Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:31])[C@@H:5]([O:27][CH:28]([CH3:30])[CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@H:15]([OH:26])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:8]=1)C.[OH-].[Na+].Cl>C(O)C>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[O:17][CH2:16][C@@H:15]([OH:26])[CH2:14][O:13][C:9]1[CH:8]=[C:7]([CH2:6][C@H:5]([O:27][CH:28]([CH3:29])[CH3:30])[C:4]([OH:31])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)[C@H](Cc1cccc(OC[C@H](O)COc2ccc(Cl)cc2Cl)c1)OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)O[C@@H](Cc1cccc(OC[C@H](O)COc2ccc(Cl)cc2Cl)c1)C(=O)O
Reaction time: 4 h
Yield: 96.7 %

Procedure:
220 mg of 3-{3-[3-(2,4-Dichlorophenoxy)-2(S)-hydroxypropoxy]phenyl}-2(S)-isopropoxypropanoic acid ethyl ester was dissolved in 4 ml of ethanol, followed by adding 1 ml of 1N sodium hydroxide. After standing as it was at room temperature for 4 hours, the solution was neutralized with 1N hydrochloric acid and extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 200 mg of the title compound as a colorless oil in the 3:2→2:3 hexane-ethyl acetate fraction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:35]([C:29]3[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:28]=3[F:27])(=[O:37])=[O:36])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To a solution of 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (35 g, 89.5 mmol) in pyridine (400 mL), 2,6-difluorobenzene-1-sulfonyl chloride (20.9 g, 98.5 mmol) was added dropwise. The reaction was stirred at rt for 2 h. Then the reaction was washed with water (400 mL), and extracted with DCM (2×400 mL). The organic layer was washed with water, brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:2) to afford the title compound (18.5 g, 36.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (d, J=5.3 Hz, 1H), 7.65-7.70 (m, 1H), 7.40-7.50 (m, 1H), 7.25-7.30 (br, 1H), 7.18-7.23 (m, 2H), 6.88-6.98 (m, 2H), 6.38 (d, J=5.3 Hz, 1H), 3.72-3.80 (m, 4H), 3.50-3.58 (m, 4H); m/z (ES+): 568 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([CH2:24][OH:25])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.[CH3:31]COCC.[N+](=C)=[N-]>ClCCl.C(=O)=O.CC(C)=O>[CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([CH2:24][O:25][CH3:31])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: COc1ccc(COC(=O)N[C@H](CO)C(=O)OCc2ccccc2)cc1
Agent: C=[N+]=[N-]
Agent: FB(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC[C@@H](NC(=O)OCc1ccc(OC)cc1)C(=O)OCc1ccccc1
Yield: 70 %

Procedure:
The N-p-methoxybenzyloxycarbonyl-D-serine benzyl ester (720 mg, 2.00 mmol) is dissolved in dry dichloromethane (20 ml) and the solution cooled in dry ice/acetone. Boron trifluoride etherate (100 μl) is added followed by the portionwise addition of diazomethane (30 mmol in 20 ml CH2Cl2) After about 30 minutes the solution is filtered and washed once with water (10 ml), then dried (MgSO4) and evaporated to dryness. The resulting residue is chromatographed on silica gel using chloroform as eluant to give the pure title compound as an oil (520 mg, 70%) which crystallises on standing to give a colourless solid of m.p. 68°-69° C.; [α]D20 --1.3° (c 4.0, CHCl3).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9](N)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.N([O-])=[O:23].[Na+]>C(O)(C(F)(F)F)=O>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:23])=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=N[O-]
Reactant: COc1nnc(-c2cc(C(N)=O)c(C)cc2C2CCC2)[nH]1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide (compound 89.8, 0.1 g, 0.33 mmol) in TFA (5 mL) at 0° C., was added NaNO2 (46 mg, 0.66 mmol). The mixture was stirred at 0° C. for 1 hour, then at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to yield 0.1 g (theoretical) of the title compound as a clear oil. m/z (ES+) 288 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C@@H:5]([NH:26]C(OC(C)(C)C)=O)[CH2:6][NH:7]C([C@@H]1CCCN(C(OCC2C=CC=CC=2)=O)C1)=O)[CH3:2].[ClH:35]>C(OCC)(=O)C>[ClH:35].[CH2:1]([O:3][C:4](=[O:34])[C@@H:5]([NH2:26])[CH2:6][NH2:7])[CH3:2]
Reactant: CCOC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](N)CN
Temperature: 0 °C

Procedure:
To a solution of N-[(R)-(1-benzyloxycarbonyl-3-piperidyl)carbonyl]-2(S)-(tert-butoxycarbonylamino)-β-alanine ethyl ester (0.4 g) in ethyl acetate (4 ml) was added 4N HCl in ethyl acetate (2.1 ml) under stirring at 0° C. After stirring at ambient temperature for 2 hours, the resulting precipitates were collected by filtration to give N-[(R)-1-benzyloxycarbonyl-3-piperidyl)carbonyl]-2(S)-amino-β-alanine ethyl ester hydrochloride (0.31 g).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:21]=[CH:20][C:14]2[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=2[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+]>C(O)C.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[CH:12]=2)[C:3]([OH:22])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc2c(c1)CCS2(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CC1CCCC1)c1ccc2c(c1)CCS2(=O)=O
Temperature: 25 °C
Yield: 64.9 %

Procedure:
3-Cyclopentyl-2-(1,1-dioxo-2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid methyl ester (184 mg, 0.57 mmol) was dissolved in ethanol (4 mL) and treated with a solution of lithium hydroxide monohydrate (34 mg, 1.43 mmol) in water (1.5 mL) at 25° C. It was stirred at 25° C. until the starting material was all consumed by TLC (˜1 hr). The reaction was then concentrated in vacuo to remove the ethanol. The remaining aqueous layer was then acidified to pH=2 with an aqueous 1N hydrochloric acid solution. This was then extracted with ethyl acetate (3×20 mL), the organic layers combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-(1,1-dioxo-2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid (114 mg, 65%) as a white solid: EI-HRMS m/e calcd for C16H20O4S (M+) 308.1082, observed 308.1075.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]2[C:19](=[O:20])[CH:18]3[CH2:21][CH2:22][N:15]2[CH2:16][CH2:17]3)=[CH:7][CH:6]=1)([O-])=O>[Pd].CO>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH:14]2[C:19](=[O:20])[CH:18]3[CH2:21][CH2:22][N:15]2[CH2:16][CH2:17]3)=[CH:9][CH:10]=1
Reactant: O=C1C2CCN(CC2)C1CCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(CCCC2C(=O)C3CCN2CC3)cc1

Procedure:
To a Parr bottle add 9.74 g (0.03 mole) of 2-[3-(4-nitrophenyl)propyl]-1-azabicyclo[2.2.2]octan-3-one hydrochloride, 150 ml of methanol and 0.5 g of 10% palladium on charcoal catalyst (wet with 2-3 ml of water). Place the bottle on a hydrogenator, flush the system three times with hydrogen and pressurize the system to 25 p.s.i. Shake the reaction mixture and follow the reaction by thin-layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 95:5). At the completion of the reaction remove the catalyst by vacuum filtration. Wash the catalyst with methanol, to the filtrate add 5 ml of concentrated hydrochloric acid. Remove the solvent in vacuo to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:34])/[C:4](/[CH3:33])=[CH:5]/[CH:6]1[CH2:11][CH:10]=[C:9]([C:12]#[C:13][C:14]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]3[CH:20]([N:26]([CH:28]4[CH2:30][CH2:29]4)[CH3:27])[CH2:19][CH2:18][C:17]([CH3:32])([CH3:31])[C:16]=3[CH:15]=2)[CH:8]=[CH:7]1.C(OC(=O)/C(/C)=C/C1CC=C(C#CC2C=C(OC)C3C(N(C4CC4)C)CCC(C)(C)C=3C=2)C=C1)C.[OH-].[K+].Cl>CO.O1CCCC1>[CH:28]1([N:26]([CH3:27])[CH:20]2[CH2:19][CH2:18][C:17]([CH3:32])([CH3:31])[C:16]3[CH:15]=[C:14]([C:13]#[C:12][C:9]4[CH:8]=[CH:7][CH:6](/[CH:5]=[C:4](\[CH3:33])/[C:3]([OH:34])=[O:2])[CH2:11][CH:10]=4)[CH:23]=[C:22]([O:24][CH3:25])[C:21]2=3)[CH2:30][CH2:29]1
Reactant: COC(=O)/C(C)=C/C1C=CC(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)=CC1
Agent: CCOC(=O)/C(C)=C/C1C=CC(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)=CC1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C#CC2=CCC(/C=C(\C)C(=O)O)C=C2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A solution of (E)-3-{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-cyclohexa-2,4-dienyl}-2-methyl-acrylic acid methyl ester (Intermediate 87, 0.12 g, 0.25 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was treated with a 3M solution of potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was recrystallized from hot acetonitrile to afford the title product as a white solid (0.055 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.[CH2:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)[CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=1
Reactant: CCc1ccc(CBr)cc1
Reactant: COc1cccc(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c(OC)cccc2OC)cc1
Reaction time: 1.5 h
Yield: 49.7 %

Procedure:
To a mixture of 1,3-dimethoxybenzene (6.9 g, 50 mmol) and tetrahydrofuran (70 mL), n-butyllithium (1.57 M in hexane, 35 mL) was added in ice and stirred for 1.5 hours. Subsequently, 4-ethylbenzyl bromide (10 g, 50 mmol) was added in ice and stirred for an additional 3.5 hours. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-85:15) to give 1,3-dimethoxy-2-(4-ethylbenzyl)benzene (6.37 g, 49%, mp 62.5-66.5° C.) as a light-yellow powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Cc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and p-tolylboronic acid to give (1H-pyrazol-3-yl)-(1-p-tolyl-isoquinolin-3-yl)-amine. LC-MS m/e 301(MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[N:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:9][CH:10]=1
Reactant: Clc1ncccc1-c1ccncn1
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Oc2ncccc2-c2ccncn2)cc1
Temperature: 200 °C

Procedure:
A mixture of 4-(2-chloro-pyridin-3-yl)-pyrimidine, 4-hydroxy-benzoic acid and Cs2CO3 in DMSO was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 200° C. for 10 minutes. The reaction mixture was cooled to RT and diluted with 60 mL of EtOAc. The product was precipitated from the solution. The mixture was then washed with 20 mL of water twice. The solid was collected by filtration and dried in an oven at 50° C. to afford off white solid as desired product. MS m/z=294 [M+1]+. Calc'd for C16H11N3O3: 293.28.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([N:16]1[CH2:21][CH2:20][C:19]([CH3:27])([C:22]([O:24]CC)=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:28][CH2:29]I.C(O)(=O)C>C1COCC1>[Cl:28][CH2:29][C:22]([C:19]1([CH3:27])[CH2:18][CH2:17][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:21][CH2:20]1)=[O:24]
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)CCl)CC1
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
Lithium diisopropylamide (30.9 mL, 46.4 mmol) was added dropwise to a solution containing ethyl N-Boc-4-methylpiperidine-4-carboxylate (2.52 g, 9.28 mmol), and chloroiodomethane (6.55 g, 37.1 mmol) in THF (100 mL) at −78° C. over 30 minutes. After addition, the reaction was stirred for 10 minutes, and then a solution of acetic acid (5 mL) in THF (45 mL) was added while keeping reaction mixture below −65° C. The reaction was stirred for an additional 10 minutes and partitioned between ethyl acetate and brine, washed with saturated bicarbonate, concentrated and purified by silica gel (10%-20% ethyl acetate in hexanes) to afford tert-butyl 4-(2-chloroacetyl)-4-methylpiperidine-1-carboxylate (1.15 g, 44.92% yield).
Reaction SMILES: [Mg].II.[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11]Br.Cl[P:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C([Li])CCC.C(OCC)C>[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][P:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1Br
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: II
Agent: [Li]CCCC
Agent: [Mg]
Solvent: CCOCC
Product: Brc1ccccc1CP(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Under nitrogen, magnesium (1.87 g) was placed in a 3-neck 250 ml round bottom flask along with about 60 ml of diethyl ether and a few crystals of iodine and a few drops of n-butyl lithium (2M). 1-bromo-2-(bromomethyl)benzene (17.5 g) was added to an addition funnel along with 20 ml of diethyl ether. This solution was added dropwise to the mixture. The reaction was refluxed for an additional ½ hour after dropwise addition was completed. Chlorodiphenylphosphine (11.3 ml) in 20 ml of diethyl ether was then added dropwise with vigorous stirring to the Grignard solution at a rate to maintain a reflux. When the addition was complete, the reaction was refluxed for an additional hour and then cooled to room temperature and quenched with aqueous hydrochloric acid (dropwise addition) under nitrogen. The layers were separated and the organic layer was washed with water. The mixture was then filtered, separated, and dried. The solvent was then removed to obtain 24.8 g of (2-bromobenzyl)diphenyl-phosphine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:19])=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=2)[CH:7]=1.[H-].[Na+].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[C:14]([O:13][C:12]([N:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]2[C:8]=1[CH3:19])[S:28]([C:22]1[CH:27]=[CH:26][C:25]([C:12]([O:13][CH3:14])=[O:18])=[CH:24][CH:23]=1)(=[O:30])=[O:29])=[O:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: Cc1c(NC(=O)OC(C)(C)C)nc2ccc(Cl)cn12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccc(Cl)cn3c2C)cc1
Reaction time: 0.17 h
Yield: 171.9 %

Procedure:
To a solution of compound 15-B (0.563 g, 2.0 mmol) in DMF (13 mL) at 0° C. was added 60% NaH (0.096 g, 2.4 mmol) and the reaction mixture was stirred for 10 minutes. Benzenesulfonyl chloride (0.563 g, 2.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of H2O and the solution was extracted with ethyl acetate. After separation of the organic and aqueous layers a sufficient amount of water was added to remove any dissolved DMF from the organic layer. The organic layer was dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford the crude product. The crude material was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give compound 15-C as a white solid (0.825 g, 86%); MS m/z (M+H+) 480.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH2:11][C:12]1[C:13]([C:17]2[N:18]([CH2:43][CH3:44])[C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:27]=[C:28]([NH:32][C:33]([C:35]5[CH:40]=[CH:39][C:38](=[O:41])[NH:37][CH:36]=5)=[O:34])[CH:29]=[CH:30][CH:31]=4)[N:22]=[CH:21][C:20]=3[N:42]=2)=[N:14][O:15][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[NH2:11][C:12]1[C:13]([C:17]2[N:18]([CH2:43][CH3:44])[C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:27]=[C:28]([NH:32][C:33]([C:35]5[CH:36]=[N:37][C:38]([O:41][CH2:3][CH2:4][N:5]6[CH2:10][CH2:9][O:8][CH2:7][CH2:6]6)=[CH:39][CH:40]=5)=[O:34])[CH:29]=[CH:30][CH:31]=4)[N:22]=[CH:21][C:20]=3[N:42]=2)=[N:14][O:15][N:16]=1
Reactant: ClCCN1CCOCC1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(=O)[nH]c4)c3)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(OCCN5CCOCC5)nc4)c3)cc21
Temperature: 80 °C
Yield: 29.2 %

Procedure:
2-Chloroethylmorpholine hydrochloride (104 mg, 0.6 mmol) was added to a slurry of the product of Step 2 (135 mg, 0.3 mmol) and powdered K2CO3 (1 g) in DMF (2 mL) and the mixture was heated to 80° C. for 3 h. The mixture was cooled, diluted with H2O and extracted with EtOAc. The combined organic extracts were washed with H2O and brine, dried (MgSO4), filtered and the filtrate was concentrated to give a yellow oil which was purified by reverse phase HPLC to give the title compound (50 mg, 30%). 1H NMR (400 MHz, CD3OD) δ ppm 9.13 (s, 1H), 8.69 (s, 1H), 8.09 (d, J=9.3, 1H); 7.92 (s, 1H), 7.69 (d, J=8.0, 1H), 7.60-7.53 (m, 2H), 7.12 (d, J=8.0, 1H), 6.67 (d, J=9.4, 1H), 4.76 (br q, 2H), 4.53 (br m, 2H), 3.83-3.70 (m, 8H), 3.33 (m, 2H), 1.46 (br t, 3H). MS (ES+) m/e 572 [M+H]+.
Reaction SMILES: [CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=[C:18]2[OH:29])[CH2:2][CH2:3][CH2:4][CH3:5].Br[CH2:31][C:32]#[N:33]>>[CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=[C:18]2[O:29][CH2:31][C:32]#[N:33])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1c(-c2ccc3nc(C(F)(F)F)cc(O)c3c2)oc2ccccc12
Reactant: N#CCBr
Product: CCCCCc1c(-c2ccc3nc(C(F)(F)F)cc(OCC#N)c3c2)oc2ccccc12

Procedure:
To a stirred solution of 6-(3-pentyl-1-benzofuran-2-yl)-4-methoxy-2-(trifluoromethyl) quinoline (0.258 g, 0.624 mmol) in CH2Cl2 (10 mL) cooled to −78° C. was added BBr3 (1.68 mL, 1.0 M in CH2Cl2, 1.68 mmol) dropwise. The reaction was stirred at this temperature for 0.5 hour and then warmed to room temperature for 18 hours. The reaction mixture was then heated at reflux for 4 hours. At this point, BCl3 (1.68 mL, 1.0 M in CH2Cl2, 1.68 mmol) and Bu4N+I− (1.24 g, 3.37 mmol) were added and the mixture was allowed to stir at room temperature for 3 days. The reaction mixture was then quenched with MeOH (˜5 mL) followed by dilution with H2O (20 mL) and EtOAc (200 mL). The organic layer was washed with brine (20 mL) and then dried (Na2SO4). After concentration, the residue was dried under high vacuum to afford the product (0.247 g, 99%) as an oil. Mass spectrum (+ESI, (M+H]+) m/z 400. Reaction of this intermediate [6-(3-Pentyl-1-benzofuran-2-yl)-4-hydroxy-2-(trifluoromethyl) quinoline] with bromoacetonitrile according to the procedure described in Step 2 of Example 1; afforded the title compound as a solid. Mass spectrum (+ESI, [M+H]+) m/z 439. 1H NMR (500 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.18-8.33 (m, 2H), 7.55-7.77 (m, 3H), 7.29-7.42 (m, 2H), 5.68 (s, 2H), 3.04 (t, 2H, J=8.2 Hz,), 1.73-1.86 (m, 2H), 1.31-1.51 (m, 4H), and 0.89 ppm (t, 3H, J=7.6 Hz).
Reaction SMILES: O=C1C2(CCN(C(OC(C)(C)C)=O)CC2)C2C(=CC([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=CC=2)N1.Br[C:33]1[CH:41]=[C:40]2[C:36]([C:37]([F:52])([F:51])[C:38](=[O:50])[N:39]2[CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])=[CH:35][CH:34]=1>>[F:51][C:37]1([F:52])[C:36]2[C:40](=[CH:41][C:33]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=[CH:34][CH:35]=2)[N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:38]1=[O:50]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: C[Si](C)(C)CCOCN1C(=O)C(F)(F)c2ccc(Br)cc21
Product: CC1(C)OB(c2ccc3c(c2)N(COCC[Si](C)(C)C)C(=O)C3(F)F)OC1(C)C

Procedure:
Following the procedure described for intermediate 7.33 (Step 2), starting from 6-bromo-3,3-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one 7.35 (84 mg), 94 mg of crude 3,3-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one 7.36 was obtained. This material was used without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[O:20][CH3:21])=[O:5])C.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>>[CH2:22]([N:24]1[C:4](=[O:5])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:20][CH3:21])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH:17]([CH3:18])[CH3:19])[C:25]1=[O:26])[CH3:23]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC(C)C
Reactant: CCN=C=O
Product: CCn1c(=O)c2cnc3c(OC)cccc3c2n(C(C)C)c1=O
Yield: 44.7 %

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (267 mg, 1.0 mmol) was treated with isopropylamine (1.5 mmol) following general procedure B to afford 4-isopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (256 mg). 3-Ethyl-1-isopropyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (14 mg) was prepared from 4-isopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and ethyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 314 [M+1]+.