Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C:37]1([O:40]C(=O)C)[CH2:39][CH2:38]1)=[O:36]>>[OH:40][C:37]1([C:35]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:36])[CH2:39][CH2:38]1
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: O=C(N[C@H]1CC[C@H](NC(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from trans-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1([C:26](=[O:40])[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])[CH:29]=2)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH3:37][N:36]([CH3:38])[C:35](=[O:39])[O:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([NH:27][C:26]([C:13]2([CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:40])[CH:29]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(CNC(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(CNC(=O)OCc3ccccc3)CCNCC2)c1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 4-((benzyloxycarbonylamino)methyl)-4-(3-(dimethylcarbamoyloxy)phenylcarbamoyl)-piperidine-1-carboxylate from step C (0.245 g, 0.441 mmol) in MeOH (2 mL) was added 4 M HCl in dioxane (0.331 mL, 1.32 mmol). The reaction was heated at 50° C. for 1 hour, and then concentrated under vacuum, re-dissolved in MeOH and re-concentrated twice to give the title compound as the hydrochloride salt. MS (ES+) [M+H]+=455.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[Cl:8][C:9]1[C:10]([N:15]2[C:19]3=[N:20][CH:21]=[N:22][C:23]([O:24][C@@H:25](CCO)[C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=4)=[O:27])=[C:18]3[CH:17]=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:8][C:9]1[C:10]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([O:24][C@H:25]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=4)=[O:27])[CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:18]=3[CH:17]=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(NC(=O)[C@H](CCO)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 45.8 %

Procedure:
Acetic anhydride (0.035 mL, 0.38 mmol) was added to (2S)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-4-hydroxy-N-(5-methylpyridin-2-yl)butanamide (Example 143) (150 mg, 0.34 mmol), N,N-Diisopropylethylamine (0.089 mL, 0.51 mmol) and 4-dimethylaminopyridine (4.17 mg, 0.03 mmol) in DCM (2 mL) at 0° C. over a period of 5 minutes under nitrogen. The resulting solution was stirred at 0° C. for 25 minutes. The volatiles were removed under reduced pressure and the crude product was purified by flash silica chromatography, eluting with 0 to 100% ethyl acetate in isohexane to afford the product (75 mg, 45.6%). 1H NMR (400 MHz, CDCl3) δ 1.95 (3H, s), 2.29 (3H, s), 2.54 (2H, q), 4.31-4.39 (2H, m), 6.00 (1H, t), 7.45-7.49 (1H, m), 7.53 (1H, d), 8.00-8.02 (1H, m), 8.10-8.14 (2H, m), 8.43 (1H, s), 8.61 (1H, q), 8.64 (1H, s), 8.80 (1H, s); m/z (ES+) (M+H)+=482; HPLC tR=2.04 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([CH3:18])([CH3:17])[CH3:16])\[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([CH3:18])([CH3:17])[CH3:16])\[CH2:7][Br:20])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1C(C)(C)C
Yield: 51.3 %

Procedure:
To a stirred mixture of (E)-3-(2-t-butyl-phenoxy)-but-2-enoic acid ethyl ester (3.20 g, 0.012 mol) in carbon tetrachloride (20 mL) under a nitrogen atmosphere was added N-bromosuccinimide (3.26 g, 0.018 mol) and benzoyl peroxide (295 mg, 0.001 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2-t-butyl-phenoxy)-but-2-enoic acid ethyl ester (2.10 g, 50%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2].Cl[S:17]([OH:20])(=[O:19])=[O:18]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1
Reactant: O=S(=O)(O)Cl
Product: O=[N+]([O-])c1ccccc1-c1ccccc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2′-Nitrobiphenyl (5 g) was added slowly to chlorosulfonic acid (25 mL) at room temperature and stirring was continued for 2 hours. The mixture was carefully dripped into ice water and extracted with DCM. The solvent was evaporated and the residue purified by column chromatography (petrol/ethyl acetate) to give the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CC(F)(F)C(F)(F)F)[C:22]([OH:24])=[O:23])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:70])([C:66]([F:69])([F:68])[F:67])CCCCCC(CCCCCC=C)C(OCC)=O>>[CH2:1]([C:3]1([C:39]2[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:47]([F:70])([F:46])[C:66]([F:69])([F:68])[F:67])[C:22]([OH:24])=[O:23])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate prepared in Example 11, the same procedure as shown in Example 13 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].Cl[C:12]([C:14]12[N:20]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15]2)=O.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:12]([C:14]34[N:20]([C:21]([O:23][CH2:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[O:22])[CH:17]([CH2:16][CH2:15]3)[CH2:18][CH2:19]4)=[N:1][C:2]=2[CH:6]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: O=C(OCc1ccccc1)N1C2CCC1(C(=O)Cl)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C2CCC1(c1nc3cc(Br)sc3c(=O)[nH]1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, the crude product (2.0 mmol) of benzyl 1-(chlorocarbonyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate produced above and tetrahydrofuran (10 mL) was added N-ethyl-N-(1-methylethyl)propan-2-amine (0.70 mL) at room temperature. After stirring for 1 hr, the reaction system was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added ethanol (10 mL) and 2M sodium hydroxide (2.5 mL), and the mixture was stirred at 100° C. overnight. The reaction system was cooled to room temperature, poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (313 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Reactant: NCc1ccccc1
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2cc(NCc3ccccc3)nc(N)n2)cc1
Temperature: 130 °C
Yield: 40.5 %

Procedure:
0.30 g (0.001 mol) of 4-amino-N-(2-amino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide and 11 ml (0.1 mol) of benzylamine were dissolved in 15 ml of ethanol and stirred in an autoclave at 130° C. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.15 g (41%) of 4-amino-N-(2-amino-6-benzylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.;221° C. (dec.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:39])[CH3:38])[C:28]([CH:40]=[O:41])=[C:27]([I:42])[C:26]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].CO>O1CCCC1>[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:35])([CH3:36])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:38])[CH3:39])[C:28]([C@H:40]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[OH:41])=[C:27]([I:42])[C:26]1=2)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: -20 °C
Reaction time: 5 h

Procedure:
1.1 ml 4-iodobenzotrifluoride are dissolved in 60 ml tetrahydrofurane and cooled to −20° C. 3.7 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane are added dropwise and the solution is stirred for further 5 hours. Then the solution is cooled to −40° C. and 1.17 g (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 5 ml tetrahydrofurane are added dropwise. The mixture is stirred for 12 hours while warming to room temperature. Then it is cooled to 0° C., 10 ml methanol are added and it is stirred for 30 minutes. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 95:5 to 80:20).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([C:16](=O)[CH3:17])=[C:11]([CH3:19])[CH:10]=2)=[N:6][CH:7]=1.CC(O)=O.[NH2:31][O:32][CH2:33][CH2:34][OH:35]>CO>[OH:35][CH2:34][CH2:33][O:32][N:31]=[C:16]([C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:10][C:11]=1[CH3:19])[CH3:17]
Reactant: CC(=O)c1cc(C)c(Nc2ncc(Cl)c(Nc3cc(C)[nH]n3)n2)cc1C
Reactant: NOCCO
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NOCCO)c1cc(C)c(Nc2ncc(Cl)c(Nc3cc(C)[nH]n3)n2)cc1C
Temperature: 60 °C

Procedure:
To a solution of 1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)ethanone (60 mg, 0.16 mmol) in MeOH (1 mL) was added AcOH (15 mg, 0.25 mmol), followed by the addition of 2-(aminooxy)ethanol (20 mg, 0.26 mmol). The mixture was heated to 60° C. for 14 h and cooled down to room temperature. The mixture was then purified directly by preparative RP-HPLC to provide 1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)ethanone O-2-hydroxyethyl oxime; ESMS m/z 430.2 (M+H+).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:10]1[C:11]([NH2:19])=[N:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=12>COCCOC>[CH2:7]([O:6][C:4]([C:3]1[N:19]=[C:11]2[N:10]=[C:14]3[N:13]([CH2:18][CH2:17][CH2:16][CH2:15]3)[N:12]2[CH:2]=1)=[O:5])[CH3:8]
Reactant: Nc1nc2n(n1)CCCC2
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(n1)nc1n2CCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl bromopyruvate (10.23 g) was added to the mixture of 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (5.8 g) in 1,2-dimethoxyethane (320 mL). The reaction mixture was stirred for 5 hours at room temperature and concentrated to 100 mL under reduced pressure. The precipitate was obtained by an addition of diethyl ether (200 mL), followed by filtration. The precipitate was dissolved in ethanol (175 mL) and stirred for 20 hours at 110° C. in shield tube. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated potassium carbonate solution and extracted with chloroform. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then eluted with ethyl acetate—methanol (1/1). The title compound was obtained as a pale yellow solid (7.56 g, 77%). 1H-NMR (400 MHz, CDCl3) δ 1.42 (t, 3H, J=7.1 Hz), 2.14–2.25 (m, 4H), 3.11 (t, 2H, J=6.1 Hz), 4.37 (t, 2H, J=5.7 Hz), 4.41 (q, 2H, J=7.1 Hz), 7.57 (s, 1H).
Reaction SMILES: N[CH:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1C(OCC)=O.Cl.[OH2:20]>>[C:8]1([N:5]2[CH2:4][CH2:3][C:2](=[O:20])[C:6]2=[O:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Agent: Cl
Product: O=C1CCN(c2ccccc2)C1=O

Procedure:
According to the procedure of Southwick [J. Org. Chem. 21, 1087 (1956)]the ethyl ester pyrrolidinone of Example S (1.0 g, 4.0 mmol) was suspended in 75 ml of 20% HCl/H2O and refluxed for 3.5 h The reaction was cooled and filtered and the filtrate was extracted with CHCl3 (4×150 ml). Concentration of the combined extracts gave an off-white solid (358 mg). 'NMR(300 MHZ, CDCl3) δ2.92 (t, 2H), 4.17 (t, 2H), 7.32 (t, 1H), 7.98 (t, 2H), 7.84 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH2:21])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[NH:10]1.[N+]([NH:26][C:27]([NH2:29])=[O:28])([O-])=O>C(O)C>[CH2:11]([O:22][NH:21][C:19]([CH:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]([CH:3]2[CH2:2][CH2:7][CH2:6][CH2:5][CH:4]2[NH:26][C:27](=[O:28])[NH2:29])[CH:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: NC(=O)C1c2ccccc2C(=O)NC1c1ccc(Cl)cc1Cl
Solvent: CCO
Product: NC(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl

Procedure:
To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-Nenzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 20 ml of ethanol was added 53 mg of nitrourea, followed by heating under reflux for 1 hour. The reaction solution was cooled and then concentrated, and the residue was purified by silica gel column chromatography (eluent:chloroform-methanol), then crystallized with acetonitrile, and collected by filtration to obtain 155 mg of (3RS,4RS)—N-(benzyloxy)-2-[(1SR,2SR)-2-(carbamoylamino)cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C@@H:7]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:6]1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:13])[C@@H:7]([C:22]([OH:24])=[O:23])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)O)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred, cold (0° C.) solution of (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester (4.4 g, 10.6 mmol) in 30 mL of methylene chloride was added 10 mL of trifluoroacetic acid dropwise. The mixture was stirred for 1 hour at 0° C. and for 8 hours at ambient temperature. Concentration provided (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic acid 4-methyl ester, which was used in the subsequent step without purification.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:4]=1N.N([O-])=O.[Na+]>O>[Cl:1][C:4]1[C:3]([F:2])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10]
Reactant: Nc1c(F)cccc1F
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cccc(F)c1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
550 g of hydrochloric acid was added to a reactor having 270 g of water placed therein, and 129 g of 2,6-difluoroaniline (b1) was further added thereto, followed by stirring for 30 minutes at 60° C. Thereafter, the mixture was cooled to −10° C., and 192.5 g of a 37.6% sodium nitrite aqueous solution was added dropwise thereto over 30 minutes in a temperature range of −10 to −5° C., followed by stirring for 30 minutes at −10° C. The resulting reaction mixture was added to another reactor having 122 g of 30% hydrochloric acid and 22 g of cuprous chloride placed therein over 90 minutes in a temperature range of 25 to 30° C., followed by stirring for 30 minutes in that temperature range. A reaction mixture obtained by the reaction was subjected to steam distillation. The resulting organic phase was washed with water in three times and then dried to obtain 124 g of 2-chloro-1,3-difluorobenzene (b2).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:4][CH:3]=1.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.ClCCl>[S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCCCCCCCCCc1ccc(I)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCCCCCc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.3 %

Procedure:
A mixture of 15-(p-iodophenyl)pentadecanol (Compound II) (200 mg; 0.47 mmol), tosyl chloride (102 mg; 0.53 mmol) and 4-dimethylaminopyridine (66 mg; 0.53 mmol) in dichloromethane (3 ml) was stirred at room temperature for 12 h. The reaction mixture was then partitioned between chloroform (40 ml), methanol (40 ml) and 0.1 N hydrochloric acid (36 ml). The chloroform layer was separated and extraction was repeated (2×40 ml of chloroform). Extracts were combined, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel in hexane-chloroform (from 95:5 to 40:60) to give Compound III, 15-(p-Iodophenyl)pentadecyl tosylate (259 mg; 95%).
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)=[CH2:2].[I:11]Cl>CN(C)C=O>[I:11]/[CH:2]=[CH:1]/[C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1
Reactant: ClI
Reactant: C=Cc1c[nH]c(=O)[nH]c1=O
Solvent: CN(C)C=O
Product: O=c1[nH]cc(/C=C/I)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
5-vinyluracil (1.1 g, 8 mmoles) was dissolved in dry dimethylformamide (40 ml). To this solution was added a solution of iodine monochloride (1.28 g, 8 mmoles) in dry dimethylformamide (20 ml). The reaction mixture was allowed to stand, with occasional shaking, for 30 minutes and then heated at 100° for 30 minutes. The solution was then evaporated under reduced pressure to a brown oil to which was added water (20 ml). The resulting dark brown suspension was filtered and the brown solid collected and dried giving crude E-5-(2-iodovinyl)uracil (1.6 g, 76% yield). For the next stage this was not purified further.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[N:28][CH:29]=1>CN(C)C=O>[CH3:16][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:24]2[CH:29]=[N:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:7][C:6]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Cc1ccc(O)cc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1NC(=O)OC(C)(C)C
Yield: 70 %

Procedure:
In the same manner as in Reference Example 33 and using tert-butyl (5-hydroxy-2-methylphenyl)carbamate (18.9 g, 85.0 mmol), cesium carbonate (41.8 g, 0.128 mol), N,N-dimethylformamide (100 mL) and 5-bromo-2-nitropyridine (16.4 g, 80.7 mmol) as starting materials, the title compound (19.5 g, 53%) was obtained as a pale-yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18].[Cl:19][C:20]1[N:21]=[C:22]([C:26](O)=[O:27])[NH:23][C:24]=1[CH3:25].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:19][C:20]1[N:21]=[C:22]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH2:17][CH3:18])=[O:27])[NH:23][C:24]=1[CH3:25]
Reactant: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: Cc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(C)[nH]1
Yield: 60 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-propoxypiperidine-1-carboxylate obtained in Example (20a) (0.22 g, 0.85 mmol), 4-chloro-5-methyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (5c) (0.11 g, 0.64 mmol), WSC hydrochloride (0.63 g, 3.28 mmol) and DMAP (84 mg, 0.69 mmol), to obtain 0.15 g of the title compound as a pale yellow solid (60%).