Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].O=[C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[C:18]#[N:19]>C(O)C>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:18]([NH2:19])=[C:13]2[C:12]([CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:10]1
Reactant: N#CC1CCCCC1=O
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1-n1nc2c(c1N)CCCC2
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of (2-methylphenyl)hydrazine hydrochloride (464 mg, 2.92 mmol) in ethanol (2 mL) was added 2-oxocyclohexanecarbonitrile (300 mg, 2.44 mmol), and the mixture was heated to 60° C. and stirred for 16 h. The flask was then cooled to rt and the solvent was evaporated to give a solid. The crude residue of 2-(2-methylphenyl)-4,5,6,7-tetrahydro-2H-indazol-3-amine hydrochloride (449 mg, 70%) was used in the next step with no further purification. ES-MS m/z 228.2 (MH+); HPLC RT (min) 1.22.
Reaction SMILES: [CH3:1][C@@:2]12[C@:10]3([C:16]([CH2:18][OH:19])=[O:17])[O:11]C(C)(C)[O:13][C@@H:9]3[CH2:8][C@H:7]1[C@@H:6]1[CH2:20][CH2:21][C:22]3[C@@:28]([CH3:29])([C@@:5]1([F:30])[C@@H:4]([OH:31])[CH2:3]2)[CH:27]=[CH:26][C:24](=[O:25])[CH:23]=3.C[C@@]12[C@@](O)(C(CO)=O)[C@H](O)C[C@H]1[C@@H]1C[C@H](F)C3[C@@](C)([C@@]1(F)[C@@H](O)C2)C=CC(=O)C=3>>[CH3:1][C@@:2]12[C@@:10]([OH:11])([C:16]([CH2:18][OH:19])=[O:17])[C@H:9]([OH:13])[CH2:8][C@H:7]1[C@@H:6]1[CH2:20][CH2:21][C:22]3[C@@:28]([CH3:29])([C@@:5]1([F:30])[C@@H:4]([OH:31])[CH2:3]2)[CH:27]=[CH:26][C:24](=[O:25])[CH:23]=3
Reactant: CC1(C)O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1
Agent: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reaction time: 0.25 h

Procedure:
Triamcinolone acetonide was combined with a polymer in a stainless steel mortar and mixed using the Turbula shaker set at 96 RPM for 15 minutes. The powder of the fluocinolone and polymer was scraped off the walls of the steel mortar and then mixed again for an additional 15 minutes. The powder blend was heated at temperatures ranging from 110° C. to 160° C., depending on the polymer used, for a total of 30 minutes, forming a polymer/drug melt. The melt was pelletized, then loaded into the barrel and extruded into filaments, and finally the filaments were cut into about 0.5 mg or about 1 mg size implants. The implants had a weight range from about 450 μg to about 550 μg, or from about 900 μg to about 1100 μg. The 1 mg size implants had a length of about 2 mm and a diameter of about 0.72 mm.
Reaction SMILES: [SH:1]CCC(OC)=O.[H-].[Na+].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]1([CH:21]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH3:22])[CH2:20][O:19]1.Cl>CN(C)C=O.O>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]([OH:19])([CH:21]([N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)[CH3:22])[CH2:20][SH:1]
Reactant: CC(n1cncn1)C1(c2ccc(F)cc2F)CO1
Reactant: COC(=O)CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(n1cncn1)C(O)(CS)c1ccc(F)cc1F
Reaction time: 0.08 h

Procedure:
Methyl 3-mercaptopropionate (0.88 ml) was added to N,N-dimethylformamide (14 ml) containing 60% sodium hydride in oil (0.32 g) under ice-cooling. After 5 minutes, a solution of 2-(2,4-difluorophenyl)-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane (0.67 g) in N,N-dimethylformamide (3.5 ml) was added over 5 minutes with ice-cooling. After 15 minutes, the reaction mixture was poured into water (150 ml), neutralized with hydrochloric acid and extracted with ethyl acetate (50 ml×3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (30 ml× 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (3 cm×10 cm) and elution was carried out with ethyl acetate-hexane (1:1). The desired fraction was concentrated and diethyl ether was added to the residue to give crude crystals (0.25 g) of 2-(2,4-difluorophenyl)-1-mercapto-3-[(1H)-1,2,4-triazol-1-yl]-2-butanol (of low polarity; compound 116, diastereomer B). The crystals were recrystallized from a mixture of chloroform and diethyl ether to give 0.21 g of compound 116. The mother liquor of the above crude crystals was further subjected to silica gel chromatography (2 cm×12 cm) and elution was carried out with ethyl acetate-hexane (1:1). The desired fraction was concentrated and diethyl ether and hexane were added to the residue to give crude crystals (0.25 g) of 2-(2,4-difluorophenyl)-1-mercapto-3-[(1H)-1,2,4-triazol-1-yl]-2-butanol (of high polarity; compound 115, diastereomer A). The crystals were recrystallized from a mixture of chloroform and diethyl ether to give crystals of compound 115 (0.11 g). Compound 115 (diastereomer A) m.p. 112°-117° C. (colorless prism)
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][NH:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Reactant: COC(CCBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(I)c(=O)n(C(=O)c2ccccc2)c1=O)OC
Yield: 91.8 %

Procedure:
3-Benzoyl-5-iodo-1H-pyrimidine-2,4-dione (Prep 36, 2.1 g, 6.13 mmol), K2CO3 (846 mg, 6.13 mmol) and 3-bromo-1,1dimethoxy-propane (1 mL, 7.4 mmol) were dissolved in dry DMF under Nitrogen (8 mL). After stirring the reaction at room temperature for 48 h, water was added and the product extracted with diethylether. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (35-65) to give 2.5 g of the title compound (91% yield).
Reaction SMILES: [CH3:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>C(OC(=O)CCC)(=O)CCC>[C:2]([O:8][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(C)O
Agent: CCCC(=O)OC(=O)CCC
Product: CCCCCC(C)OC(=O)CCC
Yield: 85 %

Procedure:
Butyric anhydride (260 ml, Aldrich) was added to 2-heptanol (162 g, 1.4 mol, Aldrich) over a 1.5 hour period at 100-140° C. The mixture was heated to 160° for 4 hours. The reaction mixture was then cooled, washed with hot water, washed with aqueous sodium carbonate to remove butyric anhydride, dried over sodium sulfate, and then concentrated. Fractional distillation of the crude residue under vacuum provided 1-methylhexyl butyrate (85-110°/78-80 mm Hg, 85% yield), the structure of which was confirmed by mass spectroscopy, nuclear magnetic resonance spectroscopy, and infra red spectroscopy (not shown).
Reaction SMILES: Cl[C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17]([O:26][CH3:27])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20]>CCOCC>[CH3:27][O:26][C:17]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:25]
Reactant: COC(=O)c1ccccc1N
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Cl
Solvent: CCOCC
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1C(=O)OC
Reaction time: 5 h
Yield: 58 %

Procedure:
trans-1-Chloro-2-ethoxycarbonylaminoindane (20 g, 0.084 moles) was treated with methyl anthranilate (60 ml) and stirred under nitrogen at 60° for 5 hr. The resulting viscous mixture was diluted with ether (500 ml), washed exhaustively with 2.5N HCl (8×250 ml), and then with saturated sodium bicarbonate followed by brine. After drying (Na2SO4) and concentration in vacuo a brown solid (25.7 g) was obtained. Crystallisation from pentane/ether afforded the title compound (14 g; 58%) m.p. 108°-110°. Concentration of mother liquors gave a less pure second crop (2.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:22][C:21]=2[NH2:31])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH:32](OCC)(OCC)OCC>C1CCN2C(=NCCC2)CC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:17]2[C:18](=[O:19])[C:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[S:22][C:21]=3[N:31]=[CH:32]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(NC(=O)c2cc(-c3ccccc3)sc2N)ccc1OCCN1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-n2cnc3sc(-c4ccccc4)cc3c2=O)ccc1OCCN1CCCC1

Procedure:
2-Amino-5-phenyl-thiophene-3-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-amide [Example E1] (28 mg, 0.064 mmol) was stirred at 95° C. in triethyl orthoformate (5 ml) for 24 h. The mixture was cooled, 4 drops of DBU added and the volatiles removed. The crude product was purified by chromatography on silica gel (eluting with dichloromethane-methanol-aq. ammonia) to give the title compound.
Reaction SMILES: C1C=CC([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([N:20]3[CH:24]=[N:23][CH:22]=[CH:21]3)C3C=CC=CC=3)=[CH:11][CH:12]=2)=CC=1.N1C=CN=C1.C1(C(Cl)=[O:37])C=CC=CC=1>>[C:13]([N:20]1[CH:21]=[CH:22][N:23]=[CH:24]1)(=[O:37])[C:10]1[CH:9]=[CH:8][CH:7]=[CH:12][CH:11]=1
Reactant: c1ccc(-c2ccc(C(c3ccccc3)n3ccnc3)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: c1c[nH]cn1
Product: O=C(c1ccccc1)n1ccnc1
Yield: 74.7 %

Procedure:
Bifonazole has also been prepared by benzoylation of imidazole with PhCOCl, yielding 74.7% of 1-benzoylimidazole which is subject to react with Gringnard's reactant 4-PhC6H4MgBr followed by a tosylation and subsequent reduction with sodium cyanoborohydride in hexamethylphosphoramide, to yield 68.2% Bifonazole (Es. Patent 539,345).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CC(C)OC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 143 was prepared from bis(4-chlorophenyl)acetic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.37 (s, 1H), 7.23–7.10 (m, 9H), 7.00 (d, 1H, J=7.9 Hz), 6.80 (d, 1H, J=7.4 Hz), 6.60 (s, 1H), 4.88 (septet, 1H, J=6.2 Hz), 4.68 (s, 1H), 4.05 (q, 1H, J=7.3 Hz), 3.32 (q, 2H, J=5.9 Hz), 2.90–2.83 (m, 2H), 2.44–2.32 (m, 3H), 1.94–1.86 (m, 2H), 1.78–1.70 (m, 2H), 1.60 (quintet, 2H, J=6.4 Hz), 1.56–1.43 (m, 1H), 1.22 (d, 6H, J=6.2 Hz); ESMS m/e: 582.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:22]=[CH:21][C:16]4[N:17]=[CH:18][N:19]([CH3:20])[C:15]=4[CH:14]=3)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1>COCCOC>[CH3:20][N:19]1[C:15]2[CH:14]=[C:13]([CH:11]([C:8]3[N:6]4[N:7]=[C:2]([C:35]5[CH:34]=[N:33][N:32]([CH2:31][CH2:30][O:29][CH:24]6[CH2:25][CH2:26][CH2:27][CH2:28][O:23]6)[CH:36]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[CH3:12])[CH:22]=[CH:21][C:16]=2[N:17]=[CH:18]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: CC(c1ccc2ncn(C)c2c1)c1cnc2ccc(Cl)nn12
Solvent: COCCOC
Product: CC(c1ccc2ncn(C)c2c1)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Temperature: 90 °C

Procedure:
(rac)-6-Chloro-3-[1-(3-methyl-3H-benzoimidazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Stage 185.2, 525 mg, 1.381 mmol) was introduced in a microwave reactor together with 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3 ,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 667 mg, 2.071 mmol) and DME (9 mL). The mixture was purged with Argon for 5 min. Pd(PPh3)2Cl2 (38.8 mg) and 2 M K2CO3 (1.864 mL) were added and the mixture was flushed with Argon before being sealed. It was then heated at 90° C. for 4,5 h. The RM was diluted with EtOAc and washed with water, brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with 40 g RediSep® silica gel column, DCM/MeOH=100:0->92:8 in 25 min). The collected fractions containing product were evaporated and the residue was dried under vacuum to afford the title compound as an oil (tR 2.39 min (conditions 8), MH+=472).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15]([CH2:18][CH2:19][OH:20])=[CH:16][O:17][C:13]=2[CH:12]=1.CCN(C(C)C)C(C)C.[O:32](S(C)(=O)=O)[S:33]([CH3:36])(=O)=[O:34]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15]([CH2:18][CH2:19][O:20][S:33]([CH3:36])(=[O:34])=[O:32])=[CH:16][O:17][C:13]=2[CH:12]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: OCCc1coc2cc(Oc3nc4ccccc4s3)ccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1coc2cc(Oc3nc4ccccc4s3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 105.3 %

Procedure:
To a solution of 2-[6-(benzothiazol-2-yloxy)-benzofuran-3-yl]-ethanol (0.32 g, 1.0 mmol) in DCM (15 mL) was added 4-dimethylaminopyridine (13 mg, 0.10 mmol), DIEA (0.22 mL, 1.2 mmol) and Ms2O (0.22 g, 1.2 mmol) and the resulting solution was stirred (rt, 15 min). The reaction mixture was diluted with DCM (40 mL). The organic layer was washed with saturated NH4Cl (2×50 mL), brine (2×50 mL), dried, filtered and concentrated in vacuo to provide the title compound as a clear oil (0.41 g, 100%). MS (ESI): mass calcd. for C18H15NO5S2, 389.5; m/z found, 390.1 [M+H]+.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:16]=1>CC(O)=O>[Cl:8][C:20]1[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[N:16][C:17]([N:21]2[CH2:22][CH2:23][CH:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:25][CH2:26]2)=[N:18][CH:19]=1
Reactant: CS(=O)(=O)NC1CCN(c2nccc(-c3ccccn3)n2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)NC1CCN(c2ncc(Cl)c(-c3ccccn3)n2)CC1
Reaction time: 2 h
Yield: 28.9 %

Procedure:
NCS (370 mg, 2.83 mmol) was added to a solution of N-(1-(4-(pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanesulfonamide (180 mg, 2.36 mmol) in AcOH (10 mL) at 60° C. and the reaction solution was stirred for 2 h. LC-MS indicated the reaction was almost complete. The reaction solution was concentrated and purified by chromatography, eluted with CH2Cl2:MeOH (6:1) to give crude product, which was further purified by Prep-HPLC to give title compound (251 mg, 29%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.68-8.70 (d, 1H), 8.29 (s, 1H), 7.75-7.79 (m, 1H), 7.70-7.72 (d, 1H), 7.31-7.34 (t, 1H), 4.60-4.63 (d, 2H), 4.18-4.20 (d, 1H), 3.53-3.57 (t, 1H), 2.94 (s, 3H), 1.99-2.02 (d, 1H), 1.39-1.49 (m, 1H); m/z for C15H18ClN5O2S 390.1 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1.CC1C(C)=C(C)C(C)[SiH-](C)(C)C=1.[K+].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC.CN(C)P(=O)(N(C)C)N(C)C>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[C:6]2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:37][CH:36]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1-c1cccs1
Agent: CC1=C[SiH-](C)(C)C(C)C(C)=C1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2cccs2)c2cc(Cl)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a cold (78°), stirred solution containing 664 mg of ethyl 5-chloro-3-thiophenylindole -2-carboxylate from Preparation 5 in 3.5 mL of dry tetrahydrofuran, under argon, was added 3.5 mL of a 0.62M solution of potassium hexamethylsilamide in toluene. The reaction mixture was stirred at -78° for 1 h and at 0° for 1 h then recooled to -78°. 0.75 mL of p-chlorobenzyl chloride. 1.0 mL of hexamethylphosphoric triamide and 20 mg of tetra-n-butylammonium bromide were then added. The resultant mixture was allowed to warm to room temperature and stirred for 18 h. Saturated aqueous ammonium chloride and ether were added. The ether layer was separated, washed with water, 10% aqueous cupric sulfate, water and brine and dried over MgSO4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.C(#N)C.Cl[C:20]1[N:25]2[N:26]=[CH:27][CH:28]=[C:24]2[N:23]=[C:22]([S:29][CH3:30])[C:21]=1[C:31]#[N:32]>O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:20]2[N:25]3[N:26]=[CH:27][CH:28]=[C:24]3[N:23]=[C:22]([S:29][CH3:30])[C:21]=2[C:31]#[N:32])=[CH:3][CH:2]=1
Reactant: NCc1ccncc1
Reactant: CSc1nc2ccnn2c(Cl)c1C#N
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1nc2ccnn2c(NCc2ccncc2)c1C#N
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A mixture comprising 460 mg of 4-picolylamine, 430 mg of triethylamine and 1 ml of acetonitrile was dropwise added to 950 mg of 7-chloro-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile and 20 ml of acetonitrile under cooling with ice, followed by stirring for about 1 hour. After completion of the reaction, about 80 ml of water was added thereto, and the precipitated crystals were collected by filtration, washed with water and dried to obtain crude crystals. The crude crystals were purified by silica gel column chromatography to obtain 970 mg of 7-(4-pyridylmethyl)amino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 3) having a melting point of from 153 to 154° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:9])[CH3:8].Cl[C:11]1[N:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1>C(COC)OC>[CH2:7]([S:9][C:11]1[N:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1)[CH3:8]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: CCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCSc1ncc(C(F)(F)F)cn1
Temperature: 0 °C

Procedure:
Potassium tert-butoxide (8.9 mmol) was added to an ice-cooled solution of ethanethiol (8.9 mmol) in dimethoxyethane (40 ml) and the mixture stirred at room temperature for 10 min before 2-chloro-5-trifluoromethylpyrimidine (8.9 mmol) in dimethoxyethane (10 ml) was added. The resultant mixture was stirred at room temperature for 2 h and at 80° C. for 30 mins. The solvent was then removed at reduced pressure and the residue distilled; yield 1.40 g (76%), b.p. 110°-112° C./40 mmHg. 1H NMR (CDCl3): δ 1.41 and 3.21 (Et), 8.65 (H-4 and H-6).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH2:11][CH3:12])[S:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CCCCO>[CH2:11]([CH:10]1[C:3]2[C:2]([N:23]3[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][S:9]1)[CH3:12]
Reactant: CCC1SCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCCCO
Product: CCC1SCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Yield: 43.7 %

Procedure:
To a solution of 4-chloro-5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidine (0.3 g, 1.5 mmol) in n-BuOH (30 mL) was added 1-Boc-piperazine (0.8 g, 4.3 mmol), and the mixture was refluxed for 30 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (4:1-1:1) to give tert-butyl 4-(5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.23 g, 44%). 1H NMR (CDCl3, 400 MHz) δ 8.54 (s, 1H), 4.61 (d, J=8.8 Hz, 1H), 4.10 (m, 2H), 3.80-3.60 (m, 8H), 2.02 (m, 1H), 1.60 (m, 1H), 1.49 (s, 9H), 0.95 (m, 3H). MS (APCI+) [M+H]+ 351.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[N:23]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:31])=[O:30])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)N3CCOCC3)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.7 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.5 g, 4.5 mmol) in pyridine (15 mL) was added morpholine-4-sulfonyl chloride (1.26 g, 6.8 mmol). The reaction was stirred at rt for 12 h. Then the reaction was washed with water (50 mL), and extracted with DCM (2×50 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:EtOAc 60:1) to afford the title compound of Step A (297 mg, 13.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=5.3 Hz, 1H), 7.27-7.36 (m, 2H), 7.21-7.26 (m, 2H), 6.98 (d, J=5.3 Hz, 1H), 3.58-3.64 (m, 4H), 3.22-3.33 (m, 1H), 3.14-3.21 (m, 4H), 1.40 (d, J=7.0 Hz, 6H). MS (ES+): 480 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13].Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>C(O)C>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: -5 °C
Yield: 36 %

Procedure:
To a solution of potassium hydroxide (0.67 g, 9.80 mmol) in ethanol (30 ml) is added 2-naphthol (1.41 g, 9.80 mmol) and 4-(2-bromoethoxy)benzaldehyde (2.25 g, 9.80 mmol). Then the mixture is heated to reflux for 8 hours. After cooled to −5° C., the precipitate is collected by filtration, washed with water, and dried under vacuum to give the title product (1.03 g, 36%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][O:13][C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:12]
Reactant: c1ccc2c(c1)CCN2
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2ccccc21
Reaction time: 16 h
Yield: 99.3 %

Procedure:
A mixture of indoline (11.97 g, 0.1 mol), methyl chloroformate (15.45 mL, 0.2 mol), triethylamine (40.4 g, 0.4 mol), and DMAP (0.5 g, 0.004 mol) in CH2Cl2 (100 mL) was stirred for 16 hours. The reaction mixture was quenched with water (10 mL). The reaction was extracted with CH2Cl2 (1×40 mL). The organic layer washed with water (1×50 mL), dried over anhydrous magnesium sulfate, filtered and the resultant filtrate was concentrated in vacuo to provide the title compound (17.6 g, 99%) which was used without further purification.