Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[H-].[Na+].[CH3:11][NH:12][C:13](=[O:15])[CH3:14]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:12]([CH3:11])[C:13](=[O:15])[CH3:14])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CNC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(C)c1ncc(Br)cn1
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-2-chloroprimidine (2.00 g, 10.34 mmol) in THF was added 60% NaH (0.34 g, 14.00 mmol) in mineral oil. After 20 minutes, N-methylacetamide (0.80 g, 11.00 mmol) was added dropwise. After 2 hours, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 30% ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford N-(5-bromo-pyrimidin-2-yl)-N-methyl-acetamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:6]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:26]1C=CC(C(C)(C)C)=C(OC2C=CC(CC)=CC=2)C=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:13]([CH3:15])([CH3:14])[CH3:16])=[CH:7][C:6]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:26])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Oc2cc(C#C[Si](C)(C)C)ccc2C(C)(C)C)cc1
Reactant: CCc1ccc(Oc2cc(Br)ccc2C(C)(C)C)cc1
Product: CCc1ccc(Oc2cc(C#C[Si](C)(C)C)ccc2C(C)(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of 2-tert-butyl-5-trimethylsilanylethynyl-1-[(4'-methyl)phenoxy]benzene (Compound U), 52 mg (0.16 mmol) 5-bromo-2-tert-butyl-1-[(4'-ethyl)phenoxy]benzene (Compound T) was converted into the title compound using 28 mg (0.04 mmol) of bis(triphenylphosphine)palladium (II) chloride, 7 mg (0.04 mmol) of cuprous iodide, 0.2 mL (150 mg, 1.5 mmol) of trimethylsilyl acetylene and 3 mL of triethylamine. An additional 28 mg (0.04 mmol) of bis(triphenylphosphine)palladium (II) chloride, and 0.2 mL (150 mg, 1.5 mmol) of trimethylsilyl acetylene were added after 3 days of heating, and the resultant mixture was then heated at 75° C. for 4 more days. Purification by flash chromatography (preabsorbed onto silica with 100% chloroform, eluted with 100% hexane) gave the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].[N:20]1(C(=N)N2C=CN=C2)C=CN=[CH:21]1>CS(C)=O>[NH2:20][C:21]1[O:13][C:12]([C:11]2[CH:16]=[CH:17][N:18]=[CH:19][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[N:14][N:15]=1
Reactant: N=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Solvent: CS(C)=O
Product: Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (1 g, 2.68 mmol) in DMSO (6 mL) were added 1,1-di-1H-imidazol-1-yl-methyleneamine (864 mg, 5.36 mmol). The reaction mixture was stirred at RT for 18 h. Quenching of the reaction by adding water (60 mL). A solid precipitated out. The solid was filtered, washed with water and cold methanol. Yield: white solid 1.0 g. LC-MS (Method A) [4.66 min; 398(M+1)].
Reaction SMILES: [F:1][As-:2]([F:7])([F:6])([F:5])([F:4])[F:3].C1([I+][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)C=CC=CC=1.[C:21]1([S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[F:1][As-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:28]1([S+:27]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: c1ccc([I+]c2ccccc2)cc1
Agent: [Cu+2]
Agent: F[As-](F)(F)(F)(F)F
Agent: O=C([O-])c1ccccc1
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of 11.75 parts of diphenyl iodonium hexafluoroarsenate, 4.065 parts of diphenyl sulfide and 0.2 part of copper benzoate was heated with stirring at a temperature of 120°-125° C. for 3 hours. The mixture was then poured while it was hot into a container whereupon the product crystallized. The product was extracted three times with diethylether and then air dried. There was obtained a 97% yield of triphenylsulfonium hexafluoroarsenate. The triphenylsulfonium hexafluoroarsenate product had a melting point of 195°-197° C. after it was further recrystallized from 95% ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Br:17]Br.CO>O>[Br:17][C:8]1[C:7]([Cl:12])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]2
Reactant: BrBr
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Clc1ccc2c(Br)c(Cl)ccc2n1
Temperature: 25 °C

Procedure:
2,6-Dichloroquinoline (30 g) and aluminium trichloride (60 g) were heated to 120° C. with stirring under a nitrogen atmosphere. Bromine (9.2 mL) was added dropwise over 1 hour and the mixture was then stirred at 120° C. for 1 hour before being cooled to room temperature. A methanol/deionised water mixture (150 mL, 1:1) was then slowly added and the mixture was concentrated in vacuo. Dichloromethane (500 mL) and deionised water (250 mL) were added, the layers were separated and the aqueous fraction was extracted with dichloromethane (2×250 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (250 mL) before being dried, filtered and concentrated. Purification by chromatography (SiO2, isohexane:dichloromethane 7:3 as eluant) gave the title compound as a solid (27 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].C(OC([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)[CH2:15][CH2:14]1)=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[N:1]1([CH2:21][CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)N1CCN(CCCOS(C)(=O)=O)CC1
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cn(CCCN2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
To a solution of imidazole 0.68 g and N,N-dimethylformamide 20 ml was added 60% sodium hydride 0.60 g under ice-cooling, followed by stirring at room temperature for 5 minutes. To the resultant mixture was added 1-ethoxycarbonyl-4-(3-mesyloxypropyl)piperazine 3.68 g and the mixture was stirred at room temperature overnight. To the reaction mixture were added saturated solution of sodium hydrogen carbonate 50 ml and ethyl acetate 200 ml and the organic layer was taken using a separating funnel, dried over anhydrous magnesium sulfate and the solvent distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent: 10% methanol-ethyl acetate), and dissolved in ethanol 25 ml. To the solution was added 10% sodium hydroxide 25 ml and the mixture refluxed overnight. After cooling, ethyl acetate 100 ml was added to the solution, the organic layer was separated, and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.39 g of 1-[3-(1-imidazolyl)propyl]piperazine.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[CH:10]=[C:9]4[N:12]=[CH:13][N:14]=[C:8]4[CH2:7][C:6]=3[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1cnc2c(c1Cl)C=C1N=CN=C1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(c1Nc1cccc(Br)c1)C=C1N=CN=C1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
A mixture of 0.2 g (0.87 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.12 mL (1.1 mmol) of 3-bromoaniline, and 0.1 g (0.87 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at reflux temperature for 45 minutes, then cooled to room temperature. The product mixture is poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried. The solid is purified by silica gel chromatography, utilizing a gradient of methylene chloride/methanol(98:2 to 93:7) to yield 0.20 g of 8-(3-bromo-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as pink solid, mp 286-288° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][C:16]#[C:17][CH3:18])[C:3]1=2.N12CCCN=C1CCCCC2.[CH3:30][N:31]=[C:32]=[O:33]>C(Cl)Cl>[CH3:30][NH:31][C:32](=[O:33])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][C:16]#[C:17][CH3:18])[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: CN=C=O
Reactant: CC#CN=C1CCc2c1n(C)c1ccc(O)cc21
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC#CN=C1CCc2c1n(C)c1ccc(OC(=O)NC)cc21
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 4-methyl-3-propynylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-ol (3.4 g) in CH2Cl2 (15.0 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (326 mg) followed by the dropwise addition of methyl isocyanate (0.8 g) in CH2Cl2 (5.0 ml). The reaction was monitored via TLC and after 1.0 hour, the solution was concentrated and the crude product was purified via flash chromatography eluting with hexane/acetone (2:1). The product which precipitated out of the pure fractions was collected to give 4-methyl-3-propynylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-yl methylcarbamate (1.2 grams) and the fractions were concentrated to give an additional 0.9 gram.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:31])([CH3:30])[CH2:22][NH:23][S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:29][N:27]([CH3:28])[S:24]([NH:23][CH2:22][C:21]([F:31])([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH:10]=2)=[CH:20][CH:19]=1)[CH3:30])(=[O:25])=[O:26]
Reactant: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1cccc(-c2ccc(C(C)(F)CNS(=O)(=O)N(C)C)cc2)c1
Temperature: 0 °C

Procedure:
In a 250 mL 3 neck flask fitted with a stirrer and thermometer, 356 mg of 2-propanesulfonyl chloride is added dropwise to 350 mg of {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(dimethylamino)sulfonyl]amine (prepared in example 38) and 380 mg of DBU in THF (125 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction is allowed to warm to room temperature and then stirred overnight at this temperature. In the morning, the reaction is concentrated under reduced vacuum. The resulting material is taken into ethyl acetate and the organic layer is washed two times with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum. This crude material is purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor with hexane/ethyl acetate eluent to provide the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].FC1C=CC(NC2CCN(C(OC(C)(C)C)=O)CC2)=CC=1>>[F:15][C:16]1[CH:17]=[C:18]([NH:19][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(F)c(F)c1
Agent: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(F)c2)CC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate and 3,4-difluoroaniline using a method similar to that described for D1 although the crude product was purified by chromatography.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][CH:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][CH:24]([O:26][C:27](Cl)=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36]>ClCCl>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][C@H:24]([O:26][C:27]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CN(C)CCN
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCN(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h
Yield: 25 %

Procedure:
Cholesteryl chloroformate (3 g, 6.7 mmoles) in 5 mL dry dichloromethane was added dropwise to a solution of N,N-dimethylethylene diamine (24 mmoles) in 4 mL dry dichloromethane at 0° C. The reaction was allowed to stir overnight. The solvent was then evaporated on a rotary evaporator and the residue was purified by recrystallisation from absolute ethanol to give a white solid (0.84 g, 25% yield, Rf=0.5 in 30% methanol in chloroform).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11](Br)=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].[CH:16]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11]([N:24]3[CH2:25][CH2:26][N:21]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:22][CH2:23]3)=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(Br)nc2[nH]1
Reactant: C1CCC(N2CCNCC2)C1
Product: CCOC(=O)c1cc2ccc(N3CCN(C4CCCC4)CC3)nc2[nH]1
Temperature: 140 °C
Yield: 39.5 %

Procedure:
A mixture of 1 g (3.7 mmol) 6-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester (prepared according to the method described in WO 2003/064423 A1) and 2.8 g (18.6 mmol) 1-cyclopentyl-piperazine (commercially available) was heated to 140° C. for 1 h. The mixture was absorbed on isolute and purified by flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate (0.1% NEt3). Evaporation of the product fractions yielded 501 mg (39%) of the title compound as white solid. MS: (m/e): 343.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[O:24][CH3:25]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:24][CH3:25])[C:16]=2[F:23])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nc(Cl)n1
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
6-Amino-2-chloro-pyrimidine-4-carboxylic acid methyl ester (2.25 g, 12 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol), and bis(triphenylphosphine)palladium(II)dichloride (842 mg, 1.2 mmol) were combined in 12 mL of dimethoxyethane and 12 mL of water. The reaction mixture was heated at 80° C. for 2 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated under vacuum. The product was purified by column chromatography to yield 6-amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (2.0 g, 53.5% yield): mp 188-190° C.: 1H NMR (CDCl3): δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[C:6]([F:15])[C:3]=1[C:4]#[N:5].O[CH2:17][C@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19]>>[NH2:20][C@H:18]([CH3:19])[CH2:17][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[C:6]([F:15])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1c(F)cc(-c2cc[nH]n2)cc1Cl
Product: C[C@@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Yield: 70.5 %

Procedure:
(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile was prepared using the method of Example 202 starting from 2-chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (5.0 g, 22.56 mmol) and (R)-tert-butyl (1-hydroxypropan-2-yl)carbamate (7.91 g, 45.1 mmol). The product was evaporated to dryness. Yield 70.5%. 1H-NMR (400 MHz; DMSO): δ 0.96 (d, 3H), 3.20-3.30 (m, 1H), 4.00-4.10 (m, 2H), 7.03 (d, 1H), 7.85-7.91 (m, 2H), 7.99 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH2:25]([Mg]Br)[CH2:26][CH3:27].[NH4+].[Cl-]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH2:25][CH2:26][CH3:27])[CH2:6][C:5]2=[O:12]
Reactant: CCC[Mg]Br
Reactant: O=c1ccoc2ccc(Br)cc12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCC1CC(=O)c2cc(Br)ccc2O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of 6-bromo-4H-chromen-4-one (12 g, 53 mmol) in CH2Cl2 (24 mL) was added TMSOTf (12.5 mL, 69.18 mmol) at ambient temperature. After stirring for 1 hour, THF (210 mL) was added to the mixture at ambient temperature and cooled to −78° C. To the mixture was added n-propylmagnesium bromide (1.05M solution in THF, 66 mL, 69 mmol). After stirring for 1 hour at −78° C., 1M aqueous NH4Cl was added to the mixture. The mixture was warmed to ambient temperature and stirred overnight. The organic and the aqueous layers were separated, and the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 10%) to afford 6-bromo-2-propyl-2,3-dihydro-4H-chromen-4-one (11.42 g).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[C:16]1([C:3]2[C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3cccc(OC(F)(F)F)c3)nc2c1
Yield: 56.3 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 3-(trifluoromethoxy)phenylboronic acid (89.6 mg, 0.43 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) afforded 67 mg (55%) of 2-phenyl-3-(3-(trifluoromethoxy)phenyl)quinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.[OH-:20].[Na+].Cl>>[CH3:19][O:18][C:14]1[C:5]2[CH:6]=[C:7]([C:8]([OH:20])=[O:13])[S:11][C:1](=[O:3])[C:4]=2[CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: COc1cccc(C(=O)O)c1C=C1SC(=S)NC1=O
Agent: Cl
Agent: [Na+]
Product: COc1cccc2c(=O)sc(C(=O)O)cc12

Procedure:
A solution of 0.6 g. (2 mM) of the benzylidenerhodanine of Example 16 in 10 ml. of 15% NaOH is refluxed under nitrogen for 0.5 hour, cooled, and poured into cold dilute HCl to form a tan precipitate. The solid is collected, washed with water and recrystallized from methanol to give 5-methoxy-1-oxo-1H-2-benzothiopyran-3-carboxylic acid as yellow needles, m.p. 283°-284°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@H:10]3[CH2:14][CH2:13][CH2:12][NH:11]3)[CH:5]=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cncc(OC[C@H]3CCCN3)c2)cc1
Yield: 134 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (300 mg, 0.84 mmol) and 4-chlorophenylboronic acid (263 mg, 1.68 mmol, Lancaster Chemical Co.) in toluene (10 mL) was added Pd(0) (25 mg) and Na2CO3 (1 mL of a 2M solution), and the mixture was heated at reflux for 6 hours. The solvent was removed under vacuum, and the residue was chromatographed on a silica gel column, eluting with 1:5 to 1:2 ethyl acetate/hexane to afford the title compound (325 mg, 100% yield). MS (DCI/NH3) m/z 389 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 1.47 (s, 9h), 1.90 (m, 2H), 2.05 (br, 1H), 3.40 (br, 2H), 3.92 (br, 1H), 4.19 (br, 2H), 4.25 (br, 1H), 7.44 (m, 2H), 7.52 (m, 3H), 8.31 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:49]([N:51]([CH2:56][CH3:57])[C:52](=[O:55])[CH:53]=[CH2:54])[CH3:50].C(#N)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:49]([N:51]([CH2:56][CH3:57])[C:52](=[O:55])/[CH:53]=[CH:54]/[C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:11]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:9])=[CH:6][CH:7]=1)[CH3:50]
Reactant: C=CC(=O)N(CC)CC
Reactant: O=C(c1ccc(Br)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)C(=O)/C=C/c1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 85 °C
Yield: 55.1 %

Procedure:
To a screw cap seal tube is added 0.83 g (2.0 mmol) of the product from Example 2, 0.25 g (0.82 mmol) of tri-o-tolylphosphine, 0.30 g (2.3 mmol) of N,N-diethyl acrylamide, 0.045 g (0.21 mmol) of palladium acetate, 40 mL of acetonitrile and 4 mL of triethylamine. The solution was purged with nitrogen then capped and heated to 85° C. for 15 hours. At the end of this time, the solution was concentrated, then taken up in 100 mL of water:ethyl acetate (1:2). The organic layer was separated and the water layer extracted once with ethyl acetate. The ethyl acetate layers were combined, dried (MgSO4) and concentrated. The residue subjected to column chromatography on silica. Elution first with 60% ethyl acetate:hexane followed by ethyl acetate:hexane:isopropanol (60:35:5) yielded 0.52 g of product (55%) which was crystallized from chloroform:acetone:hexane mp 159°-163° C. (soft).