c3ccccc3-c3ccccc32)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Using a Dean-Stark setup, a mixture containing paraformaldehyde (340 mg, 11.34 mmol), (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(m-tolyloxy)propanoic acid (789 mg, 1.890 mmol), and p-toluenesulfonic acid (32.5 mg, 0.189 mmol) was refluxed in Toluene (15 mL) for 2 hrs. The reaction was then cooled to RT, washed with sat. sodium bicarbonate solution, followed by brine, dried with MgSO4, filtered and concentrated to get the product (S)-(9H-fluoren-9-yl)methyl 5-oxo-4-((m-tolyloxy)methyl)oxazolidine-3-carboxylate (812 mg, 1.891 mmol, 100% yield) as a yellow oil. ESI-MS(+) m/z=430 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)Cl>[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=2)[CH2:22][CH2:21]1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]
Reactant: OC1CCNCC1
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CCC(O)CC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A suspension of 2.5 g. of dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 100 ml. of methylene chloride is treated with 10 g. of 4-hydroxy-piperidine and stirred at room temperature under an argon atmosphere for 70 hours. The separated precipitate is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure dimethyl racemic-6-(4-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 265°-266° C.
Reaction SMILES: OC1C=C(O)C=C[C:3]=1[CH:9]([C:20]([CH:22]([C:33]1[CH:38]=CC(O)=CC=1O)[C:23]1C=CC(OC)=[C:25]([O:31]C)[CH:24]=1)=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.C([O:43]C([O-])[O-])C.N1CCOCC1>CN(C)C=O>[OH:31][C:25]1[CH:24]=[C:23]2[C:22]([C:20](=[O:21])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)=[CH:3][O:43]2)=[CH:33][CH:38]=1
Reactant: CCOC([O-])[O-]
Reactant: COc1ccc(C(C(=O)C(c2ccc(OC)c(OC)c2)c2ccc(O)cc2O)c2ccc(O)cc2O)cc1OC
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC

Procedure:
14.4 g (0.05 mole) of 2,4-dihydroxy-phenyl-(3',4'-dimethoxy-benzyl)-ketone are reacted with 10.5 g (0.07 mole) ethyl-orthoformate in 10 ml of dimethyl-formamide in the presence of 1 ml morpholine. The reaction mixture is maintained at 80°-85° C., and in the second hour a solid precipitates. After 6 hours 1OO ml of chloroform are added to the mixture, the precipitated substance is filtered and dried. 7-hydroxy-3',4'-dimethoxy-isoflavone is obtained.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4].ClCCl.[Cl:24][C:25]([Cl:29])([Cl:28])[S:26]Cl>O>[C:3]([C:5]1[C:6](=[O:20])[N:7]([S:26][C:25]([Cl:29])([Cl:28])[Cl:24])[C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4]
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C)c1-n1cc(C#N)c(=O)n(SC(Cl)(Cl)Cl)c1=O
Temperature: 0 °C
Reaction time: 0.37 h

Procedure:
To an ice cold solution of 2.40 g of sodium hydroxide in 70 ml of water is added 14.46 g (0.06 mol) of 5-cyano-1-(2,6-dimethylphenyl)uracil. Then 100 ml of dichloromethane is added. To this mixture, at 5°, is added 6.6 ml (0.06 mol) of trichloromethane sulfenyl chloride in two volumes of dichloromethane. The mixture is stirred approximately 22 min at 5°. Then the phases are separated and the organic phase is washed with ice cold water. The dichloromethane solution is dried over magnesium sulfate, filtered and stripped. The residue is triturated with ether/pentane, filtered and dried to obtain the crude product, which is then purified by crystallization to yield 5-cyano-1-(2,6-dimethylphenyl)-3-trichloromethanesulfenyluracil, m.p. 223°-225.5°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:7]=1.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:6]2[N:5]=[N:4][C:3]([CH2:2][NH:1][C:42]([NH2:43])=[NH:37])=[N:7]2)=[O:30])[N:17]=1
Reactant: N=C(N)n1cccn1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1nnc(CN)n1)c1csc(N)n1)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1nnc(CNC(=N)N)n1)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.4 %

Procedure:
To a solution of 2-(((Z)-(2-(((2R,3S)-2-((5-(aminomethyl)-2H-tetrazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (20 mg, 0.038 mmol) and pyrazole-1-carboxamidine hydrochloride (11.6 mg, 0.079 mmol). in DMF (376 μL) was added DIPEA (26.2 μL, 0.150 mmol). After stirring at rt for 12 h the solution was concentrated in vacuo. Toluene was added and it was reconcentrated (3×). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (11 mg, 45%) as a white powder. LCMS: Rt=0.31 min, m/z=575.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 7.49-7.04 (m, 5H), 6.74 (br s, 1H), 5.26 (br s, 1H), 5.14-5.07 (m, 1H), 4.98-4.90 (m, 1H), 4.65 (br s, 2H), 4.59-4.52 (m, 1H), 1.36 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: ClCc1ccccn1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccn2)c1
Temperature: 75 °C
Yield: 54.3 %

Procedure:
A mixture of 5-nitroindazole (40.75 g, 250 mmol), picolyl chloride hydrochloride (45.1 g, 275 mmol) and potassium carbonate (72.4 g, 525 mmol) in DMF (400 ml) was heated at 75° C. for 3 hours. Additional picolyl chloride hydrochloride (4.1 g, 25 mmol) and potassium carbonate (3.45 g, 25 mmol) were added and the mixture was heated at 75° C. for 2 additional hours. After cooling, the mixture was diluted with water (800 ml). The precipitate was filtered, washed with water and dried. The resulting solid was purified by chromatography on silica gel (eluant: 50% ethyl acetate in petroleum ether) to give 5-nitro-1-(pyridin-2-ylmethyl)-1H-indazole as a solid (34.5 g, 55%); NMR Spectrum (CDCl3) 5.77 (s, 2H), 7.03 (d, 1H), 7.23 (m, 1H), 7.55 (d, 1H), 7.63 (m, 1H), 8.27-8.23 (m, 2H), 8.58 (m, 1H), 8.74 (d, 1H); Mass spectrum MH+ 255.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:13]C(=O)N(C)C)=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].C[O-].[Na+].CO.Cl>CN(C)C=O>[SH:13][C:4]1[C:3]([C:1]#[N:2])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: CN(C)C(=O)Sc1cc2c(cc1C#N)CCCC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc2c(cc1S)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of dimethylthiocarbamic acid S-(3-cyano-5,6,7,8-tetrahydronaphthalen-2-yl) ester (1.00 g, 3.84 mmol) in anhydrous N,N-dimethylformamide (10 mL) under argon was added dropwise 25% sodium methoxide in methanol (2.6 mL, 11.5 mmol, 3.0 eq) at 0° C. The resultant yellow reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into cold 2N HCl (100 mL) and then extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated at reduced pressure to give 700 mg (96%) of crude 3-mercapto-5,6,7,8-tetrahydronaphthalene-2-carbonitrile.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S([O-])([O-])=O.[Na+].[Na+].[C:27](=O)(O)[O-].[Na+].IC>O>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15]([CH3:27])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc2c(cc1S(C)(=O)=O)CCN(C(C)=O)CC2
Temperature: 70 °C

Procedure:
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (18 g, 0.056 m) was added in portions to a mixture of sodium sulfite (8.8 g, 0.069 m) and sodium bicarbonate (10.8 g, 0.115 m) in water (36 ml) stirred at 70° C. There was a vigorous evolution of gas after each addition. The mixture was stirred for fifteen minutes, treated with iodomethane (8.5 ml, 0.136 m) and refluxed for forty-five minutes. The mixture was partitioned between methylene chloride and water. The methylene chloride phase was washed with water, dried with sodium sulfate and concentrated in vacuo to give 3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 159°-162° C.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17][CH2:18][O:19][CH3:20])=[C:8]([C:21](OC)=[O:22])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].CC(C[Al]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17][CH2:18][O:19][CH3:20])=[C:8]([CH2:21][OH:22])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ncc(C(=O)OC)c1-c1ccc(Cl)cc1OCOC
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCn1ncc(CO)c1-c1ccc(Cl)cc1OCOC
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of Methyl 1-n-butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-yl carboxylate (10.00 g, 0.028 mol) in 200 mL of CH2Cl2 at 0° C. was added 85.2 mL of 1.5 M Dibal-H in toluene. After stirring for 1 h. the reaction was quenched with MeOH (100 mL) followed by addition of 35 mL of conc. HCl in 200 mL of water. The resulting mixture was stirred for 15 min. and extracted with CH2Cl2 (3×200 mL). The combined organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave 9.50 g (97%) of the title compound as a oil: MS (ESI) m/z 325 (M+H)+ ; 1H NMR (400 MHz. CDCl3) d 7.63 (s, 1H), 7.13-7.29 (m, 3H), 5.09 (s, 2H), 4.36 (dd, 2H), 3.80-3.98 (m, 2H), 3.35 (s, 3H), 1.70 (m, 2H), 1.18 (m, 2H), 0.81 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[CH2:9](Br)[CH:10]=C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8])[CH:9]=[CH2:10]
Reactant: CN1CCC[C@H]1CO
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCN1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-1-methyl-2-pyrrolidinemethanol (5.10 g, 50 mmol, Aldrich Chemical Co.) was dissolved in 50 mL of CHCl3, then 5.25 mL of allyl bromide and 8.34 mL of triethylamine were added. The reaction mixture was stirred at room temperature for 2 hours, then the volatiles were removed under reduced pressure. The residue was purified by chromatography on silica gel to give 63 g of the title product. MS (DCI/NH3) m/e: 142 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 6.05-5.90 (m, 1H), 5.33-5.17 (m, 2H), 3.77-3.68 (m, 1H), 3.58-3.47 (m, 2H), 3.32-3.20 (m, 1H), 3.16-3.05 (m, 1H), 2.90-2.78 (m, 1H), 2.53-2.40 (m, 1H), 2.02-1.73 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](Br)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>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>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34](=[O:36])(=[O:35])[NH2:37])[CH:29]=2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Reactant: Nc1ncc(Br)c2scc(-c3ccc(F)c(Cl)c3)c12
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: CN(C)C=O
Product: Nc1ncc(-c2cccc(S(N)(=O)=O)c2)c2scc(-c3ccc(F)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 14 h
Yield: 20.2 %

Procedure:
The mixture of 4-amino-7-bromo-3-(3-chloro-4-fluoro-phenyl)thieno[3,2-c]pyridine (40 mg, 0.112 mmol), Pd(PPh3)4 (19 mg, 10 mol %), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (36.8 mg, 0.224 mmol) and 2M Na2CO3 aqueous solution (0.28 ml, 0.56 mmol) in 2 ml of DME was stirred for 14 hours at 80° C. As starting material remained, same amount of reagents described above and DMF (2 ml) were added and stirred for 5 hours at 100° C. The resultant mixture was directly applied to SCX (Varian, 5 g) and eluted with 1N NH3 in CHCl3 and MeOH was collected, and the eluant was concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford the titled compound (9.8 mg) 1H NMR (400 MHz, DMSO-d6) ppm 8.12 (dd, J=1.8 Hz, 1H), 8.0 s, 1H), 7.91 (ddd, J=1.5, 1.5, 7.6 Hz, 1H), 7.85 (ddd, J=1.4, 1.4, 7.1 Hz, 1H), 7.75 (dd, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.57 (dd, J=9.0 Hz, 1H), 7.51 (ddd, J=2.2, 4.9, 8.5 Hz, 1H), 7.45 (s, 2H), 5.66 (s, 2H). MS: m/z 434 (M+H)+.