Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26](=[O:35])[C@@H:27]([CH2:29][O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH2:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1>CO>[C:44]1([CH3:54])[CH:45]=[CH:46][C:47]([S:50]([OH:53])(=[O:51])=[O:52])=[CH:48][CH:49]=1.[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([CH2:36][CH:37]([CH3:38])[CH3:39])[C:26](=[O:35])[C@@H:27]([CH2:29][O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[NH2:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@H](N)COC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@H](N)COC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.3 %

Procedure:
A solution of 0.38 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-(O-tert.butyl-D-seryl)-4-methylvalerohydrazide in 5 ml of methanol was treated with 0.144 g of p-toluenesulphonic acid. The mixture was stirred for 3.5 hours at room temperature and evaporated to give a solid. This was triturated with diethyl ether, filtered off and dried to give 0.38 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-2′-(O-tert.butyl-D-seryl)-4-methylvalerohydrazide p-toluenesulphonate in the form of a white solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22]([OH:24])=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:37][N:38]1CCOC[CH2:39]1.C(OC(Cl)=O)C(C)C.CNC>ClCCl.C1COCC1>[CH3:37][N:38]([CH3:39])[C:22](=[O:24])[CH2:21][CH2:20][C@H:19]([C@@H:18]1[C@:26]2([CH3:34])[C:15]([C:14]3[CH2:13][CH2:12][C@@H:11]4[C@:30]([C:29]=3[CH2:28][CH2:27]2)([CH3:33])[CH2:31][CH2:32][C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[C:10]4([CH3:36])[CH3:35])=[CH:16][CH2:17]1)[CH3:25]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](CCC(=O)N(C)C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Temperature: -15 °C
Reaction time: 8 h

Procedure:
3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (0.30 g) is dissolved in 10 ml of dry dichloromethane. After cooling to −15° C., 0.07 ml of N-methylmorpholine and 0.084 ml of isobutylchloroformate is added and the mixture is stirred at −15° C. for 20 minutes, whereupon 1.74 ml of a 2.0 M solution of N,N-dimethylamine in THF) is added. The mixture is stirred overnight and the temperature is slowly elevated to room temperature. After aqueous work-up and crystallization from methanol, 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid-N,N-dimethyl amide (0,231 g) is obtained. M.p. 143-145° C. 1H-NMR (CDCl3, 400 MHz)): δ=5.35 (1H, s); 3.20 (1H, m); 3.03 (3H, s); 2.95 (3H, s); 0.90 (9H, s); 0.05 (6H, m).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:7][O:6]1)[CH2:2][CH:3]=[CH2:4].[CH2:8]([O:11][CH2:12]C)[CH:9]=C>>[CH2:8]([O:11][CH2:12][CH:4]=[CH:3][CH2:2][CH2:1][CH:5]1[CH2:7][O:6]1)[CH3:9]
Reactant: C=CCCC1CO1
Reactant: C=CCOCC
Product: CCOCC=CCCC1CO1

Procedure:
The cross metathesis of (±)-2-(but-3-enyl)oxirane (3.80 g, 38.7 mmol) with ethyl allyl ether (10.0 g, 116 mmol) was performed as described previously in Example 9.2, Step A to give (±)-2-(5-ethoxypent-3-enyl)oxirane as an inseparable mixture of olefin isomers (trans:cis=10:1) after silica gel chromatography. 1H NMR (400 MHz, CDCl3): trans isomer: δ 5.73 (1H, m), 5.63 (1H, m), 3.91 (2H, m), 3.48 (2H, q, J=7.0 Hz), 2.93 (1H, m), 2.75 (1H, dd, J=5.0, 2.7 Hz), 2.22 (2H, m), 1.63 (2H, m), 1.21 (3H, t, J=7.0 Hz). cis isomer: δ 5.62 (2H, m), 4.04 (2H, m), 3.48 (2H, q, J=7.0 Hz), 2.93 (1H, m), 2.75 (1H, m), 2.49 (1H, m), 2.22 (2H, m), 1.63 (2H, m), 1.22 (3H, t, J=7.0 Hz).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH3:4].[C:6]([OH:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1>C1(C)C=CC=CC=1>[C:6]([O:14][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1
Reactant: CCCCO
Reactant: O=C(O)c1cccnc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1cccnc1
Temperature: 116 °C
Reaction time: 6 h

Procedure:
n-Butanol (177.6 g, 2.4 mol), nicotinic Acid (98.4 g, 0.8 mol) and toluene (45.0 g) were charged to a 450 ml pressure reactor kettle and equipped with mechanical stir, a pressure take-out trap, and a thermocouple. The reactor was sparged with nitrogen and heated to 116° C., sealed, then heated to 200° C. and held for 6 hours. The mixture was then removed from the reaction kettle and volatiles removed under vacuum on a rotary evaporator at 60° C. The product was then purified by combining it with 50.0 g toluene and 60.1 g 4.4% NaOH solution in a 500 mL separatory funnel. The organic layer was then separated, dried over 5 g MgSO4 and solvents removed under vacuum on a rotary evaporator at 60° C. to yield the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:9][CH2:8]1.[N:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[N:15]([C:28]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1
Reactant: O=C(Cl)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCCC1)n1c(CN2CCN(c3ccccn3)CC2)nc2ccccc21
Temperature: 25 °C
Yield: 46.6 %

Procedure:
To a stirred solution of Example 1A (0.66 g, 2.2 mmol) in dichloromethane (7 mL) was added 1-pyrrolidinecarbonyl chloride (0.28 mL, 2.2 mmol) and triethylamine (0.625 mL, 4.5 mmol). The mixture was heated in a sealed vial for 17 hours, allowed to cool to room temperature, diluted dichloromethane, washed with 5% NaHCO3, dried and concentrated under reduced pressure. The residue was purified by flash column on SiO2 eluting with 20% hexanes/ethyl acetate to give 0.4 g (40%)of the title compound. mp 120-121° C. 1H NMR (CDCl3, 300 MHz) δ 1.79-2.10 (m, 4H), 2.70 (m, 4H), 3.13 (m, 1H), 3.35-3.78 (bm, 8H), 4.32 (m, 1H), 6.65 (m, 2H), 7.30 (m, 3H), 7.49 (m, 1H), 7.76 (m, 1H), 8.28 (m, 1H). MS (DCI/NH3) m/z 391 (M+H)+. Anal. Calcd for C22H26N6O.½H2O: C, 66.14; H, 6.81; N, 21.04. Found: C, 66.22; H, 6.68; N, 21.11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21](C(F)(F)F)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:31][CH3:32])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O[Li].O>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:31][CH3:32])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(c1ccc(Nc2cc(CC)nc(-c3cccc(Cl)c3)n2)cc1)C(F)(F)F
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1ccc(Nc2cc(CC)nc(-c3cccc(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.8 %

Procedure:
To a solution of ethyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-3,3,3-trifluoropropanoate (0.130 g, 0.28 mmol) in dioxane (11 mL) and water (7 mL) was added LiOH.H2O (0.035 g, 0.84 mmol) and the mixture was stirred at rt for 12 h. After this time, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.053 g, 53%) as a white solid. MW=395.88. 1H NMR (DMSO-d6, 500 MHz) δ 9.60 (s, 1H), 8.34-8.27 (m, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.59-7.52 (m, 2H), 7.27 (d, J=8.5 Hz, 2H), 6.60 (s, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); APCI MS m/z 396 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH:11]([CH2:13][CH2:14][OH:15])[CH2:10][O:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:49][C:50]([Cl:63])=[CH:51][CH2:52][O:53][C:54]1[CH:59]=[C:58]([Cl:60])[C:57](O)=[C:56]([Cl:62])[CH:55]=1>O1CCCC1>[Cl:60][C:58]1[CH:59]=[C:54]([O:53][CH2:52][CH:51]=[C:50]([Cl:63])[Cl:49])[CH:55]=[C:56]([Cl:62])[C:57]=1[O:15][CH2:14][CH2:13][CH:11]1[CH2:10][O:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[O:12]1
Reactant: OCCC1COC(c2ccc(Cl)cc2)O1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCC2COC(c3ccc(Cl)cc3)O2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
To a mixture of 0.4 g of 2-[2-(4-chlorophenyl)-1,3-dioxolan-4-yl]ethanol, 0.46 g of triphenylphosphine and 6 ml of tetrahydrofuran was added dropwise 0.35 ml of diisopropyl azodicarboxylate, while stirring at room temperature. After further stirring for 15 minutes, a solution of 0.5 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol in 2 ml of tetrahydrofuran was added. After stirring continued at room temperature for 3 hours, the reaction mixture was concentrated, and the residue was subjected to silica gel chromatography, which afforded 0.3 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-[2-[2-(4-chlorophenyl)-1,3-dioxolan-4-yl]ethoxy]benzene (35% yield), m.p. 84.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:32][O:33][C:34]([C:36]1([NH2:45])[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35].C(Cl)CCl>CN(C=O)C>[CH3:32][O:33][C:34]([C:36]1([NH:45][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([O:11][CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH:4]=2)[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(CCOc2cc(C(=O)O)ccc2Br)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(Br)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Reaction time: 8 h
Yield: 90.3 %

Procedure:
The compound of step 2 (0.410 g, 1.22 mmol) was dissolved in DMF (5 ml), EDIA (0.790 g, 6.12 mmol), HOBT (33 mg, 0.244 mmol), and 2-amino-indane-2-carboxylic acid methyl ester hydrochloride (0.246 g, 1.47 mmol) were added, the mixture was cooled in an ice bath and EDC (352 mg, 1.84 mmol) was added. The mixture was stirred overnight. The volatiles were evaporated in vacuo, the mixture was partitioned between 2 N hydrochloric acid and EA, the organic phase was dried over magnesium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to give 0.56 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>CN(C1C=CN=CC=1)C.O1CCOCC1>[C:15]([O:14][C:12]([N:4]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:10]2[C:2]([Br:1])=[CH:3]1)=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Brc1c[nH]c2cnccc12
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(Br)c2ccncc21
Yield: 74.8 %

Procedure:
A mixture of Example 695J (0.32 g, 1.62 mmol), (BOC)2O (0.43 g, 1.94 mmol) and DMAP (50 mg) in 10 mL of dioxane was stirred overnight at room temperature. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 7:3 hexanes/ethyl acetate to provide 0.36 g (75%) of the desired product. MS (APCI) m/e 298 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 9.29 (s, 1H), 8.28 (d, J=5.09 Hz, 1H), 8.16 (s, 1H), 7.55 (d, J=5.43 Hz, 1H), 1.65 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)Cl>[CH2:30]([O:29][C:27]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][O:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6]1)=[O:28])[CH3:31]
Reactant: COC(=O)c1cccc(OCC2CCNCC2)n1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(COc2cccc(C(=O)OC)n2)CC1
Temperature: 25 °C

Procedure:
To a mixture of methyl 6-(piperidin-4-ylmethoxy)picolinate (0.3 g, 1.2 mmol), Et3N (0.2 g, 1.8 mmol) in DCM (10 ml) was added ethyl chloroformate (0.2 g, 1.8 mmol) at 0° C. The reaction was warmed to room temperature, washed with 1N HCl (20 ml), dried over Na2SO4 and concentrated under reduced pressure to give methyl 6-((1-(ethoxycarbonyl)piperidin-4-yl)methoxy)picolinate which used in the next step without further purification. Yield (0.38 g, quant.).
Reaction SMILES: I[C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][N:20]=2)[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[N:20]=[CH:21][C:22]([C:2]3[CH:11]=[N:10][C:5]4[NH:6][CH2:7][CH2:8][NH:9][C:4]=4[CH:3]=3)=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: Ic1cnc2c(c1)NCCN2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)NCCN4)cn2)CC1
Yield: 20 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (704 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a yellow solid (20% yield). M.p. 225° C. (dec), LCMS: m/z=311.13 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.35 (s, 3H), 2.49-2.56 (m, 4H), 3.36-3.42 (m, 2H), 3.53-3.63 (m, 6H), 4.90 (bs, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.77 (d, J=1.5 Hz, 1H), 7.58 (dd, J=8.8 Hz, 2.3 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)(=[O:9])=[O:8])[C:5]#[N:6].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Cl:33])[C:24]=1[NH:34][NH2:35].O>C(O)C>[NH2:6][C:5]1[N:34]([C:24]2[C:23]([Cl:22])=[CH:28][C:27]([C:29]([F:30])([F:32])[F:31])=[CH:26][C:25]=2[Cl:33])[N:35]=[C:3]([S:2][CH3:1])[C:4]=1[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=1)(=[O:9])=[O:8]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CSC(SC)=C(C#N)S(=O)(=O)c1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A suspension of 0.50 g (1.42 mmol) of 3,3-bis-methylthio-2-(3-trifluoromethylphenylsulfonyl)acrylonitrile and 0.35 g (1.42 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 10 mL of ethanol was heated at reflux for 2.5 hours, solution occurring as the reaction mixture was warmed. The mixture was stirred overnight at room temperature and was then poured into cold water. The product was extracted into ethyl acetate and the extracts were dried with magnesium sulfate and evaporated. The residues were crystallized from ether, and the product was filtered off and air dried to give 314 mg (40%) of the desired product, m.p. 201°-203° C. Anal. Calcd. for C18H11O2N3S2Cl2F6 : C, 39.28; H, 2.02; N, 7.64. Found: C, 39.35; H, 2.19; N, 7.48.
Reaction SMILES: [C:1]([C:4]([C:21]([O:23][CH3:24])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11](OC)[O:12]C)[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([C:4]([C:21]([O:23][CH3:24])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11]=[O:12])[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: CCC#CCC(C(C)=O)(C(=O)OC)C(CC(=O)OC)C(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Product: CCC#CCC(C(C)=O)(C(=O)OC)C(C=O)CC(=O)OC
Reaction time: 12 h

Procedure:
Methyl 4-acetyl-4-methoxycarbonyl-3-dimethoxymethyl-6-nonynoate (530 mg) is dissolved in 20 ml of tetrahydrofuran, and 25 ml of 1% aqueous solution of perchloric acid is added to the solution. The mixture is stirred at 26° to 28° C. for 12 hours. Subsequently the reaction mixture is neutralized with sodium bicarbonate and concentrated in a vacuum. The residue is extracted with ethyl acetate. The extract is dried and then concentrated to give methyl 4-acetyl-4-methoxycarbonyl-3-formyl-6-nonynoate (compound (7), R1 =R2 =CH3) in a yield of 98.3%.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8][OH:9])(=[O:3])[CH3:2].O>CN(C)C=O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH:8]=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCC=C(C)C=O
Yield: 91.2 %

Procedure:
To a solution of 4-acetoxy-2-methyl-2-buten-1-ol (6.69 g, 46.4 mmol) in dimethylformamide (40 ml) were added 2,2,6,6-tetramethyl-piperidine-1-oxy (0.39 g, 2.32 mmol, 5 mol %) and cuprous chloride (0.48 g, 4.64 mmol, 10 mol %). The mixture was subjected to reaction at 40° C. for 8 hours while bubbling oxygen at a rate of about 100 ml/min. After completion of the reaction, the reaction mixture was poured into ice-cooled water (30 ml) and extracted with ether (100 ml) three times. The extract was dried over anhydrous magnesium sulfate. Evaporation of the ether followed by purification by column chromatography (ethyl acetate-hexane (=1:3)) gave 4-acetoxy-2-methyl-2-buten-1-al (6.02 g, 42.3 mmol; Yield: 91.2%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][OH:9].[H-].[Na+].[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>CN(C=O)C>[CH3:19][C:18]1[CH:20]=[CH:21][C:15]([S:12]([O:9][CH2:8][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[CH3:1])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCCCC1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCC2CCCCN2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a mixture of (1-methylpiperidin-2-yl)methanol (1.00 g, 7.75 mmol) in dry DMF (5.0 mL) at 0° C. was added NaH (620 mg, 15.5 mmol, 60% in mineral oil). After being stirred for 1 h, TsCl (2.96 g, 15.5 mmol) in DMF (1.0 mL) was added. The resulting mixture was further stirred at room temperature for 10 h and then poured into the ice-water (20 mL). The resulting mixture was extracted with EtOAc (2×50 mL). The organic layers were dried over Na2SO4 and evaporated to dryness to afford the crude product, which was purified by silica gel chromatography eluting with a 20% gradient of EtOAc in petroleum ether to afford (1-methylpiperidin-2-yl)methyl 4-methylbenzenesulfonate (800 mg, 36.5% yield). LCMS (ESI) m/z: 284.2 [M+H+]
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>[Pd]>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncnc1
Reactant: Cc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1-c1cncnc1
Yield: 98.9 %

Procedure:
A suspension of 5-bromopyrimidine(1.52 g),2-methylphenylboronic acid (1.43 g), sodium carbonate (3.04 g) and 10% palladium on charcoal (50% wet, 0.85 g) was refluxed for 24 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue ethyl acetate was added and the mixture was washed with water and brine. The separated organic layer was dried over magnesium sulfate and evaporated under pressure to give 5-(2-methylphenyl)pyrimidine (1.61 g, 98.7%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:7]=1[F:31])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:38]>ClCCCl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([N:13]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=2[O-:38])[C:7]=1[F:31])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)cnc(N(CC(F)(F)c2ccccn2)C(=O)OC(C)(C)C)c1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)Cc1c(Cl)cnc(N(CC(F)(F)c2cccc[n+]2[O-])C(=O)OC(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.8 g (1.7 mmol) ethyl(2-{(tert-butoxycarbonyl)[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-5-chloro-3-fluoro-4-pyridinyl)acetate 1-6 in 3 mL 1,2-dichloroethane was added 0.44 g (1.8 mmol, 70% by weight) m-chloroperoxybenzoic acid. The reaction mixture was stirred at room temperature 16 h, heated to 60° C. 2 h, cooled, diluted with 300 mL EtOAc, washed with 200 mL 0.1M NaOH, and 200 mL brine. Dried over Na2SO4, filtered, and concentrated. Purification by automated flash chromatography (40 g silica cartridge, linear gradient 1-10% MeOH/CH2Cl2 over 25 min, 40 mL/min flow rate) followed by repurification of the mixed fractions by traditional silica gel chromatography (2×15 cm silica gel, linear gradient 2-5% MeOH/CH2Cl2) afforded ethyl(2-{(tert-butoxycarbonyl)[2,2-difluoro-2-(1-oxido-2-pyridinyl)ethyl]amino}-5-chloro-3-fluoro-4-pyridinyl)acetate 1-7. 1H NMR (400 mHz, CDCl3) δ8.20 (s, 1H); 8.18 (br d, 1H, J=5 Hz); 7.57 (br dd, 1H, J=7.7 and 2 Hz); 7.31 (br m, 2H); 5.0 (br m, 2H); 4.19 (q, 2H, J=7.14 Hz); 3.82 (s, 2H); 1.28 (s, 9H); 1.25 (t, 3H, J=7.14 Hz). Mass spectrum (electrospray) M+H=490.1
Reaction SMILES: [CH:1]1([N:4]([CH3:24])[C:5]2[C:6]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=4[S:17][C:7]=3[N:8]=[C:9]([CH2:11][C:12]([O:14]CC)=[O:13])[N:10]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([N:4]([CH3:24])[C:5]2[C:6]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=4[S:17][C:7]=3[N:8]=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[N:10]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1nc(CC(=O)O)nc2sc3c(c12)CCCC3)C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate (1.0 gm, 0.00289 mol) in THF (9 ml) and water (1 ml) was added lithium hydroxide hydrate (0.24 gm, 0.00578 mol). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was diluted with water. The aqueous layer was made acidic to pH 1 with 2N HCl and then extracted with ethyl acetate (25 ml×3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to get crude compound. It was purified by column chromatography by using 100-200 mesh silica gel and 2% MeOH: DCM as eluent to get 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetic acid as an off white solid. Yield: (0.4 gm, 43.57%); 1H-NMR: (400 MHz, DMSO-d6); δ=12.46 (s, 1H), 3.70 (s, 2H), 2.99 (s, 3H), 2.96-2.91 (m, 1H), 2.90-2.87 (m, 2H), 2.83-2.80 (m, 2H), 1.88-1.84 (m, 2H), 1.71-1.66 (m, 2H), 0.78-0.65 (m, 2H), 0.43-0.31 (m, 2H); LC-MS [M+H]=317.9; HPLC purity=99.72%.