Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([N:35]2[CH2:40][CH2:39][CH:38]([C:41]([O:43]CC)=[O:42])[CH2:37][CH2:36]2)=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([N:35]2[CH2:36][CH2:37][CH:38]([C:41]([OH:43])=[O:42])[CH2:39][CH2:40]2)=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1CCN(C(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)N2CCC(C(=O)O)CC2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
A 3.0 ml ethanol solution of 105 mg of ethyl 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}piperidine-4-carboxylate was mixed at room temperature with 1.0 ml of 1 M sodium hydroxide aqueous solution and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, acidified by adding 1 M hydrochloric acid and then extracted with chloroform and dried with anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography to obtain 86 mg of 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}piperidine-4-carboxylic acid as a white amorphous substance. A 2.0 ml 1,4-dioxane solution of 86 mg of 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}piperidine-4-carboxylic acid was mixed at room temperature with 1.0 ml of 4 M hydrogen chloride/1,4-dioxane and stirred overnight at room temperature. The reaction solution was concentrated and crystallized with 1,4-dioxane-diisopropyl ether to obtain 80 mg of 1-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}piperidine-4-carboxylic acid hydrochloride as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.N12CCCN=C1CCCCC2.[C:18]([CH:20]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)#[N:19]>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:21]2([CH2:20][C:18]#[N:19])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:25][CH2:26]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Reactant: Brc1cn[nH]c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(Br)cn2)CC1
Yield: 62.7 %

Procedure:
4-bromo-1H-pyrazole (362 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.368 ml) and tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (547 mg) in acetonitrile (10 ml) were stirred at 45° C. for 6 hours. The crude reaction was concentrated on dicalite (diatomaceous earth) and was purified by flash chromatography on silica gel eluting with 0 to 20% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-(4-bromopyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (570 mg) as a white foam. NMR Spectrum: (DMSO-d6) 1.45 (s, 9H), 1.94-2.04 (m, 2H), 2.54-2.62 (m, 2H), 2.80 (s, 2H), 2.93-3.04 (m, 2H), 3.88 (bs, 2H), 7.57 (s, 1H), 7.73 (s, 1H)
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=1)[CH3:14].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][CH2:41]O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][CH2:41][O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:25])=[CH:18][C:19]=2[F:24])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCCCN2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
Triphenylphosphine polystyrene (loading 1.0 mmol/g, 11 g, 11.0 mmol) and DEAD (2.45 g, 11.0 mmol) were added to a solution of 3-fluoro-4-hydroxy-benzoic acid ethyl ester from Example E27 (1.3 g, 7.4 mmol) and 4-(3-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E34 (1.8 g, 7.4 mmol) in tetrahydrofuran (100 ml) at 0° C. The suspension was allowed to warm to room temperature and stirred for 18 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAC) to yield the title compound (1.7 g, 57%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH:14]([C:16](=[O:52])[N:17]([CH:27]([CH3:51])[CH:28]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:29][C:30]1[O:31][C:32]([C:35](=[O:43])[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:34]=1)[CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6]([C:8](=[C:14]([C:16](=[O:52])[N:17]([CH:27]([CH3:51])[CH:28]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:29][C:30]1[O:31][C:32]([C:35](=[O:43])[NH:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:33][CH:34]=1)[CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC(C(=O)OC(C)(C)C)C(O)C(=O)N(C/C=C/c1ccccc1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Product: COC(=O)CC(C(=O)OC(C)(C)C)=C(O)C(=O)N(C/C=C/c1ccccc1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C
Yield: 76.3 %

Procedure:
92 mg of methyl (3RS,4RS)-3-(tert-butoxycarbonyl)-4-[N-[(1RS,2RS)-2-(tert-butoxycarbonyl)-1-methyl-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-{(E)-3-phenyl-2-propenyl}carbamoyl]-4-hydroxybutanoate was dissolved in 3 ml of acetonitrile and stirred with 56 mg of tetrapropylammonium perruthenate at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was roughly purified by silica gel short column chromatography [chloroform→methanol] and purified again by silica gel column chromatography [hexane/ethyl acetate=2/1→3/2] to give 70 mg (yield: 76%) of the title compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:24])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1C(O)c1ccc(Br)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1C(=O)c1ccc(Br)cc1
Temperature: 35 °C

Procedure:
To a solution of tert-butyl {2-[(4-bromophenyl)(hydroxy)methyl]-4-chlorophenyl}carbamate (10 g, 25 mmol) in 100 ml CH2Cl2, was added MnO2 (10 g, 125 mmol) and the mixture was heated to 35° C. for 48 hours. Filtration and concentration gave tert-butyl [2-(4-bromobenzoyl)-4-chlorophenyl]carbamate as a yellow solid. 1HNMR: (400 MHz, CDCl3) δ 9.77 (s, 1H), 8.39 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.49 (dd, J=8.8, 2.0 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 1.51 (s, 9H).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>>[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)=[CH:22][CH:21]=1
Reactant: NCCc1ccncc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2ccncc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-pyridin-4-yl-ethylamine and DIEA to give 2-(2-pyridin-4-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 361 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].CCCCCC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([O:14][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Yield: 100.5 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl-4-piperidone (14.9 g, 74.8 mmol) in DMF (35 mL) was added TMSCl (11.4 mL, 89.7 mmol) and then Et3 N (25.0 mL, 179 mmol) dropwise at room temperature, and the reaction mixture was heated at 80° C. for 18 hr. Hexane was added to the reaction mixture, and the resulting mixture was washed with sat. NaHCO3 and brine, dried over Na2SO4, and concentrated to dryness. Chromatography of the residue with hexane-EtOAc (5:1, v/v) as eluent gave 1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine (20.4 g, 99%) as a yellow oil. 1H-NMR (CDCl3) δ 0.19 (s, 9H), 1.46 (s, 9H), 2.05–2.15 (m, 2H), 3.48–3.56 (m, 2H), 3.83–3.91 (m, 2H), 4.79 (broad s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([N:8]1[C@H:11]([S:12]SC2SC3C=CC=CC=3N=2)[C@@H:10]([O:23][C:24](=[O:33])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]1=[O:34])=[C:5]([CH3:7])[CH3:6].[BH4-].[Na+].[C:38](Br)(=[O:40])[CH3:39].C1C=CC=CC=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:35])[C:4]([N:8]1[C@H:11]([S:12][C:38](=[O:40])[CH3:39])[C@@H:10]([O:23][C:24](=[O:33])[CH2:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]1=[O:34])=[C:5]([CH3:6])[CH3:7]
Reactant: CC(=O)Br
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SC(C)=O
Reaction time: 0.17 h

Procedure:
A solution of 687 mg (1.29 mmole) of 2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acid methyl ester in 14 ml of dimethylformamide is added to a solution, cooled to -20°, of 76 mg (2 mmole) of sodium borohydride in 10 ml of dimethylformamide and the mixture is stirred at the same temperature for 10 minutes. 7 ml of freshly distilled acetyl bromide are added to the reaction mixture, which is further stirred at 0° for 40 minutes. After adding 400 ml of benzene, the reaction mixture is washed in succession with aqueous sodium bicarbonate solution, water and sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. After chromatography over silica gel with toluene/ethyl acetate (19:1) the residue yields the title compound in the form of an oil, which is further purified on silica gel plates with toluene/ethyl acetate (4:1). The title compound is obtained in oily form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4](Cl)[C:3]=1[N:13]1[C:17]([S:18]([CH:21]([F:23])[F:22])(=[O:20])=[O:19])=[C:16]([Cl:24])[N:15]=[C:14]1[Br:25].[CH3:26][S-:27].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:3]([N:13]2[C:17]([S:18]([CH:21]([F:23])[F:22])(=[O:20])=[O:19])=[C:16]([Cl:24])[N:15]=[C:14]2[Br:25])=[C:4]([S:27][CH3:26])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[S-]
Reactant: O=S(=O)(c1c(Cl)nc(Br)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cc(C(F)(F)F)cc(Cl)c1-n1c(Br)nc(Cl)c1S(=O)(=O)C(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 35.2 %

Procedure:
To a solution of 500 mg (0.984 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-bromo-4-chlorodifluoromethylsulfonyl-imidazole in 2 ml of tetrahydrofuran was added a solution of 69 mg (0.984 mmole) of sodium methanethiolate in 0.3 ml of water. The resulting mixture was stirred at RT for 14 hours, after which it was partitioned between water and diethyl ether. The organic layer was separated, dried over anhydrous sodium sulfate and stripped of solvent. The residue was purified by preparative TLC using 20% ethyl acetate in hexane to give 180 mg (35% yield) of the product, mp 116° C.
Reaction SMILES: Cl.[CH2:2]([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.OC1C2N=NNC=2C=CC=1.[C:34]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH2:2]([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH:22][C:49](=[O:50])[C@@H:45]([NH:44][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH:46]([CH3:48])[CH3:47])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Temperature: 0 °C
Yield: 61.4 %

Procedure:
((R)-3-Amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (2.10 mmol) was dissolved in DMF (30 mL) under nitrogen and stirred at 0° C. To this was added sequentially hydroxybenzotriazole (0.91 g, 6.72 mmol), N-Cbz-L-valine (0.63 g, 2.52 mmol), triethylamine (0.58 mL, 4.2 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.48 g, 2.52 mmol). The stirred reaction mixture was allowed to warm to room temperature and continued to stir overnight. The reaction was diluted with ethyl acetate (300 mL) and was washed with brine (100 mL). The brine layer was back extracted with ethyl acetate (2×100 mL) and the organic fractions were combined and were washed with 10% citric acid (2×100 mL), saturated sodium bicarbonate solution (2×100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product which was purified by flash chromatography (as in Method A) to give (0.72 g, 1.29 mmol) of [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester as a white foam. NMR and MS spectra were substantially similar to the product obtained via Method A set forth above.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[F:10])([O-])=O.O.O.[Sn](Cl)Cl.[OH-].[Na+]>Cl>[NH2:1][C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(F)c(N)c1
Temperature: 25 °C
Yield: 103.6 %

Procedure:
To a stirred mixture of 3'-nitro-4'-fluoroacetophenone (10.04 g, 55 mmol) in 72 mL of concentrated hydrochloric acid, was added tin (II) chloride dihydrate (37 grams), in portions. After approximately one third of the material had been added, a rapid rise in the internal reaction temperature (to 95° C.) was noted. The mixture was then heated to reflux for 10 minutes, this resulted in the dissolution of all solids to give a solution. The mixture was then cooled to room temperature and poured onto an ice/water mixture (150 g). The mixture was then further cooled in an ice bath while 50% sodium hydroxide was added until pH 12 was reached. The aqueous layer was extracted twice with ether (50 mL). The combined organic extracts were washed with brine and then dried over sodium sulfate. Removal of the drying agent and in vacuo concentration of the filtrate afforded a yellow-orange oil (8.73 g) which was recrystallized on standing. This material was of sufficient purity to be used directly in the next step (Part 3).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1([CH2:32][OH:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[F:34][CH:35]([F:67])[O:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[N:42]([CH3:46])[N:41]=[C:40]2[C:47]1[N:48]=[C:49]2[C:55]([C:56](O)=[O:57])=[CH:54][N:53]([CH2:59][O:60][CH2:61][CH2:62][Si:63]([CH3:66])([CH3:65])[CH3:64])[C:50]2=[N:51][CH:52]=1>CN(C=O)C>[F:67][CH:35]([F:34])[O:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[N:42]([CH3:46])[N:41]=[C:40]2[C:47]1[N:48]=[C:49]2[C:55]([C:56]([NH:25][C:26]3([CH2:32][OH:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:57])=[CH:54][N:53]([CH2:59][O:60][CH2:61][CH2:62][Si:63]([CH3:65])([CH3:64])[CH3:66])[C:50]2=[N:51][CH:52]=1
Reactant: NC1(CO)CCOCC1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2(CO)CCOCC2)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (34.5 mg, 90.7 μmol.20), (4-aminotetrahydro-2H-pyran-4-yl)methanol (39.7 mg, 302 μmol) and 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (37 mg, 75.6 μmol) then the mixture was dissolved in DMF (3 mL) to give a light yellow solution. The reaction mixture stirred at 25° C. overnight. Solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 30 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 66.4 μmol, 87.8%) as a white solid. MS (M+H)+=603; 1H NMR (CDCl3) δ: 9.19 (s, 1H), 8.45 (s, 1H), 8.36 (s, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.45-7.51 (m, 1H), 7.33 (dd, J=9.1, 2.3 Hz, 1H), 6.55 (t, J=76.0 Hz, 1H), 5.74 (s, 2H), 4.22 (s, 3H), 3.95 (s, 2H), 3.68-3.78 (m, 4H), 3.55-3.66 (m, 2H), 2.11-2.28 (m, 2H), 1.89-2.07 (m, 2H), 0.88-1.04 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=O)[O:23]CC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([NH:37][C:22]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][CH2:11][CH:10]([C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=4)[C:14]=3[C:15]=2[CH3:30])=[O:23])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NC1CCCCC1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1c(C)c2c(c(C)c1NC(=O)NC1CCCCC1)C(c1ccc(C(C)C)cc1)CO2
Yield: 92 %

Procedure:
Using 2,2,2,-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and cyclohexylamine, the title compound was obtained in the same manner as in Example 143.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:23]I>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:20][CH3:23])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
1-t-Butoxycarbonyl-4-hydroxy-4-phenylpiperidine (300 mg, 1.1 mmol) was dissolved in tetrahydrofuran (9 ml). Thereto was added sodium hydride (43 mg, 1.1 mmol), and the resulting solution was stirred at a room temperature for 1 hour. The reaction solution was mixed with methyl iodide (0.1 ml, 1.6 mmol) and again stirred for 17 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with water and saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 240 mg of the title compound (0.82 mmol, 76% in yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40](=O)[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl-].[OH:46][NH3+:47].C(=O)([O-])O.[Na+]>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40](=[N:47][OH:46])[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:24][CH2:25]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCC(=NO)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 97.6 %

Procedure:
To 2 mL of a methanol solution containing 84 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxo-5-propionylquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 40 mg of hydroxylammonium chloride was added, and stirred at room temperature for 9.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=20:1], to give 84 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(1-(hydroxyimino)propyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=1)=[O:7].[CH2:28]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:2][C:3]2[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=2)[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:36][CH:37]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc(CCl)c2)c2ccccc21
Reactant: CC(C)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(COc3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 50 °C
Yield: 84.8 %

Procedure:
A mixture of ethyl 4-[3-[3-(chloromethyl)benzoyl]indol-1-yl]butyrate (42.5 mg) and 4-isobutylphenol (18.3 mg) and potassium carbonate (30.6 mg) in N,N-dimethylformamide (3 ml) was heated at 100° C. for 1 hour and 50° C. for 10 hours. The mixture was worked up in an usual manner and purified by thin layer silica gel chromatography eluting with a mixture of ethyl acetate and hexane (1:2) to give ethyl 4-[3-[3-(4-isobutylphenoxymethyl)benzoyl]indol-1-yl]butyrate (46.7 mg) as an oil.