Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Na].[SH:11][C:12]1[N:13]=[N:14][NH:15][CH:16]=1>CN(C)C=O>[NH:15]1[CH:16]=[C:12]([S:11][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[N:13]=[N:14]1
Reactant: N#Cc1ccc(F)cc1
Reactant: Sc1c[nH]nn1
Agent: [Na]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2c[nH]nn2)cc1
Temperature: 125 °C
Yield: 83.2 %

Procedure:
To 4-fluorobenzonitrile (6.1 g) in dry N,N-dimethylformamide (50 mL), under nitrogen, was added 4-mercapto-1,2,3-triazole sodium salt (6.2 g), and the stirred mixture heated in an oil bath at 125° C. for 18 h. The mixture was cooled to room temperature, and most of the solvent stripped at reduced pressure. The residue was partitioned between ethyl acetate and water, the organic phase washed with water, brine, then dried (sodium sulphate), and solvent stripped at reduced pressure. The residue was azeotroped with toluene, and the resulting solid triturated with isohexane, collected by filtration, washed with cold toluene, then isohexane, and dried in vacuo to give the title compound as a yellow solid (8.4 g). 1H NMR (360 MHz, CDCl3) δ 12.45 (1H, br s), 7.92 (1H, s), 7.51 (2H, d, J=8.5 Hz), 7.22 (2H, d, J=8.5 Hz).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH:17][C:18](=[O:30])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:11]=1>C1COCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][C:10]1[CH:15]=[C:14]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[N:13]=[C:12]([NH:17][C:18](=[O:30])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:11]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1nc(Cl)cc(Cl)n1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.3 %

Procedure:
Sodium hydride (272 mg, 6.8 mmol, 60% in mineral oil) was added to a solution of 2,2,2-trifluoroethanol (1.5 g, 15 mmol) in anhydrous THF (15 mL) at 0° C. and the mixture stirred for 20 min. To this mixture was added N′-[4,6-dichloropyrimidin-2-yl]-N-[4-(trifluoromethyl)phenyl]urea (1.14 g, 3.24 mmol) and stirred at 0° C. for 1 h. The cooling bath was removed and the mixture allowed to warm to room temperature. The mixture was warmed to 45° C. and stirred for additional 18 h. The mixture was poured into water and stirred for 10 min and filtered to afford 1 (1.4 g, 68% yield): m.p. 167-168° C.; 1H NMR (DMSO-d6) δ 10.44 (bs, 1H), 10.28 (bs, 1H), 7.76 (d, J=6 Hz, 2H), 7.69 (d, J=6 Hz, 2H), 6.29 (s, 1H), 5.13 (q, J=9.0 Hz, 4H); ESI/MS 476.92 (M−H), 478.95 (M+H)
Reaction SMILES: [CH2:1]([OH:16])[CH:2]([OH:15])[CH2:3][O:4][CH2:5][CH:6]([OH:14])[CH2:7][O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12].C(O)C(O)COCC(O)CO.[CH:28](=O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>[Pd]>[CH2:28]([O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8][CH2:7][CH:6]([OH:14])[CH2:5][O:4][CH2:3][CH:2]([OH:15])[CH2:1][OH:16])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCC=O
Reactant: OCC(O)COCC(O)COCC(O)CO
Agent: [Pd]
Agent: OCC(O)COCC(O)CO
Product: CCCCCCCCCCOCC(O)COCC(O)COCC(O)CO
Yield: 15 %

Procedure:
The procedure of Example 1 is repeated, except 168.2 g (0.70 mol) of triglycerol from Solvay is used in place of diglycerol, 21.88 g (0.14 mol) of decanal is used in place of nonanal, and 1.1 g of 5% Pd/C is used in place of 1.03 g of 5% Pd/C. After the reaction completion, the product is extracted with diethyl ether (30 mL×7). The solvent is evaporated and a half of the crude product is chromatographed on silica gel using straight ethyl acetate. Appropriate fractions are combined, solvent evaporated to give 8.01 g of the product as a mixture of isomers. 1H NMR (δ, CDCl3, ppm): 0.88 t (3 H, CH3), 1.26 (14 H, (CH2)7), 1.58 t (2 H, CH2), 3.4-4.2 m (21 H, triglycerol moiety+CH2O+OH groups). 13C NMR (δ, CDCl3, ppm): 14.44, 23.02, 26.41, 29.64, 29.80, 29.90, 29.93, 32.20, 29.96, 64.15 (decyl), 69.82, 69.88, 71.04, 71.13, 71.99, 72.01, 72.03, 72.06, 73.24, 73.28, 73.32, 73.36 (triglycerol). GS/MS with TMS derivatization: 668 (MW+four TMS groups).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]([C:12]3[C:13](=[O:19])[NH:14][C:15](=[O:18])[NH:16][CH:17]=3)[C:10]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.I[CH3:26]>>[CH3:26][N:16]1[CH:17]=[C:12]([CH:11]2[C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=[CH:8][C:9]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:10]2=3)[C:13](=[O:19])[NH:14][C:15]1=[O:18]
Reactant: CI
Reactant: Cc1ccc2c(c1)C=Cc1nc(C)oc1C2c1c[nH]c(=O)[nH]c1=O
Product: Cc1ccc2c(c1)C=Cc1nc(C)oc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
The title compound was prepared from the product of example 13 step (vii) (0.66 g) and iodomethane (0.49 ml) according to the method of example 1 step (viii). Purification was by chromatography eluting with 5% methanol in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](S(C)(=O)=O)[N:15]=1.[CH3:28][CH:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1C(=O)CCC1.CO>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:36][C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:28])[N:15]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1
Reactant: CC(N)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: C[C@H](Nc1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1)c1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
To a solution of 2-(2-chlorobenzyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 8, (0.10 g, 0.26 mmol) in NMP (2 mL) is added alpha-methyl benzyl amine (0.10 mL, 0.78 mmol). After stirring 1.5 hours at 90° C., the reaction mixture is diluted with methanol (to 5 mL) and purified by reversed phase liquid chromatography (CH3CN/water/1% TFA) to afford 27 mg (23%) of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=5.1 Hz, 1H), 7.38-7.12 (m, 9H), 6.52 (d, J=5.1 Hz, 1H), 5.06 (q, br, 1H), 4.07-3.95 (m, 4H), 4.02 (s, 2H), 2.58-2.45 (m, 2H), 1.58 (d, J=7.0 Hz, 3H); ESI− MS: m/z (rel intensity) 446.0 (100, M+−H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[F:30][C:31]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:32]=1[C:33](Cl)=[O:34]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:33](=[O:34])[C:32]3[CH:36]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:38]=[CH:39][C:31]=3[F:30])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3cc(C(F)(F)F)ccc3F)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 91, Step 3, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 2-fluoro-5-(trifluoromethyl)benzoyl chloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])[CH3:17]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CNC
Product: COC(=O)c1ccc(CN(C)C)c(OC)c1
Yield: 77 %

Procedure:
The title compound was prepared in 77% yield by essentially following the procedure outlined in Example 37, Part A from methyl 4-bromomethyl-3-methoxybenzoate (see Example 37, Part A) and dimethylamine.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]([CH3:11])=[CH:10][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C=O)C>[CH:20]1([O:1][C:2]2[C:7]3[O:8][C:9]([CH3:11])=[CH:10][C:6]=3[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrC1CCCC1
Reactant: Cc1cc2c(C=O)ccc(O)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(C=O)ccc(OC3CCCC3)c2o1
Temperature: 25 °C
Yield: 101.9 %

Procedure:
To a well stirred suspension of 7-Hydroxy-2-methylbenzo[b]furan-4-carbaldehyde (39.0 g, 0.221 moles) in DMF (200 mL) was added powdered potassium carbonate (76.0 g, 0.555 moles) and cyclopentyl bromide (43.0 g, 0.287 moles) and stirred at 70-75° C. for 4-5 hrs. The reaction mixture was then cooled to room temperature and water (1.5 L) was added to it. The organic material separated was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water ((2×500 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (55.0 g) as light brown viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C)C=O>[CH:22]1([CH2:21][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH:11]([F:12])[F:13])[CH:5]=[O:6])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 104.8 %

Procedure:
To a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (19.55 g, 104 mmol) and potassium carbonate (21.56 g, 156 mmol) in dimethylformamide (150 mL) under an argon atmosphere at 60° C. was added bromomethylcyclopropane (15.13 mL, 156 mmol) and the mixture was stirred and heated at 65° C. After 1.5 h, the mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethylacetate and water and was extracted four times with ethyl acetate. The organic extract was washed twice with water and was dried (sodium sulfate). The solvent was removed in vacuo to provide an oil (26.4 g).
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:4][C:5]1[C:10]([O:11][CH2:2][CH3:3])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CCI
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccnc1Br
Reaction time: 3.25 h

Procedure:
Iodoethane (26 ml) is added to a mixture of 2-bromo-3-pyridinol (Aldrich, 22.75 g), potassium carbonate anhydrous (32.541 g) and DMF (258 ml). The mixture is stirred at 80-85° for 3.25 hr, at which time the mixture is cooled in an ice water bath and potassium carbonate is then filtered off and washed with dichloromethane. The filtrate is concentrated under reduced pressure and the residue is dissolved in ethyl acetate (570 ml) and washed with water (300 ml). The aqueous layer is backwashed with ethyl acetate (500 ml) and each of the organic phases are washed with saline (114 ml). The organic phases are combined, dried with magnesium sulfate and concentrated under reduced pressure. The crude material is chromatographed (silica gel; eluting with ethyl acetate/hexane (20/80) to give 2-bromo-3-ethoxypyridine (XXVIIIa, Chart G), MS (m/z) 201, 203; IR (neat) 1448, 1294, 1389, 1420 and 1205 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[S:47][C:46]([S:48](Cl)(=[O:50])=[O:49])=[CH:45][CH:44]=1.N1C=CC=CC=1C1C=CSC=1S(Cl)(=O)=O>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:48]([C:46]2[S:47][C:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=3)=[CH:44][CH:45]=2)(=[O:49])=[O:50])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Agent: O=S(=O)(Cl)c1sccc1-c1ccccn1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(-c3ccccn3)s2)c1
Reaction time: 72 h
Yield: 33.9 %

Procedure:
To a solution of {3-[(4-thiazol-2-yl-benzylamino)-methyl-]-phenoxy}-acetic acid tert butyl ester (111 mg, 0.270 mmol), prepared in Step A of Example 13i, triethylamine (120 mg, 1.19 mmol) and dichloroethane (10 mL) was added 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (77.2 mg, 0.297 mmol). The reaction was stirred for 72 h and additional 5 pyridin-2-yl-thiophene-2-sulphonyl chloride (38.5 mg) was added. The reaction was stirred for an additional 48 h. The organic solution was washed sequentially with 5.5% HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provided the title compound of Step A (58 mg). MS 633 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([C:21](OC)=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7].[BH4-].[Li+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([CH2:21][OH:22])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13]1)=[O:7]
Reactant: COC(=O)C1(C(=O)NCc2ccccc2Cl)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CO)(C(=O)NCc2ccccc2Cl)CC1
Yield: 84.5 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(2-chlorobenzylcarbamoyl)piperidine-1,4-dicarboxylate (2.8 g, 6.8 mmol) in THF (20 mL) and CH3OH (10 mL) was added lithium borohydride (1.4 g, 68 mmol, 10 equiv.). The reaction mixture was stirred for 3 h and neutralized with HCl (1N). The residue was partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4 and concentrated to purify on RP-HPLC using a mixture of acetonitrile and H2O to give tert-butyl 4-(2-chlorobenzylcarbamoyl)-4-(hydroxymethyl)piperidine-1-carboxylate (2.2 g, 84%). LRMS (M-tBu+H+) m/z 327.0.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39]>CC(N(C)C)=O>[CH:25]([O:24][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][CH2:42][CH2:41][S:38]([CH3:37])(=[O:40])=[O:39])[N:15]=2)=[CH:23][C:20]=1[C:21]#[N:22])([CH3:27])[CH3:26]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: C=CS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NCCS(C)(=O)=O)no2)cc1C#N
Temperature: 80 °C

Procedure:
To a solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (18 mg, 0.05 mmol) in DMA (0.5 mL) was added DIEA (87 μL, 0.5 mmol) and methylvinylsulfone (53 mg, 0.5 mmol). The reaction was heated to 80° C. for 24 h. The crude reaction mixture was purified by preparative HPLC to give (R)-2-isopropoxy-5-(3-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 125. LCMS-ESI (m/z) calculated for C24H26N4O4S: 466.2; found 467.1 [M+H]+, tR=2.58 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.10 (d, J=9.0 Hz, 1H), 4.77 (hept, J=6.1 Hz, 1H), 4.33 (t, J=6.7 Hz, 1H), 3.44 (ddd, J=17.5, 8.7, 4.8 Hz, 1H), 3.36-3.10 (m, 5H), 3.03 (s, 3H), 2.57-2.43 (m, 1H), 1.98-1.83 (m, 1H), 1.46 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.04, 168.94, 162.76, 146.05, 143.49, 134.11, 133.92, 128.24, 127.03, 126.83, 123.28, 116.84, 115.33, 113.58, 103.88, 72.76, 63.05, 55.41, 42.42, 40.86, 32.98, 31.86, 21.75. Compound 126 was made in an analogous fashion.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[C:8]([Mg]Br)#[CH:9].[Cl-].[NH4+]>C1COCC1>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]([OH:7])[C:8]#[CH:9])=[CH:2]1
Reactant: O=Cc1ccoc1
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-furaldehyde (25.0 g, 0.26 mol) in THF (250 mL) at 78° C. was added ethynylmagnesium bromide (572 mL, 0.286, 0.5M THF) at the rate of 10 mL per minute. The mixture was slowly warmed to room temperature, stirred for 1 hour and then poured into a cooled ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was distilled at 50°-55° C. and 0.24 mmHg to afford 1-(3-furyl)-1-hydroxy-2-propyne.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4](=[C:20]([CH3:23])[O:21][N:22]=2)[N:5]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].[I:24]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[C:3]2[C:4](=[C:20]([CH3:23])[O:21][N:22]=2)[N:5]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:24])=[CH:11][C:10]=1[F:15]
Reactant: COC(=O)c1nc2c(C)onc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc2c(C)onc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylisoxazolo[4,3-b]pyridine-5-carboxylate (1.35 g, 4.25 mmol) in DMF (40 ml) is added N-iodosuccinimide (1.43 g, 6.37 mmol) and TFA (2.5 ml). After stirring at room temperature for 4 h, the reaction is quenched with saturated aqueous NH4Cl solution (100 ml) and extracted with EtOAc (2×100 ml). The combined organic solution is washed with brine (100 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the title compound.
Reaction SMILES: Cl.[S:2]1[C:6]2=[CH:7][CH:8]=[CH:9][NH:10][CH:5]2[CH2:4][CH2:3]1.[CH3:11][O:12][C:13](=[O:23])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])Br.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:11][O:12][C:13]([C@@H:14]([N:10]1[CH2:9][C:8]2[CH:7]=[CH:6][S:2][C:3]=2[CH2:4][CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:23]
Reactant: C1=CNC2CCSC2=C1
Reactant: COC(=O)C(Br)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 82.5 °C

Procedure:
50 g (0.284 mole) of Tetrahydrothienopyridine hydrochloride (A) was reacted with 83 g (0.315 mole) of α-bromo-2-chlorophenyl acetic acid methyl ester (B) in 2.5 Lt. DMF in presence of 83 g. (0.6 mole) potassium carbonate. The reaction mixture was heated at 80-85°C under nitrogen atmosphere for 4 Hrs. The reaction mixture was filtered at RT and washed the residue with DMF. The DMF was concentrated under vacuum to obtain a viscous liquid. To this viscous liquid, water was added and the base was extracted from the aqueous layer using methylene dichloride. The methylene dichloride was concentrated under vacuum to get pure Clopidogrel base. Yield =92%
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH:13]=[O:14])=[CH:16][CH:17]=2)[N:3]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: O=Cc1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Yield: 112.5 %

Procedure:
The procedure is carried out as in Example 1, starting with 189 mg of 2,6-dichloropurine, 5 ml of butanol and 149 mg of 4-aminoacetophenone. 308 mg of the expected product are thus obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][C@H:16]3[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[C:31]([F:37])=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>O1CCOCC1.C(#N)C>[ClH:2].[ClH:29].[Cl:29][C:30]1[C:31]([F:37])=[C:32]([NH:33][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][C@H:16]4[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COc1cc2c(Cl)ncnc2cc1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O[C@H]1CCCNC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4.0M HCl in dioxane (6.0 ml) was added to a stirred suspension of tert-butyl (3S)-3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate (3.21 g) and 3-chloro-2-fluoroaniline (0.98 ml) in acetonitrile (50 mL). The reaction mixture was heated at 80° C. and left at this temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography eluting with increasingly polar mixtures of methylene chloride/7N ammonia solution in methanol (97/3 to 95/5) to give N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride as a solid (3.20 g); 1H NMR Spectrum: (DMSO d6) 1.56 (m, 2H), 1.72 (m, 1H), 2.12 (m, 1H), 2.48-2.59 (m, 2H), 2.82 (m,1H), 3.20 (m, 1H), 3.95 (s, 3H), 4.49 (m, 1H), 7.26 (s, 1H), 7.28 (m, 1H), 7.47 (m, 1H), 7.53 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.63(s, 1H); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]=[CH:14][C:13]=2Cl)[O:9][N:8]=1.B1([C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[C:13]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:14][N:15]=[CH:16][C:17]=2[O:18][CH3:19])[O:9][N:8]=1
Reactant: COc1cncc(Cl)c1-c1nc(-c2ccccn2)no1
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1cncc(-c2cccnc2)c1-c1nc(-c2ccccn2)no1
Yield: 4.1 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-chloro-5-methoxy-pyrid-4-yl)-1,2,4-oxadiazole (75 mg, 0.260 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (75 mg, 0.46 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 30 mg, 0.026 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using 40% ethyl acetate in hexane and 100% ethyl acetate afforded 3.5 mg (4.1%) 3-(2-pyridyl)-5-[3-methoxy-5-(3-pyridyl)-pyrid-4-yl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 9.39 (s, 1H), 8.91 (d, 1H), 8.72 (d, 1H), 8.42 (d, 1H), 8.25 (d, 1H), 8.20 (s, 1H), 7.92 (dt, 1H), 7.63 (dd, 1H), 7.50 (m, 2H), 4.12 (s, 3H).