Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31](O)=[O:32].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:31]([C:27]5[N:26]([CH3:25])[CH:30]=[CH:29][N:28]=5)=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cn1ccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1nccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) in N,N-dimethylformamide (3.0 mL) were added 1-methyl-1H-imidazole-2-carboxylic acid (117 mg, 0.93 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (267 mg, 1.39 mmol) and 1-hydroxybenzotriazole (188 mg, 1.39 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate/hexane to give the title compound (66 mg, 32%) as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([NH:8][CH2:9][C:10]2[C:11]([CH3:25])=[CH:12][C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:14][C:15]=2[CH3:16])=[O:7])[CH:3]=[N:2]1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=2)[N:29]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)(=O)C.O>[Cl:38][C:32]1[CH:31]=[C:30]2[C:35]([CH:36]=[CH:37][C:28]([CH2:27][N:1]3[CH:5]=[C:4]([C:6]([NH:8][CH2:9][C:10]4[C:11]([CH3:25])=[CH:12][C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:14][C:15]=4[CH3:16])=[O:7])[CH:3]=[N:2]3)=[N:29]2)=[CH:34][CH:33]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn[nH]c1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (5-((1H-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamate (100 mg, 0.290 mmol) in acetone (2.5 ml) were added 2-(bromomethyl)-7-chloroquinoline (74.3 mg, 0.290 mmol) and K2CO3 (200 mg, 1.448 mmol). Reaction mixture was stirred for 5 h at 50° C. Reaction mixture was diluted with ethyl acetate and water. Phases were separated and organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (Method G) Rt=1.736 min, MS (Method V) [M+H]+=521.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][NH:6][CH2:7][CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH:8]2[C:20]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:22][CH:21]=3)[CH2:5][NH:6][CH2:7]2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(C(O)CNCc2cccc(C)c2)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNCc3cc(C)ccc32)cc1OC
Yield: 51.4 %

Procedure:
1.8 g of α-[[(3-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol was dissolved in 13.5 ml of trifluoroacetic acid, and after adding thereto 0.41 ml of conc. sulfuric acid under ice cooling, the mixture was allowed to react for 40 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with chloroform 2 times, and after adding chloroform, the mixture was basified by addition of 28% aqueous ammonia. By a separating procedure, the chloroform layer was collected, washed with water once, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (chloroform-methanol-28% aqueous ammonia(15:1:0.1); a material of Rf being 0.46 [Kiesel gel 60F254 plate, chloroform-methanol-28% aqueous ammonia(15:1:0.1)] was collected, recrystallized from chloroform-n-hexane, and recrystallized from the same solvent system several times, giving 870 mg of 4-(3,4-dimethoxyphenyl)-7-methyl-1,2,3,4-tetrahydroisoquinoline, m.p. 129°-131° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:16]([CH:17]=1)[C:15](=[O:18])[C:14]1[C:9](=[CH:10][CH:11]=[C:12]([C:19]([OH:21])=[O:20])[CH:13]=1)[N:8]=2)[CH3:3].Br.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31]Br)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][O:20][C:19]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]2[CH:6]=[CH:5][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:17][N:16]2[C:15]3=[O:18])=[O:21])[CH:24]=1
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cc3c(=O)n2c1
Reactant: BrCCCc1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc2nc3ccc(C(=O)OCCCc4cccnc4)cc3c(=O)n2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A suspension of 0.60 g of 8-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid, 0.63 g of 3-(3-pyridyl)propyl bromide hydrobromide and 0.62 g of potassium carbonate in 50 ml of dimethylformamide was stirred at a bath temperature of 70° C. for three hours. The mixture was diluted with dichloromethane and washed successively with water, 10% sodium hydroxide, and water and was dried over K2CO3. The residue obtained after evaporation afforded 0.40 g of 8-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid 3-(3-pyridyl)propyl ester, mp 111°-112° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([Cl:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC2CCCC2)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-chlorobenzoate (2.8 g, 10.6 mmol) and cyclopentanone (4.47 g, 53.2 mmol) in methanol (20 mL) was added acetic acid (1.3 mL, 21.2 mmol) and the reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (1.7 g, 26.6 mmol) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the product was purified by column chromatography to afford methyl 5-bromo-2-chloro-3-(cyclopentylamino)benzoate (0.5 g, 14.2%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>N1CCCCC1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:30]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Brc1cccnc1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNCC1
Product: COc1ccc(C2(C#Cc3ccncc3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 80.7 %

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.22 g, 0.70 mmol) and 3-bromopyridine (0.70 mL, 7.0 mmol) in piperidine (2 mL) under an argon atmosphere were added tetakis(triphenylphosphine)palladium(0) (0.034 g, 4%), copper(I) iodide (0.009 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80°-85° C. for 0.5 h. Ammonium chloride was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-1-one as an off-white solid (0.22 g, 80%). The product was further triturated from ether-hexanes, mp 88°-89° C. Anal. (C25H27NO3.0.375 H2O) calcd: C, 75.78; H, 7.03; N, 3.53; found: C, 75.77; H, 6.89; N, 3.40.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[CH3:13][S-:14].[Na+]>CS(C)=O>[CH3:13][S:14][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cc(Br)cnc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ncc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
The product of Example 6 (3.0 g, 0.012 mol) was dissolved with stirring in dimethyl sulphoxide (30 mL) and sodium methanethiolate (1.2 g, 0.017 mol) was added. The mixture was stirred at room temperature overnight, poured into ice-water, and extracted with hexane (2×50 mL). The organic extracts were combined, washed with water and brine, and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and purification of the residue by chromatography over silica (10% ethyl acetate:hexane) gave 2-methylthio-3-trifluoromethyl-5-bromopyridine (2.2 g) as a clear oil.
Reaction SMILES: CO[C:3]1C=C(C(F)(F)F)C=C(SC)[C:4]=1C(O)=O.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].IC>>[CH2:3]([C:25]1[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=[C:20]([C:19]([F:33])([F:34])[F:18])[C:21]=1[C:22]([OH:24])=[O:23])[CH3:4]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Solvent: CI
Product: CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O

Procedure:
The title compound, white solid, MS: m/e=285.2 [(M−H)−], was prepared in accordance with the general method of intermediate A from 2,4-bis(trifluoromethyl)benzoic acid and iodomethane.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH2:10][CH2:11][N:12]([C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:13][CH:14]=2)=[O:8])=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([CH:7]([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:16]=[CH:17][CH:18]=[CH:19][N:20]=3)[CH2:11][CH:10]=2)[OH:8])=[CH:5][CH:6]=1
Reactant: O=C(C1=CCN(c2ncccn2)CC1)c1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC(C1=CCN(c2ncccn2)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of biphenyl-4-yl-(1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanone (12.2 mg, 0.0355 mmol) in methanol (0.5 ml), was added CeCl3 heptahydate (13.2 mg, 0.0355 mmol) and sodium borohydride (1.5 mg, 0.0355 mmol) at room temperature. The mixture was stirred for 1 hour and diluted with EtOAc (10 ml). The mixture was washed with water (5 ml), brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (6% MeOH/CH2Cl2) to give the title compound (12 mg, 98%) as a white gel: 1H NMR (CDCl3, 400 MHz) δ 8.36 (d, J=6.4 Hz, 2H), 7.62-7.37 (m, 9H), 6.46 (t, J=6.4 Hz, 1H), 6.02 (m, 1H), 5.24 (m, 1H), 4.31 (m, 2H), 3.96 (m, 1H), 3.83 (m, 1H), 2.14 (m, 2H); MS calc'd for C22H22N3O [M+H]+: 344; Found: 344.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>CN(C=O)C.O>[OH:1][CH2:2][CH2:3][N:4]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)NCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(CCO)Cc2ccccc2)cc1
Reaction time: 24 h
Yield: 65.1 %

Procedure:
Part A: To a solution of 10.04 g (43 mmol) of N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide from Example 1 in 85 mL of anhydrous DMF, was added 17.8 g (128 mmol) of powdered potassium carbonate and then 8.2 g (48 mmol) of benzyl bromide. After 24 hours, ethyl acetate and water was added, the organic layer separated and washed 3×s with brine, dried with sodium sulfate, filtered and stripped to afford 14.3 g of crude product. This was recrystallized from tert-butylmethyl ether/hexane to afford 9.0 g of the desired N-(hydroxyethyl)-N-(phenylmethyl)-4-methoxybenzene-sulfonamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Br:11]Br.O>CC(O)=O>[Br:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([OH:1])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1cc(O)c(O)c(Br)c1
Yield: 47.9 %

Procedure:
To a solution of 3,4-dihydroxy benzaldehyde (15.48 g, 112 mmol) in 500 ml AcOH was added bromine (6.1 ml, 118 mmol) drop-wise in 50 ml AcOH over 10 min. After 4 h the mixture was poured into cold H2O. The precipitate was filtered, washed with cold H2O and dried in vacuum to give 3-bromo-4,5-dihydroxy-benzaldehyde (11.64 g, 48%) as a grey solid.
Reaction SMILES: C1[CH:5]2[CH:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]3[CH:2]1[CH:3]=[CH:4]2.CC(N)COCC(OCC(OCC(N)C)C)C>C(O)C>[C:11]1(=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:2][CH:3]=[CH:4][CH:5]=[C:6]12
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Agent: CC(N)COCC(C)OCC(C)OCC(C)N
Solvent: CCO
Product: O=C1OC(=O)c2ccccc21
Reaction time: 1 h

Procedure:
Stoichrometric amounts of diethylester, of BTDA (BTDE) 0.67 mole, and the monoethylester of Nadic Anhydride, (NE), 1.10 mole and the monoethylester of Phthalic Anhydride (PE), 0.12 mole were prepared by refluxing the corresponding anhydrides with an excess of ethanol (2.69 mole). The stoichrometric amount of ethanol needed for the NE+BTDA used is 2.57 moles. Thus, an excess of 0.12 moles is employed to ensure complete or near complete conversion. Since this type of reaction is an esterification, which always requires an excess of alcohol, the alcohol is not there as a solvent. The esterification reaction was for one hour at reflux (approximately 351.4K.) and was carried out in a three neck round bottom flask equipped with a mechanical stirring device. When all of the monomers had gone into solution, the refluxing was continued for one-half hour longer. The solution was allowed to cool to 310K.-320K. and then mixed with Jeffamine AP-22, 2.56 molar equivalents of amine, which had previously been warmed to 310K.-320K.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([F:32])([F:31])C(OCC)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH:25]([F:32])[F:31])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(O)cc2C1
Reactant: CCOC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccc(OC(F)F)cc2C1
Temperature: 65 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture containing 0.68 mmol 5-Hydroxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 226070-47-9), 0.68 mmol potassium carbonate and 0.68 mmol ethyl chlorodifluoroacetate in 1.5 ml DMF was stirred overnight at 65° C. The mixture was then partitioned between ethyl acetate and water and the organic phase was then separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: n-heptane/ethylacetate) to afford the title compound as a white solid (40% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:17][C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21](B2OCCCO2)=[C:20]([F:32])[CH:19]=1.[F-].[Cs+].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:21]2[CH:22]=[C:23]([O:24][CH3:25])[C:18]([Cl:17])=[CH:19][C:20]=2[F:32])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Reactant: COc1cc(B2OCCCO2)c(F)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2cc(OC)c(Cl)cc2F)cc(NC(C)=O)c1Cl
Yield: 75 %

Procedure:
A solution of 4-acetylamino-3,6-dichloropyridine carboxylic acid methyl ester (4.3 g, 0.016 mol), 2-(4-chloro-2-fluoro-5-methoxyphenyl)-[1,3,2]-dioxaborinane (4.5 g, 0.018 mol), cesium fluoride (3.5 g, 0.025 mol), and 1,4-bis(diphenylphosphino)butane (0.360 g, 0.0016 mol) in acetonitrile (100 mL) was degassed with nitrogen for 15 minutes before palladium acetate (0.180 g, 0.0016 mol) was added and the solution heated under reflux for 18 hours. Water (150 mL) was added and the resulting solid collected and dried to give 4-acetylamino-3-chloro-6-(4-chloro-2-fluoro-5-methoxyphenyl)pyridine-2-carboxylic acid methyl ester (4.5 g, 0.012 mol): mp 180-182° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]=[O:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:7]([C:6]2[O:5][CH:4]=[N:3][C:2]=2[CH3:1])[OH:8])=[CH:12][CH:11]=1
Reactant: Cc1ncoc1C=O
Reactant: Fc1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncoc1C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Methyl-5-oxazolecarbaldehyde (770 mg) in dry tetrahydrofuran (15 ml) was added dropwise to a stirred solution of 4-fluorophenyl magnesium bromide (1M solution in tetrahydrofuran, 7.3 ml) in tetrahydrofuran (30 ml) at -70° C. under an atmosphere of dry nitrogen. After 1 hour the mixture was allowed to warm to room temperature and was then poured into saturated aqueous sodium hydrogen carbonate. Extraction with ethyl acetate followed by flash chromatography gave the title compound. M.p. 102.5°-104° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[C:17]1([C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:25]([CH3:26])[C:24]([C:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:28])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)c1ccccc1
Yield: 61 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 1-phenyl-1,3-butanedione, except that the residue was purified by spontaneous crystallization from the reaction mixture. Yield: 61%; MS: m/z=402 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>CN(C=O)C>[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:2][OH:1]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(CO)nc2ccccc21
Temperature: 60 °C
Yield: 43.7 %

Procedure:
To a stirred solution of 2-hydroxymethylbenzimidazole (31.94, 0.216 mol) in dry DMF (450 mL) was added N,N-diisopropylethylamine (90 mL, 0.52 mol) followed by 2-(trimethylsily)ethoxymethyl chloride (75% in pentane, 55 g, 0.25 mol) and the mixture heated to 60° C. for 2 h. The mixture was cooled to room temperature, concentrated under reduced pressure and partitioned between EtOAc (400 mL) and distilled water (700 mL). The phases were separated and the aqueous layer extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine (1×400 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the crude oil by column chromatography on silica gel (4% MeOH/CH2Cl2) afforded the desired 1-(2-trimethylsilylethoxymethyl)-2-hydroxymethylbenzimidazole (26.28 g, 44%) as a yellow oil. 1H NMR (CDCl3) δ −0.04 (s, 9H), 0.89 (t, 2H, J=9 Hz), 1.75 (br s, 1H), 3.55 (t, 2H, J=9 Hz), 4.94 (s, 2H), 5.58 (s, 2H), 7.26-7.30 (m, 2H), 7.43-7.45 (m, 1H), 7.70-7.72 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9]CC)=O.[Li+:13].CC([N-]C(C)C)C.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].CC(O)=O>C1COCC1>[Br:1][C:2]1[C:12]2[CH2:23][C:22]([C:21]([O:25][CH3:26])=[O:24])=[C:7]([O-:9])[C:6]=2[CH:5]=[N:4][CH:3]=1.[Li+:13]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: C=CC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1=C([O-])c2cncc(Br)c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Ethyl 5-bromonicotinate (5 g, 21.7 mmol) in THF (22 mL) was added over a period of 20 min to a solution of LDA (23.9 mmol) [generated from N,N-diisopropylamine (3.41 mL, 23.9 mmol) and n-butyllithium (14.9 mL, 23.9 mmol, 1.6M in hexane) in THF (95 mL)] at −78° C. The resulting dark red solution was stirred for 30 min, then methyl acrylate (4.9 mL, 54.3 mmol) in THF (22 mL) was added over 15 min. The reaction was stirred an additional 1.5 h, then aq. 10% AcOH (43.5 mL, 76.1 mmol) was added (giving a pH of 4-5) and the reaction was allowed to warm to room temperature. Evaporation under reduced pressure afforded the title compound (in 50% purity, determined by 1H-NMR) as dark green amorphous solid. MS: 270.0 (M+H+, 1Br).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12][CH3:13])[N:9]=[C:8]([NH2:14])[N:7]=1.[I:15]N1C(=O)CCC1=O>C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:15])=[C:10]([S:12][CH3:13])[N:9]=[C:8]([NH2:14])[N:7]=1
Reactant: CSc1cc(-c2ccco2)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CSc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine and N-iodosuccinimide in acetic acid. EI-MS m/e (%): 333 (M+, 66), 206 ([M—I]+, 100), 118 (44).
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].Br[C:23]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=1[NH:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][N:2]1[CH:11]=[C:10]([C:23]2[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=2[NH:33][CH:34]2[CH2:38][CH2:37][O:36][CH2:35]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1ccc(NC2CCOC2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2NC2CCOC2)c2ccccc2c1=O
Temperature: 70 °C
Reaction time: 18 h
Yield: 43.9 %

Procedure:
A mixture of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (100 mg, 0.35 mmol), the compound from Step 1 (102 mg, 0.32 mmol), K3PO4 (186 mg, 0.88 mmol) and Pd(dppf)Cl2 (29 mg, 0.04 mmol) in dioxane (5 mL) and H2O (1 mL) was purged 3 times with nitrogen and then stirred at 70° C. for 18 hrs under N2. The mixture was filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (56.02 mg, yield: 40.1%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.54 (d, J=8.0 Hz, 1H), 7.89 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.69 (s, 1H), 7.64-7.52 (m, 2H), 7.13 (s, 1H), 7.13-7.08 (m, 1H), 6.78 (dd, J1=8.8 Hz, J2=5.6 Hz, 1H), 4.17 (s, 2H), 3.94-3.86 (m, 1H), 3.79-3.72 (m, 1H), 3.72-3.64 (m, 1H), 3.67 (s, 3H), 3.58-3.49 (m, 1H), 3.07 (s, 3H), 2.32-2.18 (m, 1H), 1.76-1.63 (m, 1H). LCMS (M+H)+=399.1 (M+H)+