Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[OH:31].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8g, 0.013 mol) NaHCO3 (1.1 g), several crystal of KI, 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone, and acetonitrile (100 ml) was refluxed for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed (water), dried (MgSO4), and the solvent was concentrated to afford 5.7 g of a thick yellow oil. The oil was chromatographed on a Waters Prep 500 LC on silica gel, eluting with 7% methanol/methylene chloride. Concentration of the appropriate fraction afforded a yellow oil, which upon standing yielded 3.5 g of the compound as a pale, yellow solid. The solid was recrystallized from ethyl alcohol to afford 2.7 g (50%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl[propoxy]-3-hydroxyphenyl]ethanone as a pale Yellow solid, m.p.=122°-124° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C(N(CC)CC)C.[CH3:16][N:17]1[CH:21]=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[N:18]1>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][N:5]([CH3:6])[S:22]([C:20]1[CH:19]=[N:18][N:17]([CH3:16])[CH:21]=1)(=[O:24])=[O:23]
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: CNCC(OC)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CN(C)S(=O)(=O)c1cnn(C)c1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cool a solution of methylaminoacetaldehyde dimethyl acetal (22.5 mL, 0.18 mol) and triethylamine (26.5 mL, 0.19 mol) to 0° C. in CH2Cl2, then add dropwise a solution of 1-methyl-1H-pyrazole-4-sulfonyl chloride (30 g, 0.17 mol). Stir the reaction mixture at room temperature overnight, dilute with CH2Cl2 (500 mL), and wash with water. Dry the combined organics over Na2SO4, filter and concentrate. The resulting oil is placed under high vacuum and within two hours a resulting off white solid is formed, which is used without further purification (38.22 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:16]=2)[NH:11][N:10]=1.[CH3:27][N:28]([CH3:37])[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CO>[CH3:27][N:28]([CH3:37])[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:15]3[CH:16]=[C:17]4[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[N:10][NH:11][C:12]4=[N:13][CH:14]=3)[CH:19]=2)=[O:23])[CH2:33][CH2:32]1
Reactant: CN(C)CCN1CCNCC1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.8 %

Procedure:
3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid (338 mg, 0.79 mmol) and O-(7-azabenzotriazol-1-yl)-N,N′,N′-tetramethyluronium hexafluorophosphate (300 mg, 0.79 mmol) were dissolved in a mixture of 20 ml of acetonitrile and 10 ml of methanol. 131 mg (0.83 mmol) of 1-(2-dimethylaminoethyl)-piperazine was added and the mixture stirred at ambient temperature for 6 h. The resulting mixture was distributed between dichloromethane and a 2 M aqueous solution of sodium carbonate. The phases were separated and the aqueous layer extracted three times with dichloromethane. The combined organic layers were combined, washed with a saturated aqueous solution of sodium bromide, dried over sodium sulfate, and evaporated. The crude material was purified by flash chromatography on silica gel using a stepped gradient of ethyl acetate and a 4:4:1 solvent mixture of ethyl acetate, dichloromethane and methanol containing 2% v/v of 35% wt ammonia in water to afford [4-(2-dimethylamino-ethyl)-piperazin-1-yl]-{3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-methanone (160 mg, 42%) as an oil. 1H-NMR (d6-CDCl3) δ: 8.87 (d) [1H], 8.36 (d) [1H], 7.75 (dd) [1H], 7.68 (t) [1H], 7.67 (m) [1H], 7.53 (m) [1H], 7.46 (mt) [1H], 7.42 (md) [1H], 7.13 (dt) [1H], 7.10 (d) [1H], 3.89 (s) [3H], 3.81-3.86 (m) [2H], 3.48-3.55 (m) [2H], 2.58-2.64 (m) [2H], 2.56 (m) [2H], 2.50 (m) [2H], 2.44-2.52 (m) [2H]. MS: m/z 485 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[NH:7][C:6]=2[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)c2nc(CF)[nH]c2c1
Reactant: Cc1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Cn1c(CF)nc2c(Br)cc([N+](=O)[O-])cc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
Into a 250 ml flask with 4-bromo-2-(fluoromethyl)-6-nitro-1H-benzo[d]imidazole (3 g, 10.95 mmol) in N,N-Dimethylformamide (DMF) (100 mL) was added 1-(bromomethyl)-3-chloro-2-methylbenzene (3.60 g, 16.42 mmol) and potassium carbonate (4.54 g, 32.8 mmol). The resulting reaction mixture was stirred 1 h at 80° C., cooled to room temperature and poured into water, extracted with ethyl acetate, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified on a silica gel cartridge and eluted with a gradient of 0% ethyl acetate/hexanes to 80% over 10 column volumes. The expected compound was collected and evaporated to yield 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-6-nitro-1H-benzo[d]imidazole (1.23 g, 2.98 mmol, 27.2% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.48 (s, 3H) 5.71 (s, 1H) 5.83 (s, 1H) 5.85 (s, 2H) 6.10 (d, J=7.58 Hz, 1H) 7.05 (t, J=7.83 Hz, 1H) 7.38 (d, J=7.83 Hz, 1H) 8.39 (d, J=2.02 Hz, 1H) 8.67 (d, 1H); LC/MS: MS (ES+) m/e 413 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][CH2:7][C@@H:8]([N:11]1[C:16](=[O:17])[CH:15]=[N:14][C:13]2[CH:18]=[CH:19][C:20]([O:22]C)=[N:21][C:12]1=2)[CH2:9]O)([CH3:4])[CH3:3].CCN(CC)CC.CS(OS(C)(=O)=O)(=O)=O>C(Cl)(Cl)Cl.O>[CH3:3][C:2]([Si:5]([CH3:24])([CH3:25])[O:6][CH2:7][C@H:8]1[N:11]2[C:12]3[N:21]([C:20](=[O:22])[CH:19]=[CH:18][C:13]=3[N:14]=[CH:15][C:16]2=[O:17])[CH2:9]1)([CH3:1])[CH3:4]
Reactant: COc1ccc2ncc(=O)n([C@@H](CO)CO[Si](C)(C)C(C)(C)C)c2n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1Cn2c(=O)ccc3ncc(=O)n1c32
Yield: 88.2 %

Procedure:
To a solution of 4-[(1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-(hydroxymethyl)ethyl]-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (1 g, 2.74 mmol) in CHCl3 (50 mL) was added Et3N (0.953 mL, 6.84 mmol) followed by a solution of methanesulfonic anhydride (0.953 g, 5.47 mmol) in CHCl3 (50 mL). The reaction mixture was stirred at reflux temperature for 5 h. The crude of reaction was diluted with water, washed with NaCl, dried (MgSO4), filtered, and concentrated. Purification by flash chromatography using a 40 g silica gel cartridge, and mixtures of DCM and MeOH as eluent afforded (2S)-2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (0.806 g, 88%) as a tan solid.
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].[P:7]([OH:10])([OH:9])[OH:8].[C:11]([OH:15])(=[O:14])[CH:12]=O.Cl>>[OH2:8].[ClH:1].[CH2:2]([N:4]([O:8][P:7]([CH2:12][C:11]([OH:15])=[O:14])([OH:10])=[O:9])[CH2:5][CH3:6])[CH3:3]
Reactant: O=CC(=O)O
Reactant: CCNCC
Reactant: OP(O)O
Agent: Cl
Product: CCN(CC)OP(=O)(O)CC(=O)O
Product: O

Procedure:
A solution of 16.3 parts by weight of diethylamine hydrochloride, 16.6 parts by weight or orthophosphorous acid, and 29.6 parts by weight of glyoxylic acid (50% aqueous solution) in 50 parts by volume of 18% hydrochloric acid is heated to reflux for 18 hours. Volatile material is then removed by vacuum distillation and the residual oil triturated with acetone to remove impurities. In this way, there are obtained 28 parts by weight of 2-diethylaminophosphonoacetic acid hydrochloride monohydrate having the following analysis by weight:
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([NH2:18])[CH3:17]>>[CH2:16]([NH:18][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CCN
Product: CCNC(=O)c1ccccc1-c1ccccc1
Yield: 94 %

Procedure:
2-Phenylbenzoic acid was converted to the acid chloride by the procedure of example b. The acid chloride was reacted with 70% aq ethylamine using General Method E1 to afford 10.59 g of N-ethyl-2-phenylbenzamide in 94% yield. m.p. 77-79° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C@H:20]4[CH2:24][CH2:23][CH2:22][O:21]4)[CH:14]=3)[C:9]2=[O:25])=[CH:4][C:3]=1[F:26].[CH3:27][N:28]([CH3:35])[C:29]1([CH3:34])[CH2:33][CH2:32][NH:31][CH2:30]1>>[CH3:27][N:28]([CH3:35])[C:29]1([CH3:34])[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C@H:20]5[CH2:24][CH2:23][CH2:22][O:21]5)[CH:14]=4)[C:9]3=[O:25])=[CH:4][C:3]=2[F:26])[CH2:30]1
Reactant: O=c1c2ccc(OC[C@H]3CCCO3)cc2ccn1-c1ccc(Br)c(F)c1
Reactant: CN(C)C1(C)CCNC1
Product: CN(C)C1(C)CCN(c2ccc(-n3ccc4cc(OC[C@H]5CCCO5)ccc4c3=O)cc2F)C1

Procedure:
2-(4-Bromo-3-fluorophenyl)-6-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-2H-isoquinolin-1-one and dimethyl-(3-methyl-pyrrolidin-3-yl)-amine were reacted according to Method R1. In this way the product was obtained with molecular weight 465.57 (C27H32FN3O3); MS (ESI): 466 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:21](=[O:22])[N:20]([CH3:23])[C:8]2[N:9]=[C:10]([NH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[CH:12][C:7]=2[CH:6]=1.C(N(CC)C(C)C)(C)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].CCCCCC>CC(C)=O>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:21](=[O:22])[N:20]([CH3:23])[CH:8]2[N:9]=[C:10]([N:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:38](=[O:40])[CH3:39])[N:11]=[CH:12][CH:7]2[CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(NC3CCOCC3)nc21
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CC(=O)N(C1=NC2C(C=N1)C=C(Oc1ccc(F)cc1F)C(=O)N2C)C1CCOCC1
Temperature: 125 °C

Procedure:
A mixture of 6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (Example 23) (1.0 g, 2.57 mmol), N,N-diisopropylethylamine (0.498 g, 0.67 mL, 3.86 mmol) in acetic anhydride (1.42 g, 1.02 mL, 13.9 mmol) was heated to 123-127° C. for 2 hours. The volatiles were evaporated at 60° C. to provide a thick residue which was dissolved in 4 mL of acetone at 67-70° C. To the resulting solution was added 5 mL of hexane maintaining a temperature of 53-55° C. This mixture was allowed to cool to ambient temperature over 18 hours. The resulting solid was filtered and washed with 3×3 mL of 1:2 acetone:hexane. The rinsed solid was suspended in 5 mL of hexane and heated to reflux for 45 minutes. After cooling to ambient temperature, the slurry was filtered and the solid washed with hexane and dried under vacuum. (0.903 g, mass spec. M+1=431, MP=185.3-186.9° C.).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH3:5][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:5][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]#[N:4])[CH2:24][CH2:23]2)=[CH:8][CH:7]=1
Reactant: N#CCCl
Reactant: Cc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(NC3CCN(CC#N)CC3)nc3ccccc32)o1
Temperature: 45 °C
Yield: 80.4 %

Procedure:
A mixture of 2 parts of 2chloroacetonitrile, 8 parts of 1-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 3.1 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred and heated overnight at 45° C. The reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 7.3 parts (80.4%) of 4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]-amino]-1-piperidineacetonitrile; mp. 177.3° C. (int. 36).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[CH3:9][N:10]([CH3:17])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:14]2[CH2:15][CH2:16][CH:11]([N:10]([CH3:17])[CH3:9])[CH2:12][CH2:13]2)[CH:3]=1
Reactant: CN(C)C1CCNCC1
Reactant: Fc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C1CCN(c2cc(Br)ccn2)CC1
Temperature: 100 °C
Yield: 96 %

Procedure:
In a pressure vessel were dissolved 4-bromo-2-fluoropyridine (1 g, 5.68 mmol) and N,N-dimethylpiperidin-4-amine (1.1 g, 8.58 mmol) in DMSO (7 ml). Potassium carbonate (2.4 g, 17.36 mmol) was added and the reaction was heated at 100° C. overnight. The reaction mixture was poured into water and extracted twice with diethylether. The organics were combined, washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 1.55 g (91% yield) of the title compound as a oil. Purity 95%.
Reaction SMILES: O(C[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](=[O:18])(=[O:17])[NH2:16])C1C=CC=CC=1.C[OH:20]>[Pd]>[OH:20][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](=[O:18])(=[O:17])[NH2:16]
Reactant: CO
Reactant: NS(=O)(=O)c1ccccc1COc1ccccc1
Agent: [Pd]
Product: NS(=O)(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of crude 1-(phenoxymethyl)-2-sulfamoylbenzene (1.6 g, 6 mmol.) in 200 mL of methanol was added Pd/C (0.64 g). The reaction mixture was stirred at room temperature for 5 hours under H2 with a pressure of 30 psi. After the material was consumed, the reaction mixture was filtered. The solvent was evaporated to give crude 1-(hydroxy)-2-sulfamoylbenzene (800 mg, 80%) which was used directly without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[Cl:40][C:41]1[CH:42]=[N:43][NH:44][CH:45]=1.N1C=CC=CC=1>O>[CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:43]3[CH:42]=[C:41]([Cl:40])[CH:45]=[N:44]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: Clc1cn[nH]c1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cc(Cl)cn2)cc1
Temperature: 50 °C
Yield: 97.4 %

Procedure:
A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.14 g), 4-chloro-1H-pyrazole (0.053 g), cuprous acetate (0.093 g) and pyridine (3 mL) was heated at 50° C. for 116 hours. The mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure. Purification of the residue by column chromatography silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 7:3 by volume) gave title compound as a colourless oil (0.13 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:32]3[C:27]([F:26])=[N:28][CH:29]=[CH:30][CH:31]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(Oc2nccnc2-c2cccnc2F)cc1)c1nc2ccccc2[nH]1
Temperature: 150 °C

Procedure:
To a microwave safe 30 ml tubes were charged with (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (0.500 g, 1.43 mmol), 2-fluoropyridin-3-ylboronic acid (0.241 g, 1.71 mmol), tetrakis(triphenylphosphine)palladium(0) (0.165 g, 0.143 mmol) and a 2M solution of sodium carbonate monohydrate (2.14 mL, 4.28 mmol) in 1,4-dioxane. The flasks were sealed and heated to 150° C. for 45 min in a microwave. The reaction mixture was diluted with DCM (75 mL), washed with water and brine. It was dried over magnesium sulfate, concentrated and dried in vacuo. It was suspended in DCM/MeOH and stirred. The insoluble material was collected by filtration, recrystallized overnight from boiling MeOH and hexane, then dried in a vacuum oven to give (1H-benzo[d]imidazol-2-yl)(4-(3-(2-fluoropyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone as yellow solid. LC/MS: MS (ESI, pos. ion) m/z: 412.1 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.C(#N)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: COc1ccccc1-c1ccnc(F)c1
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: O
Product: COc1ccccc1-c1ccnc(Nc2ccccc2)c1
Temperature: 150 °C

Procedure:
A mixture of A3 (80 mg, 0.39 mmol) and aniline (102 mg, 1.1 mmol) was heated for 20 minutes at 150° C. in a microwave oven. The title compound B1 was obtained from the residue by preparative HPLC (water/ACN gradient) as an amorphous solid (20 mg, 19%). MS (ES) C18H16N2O requires: 276. found: 277 (M+H)+.
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]([OH:16])=O)=[CH:9][CH:8]=[CH:7]2>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14](=[O:16])[CH3:1])=[CH:9][CH:8]=[CH:7]2
Reactant: [Li]C
Reactant: O=C(O)c1cccc2cc(F)ccc12
Solvent: C1CCOC1
Product: CC(=O)c1cccc2cc(F)ccc12
Reaction time: 2 h

Procedure:
Methyl lithium (1.59M solution in ether; 4.2 ml) was added dropwise to a stirred solution of 6-fluoro-1-naphthalene carboxylic acid (640 mg) in dry THF (10 ml) at -78° under nitrogen. The solution was stirred at -78° for 2 h and was slowly allowed to warm to -15°. The solution was quenched with saturated aqueous ammonium chloride (1 ml) and partitioned between 2N sodium hydroxide (25 ml) and ethyl acetate (25 ml). The organic phase was dried and evaporated to give the title compound (404 mg) as an oil, t.l.c. (System B, 1:6) Rf 0.2.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH3:2].[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:15]=1[C:16](O)=[O:17].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:16](=[O:17])[C:15]1[C:14]([OH:13])=[CH:22][CH:21]=[CH:20][C:19]=1[OH:23])[CH3:2]
Reactant: CCNCc1ccc(OC)cc1
Reactant: O=C(O)c1c(O)cccc1O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCN(Cc1ccc(OC)cc1)C(=O)c1c(O)cccc1O
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a stirred solution of N-ethyl-4-methoxybenzyl amine (1.07 g, 6.49 mmol) in DMF (10 mL) was added 2,6-dihydroxybenzoic acid (1.0 g, 6.49 mmol) followed by HOAt (0.97 g, 7.14 mmol) and EDC (1.31 g, 6.81 mmol). After stirring overnight, the reaction was diluted with EtOAc prior to washing 3× with H2O. The combined aqueous layers were extracted once with EtOAc. The organic fractions were combined, washed once with brine, and dried over Na2SO4 prior to concentrating using a rotary evaporator. The residue was chromatographed on silica gel using 75% EtOAc/hexane as the eluent. The resulting promising impure fractions were further purified by silica gel chromatography. A total of 631 mg of the desired N-ethyl-N-4-methoxybenzyl 2,6-dihydroxybenzamide was obtained.
Reaction SMILES: FC1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:16]3[C:17]([CH3:25])=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)[S:11][C:12]=2[C:13](N)=[O:14])[CH:5]=[CH:6]C=1.[O:26]1C=CC(B(O)O)=[CH:27]1.C(=O)([O-])[O-:35].[Cs+].[Cs+].COCCOC>O>[O:35]1[CH:6]=[CH:5][C:4]([C:8]2[N:9]=[C:10]([C:16]3[C:17]([CH3:25])=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)[S:11][C:12]=2[C:13]([O:26][CH3:27])=[O:14])=[CH:3]1
Reactant: Cc1nn2ccccc2c1-c1nc(-c2cccc(F)c2)c(C(N)=O)s1
Reactant: OB(O)c1ccoc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccoc1
Yield: 93.4 %

Procedure:
Using methyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (300 mg, 0.71 mmol) produced in Example 13-B (ii), furan-3-ylboronic acid (160 mg, 1.4 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (70 mg, 0.086 mmol), cesium carbonate (830 mg, 2.6 mmol), 1,2-dimethoxyethane (20 mL) and water (0.5 mL) as starting materials and in the same manner as in Example 13-B(iii), the title compound (225 mg, 93%) was obtained as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(Br)cc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Br)cc1Oc1ccccc1
Reaction time: 96 h

Procedure:
A mixture of 5-bromo-2-methylphenol (1.0 g), phenylboronic acid (1.30 g), Cu(OAc)2 (0.97 g), and triethylamine (2.98 mL) in dichloromethane (50 mL) was stirred for 4 days. The mixture was diluted with ethyl acetate, washed four times with 1M aqueous NaOH solution and once with brine, dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed on silica gel using 2% ethyl acetate in hexanes to afford the title compound.