Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[N:5]([N:7]=[C:8]([CH2:47][CH2:48][CH3:49])[C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:6]=1>C(OCC)(=O)C>[CH3:1][C:2]1[NH:3][C:4]2[N:5]([N:7]=[C:8]([CH2:47][CH2:48][CH3:49])[C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][N:25]=[N:26][N:27]=3)=[CH:15][CH:16]=2)[N:6]=1
Reactant: CCCc1nn2nc(C)[nH]c2c1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCCc1nn2nc(C)[nH]c2c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A 183 mg portion of 2-methyl-6-propyl-7-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 1c) was treated in the same manner as described in Example 12, the resulting residue was dissolved in ethyl acetate with heating and then the solution was cooled to collect the thus formed precipitate by filtration, thereby giving 85 mg of 2-methyl-6-propyl-7-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-pyrazolo[1,5-b][1,2,4]triazole in the form of colorless amorphous solid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][S:8]([OH:11])(=O)=[O:9].[Cl:12][C:13]1[O:14][CH:15]=[CH:16][CH:17]=1>>[Cl:12][C:13]1[O:14][C:15]([S:8]([Cl:7])(=[O:11])=[O:9])=[CH:16][CH:17]=1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1ccco1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Cl)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Phosphorus pentachloride (40.53 g, 0.1947 mol) was added portionwise (caution, foaming) over 5 min at 25° C. to chlorosulfonic acid (56.8 g, 32.4 mL, 0.487 mol) and the resulting solution was stirred at 25° C. for 10 min. Then, 2-chlorofuran (20.0 g, 20 0.1947 mol) was added in one portion and the resulting dark suspension was heated to 55° C. for 1.0 h during which time foaming occurred and subsided. The reaction mixture was then poured onto ice and the resulting suspension was extracted with CH2Cl2 (250 mL). The organic was filtered through a pad of celite, washed with brine (70 mL) and dried over MgSO4. The solvent was removed in vacuo to provide 5-chlorofuran-2-sulfonyl chloride as a black oil (14.1 g, 36.02%). 1H-NMR (DMSO-d6, 400 MHz) δ 7.05 (d, 1H); 6.35 (d, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1
Reactant: Oc1cccc(Br)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: FC(F)(F)c1ccc(Oc2cccc(Br)c2)nc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of 3-bromophenol (5 g, 27.54 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (4.52 g, 26.16 mmol) in DMF (30 mL) was added K2CO3 and the mixture was refluxed at 110° C. overnight. Distilled water (30 mL) and diethyl ether (30 mL) were added and the mixture was stirred for 30 min. The ether layer was dried over Na2SO4 and concentrated to give pure pure title compound (8.0 g). 1H NMR (500 MHz, CDCl3): δ 7.0 (d, 1H, J=10 Hz), 7.1 (d, 1H, J=1.5 Hz), 7.2-7.3 (m, 2H), 7.4 (d, 1H, J=8 Hz), 7.9 (m, 1H), 8.4 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.Br[C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([CH3:24])[CH:23]=1)[C:20](=[O:25])[N:19]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)[CH2:18]2.CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:15]2[CH:16]=[C:17]3[C:21](=[C:22]([CH3:24])[CH:23]=2)[C:20](=[O:25])[N:19]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:18]3)[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: NC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(NC2CCN(Cc3ccccc3)C2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 70.2 %

Procedure:
3-Amino-1-benzyl-pyrrolidine (57 mg, 0.325 mmol), 5-Bromo-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-isoindol-1-one (100 mg, 0.25 mmol), NaOtBu (168 mg, 1.75 mmol), BINAP (16 mg, 0.025 mmol) and Pd2(dba)3 (23 mg, 0.025 mmol) were dissolved in anhydrous toluene (5 mL). The mixture was immersed in a 110° C. oil bath. After eighteen hours, the reaction was cooled and poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The compound was purified by column chromatography (50% EtOAc/Hexanes) to provide the title compound as a yellow gum (87 mg, 70%). 1H NMR (300 MHz, CDCl3): δ 7.24-7.34 (m, 7H), 7.18 (d, 2H), 6.34 (d, 2H), 4.72 (s, 2H), 4.33 (d, 1H), 4.12 (s, 2H), 4.04 (m, 1H), 3.64 (collapsed dd, 2H), 2.75-2.83 (m, 2H), 2.66 (s, 3H), 2.58 (dd, 1H), 2.45 (ddd, 1H), 2.32-2.42 (m, 1H), 1.67-1.70 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CN(C=O)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:36](=[O:37])[C:35]3[C:26](=[C:27]([O:38][CH2:39][CH2:40][CH3:41])[CH:28]=[C:29]4[C:34]=3[O:33][CH2:32][CH2:31][CH2:30]4)[N:25]([CH2:42][C:43](O)=[O:44])[CH:24]=2)=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(N(CC)CC)C>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:36](=[O:37])[C:35]3[C:26](=[C:27]([O:38][CH2:39][CH2:40][CH3:41])[CH:28]=[C:29]4[C:34]=3[O:33][CH2:32][CH2:31][CH2:30]4)[N:25]([CH2:42][C:43]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[O:44])[CH:24]=2)=[CH:21][CH:22]=1
Reactant: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CC(=O)O)c13)OCCC2
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(CC(=O)NCCN4CCOCC4)c13)OCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
4-(2-Aminoethyl)morpholine (217 mg, 1.7 mmol) was added to a DMF solution (10 ml) of [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]acetic acid (580 mg, 1.39 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU, 790 mg, 2.1 mmol) and triethylamine (5 ml). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. Water and ethyl acetate were added to the residue, followed by separation. The thus-obtained organic layer was washed with water and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, giving a pale brown powder of 2-[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-oxa-1-aza-phenanthren-1-yl]-N-(2-morpholin-4-ylethyl)acetamide (115 mg, yield: 16%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1.NN>[Pd].C(O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccn2)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
2-(4-Nitrophenyl)pyridine (1.10 g) and 10% Pd/C (300 mg) were dissolved suspended in 80 mL of an 8:1 solution of 30 mL of THF and 10 mL of ethanol under an atmosphere of dry N2. To this solution was added 1.0 mL of anhydrous hydrazine. The reaction mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated under vacuum. The residue was partitioned between dichloromethane and water and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified via silica gel chromatography to give 653.3 mg of 4-(pyridin-2-yl)benzenamine.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([Si:10]([CH3:22])([CH3:21])[O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:6]([Si:10]([CH3:22])([CH3:21])[O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:1])([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(CO[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a well stirred solution of methyl-triphenyl-phosphonium bromide (3.08 g, 8.61 mmol) in tetrahydrofuran (10 mL) at 0° C. is added n-butyllithium (4.89 mL, 7.83 mmol of a 1.6 M solution). The reaction mixture is allowed to warm to room temperature, stirred for 1 h, then cooled to 0° C. 2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethanone (980 mg, 3.91 mmol) in tetrahydrofuran (30 mL) is then slowly added. The mixture is stirred at room temperature for 30 min then quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted several times with ethyl acetate. The organic layers are combined, washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified via silica gel chromatography (20% ethyl acetate in hexanes) to yield 1.3 g of the title compound as a clear oil containing ethyl acetate and was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=3)=[CH:32][C:31]=2[C:47]2[CH:52]=[CH:51][N:50]=[N:49][CH:48]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1>Cl.O1CCOCC1.CO>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([C:43]([F:44])([F:45])[F:46])[CH:37]=3)=[CH:32][C:31]=2[C:47]2[CH:52]=[CH:51][N:50]=[N:49][CH:48]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(Cl)c(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2-c2ccnnc2)cc1F
Temperature: 50 °C
Reaction time: 6 h
Yield: 68.7 %

Procedure:
5-Chloro-4-(4′-chloro-3-(pyridazin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 57, 135 mg, 0.17 mmol) was dissolved in a 4M solution of HCl in dioxane (5 mL), methanol (5 mL) added and the resulting mixture was stirred at 50° C. for 6 hours. The reaction mixture was evaporated and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate was separated, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica eluting with a gradient of dichloromethane:methanol:acetic acid 100:0:0 to 95:4:0.4 to give the title compound (75 mg, 68%) as a white solid.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.Cl.[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16].C(N(C(C)C)C(C)C)C>C(O)C>[OH:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: N[C@H]1CCCC[C@H]1O
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H]2CCCC[C@@H]2O)CS1
Yield: 36 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (870 mg) in ethanol (30 mL) were added cis-2-aminocyclohexanol hydrochloride (1.00 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (2.32 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (504 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:3]=1[CH2:25][C:26]([O:28][CH3:29])=[O:27].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:40]1[CH2:44]OC[CH2:41]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:3]=1[CH:25]([CH2:41][CH2:40][CH3:44])[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCCC3
Yield: 62.3 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.330 g; 0.8 mmol), LHMDS 1N in THF (1.2 mL; 1.2 mmol), 1-iodopropane (0.156 mL; 1.6 mmol) in DMF (4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-80%) in heptane furnished 0.226 g (62%) of the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:19]=[CH:18][C:17]3[C:8](=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[CH:12][C:11]([C:20]3NN=[N:22][N:21]=3)=[N:10]4)[N:7]=2)=NN=[N:2]1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[C:26]1([C:25]2[O:32][C:5]([C:6]3[CH:19]=[CH:18][C:17]4[C:8](=[C:9]5[C:14](=[CH:15][CH:16]=4)[CH:13]=[CH:12][C:11]([C:20]4[O:32][C:25]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:22][N:21]=4)=[N:10]5)[N:7]=3)=[N:1][N:2]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1cc2ccc3ccc(-c4nnn[nH]4)nc3c2nc1-c1nnn[nH]1
Solvent: c1ccncc1
Product: c1ccc(-c2nnc(-c3ccc4ccc5ccc(-c6nnc(-c7ccccc7)o6)nc5c4n3)o2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
Under nitrogen atmosphere, a mixture of 13 g (0.045 mol) 2,9-bis-(1H-tetrazol-5-yl)-[1,10]phenanthroline and 390 ml pyridine was added to a 250 ml three-necked flask. The mixture was then heated to 50° C., and 24.6 g (0.17 mol) benzoyl chloride was then added drop by drop. After the adding, the mixture solution was heated to reflux (110° C.) and stirred overnight. After completion of reaction, the reaction mixture was cooled to room temperature, filtered. Finally, solids were separated, washed by 100 ml methanol, filtered and purified by column chromatography to obtain white products 2,9-bis-(5-phenyl-[1,3,4]oxadiazol-2-yl)-[1,10]phenanthroline 4 g (0.008 mol, yield 17%). MS(m/z, FAB+), 468, 467, 307, 154, 105.
Reaction SMILES: [CH:1]1([CH2:4][C:5](Cl)=[O:6])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:11][CH:10]=1>ClC1C=CC=CC=1.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].[Zn]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]([CH3:21])[C:17]([C:5](=[O:6])[CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:18][C:19]=2[CH3:20])=[CH:13][CH:14]=1
Reactant: Cc1ccn(C)c1-c1ccc(Cl)cc1
Reactant: O=C(Cl)CC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)CC2CC2)n(C)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
2-cyclopropylacetyl chloride (11.83 g, 100.00 mmol) solution in chlorobenzene (60 ml) was added to the stirred solution of 2-(4-chlorophenyl)-1,3-dimethyl-1H-pyrrole (prepared according to the procedure given in Kazuhiko Taguchi et al., Tetrahedron Letters, 2005, 46, 4539-4542) (17.10 g, 83.00 mmol) and Zinc (10.87 g, 166.00 mmol) in toluene (100 ml) at 25° C. The reaction mixture was stirred at 25° C. for 3 h. The progress of the reaction was monitored by TLC. The mixture was diluted with a saturated solution of sodium bicarbonate (100 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with water (1×50 ml) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using 5-10% ethyl acetate in hexanes as an eluent to obtain the title compound 3(7.20 g, 30.1%). MS: m/z 288 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1OC1C.[Br:17]Br.[OH-].[K+]>C(Cl)Cl.O>[Br:17][C:8]1[C:7]([CH3:12])=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9]=1[CH3:11]
Reactant: BrBr
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Agent: CC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 200 g (1.23 mole) 5-t-butyl-1,3-dimethylbenzene and 83 ml (1.23 mole) propylene oxide in 500 ml of methylene chloride at 15° C. or less, 63 ml (1.23 mole) bromine was added dropwise while maintaining the solution temperature at 15° C. or less. The reaction mixture was allowed to warm to 25° C. overnight. A 200 ml solution of 5% by weight of potassium hydroxide in water was added and the resulting two phase system was stirred for 1 hr at 25° C. The organic phase was washed with water and dried over anhydrous magnesium sulfate. After solvent evaporation an oil was left which when crystallized from methanol gave 265 g (87% yield) of the title compound after drying in vacuo. The oil could also be purified by distilling at 61°-70° C. under a reduced pressure of 0.25 mm of mercury.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[C:4]=1C(O)=O>N1C2C(=CC=CC=2)C=CC=1.CCOCC>[CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([C:8]([F:11])([F:9])[F:10])[CH:4]=1
Reactant: CSc1snc(C(F)(F)F)c1C(=O)O
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: CSc1cc(C(F)(F)F)ns1
Temperature: 170 °C

Procedure:
5-Methylthio-3-(trifluoromethyl)isothiazole-4-carboxylic acid (9.4 g, 39 mmol) was dissolved in 15 mL of quinoline and 0.6 g (4.2 mmol) of cuprous oxide was added. The mixture was heated at 170° C. for about 30 min and then allowed to cool. It was then diluted with ether and the resulting solution was washed with 100 mL of 2N hydrochloric acid, dried over sodium bicarbonate, filtered, and distilled to obtain 6.55 g (85 percent of theory) of the title compound as a colorless liquid boiling at 126°-127° C. at 84 mm Hg (11 kiloPascals (kPa)) pressure.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][N:12]([CH:14]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[CH2:13][C:7]=2[CH:6]=1)=[O:3].[OH:27][P:28]([OH:31])([OH:30])=[O:29]>ClCCl>[CH3:1][C:2]([O:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][N:12]([CH:14]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[CH2:13][C:7]=2[CH:6]=1)=[O:3].[P:28]([O-:31])([O-:30])([O-:29])=[O:27]
Reactant: O=P(O)(O)O
Agent: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Solvent: ClCCl
Product: O=P([O-])([O-])[O-]
Temperature: 9 °C
Reaction time: 17 h

Procedure:
To a solution of prasugrel base (0.252 g of) in 2.0 ml of dichloromethane at 0-5° C., a dropwise solution of 55.0 μL of 85% H3PO4 (aq) was added. An oily reaction mixture was obtained and stirred at 0-5° C. for about 7 hours and for an additional 17 hours at 8-10° C. The obtained crystals were filtered and dried at 40° C./vacuum for about 5 hours. Prasugrel phosphate form P2 was obtained (0.186 g).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([NH:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=S)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.[OH:26]O>C(O)(=O)C>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([NH:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:26])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: OO
Reactant: Cc1ccc(C(=O)NC(NC(=S)Nc2cccnc2)C(Cl)(Cl)Cl)cc1
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC(NC(=O)Nc2cccnc2)C(Cl)(Cl)Cl)cc1
Reaction time: 0.5 h

Procedure:
A solution of Example 38B (250 mg, 0.200 mmol) in glacial acetic acid (4 mL) at ambient temperature was treated slowly with acetic acid (6 mL) containing 30% hydrogen peroxide (4 mL), and the reaction was stirred for 30 minutes. The precipitate which formed was filtered off, washed with water, and crystallized from ethanol. The salt was dissolved in ethyl acetate and neutralized with saturated aqueous sodium carbonate solution. The organic solution was washed with brine (5 mL), dried (Na2SO4), and concentrated to provide a white solid. Recrystallization from ethanol/diethyl ether provided 71 mg of the desired product as a white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[C:28][Si](C)(C)C)[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(O)(=O)C>[C:27]([C:23]1[N:22]=[C:21]([O:20][CH3:19])[CH:26]=[CH:25][N:24]=1)#[CH:28]
Reactant: COc1ccnc(C#C[Si](C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#Cc1nccc(OC)n1
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
Tetrabutylammonium fluoride (0.97 mL of a 1M solution in tetrahydrofuran, 0.97 mmol) was added to a stirred solution of 4-methoxy-2-[(trimethylsilyl)ethynyl]pyrimidine (Preparation 1a, 0.20 g, 0.97 mmol) in tetrahydrofuran (1.4 mL) and acetic acid (56 pt) at room temperature. After 5 minutes, 10% aqueous potassium carbonate solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was separated, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (dichloromethane) gave the title compound (0.11 g, 85%) as a pale orange solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH:20]=[C:19]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[C:18]=3[CH:17]=2)=O)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:44]2)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH:20]=[C:19]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[C:18]=3[CH:17]=2)=[S:44])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1F
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(NC(=S)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1F
Temperature: 25 °C

Procedure:
A solution of 54.4 mg (0.119 mmol) ethyl 2-fluoro-4-[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 40) and 57.7 mg (0.143 mmol) of [2,4-bis(4- methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (Lawesson's Reagent) in 12.0 ml of benzene was refluxed overnight. Upon cooling to room temperature, the mixture was filtered and the filtrate concentrated under reduced pressure. The title compound was isolated by column chromatography (10 to 25% EtOAc/hexanes) as a yellow solid. 1H NMR (CDCl3): δ 9.08 (1H, s), 7.92 (1H, br s), 7.90 (1H, t, J=8.2 Hz), 7.66 (1H, dd, J=2.0, 6.0 Hz), 7.38 (3H, m), 7.18 (4H, m), 6.01 (1H, t, J=4.7 Hz), 4.35 (2H, q, J=7.1 Hz), 2.36 (3H, s), 2.33 (2H, d, J=4.7 Hz), 1.38 (3H, t, J=7.1 Hz), 1.33 (6H, s).