Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)OC(C)(C)C)C3)ccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
A solution of 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.1 mmol) in DCM (6.5 mL) was treated with TFA (6.5 mL). The reaction mixture was stirred at RT for 4 hours then concentrated in vacuo. The residue was azeotroped with DCM then dissolved in DCM and washed with an aqueous saturated sodium bicarbonate solution (×2) followed by brine. The mixture was passed through a phase separator cartridge and concentrated in vacuo to give 235 as a pale orange gum (397 mg, quant.). LCMS: RT=3.13 min, [M+H]+=368. 1H NMR δ (ppm) (DMSO-d6): 9.34 (1H, s), 9.05 (1H, s), 8.30 (1H, d, J=8.19 Hz), 8.06 (1H, d, J=0.58 Hz), 7.23 (1H, dd, J=8.24, 1.89 Hz), 7.13 (1H, d, J=1.84 Hz), 5.82-5.72 (1H, m), 4.36-4.30 (2H, m), 4.25-4.17 (2H, m), 4.13-3.97 (3H, m), 3.43-3.37 (2H, m), 1.50 (6H, d, J=6.59 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1>[Pd].CCO.CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc([N+](=O)[O-])c2n1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cc1ccc2cccc(N)c2n1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Palladium on carbon (10%, 50 mg) was added to a solution of 2-methyl-8-nitroquinoline (500 mg, 2.66 mmol) in EtOH (40 ml) and the mixture was stirred under an atmosphere of hydrogen for 2 h. The mixture was diluted with MeOH (40 ml), filtered through celite and the filtrate was concentrated in vacuo to give the title compound (417 mg, 99%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.C(N(CC)CC)C.C([O:44][C:45]([C:48](Cl)=[O:49])([CH3:47])[CH3:46])(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:48](=[O:49])[C:45]([OH:44])([CH3:47])[CH3:46])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(O)C(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg) and triethylamine (0.40 mL) in tetrahydrofuran (5.0 mL) was added 1-chlorocarbonyl-1-methylethyl acetate (0.12 mL) at room temperature. After stirring at room temperature for 3 days, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in ethanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (1.5 mL) at room temperature. After stirring at room temperature for 24 hrs, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=9:1) to give the title compound (133 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:14]2[N:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:8]3=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CS(C)=O.[Cl-].[NH4+]>[CH2:25]([N:28]([C:2]1[C:14]2[N:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:8]3=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]
Reactant: Cc1cc(C)c(-c2c3nc(C)cc(Cl)c3n3ccncc23)c(C)c1
Reactant: CCCNCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCCN(CCC)c1cc(C)nc2c(-c3c(C)cc(C)cc3C)c3cnccn3c12
Temperature: 130 °C

Procedure:
To a solution of 4-Chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrido-[2′,3′:4,5]pyrrolo[1,2-a]pyrazine (23 mg) in DMSO (0.5 mL) is added dipropylamine (0.1 mL) and the resulting mixture is heated at 130° C. for 3.5 days. The mixture is then allowed to cool to room temperature, diluted with aqueous ammonium chloride, and extracted twice with ethyl ether. The extracts are combined, washed with saturated brine, dried (Na2SO4), filtered, concentrated in vacuo, and chromatographed (10 to 20% ethyl acetate in hexane) to give 14.3 mg of the title compound (compound 6, Table 1) as a yellow, glassy oil: 0.90 (t, 6 H), 1.6 (m, 4 H), 2.03 (s, 6 H), 2.38 (s, 3 H), 2.62 (s, 3 H), 3.2 (br, 4 H), 6.81 (s, 1 H), 7.02 (s, 2 H), 7.60 (d, 2 H), 8.6 (m, 2 H).
Reaction SMILES: Cl.[CH2:2]([O:6][NH:7][C:8]([NH:10][C:11](=N)[NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])=O)[CH2:3][CH2:4][CH3:5].C[O:23][CH:24](OC)[N:25](C)C>CC#N>[CH3:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[C:13]=1[N:12]1[CH:11]=[N:10][C:8]([NH:7][O:6][CH2:2][CH2:3][CH2:4][CH3:5])=[N:25][C:24]1=[O:23]
Reactant: CCCCONC(=O)NC(=N)Nc1c(C)cccc1C
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CC#N
Product: CCCCONc1ncn(-c2c(C)cccc2C)c(=O)n1
Reaction time: 0.08 h

Procedure:
To a magnetically stirred suspension of 12.06 g (38 mmol) of 1-N-butoxy-3-(2,6-dimethylphenyl) amidinourea hydrochloride in 25 ml of CH3CN was added 9.11 g (76 mmol) of N,N-dimethyl-formamide dimethyl acetal and another 25ml of CH3CN. All of the solid dissolved after the reaction was stirred for 5 minutes. The reaction solution was refluxed for two hours and allowed to come to ambient temperature, then concentrated in vacuo to yield the desired product as a white solid. This was combined with 200 ml of H2O to an insoluble, thin gummy solid which was transferred to a separatory funnel and extracted with CHCl3 (3×75 ml). The organic layers were combined, washed with H2O (2×75 ml) and saturated aqueous brine (1×75 ml). All aqueous washes were combined and back-extracted with (2×50 ml), dried (Mg2SO4), filtered and concentrated in vacuo to yield 1-(2,6-dimethylphenyl)-4-n-butoxyamino-1,2-dihydro-1,3,5-triazin-2-one, as a white solid containing some liquid. Tlc (3% NH4OH/iPA) shows four spots, one of same Rf as starting material. The product was triturated with iPA to yield a white solid: m.p. 144°-145° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].[CH2:29]([C:31]1[N:35]=[C:34]([CH2:36][N:37]2[C:42]3[CH:43]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[S:45][C:41]=3[C:40](=[O:52])[N:39]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[C:38]2=[O:59])[O:33][N:32]=1)[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:56]4[CH2:57][CH2:58][CH:53]([N:39]5[C:40](=[O:52])[C:41]6[S:45][C:44]([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)=[CH:43][C:42]=6[N:37]([CH2:36][C:34]6[O:33][N:32]=[C:31]([CH2:29][CH3:30])[N:35]=6)[C:38]5=[O:59])[CH2:54][CH2:55]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (99.4 mg; compound C10), 1-(3-Ethyl-[1,2,4]oxadiazol-5-ylmethyl)-6-phenyl-3-piperidin-4-yl-1H-thieno[3,2-d]pyrimidine-2,4-dione (109 mg; compound B52) and HOBT (38 mg) in DCM (2.5 ml) is added EDCI (48.9 mg). The mixture is stirred for 2.5 h at RT. EtOAc (25 ml) is added and the mixture is extracted with 1 M aqueous hydrochloride solution (5 ml) (three times). The combined aqueous phases are washed with EtOAc (15 ml) and subsequently the combined organic phases are washed with water (5 ml) (three times) and afterwards with saturated solution of sodium bicarbonate (10 ml) (three times). The organic phase is dried over magnesium sulfate, concentrated in vacuo and the resulting residue is purified by flash column chromatography [amino phase silica gel, eluation gradient: EtOAc/cyclohexane=0/100 to 20/80 (v/v)] to give the title compound as a solid.
Reaction SMILES: O[CH:2]1C2C(=CC=CC=2)C(=O)[N:3]1CC1SC=CC=1.[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([S:28][CH2:29][C:30]([NH:32][C:33]2S[CH:35]=[CH:36][N:37]=2)=[O:31])[N:20]1[CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1>>[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([S:28][CH2:29][C:30]([NH:32][C:33]2[CH:2]=[N:3][CH:35]=[CH:36][N:37]=2)=[O:31])[N:20]1[CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Reactant: O=C(CSC1c2ccccc2C(=O)N1Cc1cccs1)Nc1nccs1
Product: O=C(CSC1c2ccccc2C(=O)N1Cc1cccs1)Nc1cnccn1

Procedure:
Compound 31 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of compound 12 to compound 14 and illustrated in Scheme 1b. 1H NMR (300 MHz, DMSO): δ 10.65 (s, 1H), 9.12 (s, 1H), 8.34 (s, 2H), 7.70 (d, J=7 Hz, 1H), 7.60 (m, 2H), 7.43 (m, 2H), 7.09 (m, 1H), 6.97 (m, 1H), 5.77 (s, 1H), 5.13 (d, J=15 Hz, 1H), 4.66 (d, J=16 Hz, 1H), 3.10 (d, J=15 Hz, 1H), 2.98 (d, J=15 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: NC(=O)c1ccc(F)cc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)ccc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 8.8 mmol) and 2-amino-4-fluorobenzamide (3.50 g, 23 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4-fluorobenzamide was isolated as a white solid (1.75 g, 43% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.67 (d, J=4.03 Hz, 1 H), 6.98-7.04 (m, 1 H), 7.47 (d, J=8.23 Hz, 2 H), 7.80 (d, J=4.03 Hz, 1 H), 7.89 (s, 1 H), 7.93-8.01 (m, 3 H), 8.40 (s, 1 H), 8.47 (dd, J=11.89, 2.74 Hz, 1 H), 12.95 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[Si:12]([O:19][CH2:20][C:21]1[S:25][C:24]([NH2:26])=[N:23][CH:22]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:26][C:24]2[S:25][C:21]([CH2:20][O:19][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])=[CH:22][N:23]=2)=[N:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(N)s1
Reactant: Brc1ncc(Br)n2ccnc12
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2ncc(Br)n3ccnc23)s1

Procedure:
Prepared from Intermediate 2 and Intermediate 7 using the procedure described in Example 1, Step 1. MS (MH+, m/z) 440.
Reaction SMILES: ClC1C([C:8](O)=[O:9])=C(C2C=CC=CC=2)C(C)=CN=1.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:21]=[C:22]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:23][NH:24][CH2:25]CCO>>[F:35][C:32]([F:34])([F:33])[C:30]1[CH:29]=[C:22]([CH:21]=[C:20]([C:19]([F:37])([F:36])[F:18])[CH:31]=1)[CH2:23][NH:24][CH2:25][CH2:8][OH:9]
Reactant: Cc1cnc(Cl)c(C(=O)O)c1-c1ccccc1
Reactant: OCCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: OCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
2-Chloro-5-methyl-4-phenyl-3-pyridinecarboxylic acid was used in place of 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 in Reference Example 12, reacted with N-[3,5-bis(trifluoromethyl)benzyl]-N-(3-hydroxypropyl)amine that had been obtained in Step 1 in Reference Example 23, in place of N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-hydroxyethyl)amine, and treated in the same manner as in Step 2 in Reference Example 12, to obtain the entitled compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH2:23]([C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:33])[CH:28]=[CH:29][CH:30]=1)[CH3:24]
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: CCc1cccc(N=C=O)c1
Product: CCc1cccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 3-ethylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCCOc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCCOc2ccc(Br)cc21
Reaction time: 1.5 h
Yield: 103.7 %

Procedure:
A solution of 4-(4-bromophenoxy)butanoyl chloride (27.6 g, 100 mmol) in DCM (200 mL) was added dropwise to a solution of AlCl3 (50 g, 0.38 mol) in DCM (100 mL) at within 40 minutes, the mixture was stirred at 0 for 1.5 hours, and then stirred at room temperature overnight. the mixture was added to a stirred mixture of concentrated hydrochloric (500 mL) and ice, and then stirred for 1.5 hours. The mixture was extracted with DCM, washed with NaHCO3, dried over Na2SO4 and concentrated to give crude 7-bromo-3,4-dihydrobenz o[b]oxepin-5(2H)-one (25 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:37]([NH:36][C:34](=[O:35])[C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[S:38])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 99%).
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[N:14][CH:15]=[CH:16][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[N:14][CH:15]=[CH:16][C:10]=3[N:9]([C:17](=[O:19])[CH3:18])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2=NNc3ccncc3N2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1N=C(c2ccccc2)Nc2cnccc21
Yield: 76 %

Procedure:
3-Phenyl-1,4-dihydropyrido[3,4-e]-as-triazine is reacted with acetic anhydride as described in Example 11 to obtain 3-phenyl-1-acetyl-1,4-dihydropyrido[3,4-e]-as-triazine with a yield of 76%; m.p.: 208°-209° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[O:11][C:12]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:13]=1N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OCCC(C)C)=O.[ClH:45]>[Cu](Cl)Cl.C(#N)C>[Cl:45][C:13]1[CH:15]=[C:16]([F:32])[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:18][C:12]=1[O:11][C:10]1[CH:33]=[CH:34][CH:35]=[CH:36][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(N)cc2F)c1=O
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(Cl)cc2F)c1=O
Reaction time: 1 h

Procedure:
To a mixture of 6.46 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 2.45 g of copper chloride (I), 5.04 g of copper chloride (II) and 90 ml of acetonitrile was added dropwise 4.46 g of isoamyl nitrite at room temperature, and the mixture was stirred for 1 hour. The reaction solution was poured into 2% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica-gel column chromatography to give 4.6 g of ([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene.
Reaction SMILES: [Na].[CH3:2]I.[Cl:4][C:5]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:6]=1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[NH:10][CH:9]=1>CN(C)C=O>[Cl:4][C:5]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:6]=1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[N:10]([CH3:2])[CH:9]=1
Reactant: CI
Reactant: COC(=O)c1ccc2[nH]cc(Cc3ccc(Cl)cc3Cl)c2c1
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(Cl)cc1Cl)cn2C
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.7 %

Procedure:
60% sodium hydlide (0.07 g) and then methyl iodide (0.18 g) are added in that order to an N,N-dimethylformamide solution of 3-(2,4-dichlorobenzyl)-5-metoxycarbonylindole (0.34 g), and stirred at room temperature for 19 hours. After concentrated under reduced pressure, this is extracted with water and ethyl acetate. The resulting extract is washed with water, dried, concentrated, and purified through silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 7/1) to obtain 3-(2,4-dichlorobenzyl)-5-methoxycarbonyl-1-methylindole (55) (0.30 g).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:14][CH3:15])[OH:12]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:2]([C:15]([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])([C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4])[CH2:14][C:13]([CH2:18][OH:19])([CH2:16][OH:17])[CH2:11][OH:12])([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]
Reactant: CCC(CO)(CO)CO
Reactant: CCOC(=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C(=O)C(CC(CO)(CO)CO)(C(=O)C(=O)OCC)C(=O)C(=O)OCC
Yield: 106.2 %

Procedure:
A reaction vessel equipped with a stirrer, a condenser and a decanter was charged with 500 g (3.42 mol) of diethyl oxalate, 31.3 g (0.23 mol) of trimethylolpropane and 1 g (0.0053 mol) of p-toluenesulfonic acid one hydrate, and mixed at 130° C. for 5 hours. After removing 32.3 g of ethanol, it was then cooled and excess amount of diethyl oxalate was evaporated to obtain 106.1 g of crude triethoxalyltrimethylolpropane (yield 85%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[C:18]([O:24][CH2:25][CH3:26])[C:19]([C:21](O)=[O:22])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:25]([O:24][C:18]1[C:19]([C:21]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:22])=[CH:20][C:14]2[N:13]=[C:12]([C:8]3[C:7]([NH:6][C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:30][CH:29]=[CH:28][C:27]=4[F:31])=[CH:11][NH:10][N:9]=3)[NH:16][C:15]=2[CH:17]=1)[CH3:26]
Reactant: CCOc1cc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2cc1C(=O)O
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOc1cc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2cc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.7 %

Procedure:
A mixture of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-6-ethoxy-1H-benzimidazole-5-carboxylic acid (50 mg, 0.12 mmol), morpholine (13 μl, 0.14 mmol), EDC (29 mg, 0.15 mmol) and HOBt (21 mg, 0.15 mmol) in DMF (5 mL) was stirred at r.t. for 48 h. The reaction mixture was reduced in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried (MgSO4) and reduced in vacuo to give the title compound (29 mg) as a gray solid. (LC/MS: Rt 2.56, [M+H]+ 497.03).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:24]>CN(C)C=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:6][CH2:5][C:1]([OH:24])([CH3:3])[CH3:2])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCC(C)(C)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of Example 244A (75 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) was treated with NaH 60% dispersion in oil (9.5 mg, 0.23 mmol) followed by Example 308A (60 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 18 hours, poured into water and extracted with ethyl acetate. The organic layer was washed with H2O (2×50 mL), dried over MgSO4, filtered, concentrated under reduced pressure and dried under vacuum (˜1 mm Hg) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.17 (s, 6H), 1.32 (s, 9H), 1.76-1.91 (m, 2H), 3.79 (s, 3H), 4.14-4.31 (m, 2H), 4.43 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 7.44 (dd, J=9.0, 2.9 Hz, 1H), 7.76 (d, J=3.1 Hz, 1H); MS (ESI) m/z 411 (M+H)h Anal. Calculated for C20H27ClN2O3SC, 58.45; H, 6.62; N, 6.82. Found C, 58.30; H, 6.51; N, 6.71.