Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][NH:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH3:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1>>[CH2:1]([NH:8][C:9](=[O:10])[N:12]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH3:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN=C=O
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)CC
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)OCC)cc2)c1
Temperature: 100 °C
Yield: 97 %

Procedure:
172 μL (1 mmol) of heptyl isocyanate are added to 214 mg (0.7 mmol) of ethyl 2-[1-(3′-methylaminobiphenyl-4-yl)meth-(E)-ylidene]butyrate. The reaction mixture is heated at 100° C. in an Emrys Optimizer microwave oven for 20 minutes. The residue is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 306 mg (98%) of ethyl 2-[1-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]meth-(E)-ylidene]butyrate are obtained in the form of yellowish crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:17]=2)[C:12](=[O:26])[C:11]([C:27]([O:29]CC)=[O:28])=[CH:10]1.O.[ClH:33]>>[ClH:33].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:17]=2)[C:12](=[O:26])[C:11]([C:27]([OH:29])=[O:28])=[CH:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCNCC3)c(F)cc2c1=O
Agent: Cl
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCNCC3)c(F)cc2c1=O
Yield: 93.2 %

Procedure:
In 1.2 ml of 6N hydrochloric acid was suspended 200 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylate, and the resulting suspension was subjected to reaction under reflux for 2 hours. Subsequently, 2 ml of water was added thereto and crystals were collected by filtration and washed with 1 ml of water to obtain 190 mg (yield 93.2%) of 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid hydrochloride having a melting point of 249°-252° C. (decomp.).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].[OH:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([NH:3][C:4](=[O:5])[O-:6])[CH3:2].[CH2:22]([O:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Reactant: BrCc1ccccc1
Agent: CCNC(=O)[O-]
Product: CC1c2cc(Cl)c(OCc3ccccc3)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5, Step A) and benzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24ClNO3+H: 386, observed: 386.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25]([NH2:27])=[O:26])[CH2:23]1.C(N(CC)CC)C.O>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:30][CH2:29][CH2:28][CH:24]([C:25]([NH2:27])=[O:26])[CH2:23]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: NC(=O)C1CCCNC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(C(N)=O)C4)nc(Cl)nc32)cc1
Yield: 98.7 %

Procedure:
A solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.584 mmol), nipecotamide (75 mg, 0.586 mmol) and triethylamine (0.130 mL, 0.934 mmol) in dioxane (5 mL) was stirred at 70° C. for 20 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give 1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-3-carboxamide (250 mg).
Reaction SMILES: [CH:1]1([CH:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][OH:15])[CH:12]=3)[NH:7][CH:6]=[C:5]2[C:16]#[N:17])[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4]>[CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[O:15])[CH:12]=3)[N:7]=[CH:6][C:5]=2[C:16]#[N:17])[CH2:2][CH2:3]1
Reactant: N#CC1=CNc2ccc(CO)cc2C1C1CC1
Agent: [Mn+4]
Agent: [O-2]
Product: N#Cc1cnc2ccc(C=O)cc2c1C1CC1

Procedure:
Similar procedure as described in example 46f was used, starting from 4-cyclopropyl-6-hydroxymethyl-1,4-dihydro-quinoline-3-carbonitrile (example 57b) and manganese dioxide to give 4-cyclopropyl-6-formyl-quinoline-3-carbonitrile as a white solid. LC-MS m/e 223 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([F:39])[C:37]=1[F:38]>>[F:29][C:27]([F:30])([F:28])[C:4]1[CH:3]=[C:2]([C:34]2[CH:33]=[C:32]([F:31])[C:37]([F:38])=[C:36]([F:39])[CH:35]=2)[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(N4CCN(c5ncccc5C(F)(F)F)CC4)nc23)cc(F)c1F

Procedure:
4-Bromo-6-trifluoromethyl-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (1.99 g, 4 mmol, Example 7) reacted with 3,4,5-trifluorophenylboronic acid (1.1 g, 6 mmol, Lancaster) under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 546 (M+1).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[OH:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C@H:15]([CH2:31][NH:32][C:33]([CH2:35][NH:36][C:37]([NH2:39])=[O:38])=O)[CH2:14]1.[ClH:40]>O1CCCC1.CO.C(O)C>[ClH:40].[OH:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:19])[C@H:15]([CH2:31][NH:32][CH2:33][CH2:35][NH:36][C:37]([NH2:39])=[O:38])[CH2:14]1
Reactant: NC(=O)NCC(=O)NC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: NC(=O)NCCNC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a suspension of sodium borohydride (1.38 g) in tetrahydrofuran (50 ml) was added boron trifluoride etherate (4.49 ml) in a nitrogen stream with stirring at 0°~5° C. The mixture was stirred at the same condition for 30 minutes To the mixture was added a solution of (2S, 4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[(ureidomethylcarbonyl)aminomethyl]pyrrolidine (2.90 g) at 0°~5° C. The mixture was stirred at 0°~5° C. for 1 hour and at ambient temperature overnight. Ethanol (30 ml) was added to the reaction mixture at 0°~10° C. After stirring for 2 hours, insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a residue. A solution of the residue in a mixture of concentrated hydrochloric acid (2.9 ml) and methanol (29 ml) was stirred at ambient temperature for 20 hours. The mixture was concentrated under reduced pressure to give (2S, 4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[(2-ureidoethyl) aminomethyl]pyrrolidine hydrochloride. To a solution of the compound obtained above in a mixture of water (20 ml) and tetrahydrofuran (20 ml) was added a solution of 4-nitrobenzyloxycarbonyl chloride (1.60 g) in tetrahydrofuran (5 ml) under ice-cooling, keeping the pH between 8.5-9.5 with concentrated hydrochloric acid. The reaction mixture was extracted with ehtyl acetate (100 ml). The organic layer was washed with brine (50 ml×2), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (5:95 v/v) to give (2S, 4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[N-(4-nitrobenzyloxycarbonyl)-N-(2-ureidoethyl)amino]methylpyrrolidine (1.78 g).
Reaction SMILES: [I:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C1C(=O)NC(=O)N([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]2[OH:27])C=1.[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>COCCOC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N-]=[N+]=[N-].[K+]>[C@@H:19]1([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[I:1])[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]1[OH:27]
Reactant: Ic1ncnc2nc[nH]c12
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [K+]
Solvent: COCCOC
Product: OC[C@H]1O[C@@H](n2cnc3c(I)ncnc32)[C@@H](O)[C@@H]1O
Temperature: 35 °C
Yield: 16.7 %

Procedure:
6-Iodopurine (Sigma Chemical Co. St. Louis, Mo.) (4 mmoles, 1 g) was dissolved in 15 ml of 1,2-dimethoxyethane with heating. Fifty milliliters of a uracil arabinoside solution (10.1 mmoles) in 10 mM potassium phosphate, 0.04% potassium azide solution, pH of 7.4, were added. Purified uridine phosphorylase (6800 I.U.) and purine nucleoside phosphorylase (12000 I.U.) were added and the reaction stirred at 35° C. After 21 days an additional 4800 units of uridine phosphorylase and 20000 units of purine nucleoside phosphorylase were added. Ninety days later the reaction was filtered and the solvent removed under vacuum. The residue was suspended in 100 ml of water, heated with steam, and then filtered. The filtrate was chromatographed on a column containing XAD-2 resin (5×35 cm), eluting with 2 liters of water followed by 2 liters ethanol. Fractions containing product were combined and the solvent removed under vacuum. The residue was dissolved in 30% n-propanol/water (v/v) and chromatographed on a column containing BioRad P-2 (5×90 cm). The product was eluted with 30% n-propanol/water (v/v). Product-containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in 30% n-propanol/water (v/v) and chromatographed on a Sephadex G-10 column (5×90 cm). This column was eluted with 30% n-propanol/water (v/v). Product-containing fractions were combined and after removing the solvent under vacuum, yielded 0.253 g of 9-β-D-arabinofuranosyl-6-iodo-9H-purine that analyzed as a 1.5 hydrate. NMR and mass spectrometry were consistent with the structure. Anal. Calcd. for C10H11IN4O4.1.5 H2O: Calcd: C, 29.65; H, 3.48; N, 13.83; I, 31.32. Found: C, 29.43; H, 3.53; N, 13.66; I, 31.20.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.C(N(C(C)C)CC)(C)C.[Cl:31][CH:32]=[CH:33][C:34](Cl)=[O:35].C(=O)(O)[O-].[Na+]>O1CCCC1.CCOCC>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:34](=[O:35])/[CH:33]=[CH:32]\[Cl:31])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: O=C(Cl)C=CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cnc2ccc(NC(=O)/C=C\Cl)cc2c1Nc1cccc(Br)c1
Reaction time: 0.67 h

Procedure:
To a solution of 0.5 g (1.47 mmol) of of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile and 0.24 g (1.8 mmol) of diisopropylethyl amine in 3 ml of terahydrofuran at 0° C. with stirring was added 0.21 g (1.7 mmol) of 3-chloro-acryloyl chloride (cis/trans mixture) in 2 ml of tetrahydrofuran. After 40 min at 0° C., the mixture was poured into a saturated solution of sodium bicarbonate and then extracted ether. The organic solution was dried over magnesium sulfate and the sovent was removed. The residue chromatographed on silica gel giving 0.16 g of N-[4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-3-chloro-(E) acrylamide: mass spectrum (electrospray, m/e,): M+H 424.9, 427.0, and 0.12 g of N-[4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-3-chloro-(Z) acrylamide acrylamide: mass spectrum (electrospray, m/e,): M+H 425.0, 427.0
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].Cl.[NH2:29][OH:30].C(N(CC)CC)C.[Cl-].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19](=[N:29][OH:30])[NH2:20])[C:3]=1[S:21]([C:24]([F:26])([F:25])[F:27])(=[O:23])=[O:22]
Reactant: NO
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=NO)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 88.4 %

Procedure:
5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfonylpyrazole (0.86 g, 1.90 mmol) was dissolved in 10 ml of 1,4-dioxane and hydroxylamine hydrochloride (0.22 g, 3.17 mmol) and triethylamine (0.45 ml, 3.24 mmol) were added, and then the mixture was stirred at room temperature. Ten hours after stirring, hydroxyamine hydrochloride (0.08 g, 1.2 mmol) and triethylamine (0.14 ml, 1.01 mmol) were further added. After the completion of adding, the solution was stirred at room temperature for 23 hours. Thirty milliliters of water and 15 ml of an aqueous saturated sodium chloride solution were added and then the reaction mixture was extracted twice with 30 ml of ethyl acetate. The ethyl acetate layer was washed with 20 ml of an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a colorless crystal. This crystal was washed with a hexane-ethyl acetate mixed solvent (volume ratio=1:1) to obtain 0.82 g (1.68 mmol) of the title compound as a colorless crystal. Yield 89%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCOCC1
Product: CS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (Acros Organics Ltd.) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[C:15]([N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[C:22](Cl)[CH:21]=[N:20]1)([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[C:22]([S:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:14][CH:13]=2)[CH:21]=[N:20]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(CS)cc1
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(SCc2ccc(C(C)(C)C)cc2)cnn(C(C)(C)C)c1=O
Yield: 46.6 %

Procedure:
To 30 ml of dry tetrahydrofuran was added 0.5 g of 55% sodium hydride. The resulting mixture was kept at room temperature and added dropwise with a solution of 1.8 g of p-t-butylbenzyl mercaptan dissolved in 10 ml of tetrahydrofuran. After ten minutes passed, the resulting mixture was added dropwise with a solution of 2.0 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone dissolved in 10 ml of tetrahydrofuran. After completion of dropwise addition, the resulting mixture was reacted for 2 hours under heat-reflux. After the reaction mixture was concentrated under reduced pressure, it was poured into 50 ml of water and extracted twice with 50 ml of diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure to give 3.5 g of crude product. The crude product was recrystallized from 5 ml of hexane to obtain 1.6 g of 2-t-butyl-5-(p-t-butylbenzylthio)-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[OH-].[Na+].O>C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1
Reactant: Brc1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3ccccc32)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 3-bromoindole (prepared according to the method described in Synthesis, 1096(1982)) (196 mg, 1.0 mmol) and tosyl chloride (286 mg, 1.5 mmol) in benzene (4.5 mL) was added tetra-n-butylammonium hydrogensulfate (34 mg, 0.1 mmol) and a 5.0% aqueous sodium hydroxide (1.0 mL), and the resulting mixture was refluxed for 1 hour. After the reaction solution was cooled to room temperature, water was added to the reaction solution, and the resulting mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated, and the resulting crude product was purified by column chromatography on a silica gel (eluent; hexane:ethyl acetate=6:1) to afford the title compound (335 mg, yield: 96%) as white crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)[O-])[CH2:17]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.O.[OH-].[Na+]>C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C([O-])NC1CCN(CCCOCCc2ccc3sccc3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: NC1CCN(CCCOCCc2ccc3sccc3c2)C1

Procedure:
In 7.0 mL of ethyl acetate was dissolved 1.12 g of tert-butyl=1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinylcarbamate, and 1.86 mL of 6 mol/L hydrochloric acid was added to the solution, after which the resulting mixture was heated under reflux for 1 hour. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 10 with a 2 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=30:1 to 20:1) to obtain 0.38 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinamine as a light-yellow oil.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([CH:20]=[O:21])[N:17]=[CH:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[OH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([N:15]2[CH:19]=[C:18]([CH:20]=[O:21])[N:17]=[CH:16]2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cnc(C=O)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: O=Cc1cn([C@H]2CC[C@H](O)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (540 mg) obtained in Step 2 of this Reference Example was dissolved in tetrahydrofuran (8 mL). To this solution, a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 2.62 mL) was added, and the mixture was stirred at room temperature for 8 hours. To the reaction solution, saturated aqueous ammonium chloride was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by diol-bonded silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/1-ethyl acetate) to obtain the title compound (250 mg).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:14]=[C:13]4B3OC(C)(C)C(C)(C)O3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:39]1[CH:44]=[N:43][CH:42]=[C:41]([CH:45]2[CH2:47][CH2:46]2)[N:40]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH:45]1([C:41]2[N:40]=[C:39]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:8]5[CH:7]=[N:6][CH:5]=[C:4]([CH:1]6[CH2:2][CH2:3]6)[N:9]=5)[CH:11]=4)[N:15]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=4)(=[O:20])=[O:21])[CH:14]=3)[CH:44]=[N:43][CH:42]=2)[CH2:47][CH2:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4cncc(C5CC5)n4)ccc32)cc1
Reactant: Brc1cncc(C2CC2)n1
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4cncc(C5CC5)n4)ccc32)cc1
Temperature: 130 °C
Yield: 42.4 %

Procedure:
A glass microwave reaction vessel was charged with 5-(6-cyclopropylpyrazin-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (172 mg, 0.33 mmol), 2-bromo-6-cyclopropylpyrazine (80 mg, 0.40 mmol, Combi-Phos Catalysis Inc.), Pd2(dba)3 CHCl3 adduct (10 mg, 10.0 μmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (X-Phos) (10 mg, 0.020 mmol) and K3PO4 (213 mg, 1.00 mmol). The tube was sealed. The tube was evacuated under vacuum and back-filled with N2 (3×). Dioxane (1.9 mL) and water (0.18 mL) were added. The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 130° C. for 20 min. Water was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-50% EtOAc in hexanes, to provide 3,5-bis(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indole (72 mg, 0.14 mmol, 43% yield) as a red oil. MS (ESI, pos. ion) m/z: 508.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]=O)=[C:5](Cl)[C:6]=1[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([SH:22])[C:19]([CH3:21])=[O:20]>CN(C)C=O>[C:19]([C:18]1[S:22][C:5]2[C:6]([C:7]#[N:8])=[C:2]([NH2:1])[S:3][C:4]=2[CH:10]=1)(=[O:20])[CH3:21]
Reactant: CC(=O)CS
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc2sc(N)c(C#N)c2s1
Temperature: 60 °C
Yield: 81 %

Procedure:
A mixture of 18.7 parts of 2-amino-4-chloro-3-cyano-5-formylthiophene, 13.8 parts of potassium carbonate and 80 parts of N,N-dimethylformamide was introduced first, and 9 parts of acetonylmercaptan were then added. After the exothermic reaction had died down, the mixture was heated at 60° C. for 1 hour and then discharged onto water. The precipitate was filtered off with suction, washed with water and dried. This gave 17.9 parts (81% of theory) of 5-acetyl-2-amino-3-cyanothieno[3,2-b]thiophene.