Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[C:6]=2[CH:16]=1.[C:17](=O)=O.C(O)(C)C.CC(C)([O-])C.[K+].IC.[Br-].[K+]>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]([N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[CH3:17])[C:6]=2[CH:16]=1
Reactant: Clc1ccc2onc(Cn3ccnc3)c2c1
Reactant: O=C=O
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CC(C)O
Product: CC(c1noc2ccc(Cl)cc12)n1ccnc1
Product: Cl
Temperature: -35 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-chloro-3-[(1H-imidazol-1-yl)methyl]-1,2-benzisoxazole (500 g, 2.14 moles) in dimethylformamide (3.5 L) is cooled to -35° C. (dry ice/isopropanol bath) and is subsequently added, all at once, to a precooled (-35° C.) solution of potassium t-butoxide (266 g, 2.37 moles) in dimethylformamide (3.5 L). A deep red color develops immediately. The mixture is stirred at -35° C. for 5 minutes and is then cooled to -55° C. over a period of 10 minutes. At this point, iodomethane (433 g, 3.05 moles) is added all at once. There is an exotherm to -22° C. and then the temperature begins to decrease. At -26° C. the reaction mixture decolorizes, solid potassium bromide separates and there is a mild exotherm to -22° C. which is maintained for 5 minutes. The mixture subsequently cools quickly to -55° C. and stirring is continued for 30 minutes at this temperature. The cooling bath is then removed and the reaction temperature is allowed to rise to 0° C. over a period of 1.5 hours. The reaction mixture is then poured into water (35 L) and the mixture is extracted with ethyl acetate (20 L). The layers are separated and the organic solution is washed with water (6×6 L), dried over anhydrous sodium sulphate (5 Kg), filtered, and evaporated in vacuo. The residual oil is digested with petroleum ether (b.p 40°-60° C.) (2×2 L) at room temperature, and the solvent is then decanted and discarded. The digestion process is repeated with ether (4×3 L) and the combined ethereal extracts are dried over anhydrous sodium sulfate (500 g) and filtered. The filtrate is acidified with ethereal hydrogen chloride (500 mL, 6N) and the suspension is stirred for 30 minutes and then filtered. The filter cake is washed with ether (2×500 mL) and the product is digested in refluxing acetone (2 L) for 1 hour. The suspension is cooled to room temperature and filtered. The filter cake is washed with acetone (2×500 mL) and ether (2×500 mL) and the product is dried for 18 hours at 60° C./9 mm Hg to afford 5-chloro-3-[1-(1H-imidazol-1-yl)ethyl]-1,2-benzisoxazole hydrochloride, m.p. 161°-166° C., of formula IIa wherein R1 is methyl, R3 is 5-chloro, R2 and R4 -R6 are hydrogen.
Reaction SMILES: [CH2:1]1COCC1.[C:6]([N:16]=[C:17]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O>CO>[CH3:1][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])=[N:16][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7]
Reactant: O=C(O)CCCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Product: COC(=O)CCCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 19 h
Yield: 42 %

Procedure:
To a THF (300 mL) solution of compound 31 (50.8 g, 0.12 mol) was added carbonyldiimidazole (21.4 g, 0.132 mol). The resultant suspension was stirred for 1 h at room temperature. Methanol (75 mL) was added, followed by an additional stirring of the solution for 19 h. The solution was concentrated, and the residue was partitioned between water and ether. The organic phase was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (Et2O:hexane/1:1) to afford 22.8 g (42%) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Br)C.[C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH3:13].[Br:20][C:21]1[CH:22]=[C:23]([C:27]#[N:28])[CH:24]=[N:25][CH:26]=1.[Cl-].[NH4+]>C(OCC)C>[NH2:28][C:27]([C:23]1[CH:24]=[N:25][CH:26]=[C:21]([Br:20])[CH:22]=1)=[CH:13][C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: N#Cc1cncc(Br)c1
Reactant: CC(=O)OC(C)(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C=C(N)c1cncc(Br)c1
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
Diisopropylamine (9.2 mL, 65 mmol) was added at 0° C. to a 3M solution of ethyl magnesium bromide in diethyl ether (10.9 mL, 32.7 mmol) and additional diethyl ether (20 mL). After one hour at 0° C. tert-butyl acetate (4.3 mL, 32.7 mmol) was added and stirring was continued for 30 minutes. 5-Bromopyridine-3-carbonitrile (2.0 g, 10.9 mmol) in diethyl ether (42 mL) was added at 0° C. After two hours at 0° C. saturated aqueous ammonium chloride solution was added. Phases were separated and the aqueous phase was extracted with diethyl ether. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 0 to 60%) to yield 1.12 g tert-butyl 3-amino-3-(5-bromopyridin-3-yl)prop-2-enoate.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1I.C(N(CC)CC)C.[CH3:17][C:18]([CH3:22])([CH3:21])[C:19]#[CH:20]>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.[Cu]I.C1COCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:20]#[C:19][C:18]([CH3:22])([CH3:21])[CH3:17]
Reactant: C#CC(C)(C)C
Reactant: Cc1cccc(I)c1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(C#CC(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with bis(triphenylphosphine)palladium(II)chloride (0.042 g, 0.060 mmol) and copper(I) iodide (0.023 g, 0.120 mmol) under nitrogen atmosphere. THF (4.6 mL) was added, followed by 2-bromo-1-iodo-3-methylbenzene (0.594 g, 2 mmol), triethylamine (2.3 mL, 16.50 mmol) and 3,3-dimethylbutyne (0.251 mL, 2.040 mmol). The reaction mixture was allowed to stir at RT overnight. The reaction mixture was filtered through a plug of silica gel and the plug was rinsed with Et2O. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (0-2% EtOAc/hexanes). 2-Bromo-1-(3,3-dimethylbut-1-ynyl)-3-methylbenzene was obtained as a light-yellow clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[CH2:17][CH2:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH2:17][CH2:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(CCI)CCc1ccc(F)cc1
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CC(CCC(=O)CCc2ccc(F)cc2)[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 48.5 g (0.23 mole) of 2-(3',4'-dimethoxyphenyl)-1-nitroethane in 400 ml of dry tetrahydrofuran was added 96.0 (0.23 mole) of 40% Triton B. The solution was stirred at room temperature for 10 minutes. 66.7 g (0.23 mole) of 1-iodo-5-(4'-fluorophenyl)-3-pentanone in a minimum amount of dry tetrahydrofuran was added dropwise. The mixture was heated at 50° C. for 3 hours, then allowed to stir at room temperature overnight. Solvent was removed in vacuo and the residue taken up in ether and extracted twice with water. The organic layer was dried over anh MgSO4, filtered and concentrated at reduced pressure to obtain a crude oil. The crude material was passed through HPLC to give 79 g purified material.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[CH3:13]OC(OC)(C)C.S(=O)(=O)(O)O>CO>[C:10]([CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)([O:12][CH3:13])=[O:11]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 144 h
Yield: 96.1 %

Procedure:
Dissolve 2-indancarboxylic acid (3.82 g, 23.5 mmol) in methanol (60 mL) and treat with dimethoxypropane (5.8 mL, 47 mmol) and sulfuric acid (0.8 mL). Stir at room temperature for 6 days. Evaporate the solvent in vacuo, dilute with methylene chloride (75 mL) and wash with saturated sodium hydrogen carbonate (35 mL). Extract the aqueous phase with methylene chloride (30 mL), wash combined organics with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and pass through a plug of silica gel to give 2(carbomethoxy)indan as a yellow oil (3.98 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](O)=O)[CH3:2].C([Li])CCC.[Cl:15][C:16]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:17]=1C(Cl)=O.Cl.[O:28]1CCCC1>>[CH2:1]([O:3][C:4](=[O:9])[C:5](=[O:28])[CH2:6][C:17]1[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:16]=1[Cl:15])[CH3:2]
Reactant: O=C(Cl)c1cc(F)c(F)cc1Cl
Reactant: C1CCOC1
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: [Li]CCCC
Product: CCOC(=O)C(=O)Cc1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Malonic acid monoethyl ester (26 g, 199 mmol) was dissolved in tetrahydrofuran (500 ml) and cooled to -70°. After the addition of n-butyllithium (112.5 ml of a 1.6M solution in hexanes, 180 mmol), the reaction mixture was allowed to warm to -10°, and additional n-butyllithium was added (112.5 ml, as above). The resulting milky-white mixture was cooled to -70°, and treated with 2-chloro-4,5-difluorobenzoyl chloride (19 g, 90 mmol) in tetrahydrofuran (200 ml). After warming to room temperature, the reaction mixture was allowed to stir for an additional 2 hours, then poured into 2N hydrochloric acid (750 ml). The aqueous mixture was extracted with ethyl ether, and the combined organic layers were dried and concentrated to provide the title product as a light amber oil (20.6 g, 78.6 mmol, 87% yield), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[C:27](O)=[O:28])[CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:27]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]5[C:26]=4[N:17]=[CH:18][CH:19]=[CH:20]5)=[O:28])[CH2:12][CH:11]3[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1cccc2cccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc5cccnc45)CC3C2)n1
Yield: 65 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), quinoline-8-carboxylic acid (52.4 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (106.6 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (68.0 mg, 66.2%). MS (ESI) mass calcd. for C22H23N5O, 373.46; m/z found 374.2 [M+H]+. 1H NMR (CDCl3): 8.95 (s, 1H), 8.16 (d, J=7.9, 1H), 7.89-7.79 (m, 1H), 7.69 (d, J=6.8, 1H), 7.61-7.49 (m, 1H), 7.41 (s, 1H), 6.26 (d, J=19.1, 1H), 4.29-4.03 (m, 1H), 3.96-3.59 (m, 4H), 3.65-3.29 (m, 2H), 3.21-2.84 (m, 3H), 2.37-2.18 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]([Cl:15])=[C:6]([S:8][C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)[CH:7]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2>C(O)(=O)C>[Cl:15][C:5]1[CH:4]=[C:3]([F:16])[C:2]([N:1]2[C:20](=[O:21])[CH:19]3[C:18](=[CH:26][CH2:25][CH2:24][CH2:23]3)[C:17]2=[O:22])=[CH:7][C:6]=1[S:8][C:9]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(SC2(C(=O)O)CC2)c(Cl)cc1F
Solvent: CC(=O)O
Product: O=C1C2=CCCCC2C(=O)N1c1cc(SC2(C(=O)O)CC2)c(Cl)cc1F
Temperature: 0 °C

Procedure:
A mixture of 2.4 g of 1-(5-amino-2-chloro-4-fluoro-phenylthio)-cyclopropanecarboxylic acid, 1.5 g of 3,4,5,6-tetrahydrophthalic anhydride and 100 ml of glacial acetic acid is heated under reflux for 18 hours while stirring. The reaction mixture is then introduced into ice-water and the resulting product is extracted with ethyl acetate. Drying over sodium sulfate and concentration of the solution by evaporation yield 1.7 g of 1-[2-chloro-4-fluoro-5-(1,2,3,4,5,6-hexahydro-1,3-dioxo-isoindolyl)-phenylthio]-cyclopropanecarboxylic acid having a melting point of from +186° to +188° C.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][CH2:7][CH2:8][S:9][C:10]1[N:11]=[C:12]([O:28][CH3:29])[C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[Cl:27])(=[O:19])=[O:18])=[N:14][CH:15]=1>ClCCl>[Cl:27][C:21]1[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([NH:16][C:13]1[C:12]([O:28][CH3:29])=[N:11][C:10]([S:9][CH2:8][CH2:7][NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:15][N:14]=1)(=[O:18])=[O:19]
Reactant: COc1nc(SCCN)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)NCCSc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1
Reaction time: 1 h

Procedure:
Ethylisocyanate (0.016 g) was added to N-[5-(2-aminoethylsulphanyl)-3-methoxy-2-pyrazinyl]-2,3-dichloro-benzenesulphonamide (Example 173) (0.08 g) in dichloromethane (5 mL). After 1 h, the reaction mixture was evaporated to dryness. Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.015 g.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: OB(O)c1ccc(F)cc1Cl
Reactant: Cc1nn(C)c(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 8.3 %

Procedure:
A mixture of 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (2.50 g, 14.3 mmol), 2-chloro-4-fluorophenylboronic acid (2.98 g, 17.2 mmol), cesium carbonate (5.58 g, 17.2 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloro-methane complex (1:1) (1.16 g, 1.43 mmol) in dioxane (50 mL) was heated at 100° C. for approximately 2.5 days. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite® (diatomaceous earth) on a sintered glass frit funnel and the filtrate was concentrated under reduced pressure. The resulting material was dissolved in ethyl acetate and filtered through a plug of silica on a sintered glass frit funnel and the filtrate was concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (5 to 40% gradient of ethyl acetate in hexanes as eluant) to provide the title compound (0.32 g).
Reaction SMILES: [C:1]12([CH2:10][NH2:11])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[H-].[Na+].[CH2:14]([Br:17])[CH:15]=[CH2:16]>CN(C)C=O>[BrH:17].[CH2:16]([NH:11][CH2:10][C:1]12[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: CC1(C)C2CCC1(CN)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Br
Product: C=CCNCC12CCC(CC1)C2(C)C
Reaction time: 0.25 h

Procedure:
A mixture of 10-bornanamine (1 g.) sodium hydride (0.16 g.) and dimethyl formamide was stirred for 15 min. It was then cooled in an ice bath and allyl bromide (0.55 ml) was added. The mixture was stirred for 2 hours at room temperature and then partitioned between ether and water. The organic layer was dried (MgSO4) and evaporated. The residue (1.04 g.) was subjected to preparative layer chromatography using a mixture of 5% methanol in chloroform for development of the plates. The more polar fraction (0.6 g) was dissolved in dry ether and treated with hydrogen chloride to give 10-allylamino bornane hydrobromide (0.65 g.).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:10]=[C:11]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[NH:36][CH2:35][CH2:34]2>CN(C=O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:41])[F:42])[N:36]([C:14](=[O:22])[NH:13][C:11]1[CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:8]=[C:9]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:10]=1)[CH2:35][CH2:34]2
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: O=C(Nc1cc(-c2ccccc2)cc(-c2cccnc2)c1)Oc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(-c3ccccc3)cc(-c3cccnc3)c1)CC2
Yield: 47 %

Procedure:
The title compound (0.74 g, 47%) was prepared as an off white solid using the methodology of example 28, with phenyl N-(5-phenyl-3-(pyrid-3-yl)phenyl)carbamate (D31) (0.27 g, 0.76 mmol) and 5-methoxy-6-trifluoromethyl indoline (D11) [0.182 mg, 0.83 mmol) in DMF (10 ml). Melting point: 150°-151° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[NH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][NH2:29]>CN(C=O)C>[NH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][NH:29][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: NCc1c(N)cccc1F
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(F)c1CNC(=O)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-amino-6-fluorobenzylamine (60.0 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol) The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (80.0 mg, 94%): m.p. 165 (dec.).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:13]=[N+:14]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[N:6]([C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(I)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc(I)cc1
Temperature: 0 °C
Yield: 99 %

Procedure:
4-Iodoaniline (32, 6.00 g, 27.4 mmol) was dissolved in 25 mL TFA and stirred in ice bath. Solid NaNO2 (2.07 g, 30.1 mmol) was added in small portions. The resulting mixture was stirred for 30 min in the ice bath. Sodium azide (1.87 g, 28.8 mmol) was dissolved in 10 mL water and chilled in ice bath. This cold solution was then added to the TFA solution in three portions. The mixture was stirred in ice bath for 1 hr and concentrated in vacuo to remove TFA. The residue was taken into 600 mL DCM and washed with water three times. The organic phase was dried using MgSO4 and concentrated in vacuo to afford 1-azido-4-iodobenzene 33 as a brownish waxy solid in >99% yield. In the mean time, 5-chlorothiophene-2-carboxylic acid (4, 9.13 g, 56 mmol) was dissolved in 200 mL dry DCM along with 0.5 mL dry DMF. To the vigorously stirred solution was carefully added oxalyl chlororide (14.7 mL, 169 mmol) dropwise. The resulting solution was stirred for 3 hrs at RT and concentrated in vacuo. The residue was pumped to dryness and then dissolved in 300 mL dry DCM. To this solution was added propargylamine (5.8 mL, 84 mmol) dropwise. The mixture was stirred at RT for overnight and a lot of solid precipitated out. To this mixture was added 600 mL hexane. The mixture was vigorously stirred for a few hours and filtered for the solid (product 34). The solid (9.47 g, 85%) was washed with hexane and was pure enough for direct use without further purification. MS found for C8H6ClNOS as (M+H)+ 200.0, 202.0.
Reaction SMILES: Cl[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.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][CH2:21][CH2:20][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=[CH:10]2
Reactant: NCCOc1ccccc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: Clc1ccc2nc(NCCOc3ccccc3)ccc2c1
Temperature: 120 °C
Yield: 72.2 %

Procedure:
A stirred mixture of 2,6-dichloro-quinoline (1.0 g, 5.1 mmol) and 2-phenoxyethylamine (1.5 g, 11 mmol) was heated in the microwave for 1 h at 120° C. Purification by flash chromatography on silica gel (ethyl acetate/heptane 100:0→70:30) yielded (6-chloro-quinolin-2-yl)-(2-phenoxy-ethyl)-amine as a light yellow oil (1.1 g, 73%), MS: m/e=299.3 (M+H+).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[C:11]([OH:17])=[N:12][CH:13]=[N:14][C:15]=1[OH:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[OH:17][C:11]1[C:10]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:15]([OH:16])[N:14]=[CH:13][N:12]=1
Reactant: Oc1ncnc(O)c1Br
Reactant: SCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ncnc(O)c1SCc1ccccc1
Temperature: 100 °C
Yield: 47 %

Procedure:
Benzylmercaptan (6 ml, 0.05 mole) was added to a stirred and heated (90°) suspension of 5-bromo-4,6-dihydroxypyrimidine (9.5 g, 0.05 mole) and potassium carbonate (7.5 g, 0.055 mole) in dimethylformamide (25 ml). The reaction mixture was stirred and heated at 95-105° C. under an atmosphere of dry nitrogen for 3.5 hours. The mixture was poured into ice cold water (400 ml) with vigorous stirring and then acidified to pH 1 with hydrochloric acid. After stirring for 0.5 hours the suspension was filtered and the solid which was collected was rinsed several times with n-hexane and diethyl ether. The remaining brown solid was air dried to give 4,6-dihydroxy-5-benzylthiopyrimidine (5.5 g 50%) PMR spectrum: (d6DMSO) 3.96 (S, 2h); 7.2 (bm, 5H); 8.11 (s, 1H); 12.2 (bs, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:12][C:13]1[CH:18]=[N:17][C:16]([O:11][C:8]2[CH:9]=[N:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: CC(C)Oc1ccc(O)cn1
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1ccc(Oc2ccc(Br)cn2)cn1
Yield: 0 %

Procedure:
The mixture of Example 68B (1.0821 g, 7.064 mmol), 5-bromo-2-fluoropyridine (1.245 g, 7.074 mmol, 1.0 eq.), and K2CO3 (1.17 g, 8.47 mmol, 1.2 eq.) in dimethylsulfoxide (8 mL) was heated to 160° C. under microwave for 30 min. The reaction mixture was poured into water. The aqueous layer was extracted with ether (1×). The ether layer was washed with 10% NaOH (1×), brine (1×), dried over MgSO4, filtered and concentrated. The product was purified on silica gel eluting with ethyl acetate: hexane gradient to give the desired product as a solid (0.845 mg, 39%).