Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:5]2[CH2:6][N:7]([C:10](=[O:13])[CH2:11][CH3:12])[CH2:8][CH2:9][N:4]2[N:3]=1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:1][C:2]2[CH:14]=[C:5]3[CH2:6][N:7]([C:10](=[O:13])[CH2:11][CH3:12])[CH2:8][CH2:9][N:4]3[N:3]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: CCC(=O)N1CCn2nc(N)cc2C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC(=O)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 71.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 265b (200 mg, 1.03 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (414 mg, 1.55 mmol), Pd2(dba)3 (47 mg, 0.052 mmol), Xantphos (60 mg, 0.103 mmol), Cs2CO3 (671.6 mg, 2.06 mmol), and dioxane (20 mL). After three cycles of vacuum/argon flush, the reaction mixture was heated at 100° C. for 3 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 80:1 dichloromethane/methanol to afford 265c (280 mg, 72%) as white solid. MS-ESI: [M+H]+ 380.2
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH:34][C:26]([C:23]1[S:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH:15][C:14]3[C:9]([O:8][C@H:5]4[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]4)=[N:10][CH:11]=[CH:12][CH:13]=3)[C:17]=2[C:24]=1[CH3:25])=[O:27]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12

Procedure:
Prepared analogously to 1.4 from 0.083 g 4-[2-(trans-4-hydroxy-cyclohexyloxy)pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 26 μl N,N-dimethyl-1,3-propanediamine in THF using TBTU instead of HATU.
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.NC1C(C)=C(C(N2CCOCC2)=O)C=CC=1.[CH3:57][C:58]1[C:63]([C:64]([N:66]2[CH2:71][CH2:70][O:69][CH2:68][CH2:67]2)=[O:65])=[CH:62][CH:61]=[CH:60][C:59]=1[NH:72][C:73]([N:75]1[C:79]2[N:80]=[C:81]([N:109]3[CH2:114][CH2:113][O:112][CH2:111][CH2:110]3)[N:82]=[C:83]([C:84]3[CH:85]=[N:86][C:87]([N:90](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[N:88][CH:89]=3)[C:78]=2[CH2:77][CH2:76]1)=[O:74]>>[CH3:57][C:58]1[C:63]([C:64]([N:66]2[CH2:67][CH2:68][O:69][CH2:70][CH2:71]2)=[O:65])=[CH:62][CH:61]=[CH:60][C:59]=1[NH:72][C:73]([N:75]1[C:79]2[N:80]=[C:81]([N:109]3[CH2:114][CH2:113][O:112][CH2:111][CH2:110]3)[N:82]=[C:83]([C:84]3[CH:85]=[N:86][C:87]([NH2:90])=[N:88][CH:89]=3)[C:78]=2[CH2:77][CH2:76]1)=[O:74]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cccc(C(=O)N4CCOCC4)c3C)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: Cc1c(N)cccc1C(=O)N1CCOCC1
Product: Cc1c(NC(=O)N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)cccc1C(=O)N1CCOCC1
Yield: 40 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (150 mg) and (3-amino-2-methyl-phenyl)-morpholin-4-yl-methanone (67 mg) obtained in Step B instead of 2-methyl-5-morpholin-4-yl-phenylamine, in the same manner as Step C in Example 1-D-237, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [2-methyl-3-(morpholine-4-carbonyl)-phenyl]-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 2, to obtain the desired compound (D-243) (60 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.[Cl:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](Cl)=[N:24][N:23]=1>CC(O)(C)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:25]4[C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:22]([Cl:21])=[N:23][N:24]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: COc1cnc2c(Oc3ccc(N)cc3)ccnc2c1
Solvent: CC(C)(C)O
Product: COc1cnc2c(Oc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1

Procedure:
In a 150 mL pressure tube was dissolved 4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine (6.1 g, 23 mmol) in tBuOH (75 mL). To this solution was added 1,4-dichlorophthalazine (10.0 g, 50 mmol) and the mixture was placed in pre-heated oil bath at 100° C. A thick clay formed at the bottom of the tube after 20 minutes. LCMS on solid at the bottom of the tube showed mainly desired product with trace amounts of starting material. This solid material was dissolved and transferred to a flask using hot 90/10/1 (CH2Cl2/MeOH/ammonium hydroxide), and evaporated to dryness. The crude was dissolved in CH2Cl2 and washed with sat. sodium bicarbonate. The organic layer was separated and dried over sodium sulfate, and then concentrated. The mixture was then dissolved in approx. 30/70 MeOH/CH2Cl2, silica was added and the mix was concentrated to dryness. This silica pre-absorbed material was purified using 0 to 100% 90/10/1 (CH2Cl2/MeOH/ammonium hydroxide) to afford the title compound. MS Found: [M+H]=430.0. Calc'd for C23H16ClN5O2: 429.9.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=1)(=O)=O.O[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][S:15]([O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][CH2:6][O:5][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:9]=1)(=[O:17])=[O:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OCCc1cccc(OS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)Oc1cccc(CCOc2ccc(C=O)cc2)c1
Yield: 86.1 %

Procedure:
9.3 g (31.6 mmole) 3-(methylsulfonyloxy)phenethyl methanesulfonate, 9.91 g (82 mmole) p-hydroxybenzaldehyde and 13 g (94.8 mmole) potassium carbonate in 200 ml acetonitrile were refluxed for 4 hours. The precipitate was filtered off and the solvent was evaporated in vacuo. Dichloromethane was added and the organic phase was washed with water, dried (magnesium sulfate), filtered and the solvent was evaporated to give 8.72 g (yield 88%) of 3-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[CH2:19]([NH2:21])[CH3:20]>>[CH2:19]([NH:21][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]2)=[CH:17][CH:16]=1)[CH3:20]
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CCN
Product: CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
The title compound was prepared according to the procedures of Intermediate 3 using instead 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and ethylamine. MS (m/z): 276 (M+H)+
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.Cl[C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1COCC1.CCOC(C)=O>[C:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:2]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CCCCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCC(=O)Nc1cccc(-c2ccccc2)c1
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of biphenyl-3-amine (180) (0.171 g, 1.01 mmol) in THF (3 mL) was cooled to 0° C. then treated with methyl 8-chloro-8-oxooctanoate (181) and stirred for 2 h. The reaction mixture was then diluted with AcOEt, washed with saturated NH4Cl, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (eluent: 30 to 40% AcOEt in hexane), to provide title compound 182 (0.212 g, 69% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Br.BrC1C=CC(Cl)=CC=1C.BrN1C(=O)CCC1=O.[CH:28]1([N:34]2[C:38]3[CH:39]=[CH:40][C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:42][C:37]=3[N:36]=[C:35]2[C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][O:54][C:51]1[CH:52]=[CH:53][C:48]([C:35]2[N:34]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:38]3[CH:39]=[CH:40][C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:42][C:37]=3[N:36]=2)=[CH:49][CH:50]=1
Reactant: Clc1ccc(Br)c(CBr)c1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Agent: Cc1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3Br)cc1)n2C1CCCCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
2-Bromo-5-chlorobenzyl bromide prepared from 2-bromo-5-chlorotoluene (50 g), N-bromosuccinimide and N,N′-azobisisobutyronitrile, and ethyl 1-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylate (50 g) obtained in Example 3 were suspended in dimethylformamide (300 ml). Potassium carbonate (38 g) was added and the mixture was stirred for 1 hr at 80° C. with heating. The reaction mixture was allowed to cool and then added to a mixed solvent of water-ethyl acetate. The precipitated crystals were collected by filtration to give the title compound (50 g, yield 64%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[C:20]([N+:22]([O-])=O)[CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:8])([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:22][C:20]1[CH:19]=[C:6]([CH:5]=[C:4]([NH2:1])[CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:8]
Reactant: [H][H]
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2cc(N)cc(N)c2)c1

Procedure:
A solution of 13.29 gm. (0.04 mole) of 3,3',5-trinitrobenzanilide in 150 ml. of dioxane is hydrogenated at three atmospheres of hydrogen using 1 gm. of 10% palladium-on-charcoal catalyst. The catalyst is removed by filtration, the filtrate evaporated to dryness under reduced pressure, and the residue dried by distilling 200 ml. of benzene from the reaction mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]1([CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:23][CH2:24]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(F)cc2)CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: Fc1ccc([C@H]2CC[C@H](N3CCN(Cc4ccccc4)CC3)CC2)cc1

Procedure:
A mixture of 4-(4-fluorophenyl)cyclohexanone (7.8 mmole) and 1-(phenylmethyl)piperazine (7.8 mmole) were reacted as described in Example 8. The crude isomer mixture was purified as described in Example 62. Concentration of the fractions containing the more polar isomer gave the trans product (22%, mp: 106-106° C.). Calc'd for C23H29FN2 : C, 78.38%; H, 8.30%; N, 7.95%. Found: C, 78.02; H, 8.20%; N, 7.90%.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH2:12]([O:14][C:15]([N:17]1[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])[CH3:13].C(O)(=O)C>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([CH:20]2[CH2:21][CH2:22][CH2:23][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:18][CH2:19]2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)N1CCCC(=O)CC1
Reactant: CCOC(=O)C1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C2CCCN(C(=O)OCC)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Ethyl isonipecotate (2.54 g, 2.50 mL, 16.2 mmol) and 4-oxoazepane-1-carboxylic acid ethyl ester (3.00 g, 16.2 mmol) were dissolved in DCM (100 mL) at rt and titanium isopropoxide (5.07 g, 5.40 mL, 17.8 mmol) was added. The reaction mixture was stirred at rt for 1 h. STAB (13.7 g, 32.4 mmol) and acetic acid (0.5 mL) were added and the reaction mixture was stirred at rt overnight under nitrogen. The reaction mixture was quenched with the addition of water (5 mL) and stirred for 5 minutes. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was washed with sat. NaHCO3 sol., sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 Å, 50 mL per min, gradient 2% to 4% MeOH in DCM]) to give ethyl 4-[4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (2.56 g, 48%) as a pale yellow oil.
Reaction SMILES: [Cl:1][CH:2]1[O:14][C:3]1([CH3:13])[CH:4]([C:9]([O:11]C)=[CH2:10])[CH2:5]/[CH:6]=[CH:7]\[CH3:8].Cl>O1CCCC1>[Cl:1][CH:2]1[O:14][C:3]1([CH3:13])[CH:4]([C:9](=[O:11])[CH3:10])[CH2:5]/[CH:6]=[CH:7]\[CH3:8]
Reactant: C=C(OC)C(C/C=C\C)C1(C)OC1Cl
Agent: Cl
Solvent: C1CCOC1
Product: C/C=C\CC(C(C)=O)C1(C)OC1Cl

Procedure:
A solution of 6.75 g. (31.5 mmol.) of crude (Z)-1-chloro-1,2-epoxy-2-methyl-3-(1-methoxy-ethenyl)-5-heptene in 350 ml. of 2:1 tetrahydrofuran: 10% by weight aqueous hydrochloric acid was stirred at room temperature for 30 minutes, concentrated, extracted with diethyl ether, the ethereal extracts washed with water and saturated aqueous sodium chloride, dried (Na2SO4) and concentrated to afford (Z)-1-chloro-1,2-epoxy-2-methyl-3-acetyl-5-heptene as a yellow oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]12[C:26](=[O:27])[N:25]([CH2:28][C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]1[CH2:22][CH2:21][NH:20][CH2:19]2>CC(C)=O.O>[C:6]([C@H:4]([C@@H:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]12[C:26](=[O:27])[N:25]([CH2:28][C:29]([F:31])([F:32])[F:30])[N:24]=[C:23]1[CH2:22][CH2:21][NH:20][CH2:19]2
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: O=C1N(CC(F)(F)F)N=C2CCNCC12Cc1ccccn1
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a dry and nitrogen purged 5 L round bottom flask equipped with a mechanical stirrer, D-(−) tartaric acid (129 g, 0.86 mol) was added to the product from step C (243 g, 0.78 mol) in acetone/water (9:1, 2430 mL) at about 17° C. The mixture was stirred at room temperature overnight, filtered, the solid was collected and washed with cold acetone and dried under vacuum. The product was obtained as a yellow solid (284 g, yield 78.8%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([OH:18])=[CH:13][C:12]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][C:26]2[N:25]=[CH:24][N:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:13][C:12]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=C(Nc1cc(F)c(O)cc1F)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cc(F)c(Oc2cc(Cl)ncn2)cc1F)OCc1ccccc1
Reaction time: 2 h
Yield: 89 %

Procedure:
Benzyl(2,5-difluoro-4-hydroxyphenyl)carbamate (4.90 g) was dissolved in N,N-dimethylformamide (30 ml), then 4,6-dichloropyrimidine (2.61 g) and potassium carbonate (3.63 g) were added thereto at room temperature, followed by stirring for 2 hr. Water (90 ml) was added to the reaction mixture to precipitate crystals. The crystals were collected by filtration and washed with water (30 ml, 6 times). The crystals were hot air-dried at 60° C. for 2 days to provide the titled compound as pale brown crystals (6.108 g, 89%).
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[C:10]1(=[O:20])[O:15][C:13](=O)[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[N:21]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:22]=1[CH3:23].[OH-].[Na+].[OH-].[K+]>O>[CH:28]1[CH:27]=[C:26]2[CH:25]=[CH:24][C:22]([CH:23]3[C:10](=[O:20])[C:11]4[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:13]3=[O:15])=[N:21][C:31]2=[CH:30][CH:29]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc2ccccc2n1
Agent: O=C(O)c1ccccc1
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2C(=O)C1c1ccc2ccccc2n1
Temperature: 165 °C
Reaction time: 5.5 h

Procedure:
For example, the benzoic acid and the phthalic anhydride of the formula (5) are heated and molten at a temperature of at least 130° C. and then the quinaldine is added. In this reaction, the quinaldine and the phthalic anhydride are generally used in a molar ratio of from 1:1 to 1:5. Further, the quinaldine and the benzoic acid are generally used in a molar ratio of from 1:2 to 1:20. The molar ratio between the quinaldine and the benzoic acid can be increased or decreased according to the stirring state of the reaction mixture. After the raw materials are molten, the mixture is heated to 150 to 180° C. and stirred for 3 to 8 hours. In this case, it is possible to determine the termination point of the reaction by carrying out component analysis of the reaction mixture according to a high performance liquid chromatograph or other methods. After the termination of the reaction, the reaction mixture is cooled to 130 to 150° C. The cooled mixture is diluted with water as required. Then, an alkali aqueous solution such as an aqueous solution of 5 to 20% by weight of sodium hydroxide or potassium hydroxide is added. The benzoic acid is converted into a water-soluble alkali metal salt by the above operation, and the water-soluble alkali metal salt can be separated from a generated quinophthalone compound by means of filtration. Then, washing is carried out with water, followed by drying, whereby the quinophthalone compound which is used for forming the quinophthalone residue of the formula (4) can be obtained.
Reaction SMILES: [F:1][CH:2]1[CH:7]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]3[CH:18]=[CH:19][S:20][C:10]=23)[CH2:6][CH2:5][N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:3]1>[Pd].CO>[NH2:15][C:14]1[C:9]([NH:8][CH:7]2[CH2:6][CH2:5][N:4]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:3][CH:2]2[F:1])=[C:10]2[S:20][CH:19]=[CH:18][C:11]2=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)C(F)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3ccsc23)C(F)C1
Reaction time: 5 h
Yield: 77.5 %

Procedure:
A mixture of tert-butyl 3-fluoro-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (0.32 g, 0.81 mmol) and 10% palladium on carbon (80 mg) in methanol (8 mL) was hydrogenated under balloon pressure of H2 at room temperature for 5 h. The reaction mixture was filtered, and the filtrate was concentrated to give the desired product (0.23 g, 78%) as a mixture of cis- and trans-isomers mixture. LCMS calculated for C17H24FN4O2S (M+H)+: m/z=367.2. Found: 367.1.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=O)=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:27][NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O1CCOCC1>C(Cl)(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH3:27])=[O:17])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: CNc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CN(C(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12)c1ccccc1
Reaction time: 17 h
Yield: 15.3 %

Procedure:
To a suspension of 7-chloro-3-(carboxy)pyrazolo[3,4c][1]-benzazepine-4,10(1H,9H)-dione (500 mg, 1.72 mmol) (compound of Example 9) in carbon tetrachloride (5 mL) was added phosphorus pentachloride (358 mg, 1.72 mmol). The mixture was stirred for 17 hours, filtered and washed with carbon tetrachloride (3×10 mL). To the residue was added N-methylaniline (190 μL, 1.72 mmol) and dioxane (7 mL). The resulting mixture was stirred 17 hours. To this mixture was added water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3×100 mL). The organic layers were combined and concentrated by rotary evaporation to 50 mL. The insoluble material was removed by filtration and the organic solution was preabsorbed onto silica gel and purified by flash chromatography eluting with chloroform and chloroform:2-propanol (99:1, 98:2-90:10). The product fractions were combined and concentrated by rotarv evaporation to give the title compound as a light yellow solid (100 mg, 15.2%, m.p. 308° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.B(O)(O)[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.N1C=CC=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: NC(=O)Nc1cccc(O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2cccc(NC(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Hydroxyphenyl)urea (2.00 g), p-tolylboronic acid (3.57 g), and Cu(OAc)2 (2.63 g) were dissolved in 150 mL of THF, and 5.32 mL of pyridine was added. The reaction was stirred at room temperature overnight, then filtered through Celite with the aid of 200 mL EtOAc. The filtrate was washed with water, 0.2N CuSO4, 0.5N NaOH, and brine, and dried over Na2SO4 The solution was concentrated to a solid that was taken up in 200 mL of dichloromethane and stirred at room temperature for about 1 hour, after which time it was filtered to give 1-(3-(p-tolyloxy)phenyl)urea as white solid. The material was used in Step B without further purification.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH2:21][O:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH2:21][O:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CC[C@H](CCCCOCc1ccccc1)CCOc1cccnc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COC(=O)CC[C@H](CCCCO)CCOc1cccnc1

Procedure:
To a solution of methyl (S)-8-(benzyloxy)-4-[2-(3-pyridyloxy)ethyl]octanoate (1.1 g, 2.7 mmol) in ethanol (20 ml) is added cyclohexene (10.5 ml) followed by 20% palladium hydroxide on carbon (0.28 g). The mixture is heated at reflux for 18 hours. The catalyst is filtered off and washed with ethanol (3×10 ml). The solvent is evaporated and the residue purified by chromatography on silica gel using ethyl acetate as eluent to obtain methyl (S)-8-hydroxy-4-[2-(3-pyridyloxy)ethyl]octanoate; IR (CH2Cl2): 3600, 1732, 1282, 1230 cm-1.