Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[NH:44]1[CH2:47][CH:46]([NH:48]C(=O)OC(C)(C)C)[CH2:45]1>>[NH2:48][CH:46]1[CH2:45][N:44]([CH2:21][C:20]2[CH:23]=[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)[C:17]([NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[N:18][CH:19]=2)[CH2:47]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Product: COc1ccc(Nc2ncc(CN3CC(N)C3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.56 g, 0.969 mmol) and tert-butyl azetidin-3-ylcarbamate (Astatech, Bristol, Pa.) (0.250 g, 1.454 mmol). 1H NMR (400 MHz, d4-MeOH) δ 8.85 (d, 1H); 8.46 (d, J=2.54 Hz, 1H); 8.18 (d, J=2.35 Hz, 1H); 8.01 (dd, J=8.80, 2.74 Hz, 1H); 6.81 (d, J=8.80 Hz, 1H); 3.91 (s, 3H); 3.83-3.88 (m, 1H); 3.82 (s, 2H); 3.75 (t, J=7.92Hz, 2H); 3.36-3.40 (m, 2H); 2.47 (s, 3H). m/z (ESI, +ve ion) 394.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])=[CH:22][C:21]=1I>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:21]1[CH:22]=[C:23]([S:26]([C:29]([F:30])([F:31])[F:32])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccc(Cl)c(I)c1)C(F)(F)F
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Yield: 72 %

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-chloro-2-iodo-4-[(trifluoromethyl)sulfonyl]benzene (Intermediate 186), the title compound was obtained as a white solid in 72% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[N:45]=[C:46]([C:49](Cl)=[O:50])[S:47][CH:48]=1.COC1C=CC=CC=1C1N=C(C(O)=O)SC=1>>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:49]([C:46]2[S:47][CH:48]=[C:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[O:37][CH3:36])[N:45]=2)=[O:50])=[N:7][CH:6]=1
Reactant: COc1cc2c(Oc3ccc(N)nc3)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccccc1-c1csc(C(=O)Cl)n1
Agent: COc1ccccc1-c1csc(C(=O)O)n1
Product: COc1cc2c(Oc3ccc(NC(=O)c4nc(-c5ccccc5OC)cs4)nc3)ccnc2cc1OCC1CCNCC1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5 X13 was prepared from tert-butyl 4-(((4-((6-aminopyridin-3-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)piperidine-1-carboxylate and 4-(2-methoxyphenyl)thiazole-2-carbonyl chloride, which was prepared similar to Preparative Example 16 step 4 from commercially available 4-(2-methoxyphenyl)thiazole-2-carboxylic acid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.40 (m, 2H), 1.87 (d, J=12.6 Hz, 2H), 2.07 (m, 1H), 2.76 (t, J=11.8 Hz, 2H), 3.18 (d, J=12.6 Hz, 2H), 3.93 (s, 3H), 3.95 (s, 3H), 4.02 (d, J=6.4 Hz, 2H), 6.57 (d, J=5.2 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.39 (m, 2H), 7.53 (s, 1H), 7.90 (dd, J=2.8 Hz, J=9.0 Hz, 1H), 8.29 (d, J=9.0 Hz, 1H), 8.49 (m, 4H). MS (ES) C32H31N6O6S requires: 597. Found: 598 (M+H)+.
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[CH:35](=O)[C:36]1[O:40][CH:39]=[CH:38][CH:37]=1.[BH3-]C#N.[Na+]>CO>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:35][C:36]2[O:40][CH:39]=[CH:38][CH:37]=2)[CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccco1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3ccco3)C3CCCc4cccnc43)cc2)nc1
Yield: 52.3 %

Procedure:
To a stirred solution of N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.206 g, 0.449 mmol) in anhydrous methanol (10 mL), at room temperature, was added furfural (0.19 mL, 2.29 mmol) followed by NaBH3CN (0.070 g, 1.11 mmol) and the resultant solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and CH2Cl2 (20 mL) and 1.0 M aqueous NaOH (10 mL) were added to the residue. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography silica gel (25:1 CH2Cl2-MeOH) provided 0.103 g of the protected amine as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][CH:21]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]3[CH2:18][C:17](=[O:19])[CH2:16]3)[CH:10]=2)[N:3]=1.[BH4-].[Na+]>>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:24][CH:25]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]3[CH2:16][CH:17]([OH:19])[CH2:18]3)[CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C3CC(=O)C3)c2)N=C1N
Agent: [BH4-]
Agent: [Na+]
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C3CC(O)C3)c2)N=C1N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
A methanolic solution of 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-oxocyclobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one (0.324 gm, 0.811 mmol) at ice bath temperatures was treated all at once with NaBH4 (0.042 gm, 1.11 mmol), stirred at 0° C. for 45 minutes and concentrated in vacuo. The solid residue was partitioned between water and chloroform. The organic phase was separated, dried over sodium sulfate and evaporated to a foam. This foam was dissolved in chloroform and precipitated with hexane to give the title compound as a white solid, 0.307 g (94% yield), mp 186-190° C.; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.86 (m, 2 H) 2.53-2.60 (m, 2 H) 2.70-2.85 (m, 1 H) 2.97 (s, 3 H) 3.89-4.08 (m, 1 H) 5.08 (t, J=5.2 Hz, 1 H) 6.69 (s, 2 H) 7.10 (d, J=8.6 Hz, 3 H) 7.17 (t, J=74.2 Hz, 1 H) 7.19-7.33 (m, 3 H) 7.45 (d, J=8.8 Hz, 2 H); MS (ES) m/z 400.2 [M−H]−; HRMS: calcd for C21H21F2N3O3+H+, 402.16237. found (ESI, [M+H]+), 402.1630.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.N1[CH:16]=[CH:15]N=C1.C(Cl)(=O)C.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.O>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:6])[N:22]([CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30])[C:15]([CH3:16])=[N:1]2
Reactant: NC1CCC(=O)NC1=O
Reactant: c1c[nH]cn1
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Cc1nc2cccc(Cl)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a stirred mixture of 2-amino-6-chlorobenzoic acid (2.3 g, 13 mmol) and imidazole (1.1 g, 16 mmol) in acetonitrile (25 mL), was added acetyl chloride (1.1 mL, 16 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.2 g, 13 mmol), imidazole (2.0 g, 30 mmol) and triphenyl phosphite (4.2 mL, 16 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL) to give a white solid, which was purified with preparative HPLC (C18 20/80 CH3CN/H2O) to give 3-(5-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (1.3 g, 31% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 4.16 min (99.9%); mp: 315° C. (decomp); 1H NMR (DMSO-d6) δ2.13-2.19 (m, 1H, CHH), 2.57-2.68 (m, 5H, CH3, 2CHH), 2.78-2.85 (m, 1H, CHH), 5.23 (dd, J=5, 11 Hz, 1H, NCH), 7.51-7.58 (m, 2H, Ar), 7.74 (t, J=8 Hz, 1H, Ar), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.63, 23.48, 30.53, 56.61, 117.14, 126.18, 128.98, 132.24, 134.52, 149.27, 155.99, 158.39, 169.38, 172.56; LCMS: MH=306, 308; Anal Calcd for C14H12N3O3Cl+1H2O: C, 51.94; H, 4.36; N, 12.98; Cl, 10.95. Found: C, 51.91; H, 4.24; N, 12.93; Cl, 10.20.
Reaction SMILES: C([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C@@H:6]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][N:8]([CH2:21][CH3:22])[C:7]1=[O:23])#N.Cl.Cl.[O:33]=[C:34]1[NH:42][C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[N:35]1[CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.[CH:49]([N:52](CC)C(C)C)(C)C>C(O)CCCC>[C:49]([N:5]([C@@H:6]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:9][N:8]([CH2:21][CH3:22])[C:7]1=[O:23])[C:4]([N:46]1[CH2:47][CH2:48][CH:43]([N:35]2[C:36]3[C:37](=[N:38][CH:39]=[CH:40][CH:41]=3)[NH:42][C:34]2=[O:33])[CH2:44][CH2:45]1)=[NH:3])#[N:52]
Reactant: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=NC#N)Oc2ccccc2)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CCCCCO
Product: CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N(C#N)C(=N)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)C1=O
Yield: 4.6 %

Procedure:
A solution of phenyl N′-cyano-N-[(3R,6S)-6-(2,3-difluorophenyl)-1-ethyl-2-oxoazepan-3-yl]imidocarbamate (166 mg, 0.402 mmol) and 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (116 mg, 0.402 mmol), in 1-pentanol (10 mL) was treated with N,N-diisopropylethylamine (52 mg, 0.402 mmol). This mixture was heated to reflux for 24 h. Concentration and purification by silica gel chromatography (0%→10% methanol/dichloromethane) followed by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (10 mg). MS 537.5 (M+1).
Reaction SMILES: O([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[CH:11]=[CH:10][N:9]=1)C1C=CC=CC=1.C([O-])(=O)C.[NH4+:26].[OH-].[Na+]>O>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][N:9]=[C:8]2[NH2:26])=[CH:13][CH:14]=1
Reactant: [NH4+]
Reactant: FC(F)(F)c1ccc2ccnc(Oc3ccccc3)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nccc2ccc(C(F)(F)F)cc12
Temperature: 25 °C

Procedure:
A mixture of 1-phenoxy-7-(trifluoromethyl)isoquinoline (670 mg, 2.3 mmol), from above step D, and ammonium acetate (1.8 g, 23 mmol) was heated at 160° C. for 4 h. The mixture was cooled to room temperature and dissolved in water. Sodium hydroxide (1N solution) was added until the solution was basic and extracted with EtOAc (x4). The combined organic fractions were washed with saturated NaCl, dried over Na2SO4 and evaporated under vacuum to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1[CH:26]=O)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[CH3:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1/[CH:26]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: Cc1[nH]c2ccccc2c1C=O
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2c(C)[nH]c3ccccc23)cc(OC)c1OC
Yield: 60.7 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (2.10 g) and 2-methylindole-3-carboxaldehyde (1.59 g) except that the obtained crude crystals were recrystallized from ethanol, to give Compound 12 (2.13 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[N:22]=1>>[NH:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[NH:20][C:8]1[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(Nc2nc3ccccc3[nH]2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2-amino-1H-benzimidazole in a similar manner as described for e.g. Examples 6-9, 22-25, 28 and 32-35. 1H NMR (500 MHz, CD3CN): δ 1.00 (t, 3H), 1.43-1.53 (m, 2H), 1.76-1.85 (m, 2H), 3.71 (t, 2H), 7.12-7.19 (m, 4H), 7.34-7.68 (m, 5H), 8.03-8.06 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:26])[N:21]([CH3:27])[C:20]2=[O:28])=[CH:14][C:3]=1[C:4]([O:6][C:7]([C:10]([O:12][CH3:13])=[O:11])([CH3:9])[CH3:8])=[O:5].[Cu][C:30]#[N:31]>CN1CCCN(C)C1=O>[C:30]([C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:26])[N:21]([CH3:27])[C:20]2=[O:28])=[CH:14][C:3]=1[C:4]([O:6][C:7]([C:10]([O:12][CH3:13])=[O:11])([CH3:9])[CH3:8])=[O:5])#[N:31]
Reactant: N#C[Cu]
Reactant: COC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C)n(C)c2=O)c(F)cc1Cl
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C)n(C)c2=O)c(F)cc1C#N
Temperature: 220 °C

Procedure:
A mixture of 1.5 g of 1-methoxycarbonyl-1-methylethyl 2-chloro-5-[3,6-dihydro-3 4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoate and 0.4 g of copper(I) cyanide in 20 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is heated to 220° C. under nitrogen for 6 hours. After cooling to room temperature the mixture is filtered and the filtrate is dissolved in 200 ml of ethyl acetate. The solution is washed four times with 50 ml of water each time, the combined organic phases are dried and concentrated under reduced pressure. In this manner there is obtained 1-methoxycarbonyl-1-methylethyl 2-cyano-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoate, mass spectrum (m/e); 403 10) M+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[N:24]=[N:23]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:27]([C:25]3[N:24]=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: Cn1cc(C(=O)O)nn1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: Cn1cc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)nn1

Procedure:
Methyl-1H-[1,2,3]triazole-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-methyl-1H-[1,2,3]triazole-4-carboxylic acid. MS calcd. for C20H17ClN5O2 [(M+H)+] 394.1, obsd. 394.0.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=2)[C:22]#[N:23])[C:15]([CH:28]([CH3:30])[CH3:29])=[C:14](Cl)[N:13]=1.C([O:35][CH2:36][CH3:37])(=O)C>C1COCC1>[CH2:3]([O:10][C:12]1[N:17]=[C:16]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=2)[C:22]#[N:23])[C:15]([CH:28]([CH3:30])[CH3:29])=[C:14]([O:35][CH2:36][C:37]2[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=2)[N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C#N)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reactant: OCc1ccccc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At 0° C., NaH (60%, 118 mg, 2.88 mmol, 2.2 eq.) was added to benzyl alcohol (298 μL, 2.88 mmol) in 5 mL of THF solution. The reaction mixture was stirred at 0° C. for 5 minutes. 3-(2,6-Dichloro-5-isopropyl-pyrimidin-4-yloxy)-5-methyl-benzonitrile (422 mg, 1.31 mmol) was added. The reaction mixture was stirred at 0° C. for 15 minutes, then warmed to room temperature for 90 minutes. Ethyl acetate was added to the reaction mixture, which was then washed with brine. The organic layer was concentrated and purified (silica gel, 0-50% EtOAc/hexane) to give a white solid (372 mg, 65% pure by HPLC, 40%). LC-MS shows 466.1 (M+1).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:24])([F:23])[C:5]([F:22])([F:21])[C:6]([F:20])([F:19])[C:7]([F:18])([F:17])[C:8]([F:16])([F:15])[C:9](F)([F:13])[CH2:10][CH2:11]I>O1CCCC1>[F:13][C:9]([C:8]([F:16])([F:15])[C:7]([F:18])([F:17])[C:6]([F:20])([F:19])[C:5]([F:22])([F:21])[C:4]([F:24])([F:23])[F:3])=[CH:10][CH2:11][NH:2][CH3:1]
Reactant: CN
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Solvent: C1CCOC1
Product: CNCC=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.44 g of methylamine is condensed in a solution of 2.82 ml of 1,1,1,2,2,3,3,4,4,5,5,6,6 tridecafluor-8-iod-octane in 20 ml of anhydrous tetrahydrofuran at −40° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at −30° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. Then, the reaction solution is mixed with diethyl ether, washed with saturated common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 2.23 g of (3,4,4,5,5,6,6,7,7,8,8,8-dodecafluor-oct-2-enyl)-methyl-amine is obtained as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=O)[N:10](C)[CH:9]2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[CH:9]([NH:10][CH3:11])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CN1C(=O)OC(c2ccc(F)cc2)C1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Yield: 0.1 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-3-methyl-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (4.56 g, 12.9 mmol) in ethanol (20 ml) was added 8N aqueous sodium hydroxide solution (8.07 ml) and the mixture was heated under reflux for 3 hrs. The reaction solution was diluted with water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (1RS,2SR)-1-(4-fluorophenyl)-2-(methylamino)-3-(4-(trifluoromethyl)phenyl)-1-propanol (3.34 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1.[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH3:7][C:4]1[C:3]2[C:8]3[C:9]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=3[C:36]([C:35]3[CH:38]=[CH:39][C:32]([OH:31])=[CH:33][CH:34]=3)=[N:1][C:2]=2[NH:6][N:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1cccc(-c2c(C)n[nH]c2N)c1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(-c3ccc(O)cc3)nc3[nH]nc(C)c3c2c1OCC1CCNCC1
Temperature: 75 °C
Reaction time: 15 h
Yield: 13 %

Procedure:
To 1,1-dimethylethyl 4-({[2-(5-amino-3-methyl-1H-pyrazol-4-yl)-6-(methyloxy)phenyl]oxy}methyl}piperidine-1-carboxylate (397 mg, 0.95 mmol) was added 4-hydroxybenzaldehyde (174 mg, 1.4 mmol) and TFA (5 mL). The mixture was heated to 75° C. and stirred for 15 h. After cooling to rt, the volatile materials were removed in vacuo. The resulting residue was dissolved in a 1:1 mixture of water:acetonitrile and purified by preparative HPLC. The fractions containing the desired product were concentrated and lyophilized to provide 4-{1-methyl-8-(methyloxy)-9-[(piperidin-4-ylmethyl)oxy]-3H-pyrazolo[3,4-c]isoquinolin-5-yl}phenol trifluoroacetate (64.1 mg, 0.12 mmol, 13% yield). 1H NMR (400 MHz, DMSO-d6): δ9.81 (br s, 1H), 8.53 (br d, 1H), 8.21 (br m, 1H), 7.84 (d, 1H), 7.43 (m, 2H), 7.38 (d, 1H), 6.92 (m, 2H), 3.97 (s, 3H), 3.88 (d, 2H), 3.32 (br d, 2H), 3.00-2.92 (q, 2H), 2.80 (s, 3H), 2.26 (m, 1H), 2.04 (br d, 2H), 1.52-1.43 (m, 2H); MS (EI) for C24H26N4O3: 419 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.O1CCOCC1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[F:27])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: OB(O)c1ccccc1F
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCSc1ccccc1-c1nc2cc(-c3ccccc3F)cnc2n1C
Temperature: 80 °C
Yield: 95.5 %

Procedure:
To a mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (350 mg) and 1,4-dioxane (5 ml), 2-fluorophenylboronic acid (150 mg), tripotassium phosphate (600 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (25 mg), and tris(dibenzylideneacetone)palladium(0) (14 mg) were sequentially added, heated to 80° C., and stirred with heating for 8 hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 349 mg of 2-(2-ethylsulfanylphenyl)-6-(2-fluorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 58).