Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[N:7]=[C:6]([C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: O=[N+]([O-])c1ccc(F)c(-c2ccnc(Cl)n2)c1

Procedure:
2,4-Dichloropyrimidine (2.0 g, 13 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.9 g, 15 mmol) using the method in Example 14 part a). Purification by chromatography on silica gel eluting with dichloromethane containing 20% isohexane gave 2-chloro-4-(2-fluoro-5-nitro-phenyl)pyrimidine as a white solid: δH (400 MHz, CDCl3) 7.40 (1H, dd, J 10 and 9), 7.85 (1H, dd, J 5 and 2), 8.38-8.43 (1H, m), 8.77 (1H, d, J 6), 9.16 (1H, q, J 3).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[CH:15]=3)[CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1.Cl.[NH+]1C=CC=CC=1>>[F:22][C:16]1[CH:15]=[C:14]([C:7]2[CH:8]=[C:9]([C:12]#[N:13])[C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([OH:1])[CH:11]=3)[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: COc1ccc(-c2cc(C#N)c3cc(O)ccc3c2)cc1F
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1cc(-c2ccc(O)c(F)c2)cc2ccc(O)cc12

Procedure:
The title compound was prepared by reacting 7-hydroxy-3-(3-fluoro-4-methoxyphenyl)-1-naphthonitrile (0.12 g, 0.41 mmol) with pyridinium HCl (3 g) according to method B to yield 0.085 g (74%) of a white solid: mp 265–269 ° C.; 1H NMR (DMSO-d6): δ 7.04–7.09 (1H, m), 7.26 (1H, dd, J=2.31 Hz, J=8.88 Hz), 7.36 (1H, d, J=2.19 Hz), 6.52 (1H, d, J=2.19 Hz), 6.52 (1H, dd, J=1.76 Hz, J=8.40 Hz), 6.71 (1H, dd, J=2.22 Hz, J=12.88 Hz), 8.01 (1H, d, J=8.97 Hz), 8.37 (1H, d, J=1.83 Hz), 8.45 (1H, d, J=1.41 Hz), 10.33 (2H, bs); MS (ESI) m/z 278 (M−H)−.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([CH:30]([CH3:32])[CH3:31])=[C:27]([SH:29])[CH:28]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:29][C:27]1[CH:28]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]=1[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1ccc(C(C)C)c(S)c1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccc(C(C)C)c(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.1 mmol of 5-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 183°-184° C.). 1H NMR (DMSO-d6) δ1.15 (d, 6H), 1.85 (s, 3H), 3.22 (m, 1H), 3.80 (bs, 2H), 5.88 (bs, 1H), 6.77 (d, 1H), 7.03 (d, 1H), 7.32-7.47 (m, 10H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8](=O)[N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]2[C:5](=O)[NH:4]1.B.C1COCC1.Cl>CO>[CH2:5]1[NH:4][C@@H:3]([CH2:2][OH:1])[CH2:8][N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]12
Reactant: O=C1NC(CO)C(=O)N2CCNCC12
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: OC[C@H]1CN2CCNCC2CN1
Temperature: 80 °C

Procedure:
To a flask containing (3S,9aS or 9aR)-3-(hydroxymethyl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione and (3S,9aR or 9aS)-3-(hydroxymethyl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (D83, Diastereoisomer 1 plus D84, Diastereoisomer 2, 976 mg, 4.9 mmol) was added 1M BH3-THF solution (49 mL) under nitrogen and the reaction was brought to reflux (80° C.) overnight. The reaction flask was cooled to 0° C. and treated with 25 mL of MeOH. Conc. HCl was added and the resulting solution was heated to 60° C. for 5 h. The reaction was checked by direct MS (m/z=184 (M+BH3)). The reaction mixture was purified by SCX, obtaining 528 mg of product.
Reaction SMILES: [CH2:1]([NH:3][CH2:4]C)C.[F:6][C:7]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:8]=1[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14]Br>O1CCCC1.C(Cl)Cl>[CH3:1][N:3]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][CH2:9][C:8]1[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:7]=1[F:6])[CH3:4]
Reactant: Fc1ccc(Br)cc1COCCCCBr
Reactant: CCNCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethylamine (17.6 ml, 35.3 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (1.2 g, 3.53 mmol) in tetrahydrofuran (18 ml). The resulting mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:41]=2)[CH:36]=[C:35]1[C:48]([O:50][CH2:51][CH3:52])=[O:49].[C:53]([O:57][C:58]([NH:60][CH2:61][C:62]1([CH2:75]O)[CH2:67][CH2:66][N:65]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:64][CH2:63]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>C1COCC1>[C:71]([O:70][C:68]([N:65]1[CH2:66][CH2:67][C:62]([CH2:75][N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:41]=3)[CH:36]=[C:35]2[C:48]([O:50][CH2:51][CH3:52])=[O:49])([CH2:61][NH:60][C:58]([O:57][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:59])[CH2:63][CH2:64]1)=[O:69])([CH3:73])([CH3:74])[CH3:72]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: CC(C)(C)OC(=O)NCC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CNC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
A solution of triphenylphosphine (19.4 g, 74.1 mmol) and DIAD (14.05 mL, 74.1 mmol) in THF (700 mL) is cooled to 0° C. and stirred for 10 min. Diethyl 1H-indole-2,6-dicarboxylate (15.47 g, 59.3 mmol) is added and reaction mixture is stirred for another 10 min. tert-Butyl 4-{[(tert-butoxycarbonyl)amino]methyl}-4-(hydroxymethyl)piperidine-1-carboxylate (17 g, 49.4 mmol) is added and the reaction mixture is stirred for 48 h at room temperature. The mixture is partitioned between water and ethyl acetate. and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (2×200 mL). The combined organic layers are dried (Na2SO4), and concentrated. The residue is purified by flash column chromatography using 15% EtOAc in petroleum ether to afford the title compound (17 g, 32%) as a dark brown oil.
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:28]=[C:29]2[S:33][C:32](SC)=[N:31][C:30]2=[O:36])[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:16])[CH3:15]>C(O)C>[CH3:16][C:14]([C:17]1[CH:18]=[C:19]([CH:28]=[C:29]2[S:33][C:32]([N:5]([OH:6])[CH:2]([CH3:4])[CH3:3])=[N:31][C:30]2=[O:36])[CH:20]=[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:22]=1[OH:23])([CH3:13])[CH3:15]
Reactant: CC(C)NO
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(C)N(O)C1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A mixture of N-isopropylhydroxylamine hydrochloride (5.5 g, 0.049 mole), potassium-t-butoxide (4.83 g, 0.043 mole), and ethanol (500 mL) is stirred at room temperature for 15 minutes. 5-[(3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene]-2-(methylthio)-4(5H)-thiazolone (7.27 g, 0.02 mole) is then added and the mixture is refluxed with stirring for six hours. After removal of the solvent under reduced pressure, the cooled reaction mixture is poured into a mixture of ice-water containing 1N hydrochloric acid and extracted with ether. The organic layer is washed with water, dried, and the solvent is evaporated to give 7.7 g of a residue. The residue is flash chromatographed on silica gel (202 g), eluting first with methylene chloride and then with methylene chloride-methanol (9:1) to give 7.0 g purified product. It is recrystallized from methylene chloride-ethyl acetate-ether to give 4.2 g (54%) of pure 5-[[3,5-Bis-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2[hydroxy(1-methylethyl)amino]-4(5H)-thiazolidinone, (Z)-, mp 208° C. (dec).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:22][CH3:23])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([OH:26])=O.C(Cl)CCl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:22]([CH3:23])[CH:24]=[O:26])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Reactant: O=CO
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CN(C=O)c1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To 7-(benzyloxy)-N-methyl-9H-carbazol-2-amine (120 mg, 0.4 mmol), formic acid (55 mg, 1.2 mmol) and DMAP (5 mg, 0.04 mmol) in 3 mL of pyridine was added portionwise EDC (230 mg, 1.2 mmol). The mixture was stirred at rt for 3 h under Ar atmosphere and concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with water (2×50 mL), 0.5 M HCl (2×50 mL), and brine (50 mL), and dried over MgSO4. After solvent removal, the crude product was purified with chromatography (hexane/EtOAc) to afford N-(7-(benzyloxy)-9H-carbazol-2-yl)-N-methylformamide as a white solid (110 mg, 83%). 1H NMR (400 MHz, acetone-d6) δ 10.34 (s, 1H), 8.49 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.51 (d, J=7.2 Hz, 2H), 7.39 (m, 2H), 7.34-7.28 (m, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.08 (dd, J=8.4, 2.4 Hz, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 5.19 (s, 2H), 3.31 (s, 3H); MS (ESI) m/z 331 (M+H+).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br[CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1>C(Cl)Cl.C([O-])(=O)C.[Ag+]>[C:1]([O:4][CH2:6][C:7]1([CH3:33])[CH:11]([C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:18])[Cl:19])=[O:13])[N:10]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:9]2[S:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(=O)OCC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
Acetic acid (2 ml) was added to a solution of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) in methylene chloride (10 ml). And to this solution was added silver acetate (0.34 g) under stirring at room temperature and then the mixture was stirred for 2.5 hours. After the reaction was completed, the reaction mixture was filtered under reduced pressure and the filtrate was washed with 5% hydrochloric acid and then filtered again. The oily residue was crystallized by treating with ether and the crystals were collected by filtration and then dried to give colorless needles of 2,2,2-trichloroethyl 2-acetoxymethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.21 g), mp 116° to 118° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cc2ncnc(Cl)c2cc1F
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(F)c(F)cc34)c2)no1
Yield: 37 %

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (87 mg, 0.3 mmol) and 4-chloro-6,7-difluoroquinazoline (60 mg, 0.3 mmol) from Example 4A Step 2 as described in Example 46 to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-difluoroquinazolin-4-ylthio)phenyl)urea (50 mg, 0.11 mmol, 37%). 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.05 (s, 1H), 8.88 (s, 1H), 8.34 (dd; 1H), 8.09 (dd, 1H), 7.88 (s, 1H), 7.53 (d, 1H), 7.47 (t, 1H), 7.30 (d, 1H), 6.49 (s, 1H), 1.28 (s, 9H); LC-MS (ESI) m/z 478 (M+Na)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].Br[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].O>O1CCCC1>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCCBr
Reactant: COCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCOCCCCCCCOC
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.2 %

Procedure:
Sodium hydride (665 mg, 17 mmol, washed three times with hexane) was treated with the title product of Example 3 (2.0 g, 14 mmol) in 90 mL of tetrahydrofuran at reflux for one hour. A solution of 5-bromopentene (2.0 g, 14 mmol) in 50 mL of tetrahydrofuran was added dropwise and refluxing continued for 20 hours. After cooling to room temperature, 50 mL of water was added, the layers separated and-the aqueous phase was extracted with two portions of ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Chromatography of the crude residue on silica gel using 50-50 ethyl acetate-heptane as eluant gave the title compound (485 mg) as a yellow oil and the structure verified by NMR.
Reaction SMILES: [O:1]=[C:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3]P(OC)(=O)OC.[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1>C(COC)OC>[CH2:12]([O:11][CH2:10][C:2](=[O:1])/[CH:3]=[CH:27]/[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:18]2[NH:19][CH:20]=[CH:21][N:17]=2)=[CH:30][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCOCC(=O)CP(=O)(OC)OC
Reactant: O=Cc1ccc(Cc2ncc[nH]2)cc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCOCC(=O)/C=C/c1ccc(Cc2ncc[nH]2)cc1

Procedure:
2 g (7.93 mmol) of dimethyl 2-oxo-3-pentyloxypropanephosphonate, 1.7 g (9.13 mmol) of 4-(1-imidazolylmethyl)benzaldehyde and 1.33 g (8.74 mmol) of DBU were stirred in 150 ml of dimethoxyethane at room temperature for 31 h. The mixture was filtered through silica gel and the solvent was removed from the filtrate in vacuo. Chromatography on silica gel (chloroform/methanol/25% aqueous NH3 =20/1/0.2) produced 1.5 g (4.80 mmol, 60%) as a yellowish oil which solidified in the refrigerator, melting point 35°-36° C.
Reaction SMILES: [S:1]1[C:5]2=[N:6][C:7]([C:14]([O:16]C)=[O:15])=[C:8]([C:10]([O:12]C)=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[K+].O>CO>[S:1]1[C:5]2=[N:6][C:7]([C:14]([OH:16])=[O:15])=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cc2ccsc2nc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2ccsc2nc1C(=O)O

Procedure:
A solution containing dimethyl thieno[2,3-b]pyridine-5,6-dicarboxylate (27.75 g, 0.11 mol) and potassium hydroxide (30.98 g, 0.55 mol) in methanol (200 mL) under a N2 atmosphere is heated at reflux for two hours. The reaction mixture is cooled and sufficient water added to dissolve any solids present before evaporating the mixture to dryness. The resulting solid is dissolved in a minimum volume of water, cooled in an ice bath and acidified with concentrated H2SO4 to pH~1. Thieno[2,3-b]pyridine-5,6-dicarboxylic acid is filtered off and dried overnight to give 23.36 g mp 272°-275° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39]([NH:42][C@@H:43]([CH3:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:40]=[CH2:41]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[N:42]([CH2:39][CH:40]=[CH2:41])[C@H:43]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:50])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: C=CCN[C@@H](C)c1ccccc1
Product: C=CCN(C(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1)[C@@H](C)c1ccccc1
Yield: 36 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (S)-N-allyl-α-methylbenzylamine: yield 36%.
Reaction SMILES: BrC1C[C:5](=O)[C:4]([CH2:8]CCCCCC(OCC)=O)=[CH:3]1.[OH:19][CH:20]1[CH2:24][C:23](=[O:25])[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:21]1>C(=O)([O-])[O-].[Ag+2].C(O)(C)(C)C>[C:4]([O:19][CH:20]1[CH2:24][C:23](=[O:25])[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:21]1)([CH3:8])([CH3:5])[CH3:3]
Reactant: CCOC(=O)CCCCCCC1=CC(Br)CC1=O
Reactant: CCOC(=O)CCCCCCC1=CC(O)CC1=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)(C)O
Product: CCOC(=O)CCCCCCC1=CC(OC(C)(C)C)CC1=O

Procedure:
A stirred mixture of 6.35 g. (20 mmoles) of 4-bromo-2-(carbethoxyhexyl)cyclopent-2-en-1-one (Example 94), 3.01 g. (11 moles) of silver carbonate, and 40 ml. of t-butanol is heated at 70° C. for 17 hours. The mixture is cooled and filtered. After evaporation of t-butanol the residue is treated with aq. sodium chloride and extracted with 3:1 ether-hexane. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by chromatography on silica gel to give, in order of elution: the subject compound as an oil; λ maxMeOH. = 219 mμ (8860); ν max. = 1735 (ester carbonyl group), 1725 ketone carbonyl group), and 1365 cm-1 (tert.-butyl group); and 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one also as an oil.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:22][CH:21]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 4-methylaniline as the starting materials.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[C:34]([O-:37])(=[O:36])[CH3:35].[K+]>CN(C)C=O>[CH2:25]([C@:23]1([OH:24])[C:13]2[CH:12]=[C:11]3[N:16]([C:15](=[O:19])[C:14]=2[CH2:20][O:21][C:22]1=[O:27])[CH2:17][C:18]1[C:6]([CH2:5][CH2:4][Si:3]([CH2:2][O:37][C:34](=[O:36])[CH3:35])([CH3:33])[CH3:32])=[C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]2=[N:9][C:10]3=1)[CH3:26]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCl
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)COC(C)=O
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of Compound 3 (200 mg) and potassium acetate (200 mg) in dry N,N-dimethylformamide (4 mL) was heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and the N,N-dimethylformamide was removed under vacuum with mild heating. The obtained crude material was directly purified on a silica gel column using 1-2% ethanol in dichloromethane to obtain the required product in 72% yield (150 mg).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:10]([C:18]([C:20]2[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[N:22][O:23][C:24]=2[CH2:25]Cl)=[O:19])[N:9]=[N:8]1.C(N(CC)CC)C.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>ClCCl>[F:38][C:37]([F:39])([F:40])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:41])([F:1])[F:42])[CH:36]=1)[CH2:6][N:7]1[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[C:10]([C:18]([C:20]2[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[N:22][O:23][C:24]=2[CH2:25][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:19])[N:9]=[N:8]1
Reactant: C1COCCN1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)c1c(-c2ccccc2Cl)noc1CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)c1c(-c2ccccc2Cl)noc1CN1CCOCC1
Temperature: 25 °C
Yield: 93 %

Procedure:
Heat a mixture of [1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-chloromethyl-3-(2-chloro-phenyl)-isoxazol-4-yl]-methanone (100 mg, 0.158 mmol), triethylamine (80 mg, 0.790 mL) and morpholine (0.79 mL) at 50° C. for 18 h. Cool to RT, dilute the mixture with dichloromethane (50 mL) and wash with water (4×40 mL). Dry the organic layer with anhydrous MgSO4, filter, and concentrate in vacuo. Purify the residue by flash chromatography on silica gel to give the title compound (93% yield) as a brown oil. MS (ES) 685.2 (M++1); TLC Rf=0.1 (75% EtOAc in hexanes).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH2:31][CH3:32])([CH3:30])[CH3:29])=[CH:24][C:23]=1[C:33]([CH2:36][CH3:37])([CH3:35])[CH3:34])=[O:16].[N+:38]([C:41]1[CH:50]=[CH:49][C:44]([O:45]CCO)=[CH:43][CH:42]=1)([O-:40])=[O:39].CS(O)(=O)=O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][O:45][C:44]2[CH:49]=[CH:50][C:41]([N+:38]([O-:40])=[O:39])=[CH:42][CH:43]=2)=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH2:31][CH3:32])([CH3:30])[CH3:29])=[CH:24][C:23]=1[C:33]([CH2:36][CH3:37])([CH3:34])[CH3:35])=[O:16]
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Reactant: CCOc1cc(C(=O)NCCCOc2ccc(C(C)(C)CC)cc2C(C)(C)CC)c(O)c2ccccc12
Agent: CS(=O)(=O)O
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(OCCOc3ccc([N+](=O)[O-])cc3)c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
By heating a mixture of 5 g of Intermediate 2, 12 g of β-(4-nitrophenoxy)ethanol, and 0.3 g of methanesulfonic acid to 140-150° C for 3 hours under a reduced pressure, the desired product was obtained. The solvent used for the recrystallization of the product was acetonitrile. The melting point of the product was 166-168° C.