Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[N:6][C:7]=1[Cl:8].[C:21]1([C:27]2([NH2:31])[CH2:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN1CCOCC1>O1CCOCC1>[NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:31][C:27]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29][CH2:30]2)=[N:18][C:19]#[N:20])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: NC1(c2ccccc2)CCC1
Reactant: N#CN=C(Nc1cnc(Cl)c(N)c1)Oc1ccccc1
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: N#CN=C(Nc1cnc(Cl)c(N)c1)NC1(c2ccccc2)CCC1
Yield: 34.1 %

Procedure:
A stirred mixture of the product from Step 2 (1.5 g, 0.0052 mol), 1-phenylcyclobutylamine (0.8 g, 0.00543 mol), N-methylmorpholine (1.37 ml, 0.0125 mol) and dioxane (30 ml) was refluxed, under nitrogen for 5 hours, cooled and filtered. The solid was washed with cold dioxane and Et2O and crystallized from acetonitrile to give 0.605 g of the titled product, mp 220°-221° C.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][C:5]([C:10](O)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:2]12[CH2:9][CH2:8][C:5]([CH2:10][OH:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C(O)C12CCN(CC1)CC2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC12CCN(CC1)CC2
Yield: 99.1 %

Procedure:
Quinuclidine-4-carboxylic acid hydrochloride (3.0 g, 0.016 moles) was treated with lithium aluminium hydride (2.5 g, 0.066 moles) in tetrahydrofuran (150 ml) at ambient temperature for 18 hours. The reaction was worked up as in the method of Example 25 Step 1 to give the title compound 2.24 g (100%). MS (+ve electrospray) m/z 142 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([OH:17])[CH2:11][CH2:10]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.CCCCCC.CCOC(C)=O>CN(C=O)C.O>[Si:18]([O:17][CH:12]1[CH2:11][CH2:10][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:15][CH2:14][CH:13]1[OH:16])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: OC1CCC(c2cccc(F)c2F)CCC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2cccc(F)c2F)CCC1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 250 mL round-bottomed flask (t=g) was added 5-(2,3-difluorophenyl)cycloheptane-1,2-diol (1.454 g, 6.0 mmol) (crude material, azeotroped with dry benzene) in DMF (20 mL) to give a colorless solution. TBS-Cl (0.995 g, 6.60 mmol) and imidazole (0.980 g, 14.40 mmol) were added, and the mixture was stirred at room temperature for 5 hours. TLC (2/1 hexane/EtOAc) indicated complete conversion to two main spots. It was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried with Na2SO4 and concentrated to a colorless oil. Purification by FCC up to 30% EtOAc/hexane afforded the desired mono-protected product as a broad peak. The product fractions were pooled and concentrated to a colorless oil (1.79 g, 84% for two steps). 1H NMR (400 MHz, CDCl3) δ 7.02-6.85 (m, 3H), 3.98-3.70 (m, 2H), 3.18-3.02 (m, 1H), 2.15-1.82 (m, 4H), 1.80-1.45 (m, 4H), 0.91 (s, 9H), 0.90 (2s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using 4-methoxyphenylboronic acid (380 mg, 3.35 mmol) and 1a (400 mg, 1.68 mmol) according to Method C. Yellow solid. Yield: 400 mg, 1.51 mmol, 90%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.86 (s, 3H), 5.16 (s, 2H), 6.92 (t, J=1.3 Hz, 1H), 6.99 (d, J=9.1 Hz, 2H), 7.11 (s, 1H), 7.46 (dd, J=8.2, 2.5 Hz, 1H), 7.59 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.94 (d, J=9.1 Hz, 2H), 8.54 (d, J=2.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 55.4, 114.2, 119.0, 119.8, 128.2, 129.2, 130.3, 131.2, 135.7, 137.3, 148.5, 157.4, 160.8; MS (ESI): m/z=266.22 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].[CH2:11]([O:13][C:14]1[CH:33]=[CH:32][C:17]([O:18][CH:19]2[CH2:22][N:21]([C:23]3[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=3)[CH2:20]2)=[CH:16][CH:15]=1)[CH3:12]>C(Cl)Cl>[CH2:11]([O:13][C:14]1[CH:33]=[CH:32][C:17]([O:18][CH:19]2[CH2:20][N:21]([C:23]3[CH:28]=[CH:27][C:26]([C@@H:29]([NH:31][C:7]([C:6]4[CH:5]=[C:4]([CH3:10])[O:3][C:2]=4[CH3:1])=[O:8])[CH3:30])=[CH:25][CH:24]=3)[CH2:22]2)=[CH:16][CH:15]=1)[CH3:12]
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: CCOc1ccc(OC2CN(c3ccc([C@H](C)N)cc3)C2)cc1
Solvent: ClCCl
Product: CCOc1ccc(OC2CN(c3ccc([C@H](C)NC(=O)c4cc(C)oc4C)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 0.015 g (0.10 mmol) 2,5-dimethyl-furan-3-carbonyl chloride in 1 mL DCM is added a mixture of 0.031 g (0.10 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) and 0.010 g (0.10 mmol) TEA in 0.5 mL DCM. The mixture is stirred for 12 h at rt. The solvent is removed in vacuo and the residue is purified by HPLC to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:49][CH2:50][C:51]1[N:56]=[CH:55][C:54]([C:57](O)=[O:58])=[CH:53][CH:52]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:57]([C:54]1[CH:55]=[N:56][C:51]([CH2:50][OH:49])=[CH:52][CH:53]=1)=[O:58])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(CO)nc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
2-Aminophenyl carbamic acid t-butyl ester (Reference Compound No. 1-1, 0.60 g, 2.9 mmol), N,N-diisopropylethylamine (1.5 mL, 8.6 mmol), and HATU (1.1 g, 2.9 mmol) were added to a suspension of 6-hydroxymethylpyridine-3-carboxylic acid (Reference Compound No. 10-1) in DMF (10 mL), and then the reaction mixture was stirred at room temperature for 2 hours. Water (200 mL) was added thereto, the whole was extracted with ethyl acetate (100 mL, 50 mL), and then the organic layer was washed with brine (100 mL) twice. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 0.66 g of the title reference compound as a brown oil. (Yield 67% in 2 steps)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][C:13](=O)[N:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:7]=1[CH3:18])=[O:5])[CH3:2].B.O1CCCC1.CO>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:7]=1[CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCC(=O)N(C)C)c[nH]c1C
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CCCN(C)C)c[nH]c1C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a heterogeneous mixture of 4-(2-dimethylcarbamoyl-ethyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.01 g, 4 mmol) in THF (9 mL) was added dropwise 8 mL of borane-tetrahydrofuran complex (1M in THF). The mixture was refluxed overnight. Then 9.0 mL of MeOH was added slowly to the reaction and refluxing was continued for another 2 hr. The reaction mixture was cooled, quenched with 1N HCl and extracted with EtOAc. The aqueous layer was basified with aqueous KOH and extracted with EtOAc. The EtOAc extract was washed with brine, dried and concentrated to give 616 mg (65%) of 4-(3-dimethylaminopropyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester as a faint orange oil.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:16][C:17]([C:21]1[CH:22]=[C:23]2[CH2:46][C@@:28]3([C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:29]3=[O:45])[CH2:27][C:24]2=[N:25][CH:26]=1)([F:20])[CH2:18]O.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.Cl.[NH2:63][C@H:64]1[CH2:69][C@@H:68]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C@@H:67]([CH3:76])[N:66]([CH2:77][C:78]([F:81])([F:80])[F:79])[C:65]1=[O:82].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOC(C)=O>[F:20][C:17]([C:21]1[CH:22]=[C:23]2[CH2:46][C@@:28]3([C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[C:29]3=[O:45])[CH2:27][C:24]2=[N:25][CH:26]=1)([F:16])[CH2:18][NH:63][C@H:64]1[CH2:69][C@@H:68]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C@@H:67]([CH3:76])[N:66]([CH2:77][C:78]([F:79])([F:80])[F:81])[C:65]1=[O:82]
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CC(F)(F)F
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc(C(F)(F)CO)cnc3C2)c2cccnc21
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NCC(F)(F)c2cnc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trifluoromethanesulfonic anhydride (0.056 mL, 0.335 mmol) was added to a cooled solution of (S)-3-(1,1-difluoro-2-hydroxyethyl)-1′-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (described in Intermediate 10) (0.100 g, 0.223 mmol) and 2,6-di-tert-butyl-4-methylpyridine (0.070 g, 0.335 mmol) in CH2Cl2 (3 mL) at −78° C. The resulting mixture was warmed slowly to ambient temperature and stirred for 18 h. The reaction was diluted with EtOAc (100 mL), filtered through a pad of Celite®, washing with EtOAc, and concentrated to dryness in vacuo. The crude product dissolved in CH2Cl2 (3 mL) at ambient temperature. To this solution was added (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one HCl salt (described in Intermediate 11) (0.033 g, 0.104 mmol) and N,N-diisopropylethylamine (0.033 mL, 0.190 mmol). The resulting mixture was stirred at ambient temperature for 18 h before being partitioned between water (20 mL) and EtOAc (100 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (30 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—80:20 to 0:100, to give the title compound MS: m/z=716.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C:24]5[NH:25][CH:26]=[CH:27][N:28]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[F:36][C:37]([F:43])([F:42])[S:38](Cl)(=[O:40])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C:24]5[N:25]([S:38]([C:37]([F:43])([F:42])[F:36])(=[O:40])=[O:39])[CH:26]=[CH:27][N:28]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1ncc[nH]1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1nccn1S(=O)(=O)C(F)(F)F

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-({1-[(trifluoromethyl)sulfonyl]-1H-imidazol-2-yl}methyl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1H-imidazol-2-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 403) and trifluoromethanesulfonyl chloride following General Procedure U.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([O:17][CH2:18][CH:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][OH:21])[C:13]=2[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:35]=[C:36]=[O:37])(=O)=O.O>C(Cl)Cl>[C:36]([O:21][CH2:20][CH:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][O:17][C:14]1[C:13]2[CH:30]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:10]=[CH:11][C:12]=2[O:16][N:15]=1)(=[O:37])[NH2:35]
Reactant: CC(C)(C)OC(=O)Nc1ccc2onc(OCC(CO)NC(=O)OC(C)(C)C)c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1

Procedure:
To a solution of 0.47 g of 5-tert-butoxycarbonylamino-3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-1,2-benzoisoxazole in 10 ml of methylene chloride is added 0.21 g of chlorosulfonyl isocyanate at -45° to -40° C., and the temperature is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. Subsequently, 10 ml of water is added, and they are subjected to reaction at 20°-25° C. for one hour. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the crystals obtained are collected by filtration, to obtain 0.47 g of colorless, crystalline 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-tert-butoxycarbonylamino-1,2-benzoisoxazole.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[CH:7]=[C:8](C(OCC)=O)[O:9]2)=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[CH2:23]([OH:25])C>>[CH3:23][O:25][C:8]1[O:9][C:10]2[C:5]([C:6](=[O:17])[CH:7]=1)=[CH:4][CH:3]=[C:2]([OH:1])[CH:11]=2
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Reactant: CCO
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Product: COc1cc(=O)c2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 7-hydroxychromen-4-one-2-carboxylate (2 g, 8.538 mmol) and granulated and dried calcium chloride (1 g, 9.01 mmol) are initially introduced, and ethanol (absolute, 40 ml) is added. Sodium borohydride (1.33 g, 35.157 mmol) is subsequently added in portions with ice cooling. The reaction mixture is stirred at RT for 2 hours, then again cooled using an ice bath, and sodium borohydride (0.45 g, 11.895 mmol) is again added. The mixture is stirred overnight at RT.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[C:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][CH3:13])[CH2:7][CH2:6]1>C(OC(=O)C)C.[Pd]>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][CH3:13])[CH2:7][CH2:6]1
Reactant: COCC1CCC(=CC(=O)OC)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCC1CCC(CC(=O)OC)CC1

Procedure:
Prepared from (4-Methoxymethyl-cyclohexylidene)-acetic acid methyl ester (0.550 g, 3 mol) by hydrogenation using Pd/C (10%) (0.295 g, 0.3 mmol) in ethylacetate (15 mL). 1/3 cis/trans mixture.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:33](Cl)(=[O:38])[O:34][CH:35]([CH3:37])[CH3:36].O>ClCCl>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]([N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:34][CH:35]([CH3:37])[CH3:36])=[O:38])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:1])=[O:13])=[O:12])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)OC(=O)Cl
Reactant: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCN(c2ncc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) and TEA (92 mg) were dissolved in dichloromethane, followed by ice-cooling. Isopropyl chlorocarbonate (83 mg) was added thereto, followed by stirring at room temperature for 4 hours. Water was added thereto, followed by extraction with chloroform. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain isopropyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (155 mg).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34]>>[CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: COc1ccc2cc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)oc2c1
Product: COc1ccc2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)oc2c1

Procedure:
Using 4-{[cyclohexyl(6-methoxy-1-benzofuran-2-yl)methyl]amino}benzoic acid (300 mg) synthesized above and ethyl 3-(methylamino)propanoate (125 mg) and in the same manner as in Example A1(4), the title object compound (201 mg, 55%) was obtained as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2cccnc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2cccnc12
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of quinolin-8-ol (3 g, 0.0207 mol) in MeCN (10 mL) was added ethyl bromoacetate (4.12 g, 0.025 mol) and K2CO3 (5.75 g, 0.0414 mol). The mixture was stirred at 80° C. for 12 h, filtered and concentrated. The crude residue was purified by column chromatography. (3.9 g, yield, 82%) MS (ESI+) e/z: 232.1 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][C:14](=[O:18])[C@@H:15]([CH3:17])[NH2:16].C(N(CC)CC)C>CO>[CH3:12][O:13][C:14](=[O:18])[C@@H:15]([CH3:17])[NH:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)Nc1ncccc1[N+](=O)[O-]
Yield: 5.9 %

Procedure:
A suspension of 2-chloro-3-nitropyridine (37.76 g, 0.239 mole), (R)-alanine methyl ester hydrochloride (50 g, 0.358 mole) and triethylamine (60.3 g, 0.597 mole) in methanol (370 ml) was refluxed overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in ethyl acetate (300 ml), filtered, and rinsed with additional ethyl acetate. The filtrate and washings were combined and washed once with water. The aqueous wash was extracted with ethyl acetate and the combined organic layers were washed several times with water, dried over sodium sulfate, filtered and evaporated under reduced pressure to given an oil weighing 45.6 g (85%). Elution of a portion of the oil with 1:6 tetrahydrofuran/hexane through a silica gel column gave 3.2 g of product after evaporation of solvent. Drying of a portion of the solid under high vacuum at room temperature gave 0.98 g of title compound, mp 39°-40° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8](O)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1nccnc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nccnc1O

Procedure:
3-Hydroxypyrazine-2-carboxylic acid is converted to the corresponding ethyl ester and the ester is reduced with lithium aluminium hydride in tetrahydrofuran to give 3-hydroxy-2-hydroxymethylpyrazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:22])=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=3[CH3:18])[C:11](=[O:23])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]2)=[C:4]([CH3:29])[CH:3]=1.[N+:30]([O-])([O-:32])=[O:31].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([N+:30]([O-:32])=[O:31])=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:22])=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=3[CH3:18])[C:11](=[O:23])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]2)=[C:4]([CH3:29])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2C)c2c(C)c([N+](=O)[O-])c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2C)c2c(C)c([N+](=O)[O-])c(F)cc2c1=O
Temperature: 0 °C
Yield: 89.9 %

Procedure:
Ethyl 1-(4-fluoro-2-methylphenyl)-6-fluoro-8-methyl-7-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.1 g) was added to concentrated sulfuric acid (10 ml), and potassium nitrate (330 mg) was added to the mixture under ice cooling. The resultant mixture was stirred at room temperature for 4 days. The reaction mixture was poured into ice water and extracted with chloroform. A chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound (1.1 g) as a pale yellow amorphous substance.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:11]=1)[C:4]([O:6]CC)=[O:5])[CH3:2].CO.[OH-].[Na+].Cl>O>[CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][C:20](=[O:31])[C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=2)[CH:11]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2)c1)C(=O)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
A mixture of ethyl 2-ethyl-3-[3-[4-(trifluoromethyl)benzoylaminomethyl]-4-methoxyphenyl]propanoate (240 mg, 0.549 mmol), methanol (6 mL) and 2.5 mol/L aqueous solution of sodium hydroxide (2 mL) was stirred for 4 hours under heating at 50° C. After cooling, water (20 mL) was added and the mixture was made acidic with 1 mol/L hydrochloric acid, which was then extracted with ethyl acetate. The organic later was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated to afford 222 mg (99%) of the title compound as colorless crystals. Further, these were recrystallized from diethyl ether-n-hexane, thus affording 161 mg (72%) of purified title compound as colorless needles.