Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])=[CH:7][C:6]=1[F:18])(=O)C.Cl.C(=O)([O-])O.[Na+]>>[F:18][C:6]1[CH:7]=[C:8]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:9]=[CH:10][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1ccc(OC(F)(F)C(F)F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(OC(F)(F)C(F)F)cc1F
Yield: 81 %

Procedure:
0.60 Gram of 4-acetylamino-3-fluoro-1-(1,1,2,2-tetrafluoroethoxy)benzene and 10 ml of a 20% aqueous hydrochloric acid were added to a reactor and stirred under reflux for 2 hours. After cooling the reaction solution, a 5% aqueous sodium hydrogencarbonate solution was added to make the solution weakly alkaline. The reaction solution was then extracted with two 100-ml portions of diethyl ether. The ether layers were combined, dried and concentrated to obtain a yellow oily product as a residue. This oily product was subjected to chromatography on silica gel to obtain 0.40 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)aniline.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][C:12]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:13]=2)=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: CC(C)(C)Nc1nc(Cl)ccc1C#N
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 80 °C
Yield: 84.6 %

Procedure:
To a solution of 2-tert-butylamino-6-chloro-nicotinonitrile (4, 630 mg, 3 mmol) in DMF (100 mL) were added 2-bromo-5-hydroxy-benzaldehyde (603 mg, 3 mmol) and K2CO3 (828 mg, 6 mmol). The reaction was heated at 80° C. for 24 h. After cooling to r.t., DMF was removed in vacuo. Purification was accomplished by Biotage silica gel chromatography with a 2.5%-10% EtOAc/hexanes gradient to afford 950 mg (85% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C@H:8]([C:18](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:19])[C@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[OH:33]O.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C@H:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:10][CH3:11])[C:18]([OH:19])=[O:33])=[O:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: -10 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of [(1S,2S)-1-((S)-2-oxo-4-phenyl-oxazolidine-3-carbonyl)-2-phenyl-butyl]-carbamic acid tert-butyl ester (4.38 g, 10 mmol) in a mixture of tetrahydrofuran and water (3:1, 60 mL) at −10° C. was added sequentially a solution of hydrogen peroxide in water (11 mL, 100 mmol, 30%) and an aqueous solution (15 mL) of lithium hydroxide monohydrate (1.23 g, 30 mmol). The reaction mixture was stirred at −10° C. and the progress of the reaction was monitored by thin layer chromatography. After 3 hours, TLC analysis indicated almost complete consumption of starting material. Saturated aqueous sodium sulfite solution (100 mL) was added. The mixture was concentrated to half of its original volume under reduced pressure to remove tetrahydrofuran and then extracted with dichloromethane (2×100 mL). The aqueous layer was separated, acidified to pH=2-3 with aqueous citric acid solution and extracted with ethyl acetate (2×300 mL). The organic layers were separated, combined and dried over sodium sulfate, concentrated under reduced pressure and dried in vacuo to give (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-pentanoic acid as a white foam (1.7 g, 58%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=O)[CH2:17][CH2:16]2)[CH2:10][CH2:11][CH3:12]>C(O)C.O>[CH2:9]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[N:2][OH:3])[CH2:17][CH2:16]2)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1ccc2c(c1)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCc1ccc2c(c1)CCC2=NO

Procedure:
Hydroxylamine hydrochloride (0.89 g, 12.8 mmol) and sodium acetate (12.8 mmol) are added to a solution of 5-n-butylindan-1-one (1.0 g, 5.31 mmol) in ethanol (30 ml) and water (3 ml). The reaction is heated to reflux for 20 minutes, then water is added and the mixture is extracted with CH2Cl2. The combined organic extracts are washed with brine, dried (MgSO4) and evaporated to afford the title compound. NMR δH 0.86 (t J 7.3 3H), 1.28 (sextet J 7.3 2H), 1.52 (quintet J 7.3 2H), 2.55 (t J 8.0 2H), 2.85-3.0 (m 4H), 7.0 (d J 8.3 1H), 7.05 (s 1H), 7.45 (d J 8.3 2H)
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:14]([C:32](=[O:34])[NH2:33])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][N:45]([C:48](=[O:50])[CH3:49])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1>O1CCOCC1>[C:48]([N:45]1[CH2:44][CH2:43][N:42]([C:39]2[CH:40]=[CH:41][C:36]([NH:35][C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:23][CH2:24]4)[C:14]([C:32](=[O:34])[NH2:33])=[CH:13][N:12]=3)=[CH:37][CH:38]=2)[CH2:47][CH2:46]1)(=[O:50])[CH3:49]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc(On3nnc4ccccc43)ncc2C(N)=O)CC1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCN(C(=O)OC(C)(C)C)CC4)n3)cc2)CC1
Reaction time: 3 h
Yield: 43.4 %

Procedure:
A mixture of tert-butyl 4-((2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (0.205 g, 0.438 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (0.192 g, 0.877 mmol) and pTsOH monohydrate (0.166 g, 0.874 mmol) in dioxane (4 mL) was stirred at 100 C for 3 h. The mixture was then purified by HPLC to give tert-butyl 4-((2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (0.105 g).
Reaction SMILES: C[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[C:4]([O:10][CH3:11])=[N:5][CH:6]=[C:7]([CH:2]=1)[C:8]#[N:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncc(C#N)c(C)c1C
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ncc(C#N)cc1CBr
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-cyano-2-methoxy-3-methyl-pyridine (36) (0.25 g, 1.7 mmol) in CCl4 (10 mL) was added N-bromosuccinimide (346 mg, 1.7 mmol) and 2′,2-azobisisobutyronitrile (13.0 mg, 0.085 mmol). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and the filtrate was concentrated to afford 5-(bromomethyl)-6-methoxy nicotinonitrile (37) as a yellow solid; (180 mg, 46.9%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[CH2:23][CH:24]=[CH2:25].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH:14][CH2:25][CH:24]=[CH2:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C=CCNC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine, methyl ester (15.9g, 63mmol) in methylene chloride/cyclohexane (1:1, 600mL). Add allyl trichloroacetimidate (26g, 128mmol) and trifluoromethanesulfonic acid (5mL), 56.6mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give Nα -(benzyloxycarbonyl)-β-(allylamino)-L-alanine, methyl ester.
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH2:15][CH2:16]1)=[CH:11][CH2:10]3)[OH:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[C:38]([O:22][C@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C:3]2=[N:1][OH:2])[CH2:13]1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)c1ccccc1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)c3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Yield: 49.1 %

Procedure:
17-Oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) and dicyclohexylcarbodiimide (DCC) (0.34 g, 1.6 mmol) was dissolved in anhydrous dichloromethane (30.0 ml) and stirred. To this was added benzoic acid (0.2 g, 1.6 mmol). The reaction mixture was stirred for 48 hr at room temperature (20-25°) and completion of the reaction was monitored by TLC. The precipitated material was filtered, solvent removed under reduced pressure to give residue which was crystallized from ethyl acetate:petroleum ether (60:80) to get 17-oximino-5-androsten-3β-yl benzoate (13) (0.32 g, 64.0%) mp 165-170° C.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:11]1[C:2]([F:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(C)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1F
Yield: 56.6 %

Procedure:
To a solution of methyl 2-fluoro-3-methylbenzoate (13.8 g, 82.3 mmol) from Step A above and N-bromosuccinimide (16.0 g, 90.6 mmol) in carbon tetrachloride (82 mL) at room temperature was added a catalytic amount of benzoyl peroxide. The yellow mixture was heated under reflux until the reaction was complete by TLC (overnight) and then it was concentrated and purified by column chromatography (silica gel, 9:1 hexanes/ethyl acetate) to afford methyl 3-(bromomethyl)-2-fluorobenzoate as a light yellow oil (11.5 g, 56%): 1H NMR (500 MHz, CDCl3) δ 7.90 (t, J=8.0 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 4.53 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2](Cl)([F:10])[C:3]([F:9])([F:8])[C:4]([Cl:7])([F:6])[F:5].C(O)(C)C>>[Cl:7][C:4]([C:3]([CH:2]([F:10])[Cl:1])([F:9])[F:8])([F:6])[F:5]
Reactant: FC(F)(Cl)C(F)(F)C(F)(Cl)Cl
Solvent: CC(C)O
Product: FC(Cl)C(F)(F)C(F)(F)Cl
Temperature: 0 °C
Yield: 55.3 %

Procedure:
106.6 grams (0.45 mol) 1,1,3-trichloro-1,2,2,3,3-pentafluoropropane (produced in Part C above) and 300 gm (5 mol) isopropanol were stirred under an inert atmosphere and irradiated 4.5 hours with a 450 W Hanovia Hg lamp at a distance of 2-3 inches (5-7.6 cm). The acidic reaction mixture was then poured into 1.5 liters ice water. The organic layer was separated, washed twice with 50 ml water, dried with calcium sulfate, and distilled to give 50.5 gm ClCF2CF2CHClF, bp 54.5-56° C. (55%). 1H NMR (CDCl3): ddd centered at 6.43 ppm. J H-C-F=47 Hz, J H-C-C-Fa=12 Hz, J H-C-C-Fb=2 Hz.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:9](=[CH:19][N:20]([CH3:22])[CH3:21])[C:10]([O:12][CH3:13])=[O:11])=[O:14])=[CH:15][CH:16]=1
Reactant: COC(=O)CC(=O)NCc1ccc(Br)cc1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=CN(C)C)C(=O)NCc1ccc(Br)cc1

Procedure:
The product of Step A (5.01 g, 17.5 mmol) in THF (30 mL) was treated to dimethylformamide dimethylacetal (4.97 mL, 35.0 mmol, 94% assay) at 60° C. for about an hour. The reaction was concentrated and used directly in Step C.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:34][O:35][CH2:36]CC(NN)=O>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][CH2:34][O:35][CH3:36])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COCCC(=O)NN
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Product: COCCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), but using 3-methoxypropanehydrazide (compound 143.1) in place of acetohydrazide. m/z (ES+) 484 (M+H)+, 967 (2M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 11.50-11.33 (br s, 1H), 7.66-7.44 (m, 3H), 7.33-7.27 (m, 3H), 4.98 (d, 1H), 4.24-4.12 (m, 1H), 3.78 (t, 2H), 3.70 (d, 1H), 3.44 (s, 3H), 3.14-3.03 (m, 3H), 2.90-2.75 (m, 2H), 2.42 and 2.34 (2 singlets, amide rotamers, ArCH3, 3H), 2.17 (d, 2H), 2.08-1.88 (m, 3H), 1.84-1.51 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>C(Cl)Cl>[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]([C:27]([NH:1][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a solution of 1.5 g of methyl 6-amino-pyridine-3-carboxylate in 100 ml of methylene chloride is added 3 ml of N,N-diisopropylethylamine at room temperature. To the stirred reaction mixture is slowly added a solution of 2.5 g of [1,1'-biphenyl]-2-carbonyl chloride. The reaction mixture is stirred at room temperature for 4 hours and then quenched with water. The organic layer is washed well with water and dried over anhydrous MgSO4, filtered and evaporated in vacuo to a solid residue. The residue is stirred with ether, filtered and dried to give 3.0 g of the desired product:M+ =332.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[OH:9])=[O:2].[Br:15]N1C(=O)CCC1=O>>[Br:15][C:7]1[CH:6]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=[C:3]([CH:1]=[O:2])[C:8]=1[OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(O)c(C=O)c1
Product: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Yield: 80.1 %

Procedure:
Proceeding as in Reference 9, but substituting methyl 3-formyl-4-hydroxy-phenyl-acetate (50 g, 0.258 mol) and N-bromosuccinimide (45.92 g, 0.258 mole), gave methyl 3-bromo-5-formyl-4-hydroxyphenylacetate (56.4 g, 80%) as a yellow amorphous solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][CH:7]=[CH:8]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH:7]2[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2](=[O:1])[CH2:8]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)N1CCC=CC(=O)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1ccc(COC2CCN(C(=O)OC(C)(C)C)CC(=O)C2)cc1
Yield: 60.1 %

Procedure:
A solution of (Z)-tert-Butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (2 g, 9.48 mmol), (4-methoxyphenyl)methanol (6.55 g, 47.4 mmol) and DBU (0.14 mL, 0.95 mmol) in acetonitrile (10 mL) was heated at 60° C. for 23 hr. The solvents were removed under reduced pressure. Purification by silica gel column chromatography (0-40% EtOAc/isohexane) gave tert-butyl 5-(4-methoxybenzyloxy)-3-oxoazepane-1-carboxylate as a clear oil (1.99 g). To a solution of this oil (1.33 g, 3.8 mmol) in water/THF (20 mL/20 mL) was added NaBH4 and the mixture was stirred for 1.5 h. The THF was removed under reduced pressure and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layers were concentrated under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave tert-butyl 3-hydroxy-5-(4-methoxybenzyloxy)azepane-1-carboxylate (1.30 g) as a clear oil. This oil (1.15 g, 3.28 mmol) was dissolved in DCM (20 mL) and deoxo-Fluor® was added (50% in THF, 5.93 mL, 16.4 mmol). The mixture was stirred at room temperature for 18 hr, diluted with DCM (30 mL), cooled in an ice/water bath and quenched by dropwise addition of saturated aqueous NaHCO3 solution (50 mL). The resulting mixture was stirred for 10 min. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave tert-butyl 3-fluoro-5-(4-methoxybenzyloxy)azepane-1-carboxylate (746 mg, 39% over three steps) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.36-7.30 (m, 2H), 6.95 (d, J=8.2 Hz, 2H), 5.19-4.64 (m, 1H), 4.65-4.43 (m, 2H), 4.06-3.20 (m, 8H), 2.35-1.67 (m, 4H), 1.55-1.50 (m, 9H).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[NH:11])[NH2:10])[CH2:5][CH2:4]1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:12][C:13]1[S:16][N:10]=[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([OH:2])[CH2:4][CH2:5]2)[N:11]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)N1CCC(O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OC1CCN(c2nsc(Cl)n2)CC1
Temperature: 25 °C
Yield: 15.9 %

Procedure:
To a solution of 4-hydroxypiperidine-1-carboximidamide hydrochloride (1.80 g, 10.0 mmol) and perchloromethyl mercaptan (2.15 ml, 20.0 mmol) in dichloromethane (50 ml) was added dropwise a solution of sodium hydroxide (3.20 g, 80.0 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 350 mg (12.7%) of the desired product as a solid.
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[C:15]2[C:10]=1[C:11](=[O:34])[C:12]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:13][N:14]2[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1>CCO.CC(O)=O.[Pd]>[NH2:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[C:15]2[C:10]=1[C:11](=[O:34])[C:12]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:13][N:14]2[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cn(CCc2ccccc2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cn(CCc2ccccc2)c2cc(F)c(F)c(N)c2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To a suspension of ethyl 5-benzylamino-6,7-difluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylate (700 mg, 1.51 mmol) in a mixture of EtOH (2 mL) and AcOH (2 mL), was added 10% Pd—C (70.0 mg), the whole mixture was stirred at room temperature for 4 h under H2 atmosphere (1 atm). After insoluble materials were filtered off, the filtrate was concentrated in vacuo. To a solution of the residue in AcOH (2 mL), a suspension of 10% Pd—C (70 mg) in AcOH (2 mL) was added, the whole mixture was stirred at room temperature for 4 h under H2 atmosphere (1 atm). After insoluble materials were filtered off and washed with DMF, the combined filtrate and washing was concentrated in vacuo. Trituration of the residue with EtOH gave ethyl 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylate (499 mg, 89%) as pale brown powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11]N1C(=O)CCC1=O>>[Br:11][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccc(O)c(Br)c1

Procedure:
2-bromo-4-nitrophenol is prepared by reaction of 4-nitrophenol with N-brom-succinimide, according to the paper by T. Oberhouser in J. Org. Chem. 62, pp. 4504 and following (1997).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][C:19](Cl)=[O:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:19]([N:13]1[CH2:14][CH2:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)([C:16]#[N:17])[CH2:11][CH2:12]1)(=[O:20])[CH3:18]
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(C#N)(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A solution of 4-(4-nitro-phenyl)-piperidine-4-carbonitrile (as prepared in the previous step) in CH2Cl2 is treated with CH3COCl and DIEA. The mixture is washed with water, and the organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].[H-].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([C@@H:19]2[CH2:21][O:20]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([C@@H:19]([OH:20])[CH2:21][S:4][CH:2]([CH3:3])[CH3:1])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)S
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H]2CO2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)SC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
2-Propanethiol (98.0 μL, 1.1 mmol) was dissolved in THF (250 μL), and the mixture was cooled to 0° C. NaH (12.6 mg, 527 μmol) was slowly added in four portions and the mixture was stirred at room temperature for 10 minutes. (S)—(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (75 mg, 350 μmol) was dissolved in THF (0.1 mL) and added to the mixture. The resulting solution was placed in a microwave reactor for 30 minutes at 100° C., then cooled to room temperature. Hexanes (3×10 mL) was added, followed by water (10 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to yield the title compound as a clear oil (60 mg).