Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[I:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(N(CC)CC)C.O>C(Cl)Cl>[I:11][C:12]1[CH:13]=[N:14][N:15]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[CH:16]=1
Reactant: Ic1cn[nH]c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Oc1ccccc1)n1cc(I)cn1
Temperature: 25 °C
Reaction time: 60 h
Yield: 94.3 %

Procedure:
Phenyl chloroformate (0.75 mL, 6.0 mmol) is added dropwise to a solution of 4-iodopyrazole (1.05 g, 5.4 mmol) and triethylamine (0.9 mL, 6.5 mmol) in 15 mL CH2Cl2. The reaction is stirred at RT. After 60 h, water is added. The mixture is extracted with CH2Cl2, dried (MgSO4), filtered and concentrated. Hexane is added and the solvent is removed in vacuo. A white solid forms on standing to provide 1.6 g (95%) of phenyl 4-iodo-1H-pyrazole-1-carboxylate. MS (EI) m/z 315.1 (M+).
Reaction SMILES: O=[C:2]1[CH:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][C:4](=[O:14])[CH2:3]1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[O:14]=[C:4]1[CH2:5][CH2:6][CH:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:3]1
Reactant: O=C1CCC(C2CCCCC2)C(=O)C1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: O=C1C=C(N2CCNCC2)C(C2CCCCC2)CC1
Yield: 76 %

Procedure:
A mixture of 9.8 g (0.05 mol) of 1,3-dioxo-6-cyclohexyl-cyclohexane, 12.9 g (0.15 mol) of anhydrous piperazine and 150 ml of toluene is reacted and worked up as described in Example 1. For purification, column chromatography is included (corresponding to Example 2). (3-Oxo-6-cyclohexyl-1-cyclohexen-1-yl)-piperazine is obtained as an oil in an amount of 9.9 g (=76% yield) with an RF value of 0.36 (conditions corresponding to Example 1). The dihydrochloride has a melting point of 258°-261° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH3:17][NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CCO>[Cl:1][C:2]1[N:3]=[C:4]([N:18]([CH3:17])[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CNC1CCOCC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(c1cc(Cl)nc(Cl)n1)C1CCOCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.1 %

Procedure:
To a solution of 2,4,6-trichloro-pyrimidine (9.2 g, 50 mmol) and triethylamine (10.1 g, 100 mmol) in EtOH (100 mL) was added N-methyltetrahydro-2H-pyran-4-amine (5.17 g, 45 mmol) dropwise at −40° C. The mixture was warmed up to room temperature then stirred for 14 h., quenched with H2O (25 mL), concentrated and the residue was extracted with EtOAc (100 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatographic column on silica gel (petroleum ether/EtOAc=30/1 to 2/1) to give (2,6-dichloro-pyrimidin-4-yl)-methyl-(tetrahydro-pyran-4-yl)amine as white solid (7.8 g, 60% yield). ESI-LCMS (m/z): 263.14 [M+1]+;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:14])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.Cl[C:22]([O:24][CH3:25])=[O:23]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([O:14][C:22]([O:24][CH3:25])=[O:23])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)Cl
Reactant: CNC(=O)N(O)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CNC(=O)N(OC(=O)OC)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-hydroxy-3-methylurea (15 grams; 0.06 mol) in isopropyl alcohol (50 ml), and pyridine (8 ml) were charged into a glass reaction flask equipped with a mechanical stirrer. Methyl chloroformate (7 ml; 0.09 mol) was then slowly added, with stirring, at a temperature of 10° to 15°C. After the addition was completed stirring was continued for an additional period of one-half hour resulting in the formation of a precipitate. After this time the reaction mixture was poured onto ice and the precipitate recovered by filtration. The precipitate was recrystallized first from a benzene-hexane mixture and then from a methyl alcohol-water mixture to yield 1-(3,4-dichlorophenyl)-1-methoxycarbonyloxy-3-methylurea having a melting point of 110°C with decomposition and having the following elemental analysis as calculated for C10H10Cl2N2O4 :
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[O-:33][N+:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:6]2[N:5]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]([CH2:1][CH2:2][CH3:3])=[N:16][C:7]=2[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCC(=O)OCC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyrate (8.20 g, 25.2 mmol, available from Step 3 of Example 17) by reaction with m-CPBA (14.1 g) to provide ethyl 4-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyrate followed by reaction with p-toluenesulfonyl chloride (8.40 g, 44.1 mmol) and ammonium hydroxide solution (150 mL) to provide ethyl 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyrate as an off-white solid after recrystallization from aqueous methanol, mp 154-156° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=[O:28])[CH:8]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[H-].[Na+].[CH:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35].Cl>O1CCCC1.O>[O:28]=[C:7]([CH:8]=[CH:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC=CC(=O)CC(=O)OCC
Temperature: 45 °C
Yield: 40.2 %

Procedure:
To a solution of (3-ethoxycarbonyl-2-oxopropylidene)triphenylphosphorane (5.0 g, 12.8 mmol) in tetrahydrofuran (THF, 50 ml) were added sodium hydride (60% dispersion in oil, 1.03 g, 25.6 mmol) and then pentanal (1.10 g, 12.8 mmol) followed by stirring. After addition of water (three drops), the mixture was heated at 45° C. for 1 hour. The reaction mixture was treated with dilute hydrochloric acid and extracted with ether. The organic layer was washed with aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, dried (MgSO4), and concentrated to dryness. The resulting residue was purified by column chromatography on silica gel. The column was eluted with dichloromethane-hexane (1:1 to 3:2) to give 1.02 g (40.0%) of the title compound as an oil. The 1H-NMR spectrum indicates that the product is a mixture of keto/enol isomers.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:3][C:4]1[O:5][CH2:6][C:7](=[O:14])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:6]2[O:5][C:4]([NH:3][N:2]([CH3:1])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]2=[O:14])=[CH:22]1
Reactant: CCOC(=O)C1=C(NN(C)c2ccccc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(NN(C)c2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 10.3 %

Procedure:
To a solution of ethyl 2-(2-methyl-2-phenylhydrazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.053 g, 0.36 mmol) in ethanol (10 mL), L-proline (0.020 g, 0.17 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.015 g, y. 10%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([CH:12]2[C:25]3[C:20](=[N:21][C:22]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=4)=[CH:23][CH:24]=3)[O:19][C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:11][CH2:10][CH2:9]1)=[O:7])C.Cl>CO>[C:6]([C:8]1([CH:12]2[C:25]3[C:20](=[N:21][C:22]([C:26]4[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=4)=[CH:23][CH:24]=3)[O:19][C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:11][CH2:10][CH2:9]1)([OH:7])=[O:5]
Reactant: CCOC(=O)C1(C2c3ccccc3Oc3nc(-c4ccc(C(=O)OC)cc4)ccc32)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc3c(n2)Oc2ccccc2C3C2(C(=O)O)CCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
A 1 N aqueous solution of NaOH (5 mL, 5.00 mmol) was added to a solution of the product from Step 1 (250 mg, 0.564 mmol) in MeOH (10 mL) at room temperature. After 24 h at 80° C., the mixture was cooled to room temperature and adjusted pH2-3 with 1 N aqueous HCl. MeOH was evaporated in vacuo. The brown precipitate in the aqueous residue was collected by filtration and dried under vacuum to give 4-(5-(1-carboxycyclobutyl)-5H-chromeno[2,3-b]pyridin-2-yl)benzoic acid (210 mg, 93%). MS (ES+) m/z: 402 (M+H).
Reaction SMILES: [I:1]I.[OH-].[K+].[N+:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)([O-:7])=[O:6]>CN(C=O)C>[I:1][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)[NH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodine (1.6 g, 6.4 mmol) and KOH (0.67 g, 12 mmol) were successfully added into a solution of 5-nitro-1H-indazole (520 mg, 3.2 mmol) in DMF. The reaction mixture was stirred at room temperature for overnight and then 10% Na2S2O5 was poured into the mixture. The titled compound (0.84 g, 91%) was filtered off as a yellow solid. MS (ESI) m/z=290 [M+H]+. 1H NMR (400 MHz, d6-DMSO) δ 14.15(s, 1H), 8.36(d, J=2 Hz, 1H), 8.26 (dd, J=2 and 9 Hz, 1H), 7.78 (d, J=9 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28](=[O:37])[NH:29][C:30](=[NH:36])[N:31]2[CH:35]=[CH:34][CH:33]=N2)=[C:10]([C:13]2[CH:26]=[CH:25][C:16]([C:17]([NH:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:18])=[CH:15][CH:14]=2)[S:11][CH:12]=1.NCCC[OH:42].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28]([NH:29][C:30]([NH:31][CH2:35][CH2:34][CH2:33][OH:42])=[NH:36])=[O:37])=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[O:18])=[CH:25][CH:26]=2)[S:11][CH:12]=1
Reactant: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)n2cccn2)cc1
Reactant: NCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)NCCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a solution of 4-(4-(2-chloro-phenyl)-3-{[(imino-pyrazol-1-yl-methyl)-carbamoyl]-methyl}-thiophen-2-yl)-N-(1-ethyl-propyl)-benzamide (0.87 g, 0.16 mmol) in CH2Cl2 (2 mL) was added 3-aminopropanol (0.037 g, 0.040 mL, 0.50 mmol) and diisopropyl ethylamine (0.064 g, 0.087 mL, 0.50 mmol). The solution was stirred overnight at RT. The solvent was removed and the product purified by flash chromatography (15:1 CHCl3:MeOH) to yield 4-[4-(2-chlorophenyl)-3-(2-{[[(3-hydroxypropyl)amino](imino)methyl]amino}-2-oxoethyl)thien-2-yl]-N-(1-ethylpropyl)benzamide (0.047 g) as a white solid. mp 109-110° C. MS (ES) m/z 541.12 ([M+H]+); Anal. Calcd for C28H33ClN4O3S.0.60 H2O: C, 60.93; H, 6.25; N, 10.15. Found: C, 60.57; H, 6.07; N, 10.02.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([OH:28])[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C:15](=[O:29])[CH2:14][CH2:13]1)(=[O:3])[CH3:2].O.[BH4-].[Na+]>O1CCCC1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([OH:28])[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C@@H:15]([OH:29])[CH2:14][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.0 g of 7α-(5-acetoxypentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 65 ml of tetrahydrofuran, and 2 ml of water and 0.6 g of fine sodium borohydride are added at room temperature. After 1 hour of stirring at room temperature, the reaction mixture is added to ice water, extracted three times with ethyl acetate, and the organic phase is washed with sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum, raw yield 6.07 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[S:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10])(=[O:31])=[O:32]
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 2-methoxy-5-methylbenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 390 mg of benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-methylbenzenesulfonylamino)phenyl]-amide. LC: Tr 1.25 min; MS: 489.1 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[N:10]=[C:9]([CH3:17])[C:8]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)C.[S-2:27].[Na+].[Na+]>O>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([SH:27])[N:10]=[C:9]([CH3:17])[C:8]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(S)c([N+](=O)[O-])c1NCCCN(C)C

Procedure:
34.5 g. of 4-[[3-(dimethylamino)propyl]amino]-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester are dissolved in 100 ml. of ethanol. 15 g. of sodium sulfide in 10 ml. of water are added and the mixture is stirred without cooling for 1 hour. After this time, the precipitated 4-[[3-(dimethylamino)propyl]amino]-6-mercapto-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester is filtered off and recrystallized from methanol, yield 18 g. (53%), m.p. 131°-132°.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CS([C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2/[C:35](=[CH:40]\[O:41][CH3:42])/[C:36]([O:38][CH3:39])=[O:37])[CH:23]=1)(=O)=O.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:22]2[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3/[C:35](=[CH:40]\[O:41][CH3:42])/[C:36]([O:38][CH3:39])=[O:37])[CH:23]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(S(C)(=O)=O)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(OCc2ccc([N+](=O)[O-])cc2)ncn1
Temperature: 60 °C
Yield: 44.3 %

Procedure:
To a solution of 4-nitrobenzyl alcohol (666 mg) in DMF (8 ml) was added potassium carbonate (800 mg) followed by a solution of (E)-methyl 2-[2-(6--methanesulphonylpyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (1.0 g, prepared as described in Example 1) in DMF (3 ml). The reaction mixture was heated to 60° C. under an atmosphere of nitrogen for 5½ hours, cooled and then poured into water (40 ml). The resulting mixture was extracted with ether (×3) and the combined ether layers were dried and evaporated to yield an orange oil. Chromatography (eluent ether-hexane, 7:3) gave (E)-methyl 2-[2-(6-(4-nitrobenzyloxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (532 mg) as a glass which solidified on standing; m.p. 96-98° C.; 1H NMR: δ 3.55(3H,s), 3.75(3H,s), 5.50(2H,s), 6.15(1H,s), 7.15(1H,d), 7.3(3H,m), 7.45(1H,s), 7.58(2H,d), 8.22(2H,d), 8.42(1H,s) ppm; IR maxima: 1700, 1620, 1560, 1340 cm−1; mass spectrum m/e 437 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:32])[C@@H:16]([NH:24]C(=O)OC(C)(C)C)[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.Cl.O1CCOCC1.[S:40]1[CH:44]=[C:43]([CH:45]=O)[N:42]=[CH:41]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:32])[C@@H:16]([NH:24][CH2:45][C:43]3[N:42]=[CH:41][S:40][CH:44]=3)[CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cscn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2ccnc(N)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1cc(-c2cccc(NC(=O)[C@H](Cc3ccccc3)NCc3cscn3)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
To a solution of tert-butyl (S)-1-(3-(2-aminopyridin-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (36.C) (200 mg, 0.46 mmol) in THF (2 mL) was added 4M HCl in dioxane (2 mL, 8 mmol). The mixture was stirred at room temperature for 2 hours and then was concentrated. The residue was neutralized with saturated aqueous NaHCO3 and extracted with 4:1 DCM/isopropanol. The organic layers were combined, washed with brine, dried on MgSO4 and concentrated. The residue was dissolved in DCM and then thiazole-4-carbaldehyde (56 mg, 0.50 mmol) was added. The mixture was stirred for 1 h at room temperature at which time acetic acid (28 μL, 0.46 mmol) and sodium triacetoxyborohydride (293 mg, 1.38 mmol) were added. The mixture was stirred at room temperature for additional 2 hours, concentrated and the residue purified by reverse phase preparative HPLC to afford (2S)—N-(3-(2-aminopyridin-4-yl)phenyl)-3-phenyl-2-(thiazol-4-ylmethylamino)propanamide 36 (58 mg, 29% yield) as a white solid. LCMS ESI (pos.) m/e: 430.1 (M+1): 1H NMR (400 MHz, MeOH-D4) δ ppm 9.12 (d, J=1.96 Hz, 1H), 7.91-7.97 (m, 2H), 7.79 (d, J=1.96 Hz, 1H), 7.42-7.57 (m, 3H), 7.25-7.36 (m, 5H), 7.18-7.21 (m, 1H), 7.13-7.17 (m, 1H), 4.42-4.54 (m, 2H), 4.25 (dd, J=9.39, 5.87 Hz, 1H), 3.42 (dd, J=13.30, 5.87 Hz, 1H), 3.25 (dd, J=13.30, 9.00 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:14])[CH3:13].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]([NH:11][C:12](=[O:14])[CH3:13])[CH:4]=1)([O-:10])=[O:9]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1F
Reactant: C1CCNC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1N1CCCC1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
0.5 g (2.5 mmol) of N-(2-fluoro-5-nitrophenyl)acetamide was admixed in a pressure reaction vessel with 1 ml (12.6 mmol) of pyrrolidine and stirred at 90° C. for 2.5 hours. After the mixture had been cooled, it was diluted with 20 ml of dichloromethane, adjusted to pH 4 using citric acid solution (10%) and washed four times with water. After the organic phase had been dried, the solvent was removed under reduced pressure. In the aqueous phase, a solid is precipitated out. It was filtered off with suction and washed with water, and combined with the residue from the organic phase (yield 0.58 g, 93%). The product was reacted in stage c without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1oc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (230 mg, 0.90 mmol) [prepared according to the procedure of Example 184], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (348 mg, 0.90 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (502 mg, 1.07 mmol) in chloroform (8.5 mL). DIEA (790 μL, 4.52 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (247 mg, 0.43 mmol, 48%): LC-MS (ES) m/z=571 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][OH:13])=[N:10][C:9]2[NH:8][C:7](=[O:14])[CH2:6][S:5][C:4]=2[CH:3]=1.C1COCC1>[O-2].[O-2].[Mn+4].ClCCCl>[F:1][C:2]1[C:11]([CH:12]=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:14])[CH2:6][S:5][C:4]=2[CH:3]=1
Reactant: O=C1CSc2cc(F)c(CO)nc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=Cc1nc2c(cc1F)SCC(=O)N2
Temperature: 60 °C

Procedure:
A mixture of the alcohol (e) (971 mg), manganese dioxide (3.72 g), THF (70 ml) and 1,2-dichloroethane (70 ml) was heated at 60° C. under argon for 20 hours. Filtration through kieselguhr and evaporation of solvent gave a solid which was triturated with EtOAc/hexane 1:3 and collected by filtration (608 mg).