Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:24]2[CH:25]=[C:26]([NH:18][C:16]3[N:17]=[C:10]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:4][CH:5]=5)=[CH:14][CH:13]=[CH:12][N:11]4[N:15]=3)[CH:27]=[CH:22][CH:23]=2)[CH2:29][CH2:30]1
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: Nc1nc2c(-c3ccc(C(F)(F)F)cc3)cccn2n1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(C(F)(F)F)cc5)cccn4n3)c2)CC1

Procedure:
[3-(4-Methyl-piperazin-1-yl)-phenyl]-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.270 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow solid (0.043 g, 35%). MP=234-236° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=7.0 Hz, 1H), 8.15 (d, J=7.7 Hz, 2H), 7.76 (d, J=8.2 Hz, 2H), 7.62 (d, J=7.2 Hz, 1H), 7.48 (s, 1H), 7.25-7.19 (m, 1H), 7.02-6.97 (m, 1H), 6.92 (d, J=7.3 Hz, 1H), 6.83 (s, 1H), 6.59 (d, J=7.8 Hz, 1H), 3.30-3.25 (m, 4H), 2.62-2.57 (m, 4H), 2.37 (s, 3H). MS=435 (MH)+.
Reaction SMILES: [I-].[CH:2]1([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:37]([O:39][C:40](=[O:51])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[CH:45][CH:44]=1)=O)[CH3:38].Cl>O1CCCC1.O>[CH2:37]([O:39][C:40](=[O:51])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[CH:45][CH:44]=1)=[CH:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:38]
Reactant: CCOC(=O)C(=O)c1ccc(SC)cc1
Reactant: c1ccc([P+](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=CC1CCCC1)c1ccc(SC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A suspension of cyclopentylmethyl triphenylphosphonium iodide (151.73 g, 0.321 mol) in dry tetrahydrofuran (494 mL) was cooled to 0° C. and then treated slowly with a 1.0 M solution of lithium bis(trimethylsilyl)amide (309 mL, 0.309 mol). The bright orange reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was then treated with a solution of (4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (55.42 g, 0.247 mol) in dry tetrahydrofuran (100 mL) in small portions. The resulting reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to 25° C. where it was stirred for 6 h. The reaction mixture was then diluted with water (500 mL), at which time, the reaction mixture indicated a pH=11. The reaction mixture was adjusted to pH=6 with a 10% aqueous hydrochloric acid solution and then allowed to sit at 25° C. overnight. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then diluted with diethyl ether (1 L). A solid began to precipitate, and the reaction mixture was allowed to sit at 25° C. for 1 h. The solid was filtered and washed well with diethyl ether. The resulting two-layer filtrate was transferred to a separatory funnel, and the layers were separated. The aqueous layer was further extracted with diethyl ether (1×500 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using a plug of silica (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-acrylic acid ethyl ester (58.93 g, 82%) as a yellow oil consisting of a 1.44:1 mixture of (E):(Z) isomers. The material was used without further separation and characterization.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])[CH:17]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Yield: 84.5 %

Procedure:
A suspension of the product of Step 228c (181 mg, 0.550 mmol), 2-fluoro-5-(trifluoromethyl)pyridine (108 mg, 0.655 mmol), and K2CO3 (152 mg, 1.10 mmol) in anhydrous DMF (4 mL) was heated at 100° C. under nitrogen for 3 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL), washed with 10% aq. LiCl (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes) then lyophilized from acetonitrile/water (2:1) to afford the title compound as a white solid (220 mg, 84%). 1H NMR (500 MHz, CDCl3) δ 8.95-6.05 (m, 10H), 5.25-2.85 (m, 5H), 2.15-0.75 (m, 8H); ESI MS (M+H) 474.
Reaction SMILES: C([O:5][C:6]([N:8]([CH3:27])[N:9]1[C:18]2[C:13](=[CH:14][C:15]([I:20])=[CH:16][C:17]=2[F:19])[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]1)=O)(C)(C)C.C=O>O>[F:19][C:17]1[CH:16]=[C:15]([I:20])[CH:14]=[C:13]2[C:18]=1[N:9]([N:8]([CH2:6][OH:5])[CH3:27])[CH:10]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]2=[O:21]
Reactant: CCOC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)cc(I)cc2c1=O
Agent: C=O
Solvent: O
Product: CCOC(=O)c1cn(N(C)CO)c2c(F)cc(I)cc2c1=O
Temperature: 85 °C
Yield: 113.2 %

Procedure:
A mixture of ethyl 1-((tert-butoxycarbonyl)(methyl)amino)-8-fluoro-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Preparation 35, 0.200 g), 37% aqueous formaldehyde (4.0 mL), and water (2.0 mL) is heated in an oil bath for 2.5 h at 85° C. The mixture is cooled, diluted with ice water (30 mL), and the resulting precipitate is collected, rinsed with ice water and partially air dried. The solid is dissolved in a mixture of acetone and CH2Cl2, dried (Na2SO4), and concentrated at reduced pressure to yield 0.194 g (90%) of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 421 (M+H)+; TLC (silica gel GF): Rf=0.32 acetone/CH2Cl2 (1/4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:8]1)=[O:6].C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41](Cl)[C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)=[CH:37][CH:36]=1>C(Cl)(Cl)(Cl)Cl>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([CH:41]([NH:1][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[C:5]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:8]2)=[O:6])[C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)=[CH:39][CH:40]=1
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Reactant: Nc1cccc(C(=O)n2cc(CCCC(=O)O)c3ccccc32)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCc1cn(C(=O)c2cccc(NC(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c2)c2ccccc12
Yield: 69 %

Procedure:
To a solution of 4-[1-(3-aminobenzoyl)indol-3-yl]butyric acid (1.0 g) and diisopropylethylamine (1.3 g) in carbon tetrachloride (20 ml) was added bis(4-chlorophenyl)methyl chloride (0.84 g). The mixture was refluxed for 6 hours and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (20 ml) and diluted hydrochloric acid (30 ml) and washed with water (30 ml×3). The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by a column of silica gel to give a yellow solid of 4-[1-[3-[bis(4-chlorophenyl)methylamino]benzoyl]indol-3-yl]butyric acid (1.19 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[Br:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[C:33]([Br:32])[CH:34]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4cccc(Br)c4)c3)c2/C1=C/c1ccc[nH]1
Temperature: -70 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (50 mg, 0.148 mmol) (from Example 5 supra) and Et3N (41 μL , 0.296 mmol) in 3 mL of chloroform was cooled to −70° C. and then treated with 3-bromobenzoyl chloride (21 μL , 0.155 mmol) (Aldrich). The reaction mixture was stirred at −70° C. for 1 hr and then stirred at room temperature for 15 h. The reaction mixture was then concentrated in vacuo. The resulting yellow solid was suspended in water and collected by suction filtration to provide pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-3-bromobenzamide (yield: 70 mg, 98%) as a yellow solid (mp 251-253° C.).
Reaction SMILES: N1C=CC=CC=1.N([C@@H:10]1[C@@H:14]([CH2:15][OH:16])[O:13][C@@H:12]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:11]1)=[N+]=[N-].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[C:26]([O:16][CH2:15][C@H:14]1[O:13][C@@H:12]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:11][CH2:10]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1CC[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Reaction time: 8 h

Procedure:
To a pyridine (50 ml) solution of 3'-azido-3'-deoxythymidine (5.0 g, 18.7 mmole) 1 was added acetic anhydride dropwise in an ice-water bath. The mixture was allowed to stand overnight in the refrigerator. The solution was then poured into CHCl3 (20 ml), washed with H2O (200 ml×2), with a saturated solution of sodium bicarbonate and then H2O (200 ml×2). The organic layer was then dried (MgSO4). After removing the solvent, a syrup (6.5 g) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13].[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=1>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=1)=[O:17])(=[O:14])=[O:13]
Reactant: COCCOc1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(C)nc(N)n1
Solvent: C1COCCO1
Product: COCCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1

Procedure:
9.0 g of 2-methoxyethoxy-phenylsulfonyl isocyanate and 4.9 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine are refluxed in 60 ml of absolute dioxane for 3 hours. The mixture is treated with activated carbon, filtrated and evaporated to 1/5 of the original volume. After addition of ether 13.0 g of N-(2-methoxyethoxy-phenylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea crystallise therefrom, m.p. 134°-138° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[C:10][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[CH:10]
Reactant: Cc1cccc(C)c1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#Cc1c(C)cccc1C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To an ice cold solution of (2,6-dimethylphenylethynyl)-trimethylsilane from the previous step in THF (20 mL) was added tetrabutylammonium fluoride in THF (17 mL of 1 M solution) dropwise. After stirring 18 h, the solution was diluted with hexane and extracted with water and brine. The organic layer was dried, filtered, and solvent removed under reduced pressure. The residual oil was redissolved in hexane and filtered through a silica gel plug, then chromatographed using hexane as eluent to give 2,6-dimethylphenylacetylene.
Reaction SMILES: N1C=CC=CC=1.[Si:7]([O:14][CH2:15][CH:16]([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[OH:17])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[C:36](Cl)(=[O:58])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=[CH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57].O>C1(C)C=CC=CC=1>[Si:7]([O:14][CH2:15][CH:16]([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:17][C:36](=[O:58])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=[CH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OC(COCCCCCCCCCCCCCCCC)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 81.3 %

Procedure:
Anhydrous pyridine (0.15 mL) and toluene (10 mL) were added to 3a (249.0 mg, 0.578 mmol) and stirred at RT under dry argon. Docosahexaenoyl chloride (200.0 mg, 0.578 mmol) in toluene (5 mL) was then added dropwise to the reaction mixture over a period of 20 min and stirred at RT for 96 hours. The reaction mixture was poured into water (100 mL), extracted with diethyl ether (100 mL, 3×), washed successively with 0.25 M H2SO4 solution (100 mL), saturated aqueous NaHCO3 (100 mL) and water (100 mL), and dried over anhydrous Na2SO4. After removal of solvent, the crude product was chromatographed on silica gel using hexane-dichloromethane to obtain product 4a (348.4 mg, 81.4% yield). 1H NMR (in CDCl3): δ in ppm 0.89 (18H, m), 1.24 (29H, m), 1.53 (2H, m), 2.06 (2H, m), 2.40 (4H, m), 2.83 (10H, m), 3.40 (3H, m), 3.55 (2H, m), 3.71 (2H, m), 5.36 (12H, m); 13C NMR (in CDCl3): δ in ppm 14.2, 14.4, 20.7, 22.2, 25.7 (2), 25.8, 26.0, 26.1, 26.3, 29.5, 29.7, 29.8, 29.9, 32.0, 35.3, 65.4, 71.7, 72.9 (2), 127.1, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5, 128.7, 129.2, 129.3, 130.1, 132.1, 168.8.
Reaction SMILES: [NH2:1][C:2]([CH2:4][C:5]1[C:6](=[O:22])[N:7]([CH2:19][C:20]#[CH:21])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]=1[CH2:11][CH3:12])=O.N1C=CC=[CH:25][CH:24]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1.CCOCC>[CH2:11]([C:10]1([CH2:24][CH3:25])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]([CH2:19][C:20]#[CH:21])[C:6](=[O:22])[CH:5]1[CH2:4][C:2]#[N:1])[CH3:12]
Reactant: c1ccncc1
Reactant: C#CCn1c(-c2ccccc2)nc(CC)c(CC(N)=O)c1=O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: C#CCN1C(=O)C(CC#N)C(CC)(CC)N=C1c1ccccc1
Temperature: 0 °C
Yield: 49.8 %

Procedure:
A stirred suspension of 0.25 g (0.85 mmol) of 5-aminocarbonylmethyl-6-ethyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 275) in 12 mL of THF was cooled in an icebath and 0.15 mL (1.9 mmol) of pyridine was added followed by 0.13 mL (0.92 mmol) of trifluoroacetic anhydride. The mixture was stirred in the ice bath for 4 h, diluted with 80 mL of ether, washed with 20 mL of saturated aqueous NaHCO3 and dried over MgSO4. Removal of the solvent left 0.24 g of crude product as a yellow solid. Flash chromatography on 30 g of silica gel, eluting sequentially with 50, 75 and 100% ether in hexanes afforded 0.13 g of 6-ethyl-5-cyanomethyl-6-ethyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 277) as a white solid, m.p. 178°-180° C. 1 H-NMR (CDCl3) 1.3(3H,t), 2.4(1H,t), 2.75(2H,q), 3.75(2H,s), 4.6(2H,d), 7.55(3H,m), 7.7(2H,m).
Reaction SMILES: B(F)(F)F.CCOCC.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)=O)=[CH:13][CH:12]=1.[NH2:27][N:28]1[C@@H:32]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:31][CH2:30][C:29]1=[O:42]>O1CCCC1>[CH2:35]([O:34][CH2:33][C@@H:32]1[N:28]([N:27]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH2:17][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[C:29](=[O:42])[CH2:30][CH2:31]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1cccc(C(=O)Cc2ccc(F)cc2)n1
Reactant: NN1C(=O)CC[C@@H]1COCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(C(Cc2ccc(F)cc2)=NN2C(=O)CC[C@@H]2COCc2ccccc2)n1
Reaction time: 0.5 h

Procedure:
Boron trifluoride etherate (0.25 mL, 1.98 mmol) is added to a solution of 2-(4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethanone (0.45 g, 1.98 mmol) in tetrahydrofuran (6.6 mL) under nitrogen and stirred for 30 min. A solution of (R)-1-amino-5-benzyloxymethyl-pyrrolidin-2-one (0.43 g, 1.98 mmol) in tetrahydrofuran (1.0 mL) is added and the resulting mixture is stirred for 1 h. The mixture is concentrated in vacuo and the residue chromatographed on a SiO2 column (30% ethyl acetate/hexanes) to yield the title compound, 380 mg (45%), as a yellow foam.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>CO.ClCCl>[CH2:6]([NH:1][CH2:2][C@H:3]([OH:5])[CH3:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H](O)CN
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](O)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
A 100-mL round bottomed flask equipped with a magnetic stir bar was charged with (R)-1-aminopropan-2-ol (1.0 g, 13.31 mmol), dichloromethane (25 mL), benzaldehyde (1.349 mL, 13.31 mmol), and magnesium sulfate (4.81 g, 39.9 mmol), and the mixture stirred at rt for 24 h. The slurry was filtered through a medium frit Buchner funnel and the solids were washed with additional dichloromethane. The filtrate was concentrated to a colorless syrup. The crude imine (2.171 g, 13.3 mmol) was dissolved in methanol (30 mL) and treated with sodium borohydride (0.503 g, 13.30 mmol) in two portions (0.200 g then 0.303 g 5 min later) at rt. The solution was stirred at rt for 4 h and then concentrated under reduced pressure. The residue was dissolved in 1 N aqueous hydrogen chloride solution (40 mL). This aqueous solution was washed with ethyl acetate (2×40 mL). The aqueous layer was made basic by the addition of 10 N aqueous sodium hydroxide solution (8 mL) and extracted with dichloromethane. The dichloromethane layer was washed with 5% aqueous sodium chloride solution (20 mL) and concentrated under reduced pressure to afford (R)-1-(benzylamino)propan-2-ol (1.61 g, 73%) as a colorless syrup. MS (ESI, pos. ion) m/z 166 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.ClCCl>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: c1ccc2c(c1)CCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)CCO2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of 25.5 g (0.212 mol) of 2,3-dihydrobenzofuran in 175 mL of acetic acid was added about one quarter of 4.5 mL (0.227 mol) of 70% aqueous nitric acid dropwise. The reaction was monitored by TLC (EtOAc-hexanes, 15:85). The mixture was warmed to 70° C. where the reaction began. The remainder of the nitric acid was then added while maintaining the reaction at 70° C. After 30 minutes, the reaction was cooled and poured into 1.5 L of ice water. The black solid was collected by filtration washing with water. The solid was partitioned between 500 mL of saturated aqueous sodium bicarbonate and 150 mL of EtOAc. The aqueous layer was separated and extracted with three 150 mL portions of EtOAc. The combined organic layers were washed with three 100 mL portions of saturated aqueous sodium bicarbonate, 100 mL of saturated aqueous ammonium chloride, 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford a red oil/solid. The mixture was dissolved in dichloromethane and passed through a pad of silica gel, eluting with dichloromethane, and concentrated. The resulting red mixture was triturated with ether-hexanes (1:1) and filtered to afford 10.5 g (29%) of 5-nitro-2,3-dihydrobenzofuran as a tan solid.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH2:36][CH2:37][OH:38].O>CN(C)C=O>[C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[N:15]([CH2:35][CH2:36][CH2:37][OH:38])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: OCCCBr
Reactant: CSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CCCO)c2C)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-methylthiophenyl)methyl]-1H-pyrazole (0.020 g) and cesium carbonate (0.11 g) in N,N-dimethylformamide (0.5 mL) was added 3-bromopropanol (0.022 mL), and the mixture was stirred at 40° C. overnight. To the reaction mixture was added water, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=5/1) to give 3-(β-D-glucopyranosyloxy)-1-(3-hydroxypropyl)-5-methyl-4-[(4methylthiophenyl)methyl]-1H-pyrazole (0.011 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].I[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:14])[CH:8]=[C:9]2[C:13]=1[N:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:11]=[CH:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2cn[nH]c12
Reactant: CC(C)CI
Product: COC(=O)c1cc(Cl)cc2cnn(CC(C)C)c12
Yield: 48 %

Procedure:
Compound 9 was prepared following general method 1, using 5-chloro-1H-indazole-7-carboxylic acid methyl ester (see WO2011008572 which is incorporated by reference in its entirety) as starting material and 1-iodo-2-methylpropane as alkylating agent. Yield: 48%.