Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:7][CH2:6]2.C[CH:26]([C:33]1([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[C:40]1(C)C=C(C)C=C(C)C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:36]1[CH2:35][CH2:34][C:33]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH3:40])=[CH:31][CH:32]=3)([OH:39])[CH2:38][CH2:37]1)[CH2:7][CH2:6]2
Reactant: Cc1cc(C)cc(C)c1
Reactant: COc1ccc2c(c1)CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CC(c1ccccc1)C1(O)CCNCC1
Product: COc1ccc2c(c1)CCC(CN1CCC(O)(Cc3ccc(C)cc3)CC1)C2
Yield: 67.3 %

Procedure:
(RS)-Toluene-4-sulfonic acid 6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl ester (1.32 g, 3.81 mmol) and 4-(methyl-benzyl)-piperidin-4-ol (3.13 g, 15.24 mmol) in mesitylene (100 ml) was heated at 140° C. for 20 hr. Following evaporation of the solvent the crude material was partioned between CH2Cl2 (50 ml) and 5% NaHCO3 (30 ml), the aqueous phase was extracted with CH2Cl2 (2×100 ml) washed with satd. NaCl solution (50 ml), dried (Na2SO4), filtered and evaporated. The crude product was chomatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc-n-Hexane (1:3) then (1:1), to afford (RS)-1-(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol as a white solid (972 mg, 2.56 mmol, 67.3%), Mp. 91-94° C., MS m/e=380.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:20]1[C:25]([C:26]2[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([NH2:33])[N:27]=2)=[CH:24][C:23]([O:34][CH3:35])=[CH:22][N:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[NH2:33][C:28]1[N:29]=[C:30]([CH3:32])[N:31]=[C:26]([C:25]2[C:20]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:21][CH:22]=[C:23]([O:34][CH3:35])[CH:24]=2)[N:27]=1
Reactant: COc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Reactant: Nc1cnc(Cl)c(NS(=O)(=O)N2CCOCC2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnc(Nc2cnc(Cl)c(NS(=O)(=O)N3CCOCC3)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 11.2 %

Procedure:
To a stirred solution of N-(5-amino-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.0819 g, 0.280 mmol) and 4-(2-fluoro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 330 step 5, 0.0621 g, 0.264 mmol) in DMF (1 mL) in 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 1.06 mL, 1.06 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 45 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (20 mL). The aqueous phase was acidified to pH 3 to 4 then extracted with 25% isopropanol in chloroform (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC using a Phenomenex, Gemni 5 micron C18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The fraction was collected and the solvent was evaporated to give a red solid. The solid was partitioned between tris-HCl buffer (1 M, pH 7.0) and 25% IPA in CHCl3. The aqueous phase was acidified to pH about 3 then extracted with 25% IPA in CHCl3. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. This material was dissolved in about 1 mL DMSO and about 2 mL of water was added. The resulting solid was collected via filtration and washed with copious amount of water and dried to afford N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-methoxypyridin-2-ylamino)-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.015 g, 11% yield) as a dark yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (br. s., 1H) 9.73 (br. s., 1H) 8.79 (br. s., 1H) 8.52 (br. s., 1H) 8.38-8.47 (m, 1H) 8.18 (br. s., 1H) 7.76-7.99 (m, 2H) 3.86 (br. s., 3H) 3.57-3.66 (m, 4H) 3.09-3.21 (m, 4H) 2.45 (br. s., 3H). m/z (ESI, positive ion): 508.0 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].O=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18].C(N(CC)CC)C>C(O)C>[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][OH:8])#[N:18]
Reactant: COC(=O)[C@H](N)CO
Reactant: N#CCCCCCC=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CO)NCCCCCCC#N
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of D-serine methyl ester hydrochloride (0.91 g) in ethanol (18 mL) was added 7-oxoheptanenitrile (0.67 g) and triethylamine (0.6 mL) (see: Kubodera, N. et al, Heterocycles 1982, 19, 1285) and the mixture was stirred under N2 for 1 h. To the solution was then added Na(CN)BH3 (0.4 g) and the resultant cloudy suspension was further stirred under N2 for 1 h. The mixture was quenched with water and concentrated in vacuo and the residue diluted with ethyl acetate/saturated NaHCO3. The organic layer was separated and the aqueous layer extracted with ethyl acetate (3×). The organic layers were washed with water, brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by chromatography. Eluting with 5–10% (v) methanol in dichloromethane gave the desired product 2-1 (620 mg). 1H NMR (400 MHz, CDCl3): δ 3.78 (m, 1H), 3.77 (s, 3H), 3.59 (dd, 1H), 3.38 (dd, 1H), 2.72 (m, 1H), 2.53 (m, 1H), 2.36 (t, 2H), 1.70 (m, 2H), 1.55–1.35 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([C:26]([CH3:31])([CH3:30])[C:27](O)=[O:28])[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[Cl-].C[NH3+].[CH3:35][N:36](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([C:26]([CH3:30])([CH3:31])[C:27]([NH:36][CH3:35])=[O:28])[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C(C)(C)C(=O)O)c3)cc12
Agent: C[NH3+]
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)C(C)(C)n1cc(-c2cnc3[nH]cc(C(C)c4c(Cl)ccc(F)c4Cl)c3c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-{3-[1-(2,6-Dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazol-1-yl)-2-methylpropionic acid (20 mg, 0.04 mmol), methylammonium chloride (14.6 mg, 0.217 mmol), TBTU (28 mg, 0.087 mmol), DIPEA (37.8 μL, 0.217 mmol) and DCM (0.6 mL, 9 mmol) was stirred at rt for 1 h. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (eluent: 2% MeOH in DCM) to give desired product. MS (ES+): m/z 474.09, 476.03 (100, 90) [MH+]. HPLC: tR=3.45 min (ZQ3 polar—5 min). 1H NMR (400 MHz, CD3OD): δ=1.81 (s, 6H), 1.88 (d, J=7.3 Hz, 3H), 2.71 (s, 3H), 5.29 (q, J=7.2 Hz, 1H), 7.14-7.23 (m, 1H), 7.36 (d, J=1.5 Hz, 1H), 7.43 (s, 2H), 7.65 (s, 1H), 8.00 (s, 1H), 8.39 (br. s., 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccccc2)c1

Procedure:
A mixture of 1564 g. (10.2 mole) of methyl 3- hydroxybenzoate, 1407.6 g. (10.2 mole) potassium carbonate and 1285.2 g. (10.2 mole) benzyl chloride in 5 l. of acetone is heated at reflux for 22 hours. The reaction mixture is then cooled, filtered and the filtrate evaporated. The residue is crystallized in a small volume of pentane to give a quantitative yield of the title compound.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][N:10]([CH3:21])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]#[CH:20])[OH:18])=[CH:13][CH:12]=1.C(NCC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:9][N:10]([CH3:21])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]#[C:20][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[OH:18])=[CH:13][CH:12]=1
Reactant: C#CC(O)c1ccc(N(C)C)cc1
Reactant: Brc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CN(C)c1ccc(C(O)C#Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
Place 4-bromopyridine hydrochloride (0.78 g, 4 mmol), 4-dimethylamino-α-(ethynyl)-benzenemethanol (0.88 g, 5 mmol) and diethylamine (25 mL) under nitrogen atmosphere. Add bis(triphenylphosphine)palladium(II) chloride (140 mg) then copper(I) iodide (20 mg). Stir overnight at room temperature and filter. Evaporate the solvent in vacuo and filter through silica gel (2:1 ethyl acetate/hexane). Evaporate the solvent in vacuo and recrystallize (25% ethyl acetate/hexane) to yield 0.5 g of the title compound; mp 117° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.Cl[C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:16][O:17][C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1
Reactant: OCc1ccc(Oc2ccc(F)cc2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)cc3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluoro-4-(4-fluorophenoxyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH3:9][C:10]([N+:17]#[C-:18])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].[CH:19](=O)[CH3:20]>Cl(O)(=O)(=O)=O>[CH3:19][C:20]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]2[C:18]=1[NH:17][C:10]([CH3:16])([CH3:9])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC=O
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: Cc1ccc(N)nc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccc2nc(C)c(NC(C)(C)CC(C)(C)C)n2c1

Procedure:
Compound (17) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-5-methylpyridine solution (0.1 M, DCM), 0.575 ml of 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, DCM), 0.500 ml of acetaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[O:14][C:12](=O)[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH2:28])=O>O>[NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:28][C:12](=[O:14])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21
Reactant: NC=O
Solvent: O
Product: O=C1NC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21

Procedure:
A suspension of 21.9 g (66.3 mmol) of 4,5-bis(anilino)phthalic anhydride in60 ml of formamide under argon atmosphere is heated at 125°-130° for 5 hours. The reaction mixture is cooled to 70°, and 250 ml of water are slowly added. This mixture is cooled to 0° for 30 minutes, and the reddish crystals are filtered off, washed with water and dried. Recrystallization from DMF/water yields the title compound in the form of orange crystals, m.p. 205°-207° C., FAB-MS: 330 [M+ +H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.[CH2:37]([NH2:39])[CH3:38].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:39][CH2:37][CH3:38])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1F
Yield: 114.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in toluene (8 ml) and triethylamine (1.0 ml) with heating, and a solution of triphosgene (47 mg) in toluene (1.0 ml) was then added to the solution. The mixture was heated under reflux for 5 min. Next, ethylamine hydrochloride (60 mg) was added to the reaction solution, and the mixture was heated under reflux for additional 5 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 70 mg (yield 53%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CC(C)=O.CN(C=O)C>[CH:21]1([N:20]([C:16]2[S:15][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:17]=2)[CH3:19])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: N#C[S-]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CNC1CCCCC1
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: CN(c1nc(=O)c2cccnc2s1)C1CCCCC1
Yield: 46.8 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.749 g (11.10 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 888 mg of ammonium thiocyanate, 15 ml of acetone, 1.32 g of N-methylcyclohexylamine and 10 ml of acetone were used. The resulting crude product was then recrystallized from ethanol to obtain 1.43 g of 2-(N-cyclohexyl-N-methylamino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=1)=[O:15].[Na+].[I-].[CH2:25]([NH2:27])[CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:20]=[C:19]([CH2:21][NH:27][CH2:25][CH3:26])[O:18][N:17]=1)=[O:15]
Reactant: CCN
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(CCl)on1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNCc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1
Yield: 50 %

Procedure:
A mixture of the intermediate 7: N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(chloromethyl)isoxazole-3-carboxamide (0.088 g; 0.260 mmol) NaI (0.078 g; 0.520 mmol) and ethylamine (1.30 mL; 2M in THF) in THF (1 mL) was irradiated in a microwave oven at 130° C. for 10 min and concentrated under reduced pressure. The crude material was purified by flash chromatography (eluent 2 to 10% MeOH in dichloromethane) to afford N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-((ethylamino)methyl)isoxazole-3-carboxamide 0.044 g (50%).
Reaction SMILES: [CH2:1](O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:23][C:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[NH:26][N:25]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O.C1(C)C=CC=CC=1>[Br:23][C:24]1[N:25]([CH2:1][CH3:2])[N:26]=[C:27]2[CH:32]=[CH:31][CH:30]=[N:29][C:28]=12
Reactant: CCO
Reactant: Brc1n[nH]c2cccnc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCn1nc2cccnc2c1Br
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethanol (0.118 ml) and triphenylphosphine (530 mg) in THF (3 ml) was added 3-bromo-1H-pyrazolo[4,3-b]pyridine (200 mg), and the mixture was heated at 50° C. A toluene solution (1.9 M, 1.06 ml) of DIAD was added dropwise at 50° C., and the mixture was stirred for 30 min. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (71 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#N)[CH:7]=[CH:8][C:9]=1[F:10].[CH3:14]I.C[N:17]([CH:19]=O)C>>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([CH3:12])([CH3:14])[C:19]#[N:17])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: N#CCc1ccc(F)c(Cl)c1
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C#N)c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
NaH (60% dispersion in mineral oil, 13.3 g, 333 mmol) was suspended in DMF (151 mL, 151 mmol), cooled to 0° C., and then a solution of 3-chloro-4-fluorophenylacetonitrile (25.65 g, 151 mmol) and MeI (23.6 mL, 378 mmol) in DMF was added dropwise via addition funnel. The reaction mixture was slowly warmed to ambient temperature and stirred for 3 hours. The reaction mixture was quenched with water, diluted with 200 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed with water (2×100 mL), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (21.01 g) as a colorless oil after flash chromatography.
Reaction SMILES: [Si]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH:18]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:12][C:11]=2[CH:10]=1)(C(C)(C)C)(C)C.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C)C1C=CN=CC=1.O>[CH3:39][C:38]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH:18]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:12][C:11]=2[CH:10]=1)=[O:40]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-(Tert-butyldimethylsilyloxy)-5-(α-cyclopropylformyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3.0 g) was dissolved in the solvent described in Table 1 to form a solution and the solution was cooled to 0° C. Triethylamine (1.02 g) was then added followed by 4-dimethylaminopyridine (DMAP) (0.02 g). After the reaction mixture was stirred for 10 minutes at the same temperature, acetic anhydride (0.83 g) was added to the solution. The reaction was monitored by Thin Layer Chromatography (TLC) (petroleum ether/ethyl acetate=10/1 or 5/1) until the reaction was completed. After the reaction was completed, cold water was added to the reaction mixture and the mixture was stirred for 15 minutes. It was then cooled to −5° C. and further stirred for 3 hours before collecting the crystal as prasugrel free base. Solid precipitate was collected. The yield of prasugrel was calculated and the results were shown in Table 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:7][S:8]([OH:11])(=[O:10])=[O:9].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[NH+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:9][S:8](=[O:11])(=[O:7])[O-:10])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(O)O
Reactant: c1ccncc1
Product: CC(=O)OS(=O)(=O)[O-]
Product: c1cc[nH+]cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 30 ml of acetic anhydride and 8.05 ml (0.1 mole) of pyridine is cooled to 0° C., and 5.4 ml of conc. H2SO4 is added dropwise at 0° C. under stirring. After 10 minutes, the crystals are filtered, washed with diethyl ether and dried under vacuum over P2O5 and KOH. Yield: 18.4 g (84%). IR: 1050 cm-1 sharp band, characteristic for sulfates and sulfate esters. Decomposes above 60° C., very hygroscopic. MW: 219.2 (C7H9O5NS).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH3:21])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]14[O:20][CH2:19][CH2:18][O:17]1.CC1C=CC=C(C)N=1>Cl([O-])(=O)(=O)=O.C([N+](CC)(CC)CC)C.CN(C)C=O.CO>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]2[C:9]3=[CH:10][CH2:11][C@@:12]4([CH3:21])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]14[O:17][CH2:18][CH2:19][O:20]1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: Cc1cccc(C)n1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CCC21OCCO1
Reaction time: 0.92 h
Yield: 78.7 %

Procedure:
A solution of 2.3 grams of 3-methoxy-13β-methyl-17,17-(ethylenedioxy)gona-1,3,5(10)-triene, 1.1 milliliters of 2,6-dimethylpyridine, and 1.4 grams of tetraethylammonium perchlorate in 45 milliliters of N,N-dimethylformamide and 50 milliliters of methanol was electrolyzed between the same pair of electrodes that were described in Example 1, spaced from each other at a distance of 1.5 centimeters, with a current of 600 milliamperes for a period of 55 minutes. At the end of the electrolysis all traces of methanol were distilled from the solution at a subatmospheric pressure and the solution was then acidified with anhydrous p-toluenesulfonic acid, allowed to stand at room temperature for a period between 20 and 30 minutes and then made alkaline with a saturated solution of sodium bicarbonate. A portion of the product precipitated during the addition of the bicarbonate solution and water was then added to complete its precipitation. In this manner, 1.8 grams of 3-methoxy-13β-methyl-17,17-(ethylenedioxy)gona-1,3,5-(10),9(11)-tetraene having a melting point of 146°-149° C. was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:18])[C:6]2[C:11]([CH3:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:7]=2[N:8]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O)CO.C(N(CC)CC)C>O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:2][C:3]2[NH:4][C:5](=[O:18])[C:6]3[C:11]([CH3:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][C:7]=3[N:8]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1sc2nc(CCl)[nH]c(=O)c2c1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: OCCO
Product: CCOC(=O)c1sc2nc(CN3CCN(C(=O)OC(C)(C)C)CC3)[nH]c(=O)c2c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
A mixture of 1.15 g of ethyl 2-chloromethyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, 745 mg of tert-butoxycarbonylpiperazine, 20 mL of ethylene glycol and 400 mg of triethylamine was stirred at 80° C. for 3 hours. Thereafter water was added to the reaction mixture, followed by extraction with chloroform, drying over anhydrous magnesium sulfate, and removal of the solvent by distillation under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate:chloroform:hexane=2:1:1) to provide 1.36 g (78%) of the title compound.