Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[N:21][CH:22]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][N:21]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)nc1
Temperature: 100 °C
Reaction time: 42 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.6 g, 2.419 mmol) in toluene (4.84 mL) was added 5-methyl-2-(tributylstannyl)pyridine (1.02 g, 2.66 mmol), and palladium tetrakistriphenylphosphine (0.280 g, 0.24 mmol). The reaction was stirred at 100° C. and stirring continued for 42 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(5-methyl-2-pyridinyl)-quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH:29](O)=[O:30]>C1(C)C=CC=CC=1>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[C:12]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=3[NH:1][CH:29]=[O:30])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Reactant: O=CO
Solvent: Cc1ccccc1
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2NC=O)c1C
Reaction time: 9 h
Yield: 59.4 %

Procedure:
To a solution of the compound of Example 32 (0.20 g, 0.5 mmol) in toluene (2 mL), formic acid (0.21 g, 4.5 mmol) was added. The mixture was heated at reflux for 3 hours, additional formic acid (0.23 g, 5 mmol) was added and heating was continued for 9 hours. The mixture was concentrated and the residue was chromatographed on silica gel to provide the title compound (127 mg, 59%) as an off-white solid, m.p. 87-95° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH:15]1[CH2:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[N:43](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:42]=[N:41][N:40]=3)=[CH:29][CH:28]=2)[C:16]1=[O:63])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH:15]1[CH2:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[CH:31][CH:32]=2)[C:16]1=[O:63])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Yield: 70 %

Procedure:
The intermediate obtained in Step B (349 mg, 0.40 mmol) was dissolved in 5 mL of methanol and hydrogenated at room temperature and one atmosphere over 70 mg of 20% Pd(OH)2 /C for 16 hours. The reaction mixture was filtered through Celite and solvent removed under vacuum. The crude product was purified by flash chromatography on silica, eluting with 10% methanol/ethyl acetate to afford 168 mg (0.28 mmol, 71%) of product. 1H NMR (200 MHz, CD3OD): 1.41 (s,9H), 1.72 (m,2H), 2.0-2.6 (m,6H), 3.24 (t,7 Hz,2H), 4.32 (m,1H), 4.85 (d,14 Hz,1H), 5.20 (d,14 Hz,1H), 6.9-7.7 (m,12H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[Cl:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:40]=1B(O)O.O1CCOCC1>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.O>[Cl:38][C:39]1[CH:44]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:42]=[CH:41][C:40]=1[C:10]1[CH:11]=[CH:2][CH:3]=[C:8]2[C:9]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:13])=[O:14])=[CH:7]2
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Temperature: 100 °C
Yield: 10 %

Procedure:
A pressure vessel was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D) (110 mg, 0.211 mmol), potassium carbonate (146 mg, 1.057 mmol), (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (56.9 mg, 0.254 mmol), tetrakis(triphenylphosphine)palladium(0) (24.42 mg, 0.021 mmol), dioxane (1409 μl) and water (705 μl). The reaction was heated in a microwave at 100° C. for 30 min. The mixture was then cooled to room temperature and the organic layer was separated from the aqueous layer by pipet. The resulting organic layer was then injected as is onto a reverse phase HPLC (Column: Gemini 150×30 mm, 5 μm, Phenomenex, Torrance, Calif., Flow rate: 40 mL/min, Mobile phase: 0.1% TFA in ACN and water). The fractions containing product were combined and saturated aq. NaHCO3 (15 mL) was added. The aqueous layer was washed with ethyl acetate (1×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under a vacuum to provide 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (10 mg, 0.021 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.22 (d, J=8.90 Hz, 1H) 7.36 (dd, J=7.09, 1.03 Hz, 1H) 7.43-7.58 (m, 4H) 7.65 (d, J=7.92 Hz, 1H) 7.85 (s, 1H) 7.99-8.09 (m, 2H) 8.31 (d, J=1.76 Hz, 1H); m/z (ESI) 470 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.C(O[I:20](C1C=CC=CC=1)OC(=O)C)(=O)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[I:20][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:7]1([C:11]([OH:13])=[O:12])[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(O)C1(c2ccccc2)CCC1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: II
Solvent: CN(C)C=O
Product: O=C(O)C1(c2ccccc2I)CCC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of 1-phenyl-1-cyclobutanecarboxylic acid (2.00 g, 11.4 mmol) in DMF (10 mL) containing palladium (II) acetate (0.109 g, 0.567 mmol), iodine (2.16 g, 8.51 mmol) and (diacetoxyiodo)benzene (2.47 g, 8.51 mmol) was stirred at 60° C. for 18 hours in the absence of light. Additional iodine (2.16 g, 8.51 mmol) and (diacetoxyiodo)benzene (2.47 g, 8.51 mmol) were added and stirring was continued at 60° C. for 8 hours. A final addition of iodine (2.16 g, 8.51 mmol) and (diacetoxyiodo)benzene (2.47 g, 8.51 mmol) was performed and stirring was continued at 60° C. for 16 hours. The reaction mixture was partitioned between EtOAc and water and the aqueous phase was extracted several times with EtOAc. The combined organic fractions were washed with 10% sodium metabisulfate (3×30 mL), 10% citric acid (2×30 mL), water, brine, and then dried (MgSO4), filtered and the solvent evaporated. The crude product was dry loaded onto silica gel and the product was separated using silica column chromatography (Biotage Isolera, 40 g SiO2 Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A52 as a cream solid (425 mg, 12%). LCMS-A: rt 5.711 min.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:10]1([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:2]1=[O:1])[CH3:32]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1C(Cc2ccncn2)c2ccccc2N1c1ccccc1
Product: CCOC(=O)CCCC1(Cc2ccncn2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 55 %

Procedure:
By substituting 2,3-dihydro-2-oxo-1-phenyl-3-(4-pyrimidinylmethyl)-1H-indole and ethyl 4-bromobutyrate in Example 1, the desired product was obtained in 55% yield as an oil; NMR(CDCl3TMS) δ1.22 (t, 3H, J=7 Hz); 1.42 (m, 1H); 1.53 (m, 1H); 2.06 (m, 1H); 2.25 (m, 3H); 3.25 (d, 1H, J=14 Hz); 3.55 (d, 1H, J=14 Hz); 4.09 (q, 2H, J=7 Hz); 6.63 (d, 1H, J=8 Hz); 6.98 (m, 1H); 7.07 (m, 2H); 7.26 (m, 3H); 7.40 (m, 1H); 7.50 (m, 2H); 8.42 (d, 1H, J=5 Hz); 8.90 (s, 1H). IR(KBr): 1728, 1583, 1501, 1481, 1466, 1376, 1326, 1182, 1157, 758, 700 cm-1 ; mass spec m/e 416 (M+1); high resolution mass spec m/e calcd 416.197417, m/e found 416.196591 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](=[S:24])[NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:26][C:27](=O)[CH3:28].C(O)C>ClCCl>[CH3:28][C:27]1[N:23]=[C:22]([C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:24][CH:26]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: ClCCl
Solvent: CCO
Product: Cc1csc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)n1
Yield: 60.7 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbothioamide (100 mg, 0.29 mmol), chloroacetone (46 μL, 0.57 mmol) and ethanol (5 mL) were combined and heated at reflux for 18 hours. The reaction mixture was concentrated in vacuo to give a cream coloured solid. This was dissolved in dichloromethane (100 mL) and washed with saturated NaHCO3 solution (50 mL). The organic extract was dried using Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography using 15 g of silica gel, eluting with dichloromethane:methanol:ammonia (97:3:0.3) to dichloromethane:methanol:ammonia (94:6:0.6) to give the title compound as a white solid (68 mg, 61%). 1H NMR (400 MHz, CDCl3) δ7.3 (d, 2H), 6.9 (d, 2H), 6.75 (s, 1H), 4.0 (t, 2H), 3.83 (m, 2H), 3.7 (m, 2H), 2.75-2.58 (m, 8H), 2.4 (s, 3H), 2.35 (m, 2H), 2.03 (m, 2H), 1.8 (m, 4H)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]4[N:38]([CH3:39])[N:37]=[C:36]([NH2:40])[CH:35]=4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=[CH:23][C:16]1=2.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]4[N:38]([CH3:39])[N:37]=[C:36]([NH:40][C:1](=[O:3])[CH3:2])[CH:35]=4)[CH2:28][CH2:29]3)=[CH:21][CH:22]=[CH:23][C:16]1=2
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(N)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(OCCCN2CCN(c3cccc4sccc34)CC2)n(C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Acetic anhydride (1 ml) and triethylamine (0.09 ml, 0.65 mmol) were added to a dichloromethane solution (4 ml) of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl-amine (0.20 g, 0.54 mmol) and the mixture was stirred at room temperature for 6 hours. An aqueous potassium carbonate solution was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain N-{5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}acetamide (0.19 g, 89% yield) as white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:17][CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: NCCc1c[nH]c2ccccc12
Product: Oc1cccc(Nc2nc(NCCc3c[nH]c4ccccc34)ncc2F)c1
Yield: 52.4 %

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and tryptamine (100 mg, 0.62 mmol) gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(indol-3-yl)ethyl]-2,4-pyrimidinediamine (40 mg, 53%). 1H NMR (CD3OD): δ 3.01 (t, J=7.2 Hz, 2H), 3.61 (t, J=7.2 Hz, 2H), 6.51 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.96 (td, J=0.9 and 7.2 Hz, 1H), 7.03-7.09 (m, 3H), 7.22 (d, J=7.5 Hz, 1H), 7.28-7.32 (m, 2H), 7.53 (d, J=7.8 Hz, 1H), 7.72 (d, J=4.5 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −171.72; LCMS: ret. time: 20.17 min.; 95.66%; MS (m/e): 364.05 (MH+).
Reaction SMILES: [C:1]([NH:3][CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([CH3:17])[NH:15][CH:16]=2)=[CH:8][CH:7]=1)#N.CN>>[CH3:1][NH:3][CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([CH3:17])[NH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: Cc1nc(-c2ccc(N=CNC#N)cc2)c[nH]1
Agent: CN
Product: CNC=Nc1ccc(-c2c[nH]c(C)n2)cc1
Yield: 56.1 %

Procedure:
N-Cyano-N'-[4-(2-methyl-imidazol-4-yl)phenyl]-formamidine (2.25 g) was added all at once to a solution of methylamine 33% aqueous (22.5 ml). After a few minutes the solid which separated out was filtered off, washed with water and dried to give 1.2 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]#[N:6].[CH3:17][O:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.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>[CH3:17][O:18][C:19]1[C:24]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]#[N:6])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: COc1ncccc1B(O)O
Reactant: N#Cc1ccc(Oc2ccccc2)c(Br)c1
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: O
Solvent: C1COCCO1
Product: COc1ncccc1-c1cc(C#N)ccc1Oc1ccccc1
Temperature: 100 °C
Yield: 108.7 %

Procedure:
A mixture of 3-bromo-4-phenoxybenzonitrile (Preparation 21, 0.21 g, 0.7 mmol), (2-methoxypyridin-3-yl)boronic acid (0.2 g, 1.1 mmol) and sodium hydrogen carbonate (0.19 g, 2.1 mmol) was suspended in dioxane (10 mL) and water (3 mL). The reaction mixture was degassed for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.050 g, 0.07 mmol) was added and the mixture heated at 100° C. for 1 hour. After the reaction was allowed to cool to room temperature, the reaction was partitioned between EtOAc (50 mL) and water (15 mL). The organic layer was filtered through a pad of celite and the solvent removed in vacuo to provide a crude brown solid. The crude material was purified by silica gel chromatography eluting with 30% EtOAc in Heptane to afford the title compound as a yellow solid (0.23 g).
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[O:37][CH:36]=[C:35]([CH:38]=[O:39])[CH:34]=1)CCC>O1CCOCC1>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]2[C:4]3[CH:3]=[C:2]([C:33]4[O:37][CH:36]=[C:35]([CH:38]=[O:39])[CH:34]=4)[N:27]=[CH:26][C:5]=3[N:6]=[CH:7][N:8]=2)=[CH:12][CH:13]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4cnc(Cl)cc34)cc2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C=O)co1
Solvent: C1COCCO1
Product: O=Cc1coc(-c2cc3c(Nc4ccc(OCc5cccc(F)c5)cc4)ncnc3cn2)c1

Procedure:
(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine (1 g) and 5-(tributylstannyl)-furan-3-carbaldehyde (J. Org. Chem. (1992), 57(11), 3126-31) (1.84 g) in dioxan (35 ml) were reacted together as in Procedure B. The solvent was evaporated and the residue suspended in dichloromethane. The mixture was filtered through Celite® and then evaporated. The residue was triturated with hexane giving a beige solid (1 g); m/z 441 (M+1)+.
Reaction SMILES: CC(C([NH:7][C:8]1[N:17]=[C:16]([NH:18]C(C(C)(C)C)=O)[C:15]2[CH2:14][C:13](=[N:25][O:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[CH2:12][CH2:11][C:10]=2[N:9]=1)=O)(C)C.Cl.O>O1CCCC1>[NH2:7][C:8]1[N:17]=[C:16]([NH2:18])[C:15]2[CH2:14][C:13](=[N:25][O:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=NOc1cc(Cl)cc(Cl)c1)CC2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(N)c2c(n1)CCC(=NOc1cc(Cl)cc(Cl)c1)C2
Temperature: 25 °C

Procedure:
A suspension of 2.5 grams (0.005 mole) of 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-(3,5-dichlorophenoxyimino)-5,6,7,8-tetrahydroquinazoline in 40 mL of tetrahydrofuran is stirred, and a methanolic solution saturated with hydrogen chloride is added portionwise until a clear solution is obtained. After this time about 2 mL of water is added, and the reaction mixture is heated to reflux where it is stirred for about 4 hours. The reaction mixture is then cooled to ambient temperature and is washed with acetone. The reaction mixture is concentrated under reduced pressure, yielding 2,4-diamino-6-(3,5-dichlorophenoxyimino)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[CH:10]=[O:11].B.O1CCCC1>O1CCCC1>[OH:11][CH2:10][C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=1
Reactant: Cn1cc([N+](=O)[O-])cc1C=O
Agent: B
Solvent: C1CCOC1
Product: Cn1cc([N+](=O)[O-])cc1CO
Temperature: 0 °C
Yield: 89.7 %

Procedure:
Compound 22-1 (550 mg) was dissolved in anhydrous tetrahydrofuran (30 ml) and cooled to 0° C. To the solution was slowly added dropwise 1M borane-tetrahydrofuran (3.25 ml), followed by refluxing at 80° C. for 3 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure to be removed, and then the residue was purified by column-chromatography (ethyl acetate/hexane=2/1) to yield the compound 22-2 (500 mg, 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:21][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1ccc(N)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: CCCCOc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-butoxyaniline to yield 2-[(4-butoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[CH3:27][NH2:28]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:28][CH3:27])[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: CN
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1F
Temperature: 40 °C
Reaction time: 16 h

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (60 mg) and a 40% aqueous solution (110 mg) of methylamine were added to pyridine (1,160 mg), and the mixture was stirred at 40° C. for 16 hours. The solvent was distilled off under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed successively with ethanol and diisopropyl ether to obtain the title compound (58 mg) as a colorless powder.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:9][N:10]2[C:13]2[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)=[CH:6][CH:5]=1.Br[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.O>CN(C)C=O>[CH:30]1([O:3][C:4]2[CH:12]=[C:11]3[C:7]([C:8]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:9][N:10]3[C:13]3[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=3)=[CH:6][CH:5]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(O)cc32)n1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(OC4CCCC4)cc32)n1
Reaction time: 0.08 h
Yield: 29.1 %

Procedure:
Sodium hydride (added with 40% mineral oil, 13.5 mg, manufactured by Kanto Chemical Co., Inc.) was added to a solution of ethyl 2-(6-hydroxy-3-phenyl-1H-indazol-1-yl)thiazole-4-carboxylate (20 mg), which had been synthesized from the compound of Reference Example 20 according to the method of Example 3, in N,N-dimethylformamide (1 mL, manufactured by Kanto Chemical Co., Inc.) under ice cooling, and the mixture was stirred for 5 minutes at the same temperature. Subsequently, bromocyclopentane (269 mg, manufactured by Kanto Chemical Co., Inc.) was added, and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether (3×10 mL), washed with brine (10 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1), to give 6.9 mg of the title compound. LC-MS: HPLC retention time 2.13 minutes, m/z 434 (M+H), condition C-1.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[F:19][CH:20]([F:30])C1C=CC=CC=1B(O)O>>[F:19][CH:20]([F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: OB(O)c1ccccc1C(F)F
Product: O=C(O)c1csc(-c2ccccc2C(F)F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2-(difluoromethyl)phenyl)boronic acid gave the title compound.