Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27](Cl)[C:28](OCC)=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][C:8]2=[O:34])(=O)C.[NH2:36][C:37](N)=[S:38].S1(CCCC1)(=O)=[O:41].Cl>O.COCCO>[OH:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]3[S:38][C:37](=[O:41])[NH:36][C:28]3=[O:29])=[CH:24][CH:25]=1)([CH3:17])[CH2:9][C:8]2=[O:34]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Reactant: NC(N)=S
Reactant: O=S1(=O)CCCC1
Agent: Cl
Solvent: O
Solvent: COCCO
Product: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reaction time: 60 h

Procedure:
A mixture of 1.3 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate (prepared as described in Preparation 45), 0.4 g of thiourea and 2 g of sulfolane was heated at 120°-130° C. for 4 hours under a nitrogen stream. Then 15 ml of ethylene glycol monomethyl ether, 4 ml of water and 2 ml of concentrated hydrochloric acid were added, in that order, to the reaction mixture, and heating was continued, but at 70°-90° C., for a further 2.5 days. Water was then added to the reaction mixture, after which it was extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. Benzene was distilled off from the extract. The residue was subjected to silica gel column chromatography, eluted with a 5:3 by volume mixture of hexane and ethyl acetate, to yield 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione. Its softening point was 79°-83° C.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([S:58]([CH:61]([CH3:63])[CH3:62])(=[O:60])=[O:59])=[C:46]([CH:57]=2)[CH2:47][N:48]([CH3:56])[C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:40])=[C:32]([CH2:64][CH3:65])[CH:31]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1>>[C:51]([O:50][C:49]([N:48]([CH2:47][C:46]1[CH:57]=[C:42]([NH:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([B:25]([OH:27])[OH:26])=[CH:31][C:32]=2[CH2:64][CH3:65])[CH:43]=[CH:44][C:45]=1[S:58]([CH:61]([CH3:63])[CH3:62])(=[O:60])=[O:59])[CH3:56])=[O:55])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCc1cc(Br)ccc1CCCC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: CCc1cc(B(O)O)ccc1CCCC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN(C)C(=O)OC(C)(C)C)c1
Yield: 67 %

Procedure:
Using a procedure analogous to that described for the preparation of 6D, 21C (0.513 g, 0.86 mmol) was coupled to 5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] (0.215 g, 0.952 mmol) and hydrolyzed to give boronic acid 21D (0.278 g, 67%). MS (ESI) m/z 561.48 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:24]([O:23][C:21]([C:3]1[C:4]([CH3:20])=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[C:10]([O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:33][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:17])[CH:9]=[CH:8][CH:7]=2)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: NC1CCCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cycloheptanamine as a brown solid (43%). MS 456 (MH+).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.CCO.C1COCC1.[ClH:28]>O.[Pd]>[Cl-:28].[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:19]=[CH:18][C:15]([CH2:16][NH3+:17])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)B(O)OC3)cc1
Reactant: Cl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: [Cl-]
Product: [NH3+]Cc1ccc(Oc2ccc3c(c2)B(O)OC3)cc1
Reaction time: 19 h
Yield: 57.1 %

Procedure:
To the solution of 4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)benzonitrile (1 g, 3.98 mmol) in a mixed solvent of EtOH (100 mL) and THF (25 mL) under N2 was added Pd/C (10 wt. %, 0.169 g). The reaction mixture was hydrogenated with a H2 balloon at room temperature with stirring for 19 h. The mixture was filtered, rotary evaporated and purified by silica gel column eluted with MeOH containing 0.6% v. NH4OH (3 mL 28-30% NH4OH to 500 mL MeOH). The white solid obtained was dissolved in water (80 mL) and 6N HCl (2 mL) was added, filtered and the filtrate was freeze-dried to give the desired salt (4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)phenyl)methanaminium chloride as white solid (0.663 g, 2.27 mmol, yield 57.1%). M.p.>230° C. 1H NMR (DMSO-d6, 300 MHz): δ 9.23 (br. s, 1H), 8.38 (br. s, 3H), 7.49 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.16 (dd, J=8.1 & 2.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 4.97 (s, 2H) and 3.97 (q, J=5.4 Hz, 2H) ppm. Purity (HPLC): 91.1% at 220 nm and 86.1% at 254 nm. MS: m/z=256 (M+1, ESI+) and m/z=254 (M−1, ESI−).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1([CH:15]([OH:29])[CH2:16][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([CH3:19])[CH3:18])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1([C:15](=[O:29])[CH2:16][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([CH3:19])[CH3:18])[CH2:13][CH2:14]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)C1(F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C1(F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
6 mL of a 2 M solution of oxalyl chloride in dichloromethane was diluted with 5 mL of dichloromethane and cooled on dry ice/acetone bath. To this solution was added dropwise a solution of 1.5 mL of DMSO in 5 mL of dichloromethane. After 10 minutes, a solution of the crude 1-(1-fluorocyclopropyl)-3-(5-fluoro-2-methoxyphenyl)-3-methylbutan-1-ol (0.8 g, 3 mmol) in 4 mL of dichloromethane was added and the mixture was stirred for 15 minutes. 4 mL of triethylamine was added, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature, quenched with water, and diluted with hexanes. The organic layer was separated, washed with water, dried, filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluent: hexanes to hexanes-ethyl acetate (10:1), gradient) to give 0.68 g of the title product as an oil which was used without additional purification.
Reaction SMILES: [CH3:1]O.[CH:3]1([CH2:6][NH2:7])[CH2:5][CH2:4]1.CC(C)([O-])C.[K+].S(OC)(OC)(=O)=O.[C:21](=[S:23])=[S:22]>O>[CH:3]1([CH2:6][NH:7][C:21](=[S:23])[S:22][CH3:1])[CH2:5][CH2:4]1
Reactant: NCC1CC1
Reactant: S=C=S
Reactant: CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CSC(=S)NCC1CC1
Reaction time: 0.5 h

Procedure:
To a methanol solution of 14.2 g of cyclopropylmethylamine and 22.5 g of potassium tert-butoxide, 20 g of carbon disulfide was added dropwise under cooling with ice. After 30 minutes, 25.2 g of dimethyl sulfate was added thereto under the same condition as above and the reaction was conducted for 1 hour. After adding water to the reaction solution, the mixture was extracted with toluene and the toluene layer was washed with water. After drying the toluene solution with anhydrous magnesium sulfate, toluene was distilled off to obtain 26.3 g of methyl cyclopropylmethyldithiocarbamate. To the dithiocarbamate thus obtained, an aqueous solution of 12.7 g of sodium azide was added and reacted at 100° C. until the evolution of methylmercaptan was ceased. After allowing to cool off, the reaction solution was washed with ethyl acetate. To the aqueous layer, ethyl acetate was added, acidified with diluted hydrochloric acid and then the acidic materials were extracted with ethyl acetate. The ethyl acetate solution was washed with saturated saline, dried over anhydrous magnesium sulfate and then ethyl acetate was distilled off under reduced pressure to obtain 10 g of 1-cyclopropylmethyl-4-H-tetrazolin-5-thione. The product was dissolved in 10 ml of an aqueous solution of 3.2 g of sodium hydroxide and 6 g of propylene oxide was added thereto under cooling with ice. The reaction solution was stirred overnight. Then, the reaction solution was acidified with concentrated hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1:1) to obtain 5.0 g of 1-cyclopropylmethyl-5(4H)-tetrazolinone. m.p.: 61-64° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:16]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:17][CH2:18][C:19]([CH3:21])=O.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[CH2:1]1[O:4][C:19]([CH3:21])([CH2:18][CH2:17][C:16]([O:23][CH2:24][CH3:25])=[O:22])[O:3][CH2:2]1
Reactant: OCCO
Reactant: CCOC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCC1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of about 110.86 g of ethylene glycol, about 2 g of p-toluenesulfonic acid and about 800 ml of toluene was refluxed using a Dean-Stark trap until no more water came off. An about 250 g portion of ethyl levulinate was added and refluxing was continued until no more water came off. The mixture was then cooled to room temperature, poured into saturated sodium bicarbonate, the organic layer dried and the solvent removed. The residue was distilled (about 67°-70° C., 0.35 mm) and the distillate stirred for about 20 minutes with about 6 g of sodium borohydride in ethanol. The solvent was removed, the residue dissolved in ether, washed with saturated sodium bicarbonate, dried and then distilled (about 41°-45° C., 0.3 mm), giving about 83 g of the desired title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2.[C:17]1([CH2:23][CH2:24]O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(C=C1CCP(C)C1(C)C)#N>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2
Reactant: OCCc1ccccc1
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Agent: CP1CCC(=CC#N)C1(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2CCc1ccccc1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A 211 mg portion of ethyl 2,3-dimethyl-1H-indole-5-carboxylate was dissolved in 10 ml of toluene, and 0.232 ml of 2-phenylethanol and 224 mg of cyanomethylene trimethylphospholan were added at room temperature, followed by stirring at 100° C. for 17 hours. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:49 to 1:9) to obtain 107 mg of ethyl 2,3-dimethyl-1-(2-phenylethyl)-1H-indole-5-carboxylate as a colorless oily material.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20](=[O:25])[C:19]=1[CH2:26][NH:27][C:28](=[O:54])[C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([N:44]([CH2:51][CH3:52])[CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[C:30]=1[CH3:53].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[C:7]([C:6]1[CH:9]=[C:2]([C:33]2[CH:32]=[C:31]([N:44]([CH2:51][CH3:52])[CH:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[C:30]([CH3:53])=[C:29]([C:28]([NH:27][CH2:26][C:19]3[C:20](=[O:25])[NH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])=[O:54])[CH:34]=2)[CH:3]=[CH:4][C:5]=1[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[N:8]
Reactant: CCN(c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: N#Cc1cc(Br)ccc1CN1CCOCC1
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: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)c(C#N)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 5.9 %

Procedure:
To a stirred solution of 5-bromo-2-(morpholinomethyl)benzonitrile (190 mg, 0.68 mmol) and N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (200 mg, 0.45 mmol) in dioxane (6 mL), aqueous 2M Na2CO3 solution (0.81 mL, 1.63 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (52 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (16 mg, 6%). LCMS: 598.20 (M+1)+; HPLC: 89.15% (@ 254 nm) (Rt; 4.039; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (bs, 1H), 8.20 (t, 1H), 8.15 (s, 1H), 7.94 (d, 1H, J=6.8 Hz), 7.63 (d, 1H, J=8.4 Hz), 7.51 (s, 1H), 7.31 (s, 1H), 5.86 (s, 1H), 4.29 (m, 2H), 3.84-3.82 (m, 2H), 3.66-3.58 (m, 6H), 3.32 (m, 5H), 3.11-3.03 (m, 4H), 2.25 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.65-1.51 (m, 4H), 0.82 (t, 3H, J=6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[C:18][Si](C)(C)C)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[CH:18])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2
Reactant: C[C@@H](C1CC1)N1Cc2cc(C#C[Si](C)(C)C)cc(Cl)c2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#Cc1cc(Cl)c2c(c1)CN([C@@H](C)C1CC1)C2=O
Temperature: 25 °C
Yield: 64.9 %

Procedure:
7-chloro-2-((S)-1-cyclopropylethyl)-5-(2-(trimethylsilyl)ethynyl)isoindolin-1-one (40.88 g, 123.17 mmol) was dissolved in 250 mL of ethanol and stirred at room temperature. To the reaction mixture was added a solution of potassium hydroxide (0.10 g, 1.85 mmol) in 20 mL of water. The reaction immediately turned black and was allowed to continue stirring for 90 minutes at room temperature. The volatiles were removed under reduced pressure and the product purified by flash chromatography on silica gel eluting with a gradient of 0 to 40% ethyl acetate in hexane. This afforded the desired product as a light tan solid (20.75 g, 69.7%). 1H NMR (300 MHz, CDCl3) δ ppm 0.34-0.50 (m, 3H) 0.58-0.69 (m, 0.93-1.07 (m, 1H) 1.34 (d, 3H) 3.22 (s, 1H) 3.76 (dq, 1H) 4.31-4.54 (m, 2H) 7.45 (s, 1H) 7.51 (s, 1H). MS ESI m/z=260 (M+H). HPLC Method B: 0.80 min.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:1]([C:4]1[C:5](=[O:19])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:7]([CH3:11])=[CH:8][C:9]=1[O:10][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(O)cc(C)n(-c2ccccc2Cl)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(OCc2ccccc2)cc(C)n(-c2ccccc2Cl)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of 3-acetyl-1-(2-chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.56 g, 2.02 mmol) in DMF (5.0 mL), benzyl bromide (0.3 mL) and potassium carbonate (0.3 g, 2.16 mmol) were added. The mixture was stirred at room temperature for 3 h, and at 65° C. for 1 h under argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was partitioned between 5% citric acid (25 mL) and EtOAc (50.0 mL). The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated to dryness. The resulting residue was purified by silica gel flash chromatography using 50% EtOAc in hexanes to afford the title compound (0.58 g, 75%) as a pale yellow amorphous substance: 1H-NMR (CD3OD) δ: 7.65-7.3 (m, 9H), 6.5 (s, 1H), 5.31 (s, 2H), 2.42 (s, 3H), and 2.01 (s, 3H); ER-MS m/z=368 (MH+); HR-MS m/z calcd C21H19NO3Cl, 368.1060, found 368.1053.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C)C=O.[OH-].[Na+]>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1N1CCOCC1
Temperature: 50 °C

Procedure:
Refer to synthesis of (D46) for preparation of 2,6-dichloro-nicotinamide (1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1) (1.85 g, 9.70 mmol) and morpholine (1.69 mL, 19.4 mmol) in anhydrous dimethylformamide (20 mL) was heated to 50° C. for 2.5 h. The reaction was then cooled to room temperature and diluted with 0.1 M NaOH (600 mL) and extracted with ethyl acetate (3×500 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give the title compound (2.49 g) as an orange oil, which later solidified upon standing. Compound 6-Chloro-2-morpholin-4-yl-nicotinamide (2) was carried forward without further purification. 1H NMR 400 MHz (d6-DMSO) 87.89 (br s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.56 (br s, 1H), 6.88 (d, J=7.8 Hz, 1H), 3.67 (br t, J=4.7 Hz, 4H), 3.31 (br t, J=4.7 Hz, 4H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[C:6]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[CH2:2][CH2:3][CH3:4].[O-:20][C:21]#[N:22].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO>[CH2:1]([N:5]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[C:6]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:21]([NH2:22])=[O:20])[CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#C[O-]
Reactant: CCCCn1c(CC)ccc1Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCn1c(CC)ccc1Cc1cccc(NC(N)=O)c1
Yield: 94.6 %

Procedure:
A stirred solution of 3.1 g (12 mmol) of 1-butyl-2-(3'-aminobenzyl)-5-ethylpyrrole in 250 ml of dry methylene chloride and 50 ml of anhydrous methanol was treated, at room temperature and under nitrogen atmosphere, with 1.7 g (26 mmol) of sodium cyanate, followed by the dropwise addition, over a 2 hour period, of 2.3 ml (29 mmol) of trifluoroacetic acid in 100 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 additional hours, 2 g (18 mmol) of sodium carbonate were then added and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on 300 g of silica gel, using methylene chloride-methanol (97:3) as eluant, thus obtaining 3.4 g (93%) of the title compound, 1-butyl-2-(3'-ureidobenzyl)-5-ethylpyrrole, which was recrystallized from ether-hexane.
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C@@H:8]2[CH2:13][O:12][C:11]3=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:10]3[CH2:9]2)=[CH:4][CH:3]=1.[C:22]([Si](C)(C)C)#[CH:23]>CN(C=O)C.CCN(CC)CC.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:22]([C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C@@H:8]2[CH2:13][O:12][C:11]3=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:10]3[CH2:9]2)=[CH:4][CH:3]=1)#[CH:23]
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(I)cc1)C2
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(CO[C@@H]2COc3nc([N+](=O)[O-])cn3C2)cc1
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A mixture of iodide 43 (see Example 2C) (1.00 g, 2.49 mmol) and copper iodide (51 mg, 0.27 mmol) in DMF (10 mL) and Et3N (10 mL) was purged with N2. Ethynyltrimethylsilane (1.0 mL, 7.1 mmol) and PdCl2(PPh3)2 (93 mg, 0.13 mmol) were added and the mixture was stirred under N2 for 0.5 h. The resulting mixture was partitioned between EtOAc and water, the organic fraction was dried, and the solvent was removed. The residue was dissolved in THF (50 mL) and tetra-n-butylammonium fluoride (5 mL of a 1M solution in THF, 5 mmol) was added. The solution was stirred for 2 h and then concentrated. The residue was partitioned between EtOAc and water, and the organic fraction was dried and concentrated. Column chromatography of the residue on silca gel using gradient elution (1:1 hexanes EtOAc to EtOAc) gave (6S)-6-[(4-ethynylbenzyl)oxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (129) (0.530 g, 71%) as a white solid: mp 162-164° C.; 1H NMR [(CD3)2SO] δ 8.01 (s, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 4.62-4.71 (m, 3H), 4.47 (d, J=11.9 Hz, 1H), 4.20-4.30 (m, 3H), 4.14 (s, 1H). Anal. (C15H13N3O4) C, H, N.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH2:21][C:22]#[C:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[S:20][CH2:21][CH:22]([C:23](=[O:6])[CH2:24][O:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:18]=2[CH:19]=1
Reactant: COc1ccc(SCC#CCOc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(C(=O)COc1ccccc1)CS2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of m-chloroperoxybenzoic acid (55% purity; 15.2 g) in chloroform (300 ml) was added dropwise over 2.5 hours to a stirred, ice-cold solution of 1-(4-methoxyphenylthio)-4-phenoxybut-2-yne(13.7 g) in chloroform (125 ml), then the mixture was stirred at ambient temperature for 18 hours and filtered. The filtrate was washed with 5% sodium carbonate solution (3×150 ml) and water (3×100 ml), then dried (MgSO4) and filtered. The filtrate was heated under nitrogen at an external temperature of 80°-85° C. for 6 hours, allowed to stand at ambient temperature for 18 hours, heated at an external temperature of 80°-85° C. for a further 1.5 hours, then allowed to cool. The solvent was removed in vacuo, the residue was dissolved in dichloromethane (250 ml), and the solution was shaken vigorously for a few seconds with 5M aqueous sodium hydroxide solution (150 ml). The organic solution was separated, washed with water (2×150 ml), dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography over silica using 12.5-25% mixtures of ethyl acetate and petroleum ether (b.p. 60°-80° C.) as eluants. Appropriate fractions were combined, and the solvents removed in vacuo to leave 1-(5-methoxy-2,3-dihydrobenzo[b]thiophen-3-yl)-2-phenoxyethanone as a gum (4.5 g).