Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[N:34][C:35]=2[Sn](CCCC)(CCCC)CCCC)[CH:32]=1.CN(C=O)C>CCOCC.C(OCC)(=O)C.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.[Cu]I>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:35]3[N:34]=[CH:33][N:31]4[CH:32]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=34)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncn2cc(F)ccc12
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ncn4cc(F)ccc34)nc12
Temperature: 90 °C
Yield: 32.3 %

Procedure:
To a mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (250 mg, 585 μmol), 6-fluoro-1-(tributylstannyl)imidazo[1,5-a]pyridine (400 mg, 564 μmol), tetrakis(triphenylphosphine)palladium (0) (33.8 mg, 29.2 μmol) and copper (I) iodide (22.3 mg, 117 μmol) was added DMF (5.85 mL) and the reaction mixture heated to 90° C. under N2. After 16 h the reaction was diluted with ether, ethyl acetate and water. The organic phase was separated and washed with water (1×) and brine (2×) then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, 30-80% ethyl acetate/hexanes) gave N-tert-butyl-2-(6-fluoroimidazo[1,5-a]pyridin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (88 mg, 182 μmol, 31.2%) as a yellow solid. MS (M+H)+=483.3; 1H NMR (CDCl3-d) δ: 9.34 (s, 1H), 8.54 (m, 1H), 8.34 (s, 2H), 8.04 (m, 1H), 7.98 (s, 1H), 6.9 (m, 1H), 5.74 (s, 2H), 3.61 (d, J=8.3 Hz, 2H), 1.66 (s, 9H); 0.98 (t, J=8.3 Hz, 2H), 0.0 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[CH:16]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[CH:16]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)CC1CCN(C(=O)Nc2ccc([N+](=O)[O-])cc2)Cc2ccccc21
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CCN(C(=O)Nc2ccc(N)cc2)Cc2ccccc21

Procedure:
Methyl 2-(2-(N-(4-aminophenyl)carbamoyl)-1H,3H,4H,5H-benzo[e]azapin-5-yl)acetate was prepared by hydrogenation of methyl 2-(2-(N-(4-nitrophenyl)carbamoyl)-1H,3H,4H,5H-benzo[e]azapin-5-yl)acetate with Pd/C in methanol. EI-MS m/z 354 (M+H)+
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:23]=1[C:24]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: O=C(c1ccc(OCc2ccccc2)cc1OCc1ccccc1)N1CCC(Cc2ccccc2)CC1

Procedure:
Condensation between 4-benzylpiperidine (438 mg) and 2,4-dibenzyloxybenzoic acid is carried out in the same manner as in Example 4, i) to obtain 1-(2,4-dibenzyloxybenzoyl)-4-benzylpiperidine (1.0 g) in the colorless oily form.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][C:40]([F:43])([F:42])[F:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:39][C:40]([F:43])([F:41])[F:42])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)c(OC(F)(F)F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(OC(F)(F)F)c2)CC1
Yield: 11.5 %

Procedure:
A mixture of 0.10 g (0.32 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.11 g (0.35 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-3-trifluoromethoxy-benzamide, 0.090 g (0.48 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight, then cooled and diluted with dichloromethane and saturated sodium carbonate. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 0.022 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-3-trifluoromethoxy-benzamide (I-181) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)CN1CCN(c2ccc(F)cc2)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCN(c2ccc(F)cc2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 27.7 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(4-fluorophenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 218, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(4-fluorophenyl)piperazin-1-yl)acetamido)propanamide (13.3 mg, 27.7%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 8.01 (d, 1H), 7.60 (d, 2H), 7.26-7.30 (m, 5H), 7.19-7.25 (m, 2H), 6.98-7.01 (m, 6H), 6.92-6.95 (m, 2H), 4.70 (m, 1H), 4.52 (s, 2H), 3.72-3.80 (m, 2H), 3.07 (m, 6H), 2.59-2.65 (m, 4H). MS (EI) for C34H34F2N4O4. found 601.6 (MH+).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[NH:12][CH:13]([CH3:30])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[F:36][C:2]([F:35])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[N:12]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:13]([CH3:30])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[C:10]3=[N:9]2)=[CH:33][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: CC1Nn2c(nn(Cc3ccc(C(F)(F)F)cc3)c2=O)C(c2ccc(Cl)cc2)=C1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1C(c2ccc(Cl)cc2)=C(c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n2N1Cc1ccccc1
Temperature: 80 °C
Yield: 11.5 %

Procedure:
To a solution of 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (15 mg, 0.028 mmol) prepared as described in Example 469 in DMF (0.5 mL) at RT was added K2CO3 (11.6 mg, 0.084 mmol), followed by benzyl bromide (9.6 mg, 0.056 mmol). The reaction was heated at 80° C. for overnight. The reaction was filtered. The collected solution was concentrated under educed pressure. The crude product was purified using reverse phase HPLC to give the title compound, 2-(4-(Trifluoromethyl)benzyl)-5-benzyl-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (2 mg, 11%) as a white solid. HPLC retention time: 4.44 min; MS [M+H]+: found 621. 1H NMR (CDCl3, 400 MHz) δ 7.60 (d, 2H), 7.45 (d, 2H), 7.33-7.29 (m, 5H), 7.23-7.13 (m, 4H), 7.05-7.00 (m, 2H), 6.87-6.81 (m, 2H), 5.04 (s, 2H), 4.26-4.15 (m, 2H), 3.98-3.93 (q, 1H), 1.30 (d, 3H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C:12]([C:15]1[N:20]=[CH:19][C:18]([C:21](=[C:39]([CH3:41])[CH3:40])[C:22]([O:24][CH2:25][C:26]2[C:31]([F:32])=[C:30]([F:33])[C:29]([CH2:34][O:35][CH3:36])=[C:28]([F:37])[C:27]=2[F:38])=[O:23])=[CH:17][N:16]=1)([CH3:14])[CH3:13].C(O)(=O)C>O1CCCC1>[CH3:14][C:12]([C:15]1[N:16]=[CH:17][C:18]([CH:21]([C:39]([CH3:41])=[CH2:40])[C:22]([O:24][CH2:25][C:26]2[C:31]([F:32])=[C:30]([F:33])[C:29]([CH2:34][O:35][CH3:36])=[C:28]([F:37])[C:27]=2[F:38])=[O:23])=[CH:19][N:20]=1)([CH3:11])[CH3:13]
Reactant: COCc1c(F)c(F)c(COC(=O)C(=C(C)C)c2cnc(C(C)(C)C)nc2)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=C(C)C(C(=O)OCc1c(F)c(F)c(COC)c(F)c1F)c1cnc(C(C)(C)C)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A 1 molar solution of lithium hexamethyldisilazide (0.125 cm3) in dry tetrahydrofuran was added to a stirred solution of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]-3-methylbut-2-enoate (0.05 g) in dry tetrahydrofuran (1 cm3) whilst the reaction temperature was maintained at -78° C. After 30 minutes, acetic acid (0.01 g) was added in one portion, and the stirred reaction mixture was allowed to warm to the ambient temperature, and quenched with water. Extraction into ethyl acetate, and concentration by removal of the solvent under reduced pressure gave 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (RS)-2-[2-(1,1-dimethylethyl)pyrimidin-5-yl)-3-methylbut-3-enoate (0.05 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([NH:15][CH:16]([CH:28]([CH3:30])[CH3:29])[CH:17]([OH:27])[C:18]([F:26])([F:25])[C:19](=[O:24])[NH:20][CH2:21][CH2:22][CH3:23])=[O:14])[C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([NH:15][CH:16]([CH:28]([CH3:30])[CH3:29])[C:17](=[O:27])[C:18]([F:26])([F:25])[C:19](=[O:24])[NH:20][CH2:21][CH2:22][CH3:23])=[O:14])[C:8]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCNC(=O)C(F)(F)C(O)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(C)=O)c1=O)C(C)C
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCNC(=O)C(F)(F)C(=O)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(C)=O)c1=O)C(C)C
Reaction time: 1 h

Procedure:
2-(5-Acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-[3,3-difluoro-2-hydroxy-1-isopropyl-3-(N-propylcarbamoyl)propyl]acetamide. To a solution of the product from Example 8.a. (0.23 g) in tetrahydrofuran (5 mL) was added triethylamine (0.08 mL). Acetyl chloride (0.04 g) was added, resulting in gas evolution and precipitate formation. After 1 hour, additional triethylamine (0.04 mL) and acetyl chloride (0.02 mL) were added. After 15 minutes, the reaction was diluted with ethyl acetate and washed with water. The aqueous phase was made basic with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried. Evaporation gave a material which solidified upon further evaporation from dichloromethane:hexane. The solid (0.313 g) was not further purified; TLC: Rf =0.19, methanol:dichloromethane (5:95); 300 MHz NMR: 2.15 (s,3), 7.87 (d,1), 8.34 (t,1), 8.82 (s,1), 9.54 (s,1); MS: m/z=508 (M+1).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C1COCC1>[CH2:18]([O:17][C:15]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([OH:13])=[O:12])[CH:6]=2)[CH2:1]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 14.2 g 2-benzyl 6-methyl 3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate, 50 ml THF and 32 ml of a 2M aqueous LION solution is stirred at ambient temperature overnight. The reaction mixture is added to 50 g of ice and the pH as adjusted to 2. The organic phase is separated, dried, and evaporated. 13.59 g of a colorless solid are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[C:3]=1[O:10][CH2:11][CH:12]1[O:14][CH2:13]1.[OH-].[Na+].O>C(O)C>[OH:14][CH2:13][CH:12]1[CH2:11][O:10][C:3]2[C:4]([Cl:9])=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[O:1]1
Reactant: Oc1ccc(Cl)c(Cl)c1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCC1COc2c(ccc(Cl)c2Cl)O1
Yield: 99.3 %

Procedure:
To a solution of 1.128 g of 1-hydroxy-2-(2,3-epoxypropyloxy)-3,4-dichlorobenzene dissolved in 10 ml of ethanol is added 4 ml of 2N sodium hydroxide. The mixture is heated at 80° C. for 5 minutes, to which water is then added and extracted with ether. The organic layer is washed with water, then dried and evaporated to give 1.120 g of the objective 3-hydroxymethyl-7,8-dichloro-1,4-benzodioxane (IIb) as an oil. Yield 99%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CN1CCCC1=O.[F:24][C:25]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[C:31]2[C:26]=1[C:27](=[O:47])[C:28]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)=[CH:29][NH:30]2>C(OCC)(=O)C.O>[F:24][C:25]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[C:31]2[C:26]=1[C:27](=[O:47])[C:28]([C:39]1[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)=[CH:29][N:30]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCN3CCOCC3)c12
Temperature: 55 °C
Reaction time: 45 h
Yield: 75.2 %

Procedure:
Potassium carbonate (2.1 g, 15.2 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (1.36 g, 7.31 mmol) were added to an N-methylpyrrolidone (NMP) solution (5 ml) of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1 H-quinolin-4-one (1.0 g, 3.05 mmol) and then stirred at 50 to 60° C. for 45 hours. Water and ethyl acetate were added to the reaction mixture, followed by separation. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=50:1→30:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, giving a white powder of 5-fluoro-3-(4-methoxyphenyl)-1-(2-morpholin-4-ylethyl)-8-propoxy-1H-quinolin-4-one (1.01 g, yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11].Cl.[O:13]1CCOC[CH2:14]1.C(Cl)(Cl)=O>C1COCC1>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N:11]=[C:14]=[O:13]
Reactant: Nc1ccc2c(c1Cl)OCO2
Reactant: C1COCCO1
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Product: O=C=Nc1ccc2c(c1Cl)OCO2
Temperature: 70 °C

Procedure:
To a vial containing 4-chlorobenzo[d][1,3]dioxol-5-amine (28.8 mg, 0.168 mmol, 1 equiv.) in 1 mL THF was added 4M HCl in 1,4-dioxane (0.042 mL, 1 equiv.) followed by phosgene (20% in toluene; 0.360 mL, 0.684 mmol, 4 equiv.). The vial was capped and heated to 70° C. for 1 h, the solvent was removed under, the residue redissolved in toluene and solvent was again removed under vacuum to eliminate any remaining phosgene yielding 4-chloro-5-isocyanatobenzo[d][1,3]dioxole used as such in the next step.
Reaction SMILES: BrC1C=CC=C(COCOC)C=1.C[Si](C#C)(C)C.C(N(CC)C(C)C)(C)C.[CH3:28][O:29][CH2:30][O:31][CH2:32][C:33]1[CH:34]=[C:35]([C:39]#[C:40][Si](C)(C)C)[CH:36]=[CH:37][CH:38]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cu]I.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.O1CCCC1.CN1CCCC1=O>[C:39]([C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][O:31][CH2:30][O:29][CH3:28])[CH:34]=1)#[CH:40]
Reactant: COCOCc1cccc(C#C[Si](C)(C)C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C#Cc1cccc(COCOC)c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 1-bromo-3-methoxymethoxymethyl-benzene (3.0 g, 13 mmol) described in Manufacturing Example 214-1-1, trimethylsilylacetylene (2.6 g, 26 mmol), N,N-diisopropylethylamine (3.4 g, 26 mmol), copper (I) iodide (500 mg, 2.6 mmol), and 1-methyl-2-pyrrolidone (30 mL) was added tetrakis(triphenylphosphine)palladium (0) (1.5 g, 1.3 mmol), which was stirred for 15 minutes at 60° C. This mixture was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=8:1) to obtain a mixture of (3-methoxymethoxymethyl-phenylethynyl)-trimethyl-silane and 1-bromo-3-methoxymethoxymethyl-benzene (3.0 g of mixture, including approximately 30% (3-methoxymethoxymethyl-phenylethynyl)-trimethyl-silane). Tetrabutylammonium fluoride (2 mL, 1 M tetrahydrofuran solution) was added to a tetrahydrofuran (20 mL) solution of this mixture, which was stirred for 15 minutes at room temperature. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain 1-ethynyl-3-methoxymethoxymethyl-benzene (470 mg). To a methanol (10 mL) solution of this 1-ethynyl-3-methoxymethoxymethyl-benzene (470 mg, 2.6 mmol) was added 5 N hydrochloric acid, which was stirred for 25 minutes at 70° C. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure to obtain the title compound (350 mg, 20%).
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[CH3:14]>CO.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([CH3:15])([OH:16])[CH3:1])=[C:6]([CH3:14])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1OCC(C)(C)O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)ccc1OCC(C)(C)O
Reaction time: 18 h
Yield: 91.7 %

Procedure:
A mixture of 2-methyl-1-(2-methyl-4-nitrophenoxy)propan-2-ol (7.30 g, 32.4 mmol) and 10% Pd/C (0.345 g, 3.24 mmol) in MeOH (150 mL) was hydrogenated at 1 atm of H2 for 18 hours. After removal of the Pd/C by filtration, the solution was concentrated to yield 1-(4-amino-2-methylphenoxy)-2-methylpropan-2-ol (6.10 g, 29.7 mmol, 92% yield) as clear gum which was carried forward without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)=[CH:18][CH:17]=1>>[C:1]([O:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)=[CH:20][CH:21]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: CC(=O)Oc1cc(Cl)ccc1C(=O)O
Product: CC(=O)Oc1cc(Cl)ccc1C(=O)Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Yield: 74 %

Procedure:
Using 2-acetoxy-4-chlorobenzoic acid and 1-(4-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+]>O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[C:9](=[O:15])[CH:8]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc(Br)cc1
Reactant: COc1cc2c(c(OC)c1)C(=O)CCC2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2CCc3cc(OC)cc(OC)c3C2=O)cc1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
The title compound was synthesized by referring to J. Am. Chem. Soc., 1997, 119 (45), 11108. To a solution of 6,8-dimethoxy-3,4-dihydro-2H-naphthalen-1-one (11.9 g) in tetrahydrofuran (200 ml) were sequentially added 4-bromoanisole (16.2 g), sodium tert-butoxide (11.1 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.3 g) and tris(dibenzylidene)acetone dipalladium(0) (792 mg), and the solution was stirred for 1.5 hours at 75° C. under a nitrogen atmosphere. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo; the resulting crude crystal was suspended in diethyl ether and then filtered. The mother liquor was concentrated in vacuo, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system); the resulting crystal was suspended in diethyl ether, then filtered, and combined to provide the title compound (14.2 g).
Reaction SMILES: C([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10](=[O:16])[NH:11][CH2:12][CH:13]([F:15])[F:14])(C)(C)C.ClCCl>Cl.O1CCOCC1>[F:14][CH:13]([F:15])[CH2:12][NH:11][C:10]([CH2:9][CH2:8][NH:7][C:6](=[O:5])[OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCC(F)F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)NCCC(=O)NCC(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[2-(2,2-Difluoro-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (2.75 g, 10.9 mmol) was suspended in 4M hydrochloric acid in dioxane (30 ml) and stirred at RT for 18 h. Dichloromethane was added (50 ml) and the solid filtered off and dried in vacuo (2.02 g, 100%).