Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Br
Reactant: Ic1ccc(-c2nc3ccccc3o2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Product: Brc1ccccc1-c1ccc(-c2nc3ccccc3o2)cc1
Temperature: 90 °C
Reaction time: 10 h
Yield: 28.6 %

Procedure:
Into a 100 mL three-neck flask were put 7.0 g (22 mmol) of 2-(4-iodophenyl)benzoxazole, 4.4 g (22 mmol) of 2-bromophenylboronic acid, 0.049 g (0.22 mmol) of palladium(II) acetate, and 0.46 g (1.5 mmol) of tri(o-tolyl)phosphine. Into the mixture were added 60 mL of 1,2-dimethoxyethane (DME) and 30 mL of a 2M aqueous solution of potassium carbonate. After the mixture was degassed under low pressure, the atmosphere in the flask was substituted by nitrogen. This mixture was stirred at 90° C. for 10 hours. After the stirring, toluene was added into the mixture and the organic layer was washed with a saturated aqueous solution of sodium carbonate and brine in this order. After the washing, magnesium sulfate was added into the organic layer to dry the organic layer. After the drying, the mixture was subjected to suction filtration to give a filtrate. The obtained filtrate was subjected to suction filtration through Celite (manufactured by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855) to give a filtrate. The obtained filtrate was concentrated, and purification by silica gel column chromatography was performed. The column chromatography was performed first using a mixed solvent of chloroform and hexane (chloroform:hexane=1:4) as a developing solvent and then using a mixed solvent of chlorofoini and hexane (chloroform:hexane=1:1) as a developing solvent. An obtained fraction was concentrated to give a solid. The obtained solid was recrystallized with a mixed solvent of chloroform and hexane to give 2.2 g of a powdery white solid in a yield of 29%.
Reaction SMILES: [Br:1]Br.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:7][C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[CH2:9]1>>[Br:1][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([CH3:18])([CH3:7])[CH2:9][C:10]2=[O:17])=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CC(=O)c2cc(Br)ccc21
Yield: 27 %

Procedure:
Bromine (0.2 ml, 3.8 mmol, 1.2 eq.) was added to a mixture of AlCl3 (1.04 g, 7.8 mmol, 2.5 eq.) and 3,3-dimethyl-indan-1-one (500 mg, 3.1 mmol) at 100° C. and the reaction mixture was heated at same temperature for 40-45 min. TLC (10% ethyl acetate/hexanes) showed the major product formation with little starting material and dibromo product. The reaction mass was quenched with crushed ice and extracted with ethyl acetate (3×50 ml). The organic part was separated, dried over Na2SO4 and evaporated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 10% ethyl acetate/hexanes) to give the desired compound as a pale yellow solid. Yield: 27% (280 mg, 0.85 mmol).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.C([Li])CCC.CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1.CCCCC>[F:11][C:4]1[CH:3]=[C:2]([CH:19]=[O:20])[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c2occc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc2ccoc12
Temperature: -97.5 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
7-Bromo-5-fluoro-benzofuran (7 g, 32 mmol, Step B) was dissolved in a mixture of tetrahydrofuran (350 mL) and pentane (100 mL), cooled to −95 to −100° C., and treated with n-butyl lithium (14 mL, 35 mmol, 2.5M in hexane, Aldrich). After stirring for 5 minutes, a solution of dimethylformamide (5 mL) in tetrahydrofuran (15 mL) was added dropwise and the reaction temperature raised to −20° C. This was treated with aqueous ammonium chloride (50 mL) and stirred for 0.5 hour at ambient temperature. The reaction mixture was concentrated in vacuo and diluted with hexane. The organic fraction was washed with water and dried (Na2SO4). Removal of solvent afforded crude 5-fluoro-benzofuran-7-carbaldehyde (˜30%) as an oil. Purification was by silica gel chromatography (5–10% ethyl ether/hexane). HRMS, observed: 163.0201; Calcd for (M+H)+: 163.0195
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([N:26]([CH:28]([C:41]1[CH:46]=[CH:45][N:44]=[C:43]([F:47])[CH:42]=1)[CH:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[CH3:27])=O)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([N:50](CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH2:23][C:24]1[N:26]([CH3:27])[C:28]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([F:47])[CH:42]=2)=[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=2)[N:50]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CC)CC
Reactant: CN(C(=O)CCNC(=O)OCc1ccccc1)C(c1ccnc(F)c1)C(O)c1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cn1c(CCNC(=O)OCc2ccccc2)nc(-c2cccc(C(F)(F)F)c2)c1-c1ccnc(F)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 77.6 %

Procedure:
Oxalyl chloride (0.34 mL, 3.9 mmol) was added to a solution of dimethyl sulfoxide (0.41 mL, 5.8 mmol) in methylene chloride (10 mL) at −78° C. After 20 min. at −78° C., 3-(benzyloxycarbonyl-amino)-N-[1-(2-fluoro-pyridin4-yl)-2-hydroxy-2-(3-trifluoromethyl-phenyl)ethyl]-N-methyl-propionamide (1.0 g, 1.9 mmol) in methylene chloride (10 mL) was added and the reaction solution was stirred at −78° C. for 2 hrs. Triethylamine (1.3 mL, 9.6 mmol) was added and the cooling bath was removed. The solution was diluted with ethyl acetate (150 mL), washed with aqueous ammonium chloride (75 mL) and brine (75 mL), dried (sodium sulfate), and concentrated. Some non-polar impurities were removed by passing the residue through silica gel, eluting with 50% ethyl acetate in hexane. The ketone was then transferred to a flask containing anhydrous ammonium trifluoroacetate (4 g) using a minimum amount of ether-methylene chloride. The mixture was placed under vacuum to remove the solvent, and then placed in a preheated oil bath (150° C.). Once all solid had melted and efficient stirring was achieved (approx. 10 min.) the formation of the imidazole was found to be complete. The heating bath was removed and the solids were partitioned between ethyl acetate and water (150/50 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated. The product was purified by filtration through silica gel (imidazole is the least polar component) using ethyl acetate to yield 735 mg of a foam.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][C:6](=[CH:9][CH2:10][CH3:11])[CH:7]=[O:8].[Cl-].[NH4+]>O1CCCC1>[C:1]([CH:7]([OH:8])[C:6]([CH3:5])=[CH:9][CH2:10][CH3:11])#[CH:2]
Reactant: C#C[Mg]Br
Reactant: CCC=C(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)C(C)=CCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 364.8 %

Procedure:
To a solution of ethynyl magnesium bromide (prepared from 2.91 g of magnesium) in 100 ml of tetrahydrofuran, was added dropwise 9.8 g of 2-methyl-2-pentenal at a temperature from 0° C to 10° C under cooling with ice-bath. The resulting reaction solution was stirred for 3 hours at room temperature to complete the reaction and then the reaction solution was poured into a saturated ammonium cloride solution with 50 g of ice. After stirring, the solution was extracted twice with 100 ml of ether and the organic layers were combined, and then washed with 50 ml of a saturated sodium chloride solution. After the organic layer had been dried over anhydrous sodium sulfate, the ether was evaporated. The remaining liquid was purified by distillation at reduced pressure to obtain 10.2 g of a colorless oily 1-ethynyl-2-methyl-2-pentenyl alcohol, b.p. 85°-88° C/20 mmHg.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].[CH3:7][CH:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]1=O>>[C:1]([NH:5][N:6]=[C:9]1[CH2:10][C:11]([CH3:14])([CH3:13])[CH2:12][CH:8]1[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NN
Reactant: CC1CC(C)(C)CC1=O
Product: CC1CC(C)(C)CC1=NNC(C)(C)C

Procedure:
2,4,4-Trimethylcyclopentanone t-butylhydrazone was prepared by refluxing an aqueous solution of t-butylhydrazine with an equimolar amount of 2,4,4-trimethylcyclopentanone.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[CH2:1]([NH:8][C:10](=[O:11])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCc1ccccc1)Oc1ccccc1
Reaction time: 72 h

Procedure:
Benzylamine (53.5 g.) is added during 30 minutes to a stirred suspension of phenyl chloroformate (78.3 g.) and anhydrous potassium carbonate (151.8 g.) in dioxan (500 ml.) and the mixture is stirred at laboratory temperature for 72 hours and then poured into water. The mixture is extracted with ethyl acetate and the extract is washed with water, dried over magnesium sulphate and evaporated to dryness. The residue is stirred with petroleum ether (b.p. 60°-80° C.) and the mixture is filtered. There is thus obtained as solid residue phenyl N-benzylcarbamate, which is used without further purification.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[C:19](=O)([O-])O.[Na+]>CO>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:15]=1)[C:12]([O:14][CH3:19])=[O:13]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
2 ml of concentrated sulfuric acid was added to a methanol (200 ml) solution of 10 g of 5-fluoro-2-nitrobenzoic acid, and heated under reflux for 22 hours. 200 ml of aqueous sodium hydrogencarbonate solution was added to it, and the formed solid was taken out through filtration. This was dried under reduced pressure to obtain 10.7 g of the entitled compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]([C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)[C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C>[CH2:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=1[O:1][CH:22]([C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)[C:23]([O:25][CH3:26])=[O:24])[CH2:13][CH3:14]
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: CCCc1cc(S(N)(=O)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(S(N)(=O)=O)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3.06 g (14.23 mmol) of the product of Step B dissolved in 25 mL of anhydrous DMF was added 4.87 g (15.0 mmol) of cesium carbonate and the reaction mixture was magnetically stirred under a nitrogen atmosphere at room temperature for 15 minutes. Methyl α-bromo-3,4-methylenedioxyphenylacetate (4.08 g, 15.0 mmol) was then added and the reaction mixture was stirred for an additional 3 hours. The reaction mixture was then partitioned between EtOAc (80 mL) and 10% aqueous citric acid (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3, satuarated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was dried in vacuo to afford 5.90 g (5.79 theoretical) of the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=[O:6].[Cl:11]C1C=CC=CC=1Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[C:5]([Cl:11])=[O:6]
Reactant: Clc1ccccc1Cl
Reactant: Cc1cc(C)cc(C=O)c1
Product: Cc1cc(C)cc(C(=O)Cl)c1
Reaction time: 6 h
Yield: 70 %

Procedure:
Into a 2-L three-necked flask equipped with a gas blowing tube, a reflux condenser and a stirrer, were charged 269.7 g (2 mol) of 3,5-dimehtylbenzaldehyde and 800 g of o-dichlorobenzene. The temperature of the reaction system was controlled to 5° C. while introducing a nitrogen gas. After bubbling the reaction solution by blowing a nitrogen gas for one hour, the feed of nitrogen was stopped and the feed of chlorine was started. Simultaneously with the feed of chlorine, the irradiation of light from a mercury lamp was started. The photochlorination was completed after 6 h. The quantitative analysis by gas chromatography showed the production of 1.4 mol of 3,5-dimethylbenzoyl chloride (yield: 70%). By vacuum distillation, 236 g (1.4 mol) of 3,5-dimethylbenzoyl chloride was isolated (yield: 68%). The results of total elements analysis by ICP showed that a total content of residual group 3 to group 12 metals was 500 ppm or lower in which the highest was 10 ppm of Fe and the second highest was 30 ppm of Zn.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:18]([NH2:21])([CH3:20])[CH3:19])[CH:15]=[CH:16][CH:17]=3)[N:9]([CH3:22])[N:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:32]1([NH:36][S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([NH:36][S:37]([NH:21][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:10]3[N:9]([CH3:22])[N:8]=[C:7]([CH2:6][C:5]4[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=4)[CH:11]=3)[CH:13]=2)([CH3:20])[CH3:19])(=[O:39])=[O:38])[CH2:35][CH2:34][CH2:33]1
Reactant: Cn1nc(Cc2ccc(F)cc2)cc1-c1cccc(C(C)(C)N)c1
Reactant: O=S(=O)(Cl)NC1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nc(Cc2ccc(F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)NC2CCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The crude amine was dissolved in CH2Cl2 (5 mL) and Et3N (222 μL, 1.6 mmol) and crude cyclobutylsulfamoyl chloride (136 mg, ca. 0.8 mmol) were added and the reaction was stirred at RT for 30 min. The reaction was evaporated under reduced pressure and diluted with MeCN:DMSO (1:1, 2 mL) and filtered. The filtrate was injected on to a reverse phase HPLC system and the title compound was isolated, after basic workup, as a yellow gum (4 mg, 1% over 2 steps). 1H NMR (CDCl3, 500 MHz) δ 7.52-7.48 (2H, m), 7.41 (1H, t, J=8.6 Hz), 7.31-7.23 (3H, m), 6.98 (2H, t, J=8.8 Hz), 6.02 (1H, s), 4.49 (1H, s), 4.10 (1H, d, J=8.4 Hz), 3.96 (2H, s), 3.85 (3H, s), 3.82-3.73 (1H, m), 2.30-2.21 (2H, m), 1.90-1.79 (2H, m), 1.73 (6H, s), 1.72-1.63 (2H, m). MS (ES+) C24H29FN4O2S requires 456: found: 457 (M+H+).
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[H-].[Na+].[C:9]([C:12]1[C:17]([CH3:18])=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:11])[CH3:10].O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:18][C:17]1[C:12]([C:9](=[O:11])[CH2:10][C:1]([O:4][CH3:5])=[O:6])=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: CC(=O)c1nccnc1C
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CC(=O)c1nccnc1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
21.4 g of dimethyl carbonate was added dropwise to a stirred mixture of 5.7 g of sodium hydride and 100 ml of toluene at room temperature. Then the mixture was heated to 80° C. and a solution of 16.1 g of 2-acetyl-3-methylpyrazine in 75 ml of toluene was added dropwise and the mixture was stirred at 75° C. for one hour. The mixture was cooled, 100 ml of water was added and the mixture was acidified with glacial acetic acid. The organic phase was separated, dried (Na2SO4) and stripped of volatiles. The residue was flash chromatographed on silica gel, with a 9:1 v:v mixture of methyl chloride and ethyl acetate as eluent. The second set of fractions was stripped of solvent to give methyl 3-(3-methyl-2-pyrazinyl)-3-oxopropionate (31A), as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:19]CC4C=CC(OC)=CC=4)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:29]#[N:30])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][N:15]=1)[N:12]=[CH:11][C:10]([C:29]#[N:30])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COc1ccc(CNc2cc3c(Nc4cccc(Br)c4)c(C#N)cnc3cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: N#Cc1cnc2cnc(N)cc2c1Nc1cccc(Br)c1
Reaction time: 20 h
Yield: 84.6 %

Procedure:
To 400 mg of 4-(3-bromo-phenylamino)-6-(4-methoxy-benzylamino)-[1,7]naphthyridine-3-carbonitrile in 10 mL of methylene chloride was added 10 mL of trifluoroacetic acid. After stirring under an inert atmosphere for 20 hours, 10 mL of toluene was added and the solvents were stripped on a rotary evaporator. The product was purified by flash chromatography with a gradient of 0-5% methanol/chloroform to give 250 mg of 6-amino-4-(3-bromo-phenylamino)-[1,7]naphthyridine-3-carbonitrile as an off-white solid: melting point 185-190° C. (decomposed); mass spectrum (m/e): M+H 340.0, 342.1.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([SnH:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8]>C1(C)C=CC=CC=1>[CH2:14]([Sn:9]([CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH3:13])/[CH:3]=[CH:2]/[CH2:1][OH:4])[CH2:15][CH2:16][CH3:17]
Reactant: C#CCO
Reactant: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC[Sn](/C=C/CO)(CCCC)CCCC

Procedure:
To a mixture of propargyl alcohol (2.24 g) and α,α'-azoisobutyronitrile (0.10 g) in anhydrous toluene (150 ml) is added tributyltin hydride (12.9 ml) and the mixture heated at reflux for about 2.5 hours, cooled and concentrated in vacuo. The crude product is purified by flash chromatography in 15% ether in hexane to give the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[CH:2]=1.[CH3:17][N:18]=[C:19]=[O:20].CCN(CC)CC.O>C1COCC1>[CH3:17][NH:18][C:19]([N:13]1[C:14]2[C:9](=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:16][N:15]=2)[CH2:10][CH2:11][CH2:12]1)=[O:20]
Reactant: CN=C=O
Reactant: c1cncc(-c2cnc3c(c2)CCCN3)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CCCc2cc(-c3cccnc3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
A solution of 6-pyridin-3-yl-1,2,3,4-tetrahydro-[1,8]naphthyridine (40 mg, 0.19 mmol) in 2 mL of THF is added to methyl isocyanate (16 mg, 0.28 mmol) followed by the addition of Et3N (61 mg, 0.60 mmol). The mixture is stirred at ambient temperature for 16 hrs. To the mixture is added 0.5 mL of water, stirred for 5 minutes and concentrated in vacuo. The residue is dissolved in 1 mL of DMF, filtered and purified by reverse phase HPLC to give 23 mg of the titled product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[C:19]([F:22])([F:21])[F:20])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:27].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:23])[N:7]([CH3:27])[C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[C:19]([F:22])([F:21])[F:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cccnc2)nc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 55.7 %

Procedure:
To a solution of (2-pyridin-3-yl-4-trifluoromethyl-thiazol-5-yl)-carbamic acid tert-butyl ester (4.7 g, 13.6 mmol) in DMF (70 mL) at 0° C. was added sodium hydride (NaH, 0.65 g, 16.3 mmol, 60% dispersion in mineral oil) in one portion and the mixture was stirred for 50 min. Iodomethane (0.89 mL, 14.3 mmol) was added in one portion, and after 5 min the reaction mixture was warmed to room temperature and stirred for 5.5 h. Water and ethyl acetate were added, the resulting biphasic mixture was separated and the aqueous layer was extracted one time with ethyl acetate. The combined organic extracts were washed twice with brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a clear orange oil (2.72 g, 56%); IR (KBr) 3428, 2981, 1728, 1561 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=2.5 Hz, 1H), 8.72 (dd, J=4.9, 1.1 Hz, 1H), 8.26 (dt, J=8.0, 1.7 Hz, 1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 3.28 (s, 3H), 1.45 (s, 9H); ESIMS m/z 360.6 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH:12]([CH2:14][CH3:15])[CH3:13]>>[CH3:13][CH:12]([O:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH2:9][OH:10])[CH2:14][CH3:15]
Reactant: OCc1ccc(Cl)cc1O
Reactant: CCC(C)Br
Product: CCC(C)Oc1cc(Cl)ccc1CO

Procedure:
The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol (PREPARATION 7) and 2-bromobutane according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 0.98 (3H, t, J=7.6 Hz), 1.32 (3H, d, J=6.0 Hz), 1.65-1.79 (2H, m), 2.30 (1H, t, J=6.8 Hz), 4.32-4.40 (1H, m), 4.62 (2H, d, J=6.4 Hz), 6.85 (1H, d, J=1.6 Hz), 6.89 (1H, dd, J=1.6 Hz, 7.6 Hz), 7.19 (1H, d, J=8.4 Hz).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CC([O-])(C)C.[Na+].[CH3:16][O:17][C:18]([C:20]1[S:31][C:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[OH:32])=[O:19].O>CN(C=O)C>[CH3:16][O:17][C:18]([C:20]1[S:31][C:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[O:32][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:19]
Reactant: COC(=O)c1sc2c(sc3ccccc32)c1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc2c(sc3ccccc32)c1OCC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
tert-Butyl bromoacetate (0.082 ml, 0.56 mmol, 1.3 equiv) was added to a mixture of NaOt-Bu (50 mg, 1.2 equiv) and 1-hydroxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (113 mg, 0.43 mmol, 1 equiv) in DMF (10 ml). The resulting mixture was stirred at 60° C. for 16 hr. Addition of water followed by extraction with EtOAc and washing with water left crude product. Purification by column chromatography gave 140 mg (86%) of 1-tert-butoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as an orange solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>CC(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 70 °C
Yield: 53.3 %

Procedure:
Sodium hydroxide (15 mg) was added to a solution of ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D36) (110 mg) in iPrOH (4 mL) and water (4 mL). The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitate was purified by Mass Directed Auto Prep to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E13) (55 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.40 (6H, d), 2.63 (2H, t), 3.00 (2H, t), 5.46 (1H, m), 7.21 (1H, t), 7.27 (1H, d), 7.82 (1H, d), 7.93 (1H, d), 8.75 (1H, d), 9.06 (1H, d), 10.87 (1H, s), 12.08 (1H, br s). MS (ES): C21H19ClN4O4 requires 426. found 427.1 (M+H+).