Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:14][CH:15]=O)[C:4](=[O:17])[CH:3]=1.[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]([CH:37]3[CH2:42][CH2:41][N:40]([CH2:15][CH2:14][N:5]4[C:6]5[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=5)[C:2]([CH3:1])=[CH:3][C:4]4=[O:17])[CH2:39][CH2:38]3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: COc1ccc2c(c1)c(C)cc(=O)n2CC=O
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)c(C)cc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To 25 mL of a chloroform solution containing 71 mg of (4-methyl-6-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde and 108 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 18 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 121 mg of sodium triacetoxyborohydride was added, and stirred for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, 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 60, eluent; chloroform:methanol=20:1], to give 140 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methyl-6-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](OS(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2].[N-:70]=[N+:71]=[N-:72].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:70]=[N+:71]=[N-:72])[CH:46]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 70 °C
Yield: 45.2 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(o-nitrophenylsulfonyloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (66 mg) in N,N-dimethyl formamide (1 ml) was added an excess of sodium azide (22 mg) and the mixture heated to 70° C. After 2.5 hours the reaction was cooled to room temperature, diluted with ethyl acetate, extracted from half-saturated ammonium chloride, and washed with brine. The combined organics were dried over sodium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (25 mg).
Reaction SMILES: [C:1]([C:3]([C:15]#[N:16])=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)#[N:2].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[NH2:22]>>[F:17][C:18]([F:30])([F:31])[C:19]1[CH:20]=[C:21]([NH:22][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([CH:4]=[C:3]([C:1]#[N:2])[C:15]#[N:16])[CH:6]=[CH:7][C:8]=2[OH:14])[CH:23]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:25]=1
Reactant: N#CC(C#N)=Cc1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: N#CC(C#N)=Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 9.1 %

Procedure:
Using 5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH3:11][SiH:12]([CH3:14])Cl.Cl>BrCCBr.O1CCCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([SiH:12]([CH3:14])[CH3:11])=[CH:6][CH:5]=1
Reactant: COc1ccc(Br)cc1
Reactant: C[SiH](C)Cl
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc([SiH](C)C)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
In a flask under a nitrogen atmosphere were placed 2.54 g (0.104 mole) of magnesium metal and approximately 25 mL of dry tetrahydrofuran. To this mixture was added a few drops of 1,2-dibromoethane. This was followed by the slow addition of a solution of 19.54 g (0.104 mole) of 4-methoxybromobenzene in 30 mL of tetrahydrofuran. After completion of addition, this reaction mixture was heated at reflux for one hour and was then cooled to room temperature. Slowly 9.89 g (0.105 mole) of dimethylchlorosilane was added to the reaction mixture which was then heated at reflux for one hour. To this was added 50 mL of 1 N hydrochloric acid, and the organic and aqueous phases were separated. The aqueous phase was extracted three times with 50 mL of diethyl ether, and these washes were combined with the organic phase. The combined extracts were then washed with 200 mL of a saturated, aqueous solution of sodium chloride and were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, leaving a residue. Distillation of this residue yielded 14.4 g of (4-methoxyphenyl)dimethylsilane as a clear, yellow liquid, b.p. 80-90° C. at 9 mm of Hg. The proton nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[O:39]1[CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41][CH2:40]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[O:39]1[CH2:40][CH:41]=[C:42]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:26][CH2:27]4)[CH:20]=[N:19][CH:18]=2)[CH2:43][CH2:44]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5=CCOCC5)cc34)n2)C1
Temperature: 150 °C
Yield: 80.2 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (260 mg, 0.445 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (140 mg, 0.667 mmol), potassium phosphate (283 mg, 1.334 mmol), and PdCl2(Amphos) (31.5 mg, 0.044 mmol) in dioxane (4044 μL) and water (404 μL) was heated in the microwave for 10 min at 150° C. The crude was purified via automated flash chromatography (silica gel) with 100% hexanes to 40% EtOAc/hexanes to give (4R)-tert-butyl 4-(6-(5-(3,6-dihydro-2H-pyran-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (210 mg, 0.357 mmol, 80% yield) as a colorless oil. MS (ESI, pos. ion) m/z: 588.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[C:7]([C:11]([OH:13])=O)=[CH:8][S:9][CH:10]=1.[Cl-].[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH3+:30])[CH3:29])=[CH:24][CH:23]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[C:7]([C:11]([NH:30][C@H:28]([C:25]2[CH:26]=[CH:27][C:22]([C:20]([O:19][CH3:18])=[O:21])=[CH:23][CH:24]=2)[CH3:29])=[O:13])=[CH:8][S:9][CH:10]=1
Reactant: O=C(O)c1cscc1Cc1cccc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)[NH3+])cc1
Agent: [Cl-]
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cscc2Cc2cccc(Cl)c2)cc1

Procedure:
4-(3-Chlorobenzyl)thiophene-3-carboxylic acid from Example 3, Step 3 (380 mg, 1.50 mmol) was reacted with (1S)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride from Example 1, Step 9 under conditions similar to Example 1, Step 10. After chromatography on silica gel (EtOAc/hexane 40:60 to 95:5), the desired product was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C:6]1([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])[CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+].[CH3:23]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([C:6]2([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[OH:11])[CH2:9][CH2:8][CH2:7]2)[CH3:23])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1ccccn1)C1(Cc2cccc(Cl)c2)CCC1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(c1cccc(Cl)c1)C1(C(O)c2ccccn2)CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
To a solution of Example 44C (0.5 g, 1.67 mmol) in 20 mL of methanol was added NaBH4 (0.076 g, 2 mmol) in small portions at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was concentrated and the residue was purified by prep TLC (petroleum ether: ethyl acetate=7:1) to afford the title compound (0.35 g, total yield 23.6%). 1H NMR (400 MHz, CDCl3): δ=8.58 (d, J=2.0 Hz, 1H), 7.65-7.62 (m, 1H), 7.27-7.12 (m, 6H), 4.78 (s, 1H), 4.16 (brs, 1H), 3.12-3.00 (m, 1H), 2.17-1.80 (m, 4H), 1.36 (d, J=6.0 Hz, 3H), 1.26-1.17 (m, 1H), 0.95-0.80 (m, 1H). LC-MS: m/z 302 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=O)[CH3:2]>Cl>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)N1CCC(CCCC(=O)c2ccc(F)cc2)CC1
Agent: Cl
Product: O=C(CCCC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 161.6 %

Procedure:
A solution of 1-acetyl-4-[3-(4-fluorobenzoyl)propyl]piperidine (1.7 g) in concentrated hydrochloric acid (15 ml) was refluxed for 16 hours and the hydrochloric acid was then distilled off under reduced pressure. The residue was dissolved in water and the solution was made weakly basic (pH ca.8) with 5% aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was washed with water and dried over anhydrous sodium sulfate and the solvent was distilled off to recover 1.3 g of residue. To a solution of this residue (1.3 g) in ethanol (10 ml) was added 0.94 g of potassium carbonate and 0.9 g of benzyl bromide was added dropwise with ice-cooling. The mixture was stirred at room temperature for 2 hours and then filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with dichloromethane and the extract was washed with water and dried over anhydrous sodium sulfate. Finally the solvent was distilled off to give 1.6 g of 1-benzyl-4-[3-(4-fluorobenzoyl)propyl]piperidine melting at 53°-55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14]O)=[CH:4][CH:3]=1.[Li+].[Br-].P(Br)(Br)[Br:19].O>CN(C=O)C>[Br:19][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1-c1ccc(Cl)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccccc2CBr)cc1
Reaction time: 1 h

Procedure:
To a mixture of Example 37A (7.9 g) and LiBr (3.45 g) in DMF (100 mL) at 0° C. was added PBr3 (3.77 mL) and the reaction was stirred for 1 hour. The reaction was poured into water (400 mL), and the mixture was extracted with ether (3×200 mL). The combined ether layers were washed with 3× water, and brine, dried over Na2SO4, and condensed to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH:14]2[O:16][CH2:15]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(F)ccc1OCC1CO1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture consisting of 31.4 g of 4-fluoro-2-nitrophenol, 100 ml of epichlorohydrin, 9.1 g of sodium hydroxide, 40 ml of water and 900 ml of ethanol was stirred at 80° C. for 10 hours. After cooling the reaction solution to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated to dryness under a reduced pressure. The resulting residue was dissolved in an ether-hexane (1:1) mixed solvent, washed with water and saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The residue was applied to a silica gel column chromatography and developed with a chloroform-hexane (3:1) mixed solvent, and then the fractions containing the compound of interest were concentrated to obtain 27.9 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCCc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCc3cccnc3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL) and the solution was treated with 3-(2-aminoethyl)pyridine (0.012 mL, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(2-(pyridin-3-yl)ethyl)aminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:31])[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]3([CH2:15][CH2:14][CH2:13]3)[S:11](=[O:27])(=[O:26])[C@@H:10]2[CH2:28][CH2:29][OH:30])[C:5](F)=[N:6][CH:7]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[O:30][CH2:29][CH2:28][C@H:10]3[C@@:9]([CH3:31])([C:4]=2[CH:3]=1)[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]1([CH2:15][CH2:14][CH2:13]1)[S:11]3(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)[C@@H](CCO)S(=O)(=O)C12CCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(Br)cnc3OCC[C@@H]2S(=O)(=O)C12CCC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
A solution of tert-butyl ((6R,7R)-7-(5-bromo-2-fluoropyridin-3-yl)-6-(2-hydroxyethyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (1.04 g, 1.998 mmol) in THF/DMF (20/2 mL) was brought to 0° C. followed by the addition of sodium hydride, 60% dispersion in mineral oil (0.200 g, 5.00 mmol) in one portion. After one min stirring at 0° C. the ice bath was removed. The reaction became yellow. More sodium hydride, 60% dispersion in mineral oil (0.200 g, 5.00 mmol) was added at rt and stirred for 20 min more. The reaction went to completion (3:1 mixture of epimers). The mixture was brought to 0° C. and carefully quenched with saturated NH4Cl and water was added. The reaction mixture was extracted with EtOAc and the combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-30% EtOAc/hexanes to afford each isomer as a white solid tert-butyl ((4a′S,11b′R)-10′-bromo-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate (0.46 g, 0.919 mmol, 46.0% yield). LC/MS (ESI+) m/z=521.8 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=O)[CH2:6]2.[ClH:12].[NH2:13][OH:14]>CO>[ClH:12].[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=[N:13][OH:14])[CH2:6]2
Reactant: NO
Reactant: CN1C2CCCC1CC(=O)C2
Agent: Cl
Solvent: CO
Product: CN1C2CCCC1CC(=NO)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.5 %

Procedure:
A mixture of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (0.658 g, 4.29 mmol) and hydroxylamine hydrochloride (0.312 g, 4.49 mmol) in methanol (6 mL) was stirred for 20 h at room temperature, during which time a white precipitate formed. This solid was collected by filtration, rinsed with additional methanol (2×10 mL), and dried under vacuum for 1 h to afford 0.672 g (76% yield) of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) d 10.82 (s, 1H), 3.71-3.52 (m, 2H), 3.34-3.23 (m, 1H), 3.12 (d, J=17.5 Hz, 1H), 2.90-2.79 (m, 3H), 2.73-2.55 (m, 1H), 2.42 (d, J=16.8 Hz, 1H), 2.27-2.05 (m, 2H), 1.87-1.42 (m, 4H); MS (ESI) m/z 169 [M+H]+
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH:34][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)[CH:18]=1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Reactant: NCCc1ccccc1F
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCCc3ccccc3F)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(2-fluorophenyl)ethylamine gave the title compound as an oil.
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:25][CH:26]([CH2:40][CH3:41])[C@@H:27]([C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=1)[OH:28]>>[N:1]1([C:7](=[O:24])[CH2:8][C@@H:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([NH:25][C@H:26]([C:27]([C:29]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:30]=2)=[O:28])[CH2:40][CH3:41])=[O:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1nc(-c2ccccc2)no1

Procedure:
It is similarly prepared according to general procedure given for Example 2 above but using 4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyric acid and (S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: C([O-])(=O)C.[CH:5]1([C:8]2[N:9](C(OCC(C)C)=O)[C:10]3[C:11]([N:27]=2)=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]4[O:25][CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[CH:26]=2)[CH:15]=3)[CH2:7][CH2:6]1.Cl[C:36]1[C:45]2[CH2:44][C:43]([CH3:47])([CH3:46])[CH2:42][CH2:41][C:40]=2[N:39]=[C:38]([CH2:48][N:49]([CH3:51])[CH3:50])[N:37]=1>>[CH:5]1([C:8]2[NH:9][C:10]3[C:11]([N:27]=2)=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]4[O:25][CH2:24][CH2:23][N:22]([C:36]5[C:45]6[CH2:44][C:43]([CH3:46])([CH3:47])[CH2:42][CH2:41][C:40]=6[N:39]=[C:38]([CH2:48][N:49]([CH3:51])[CH3:50])[N:37]=5)[CH2:21][C:20]=4[CH:26]=2)[CH:15]=3)[CH2:7][CH2:6]1
Reactant: CN(C)Cc1nc(Cl)c2c(n1)CCC(C)(C)C2
Reactant: CC(C)COC(=O)n1c(C2CC2)nc2ncc(-c3ccc4c(c3)CNCCO4)cc21
Agent: CC(=O)[O-]
Product: CN(C)Cc1nc2c(c(N3CCOc4ccc(-c5cnc6nc(C7CC7)[nH]c6c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared as acetate according to the method of example 6 by using 2-methylpropyl 2-cyclopropyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate (reagent preparation 19) in step 1 and 1-(4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)-N,N-dimethylmethanamine (reagent preparation 17) in step 3. 1H NMR (400 MHz, d6-DMSO): 8.49 (s, 1H), 7.98 (s, 1H), 7.68 (d, 1H), 7.51 (dd, 1H), 7.01 (d, 1H), 4.63 (s, 2H), 4.30 (m, 2H), 3.85 (m, 2H), 2.68 (m, 2H), 2.44 (s, 2H), 2.14 (m, 1H), 2.10 (s, 6H), 1.88 (s, 2H), 1.59 (m, 2H), 1.10 (m, 4H), 0.85 (s, 6H). MS (EI) for C31H37N7O: 524 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[NH:11][C@@H:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH:10]([NH:11][C@@H:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C(N[C@H](C)C2CCCCC2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(N[C@H](C)C2CCCCC2)c2cccc(N)c2)cc1
Yield: 76.6 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[(R)-1-cyclohexylethyl]amine (2.60 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3.35 g) and sodium borohydride (1.12 g) were reacted, to afford the title compound (1.83 g) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=2)[C:12](=[O:28])[C:11]([CH3:30])([CH3:29])[CH2:10]1>N1C=CC=CC=1>[CH3:29][C:11]1([CH3:30])[C:12](=[O:28])[C:13]2[C:18](=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:9]([N:8]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH2:10]1
Reactant: O=C(Cl)CCCCl
Reactant: CC1(C)CN(N)c2cc(S(=O)(=O)c3ccccc3)ccc2C1=O
Solvent: c1ccncc1
Product: CC1(C)CN(N2CCCC2=O)c2cc(S(=O)(=O)c3ccccc3)ccc2C1=O
Temperature: 0 °C
Yield: 41 %

Procedure:
While stirring under chilling with ice water, 220 μl of chlorobutyryl chloride were added to a solution of 550 mg of 1-amino-2,3-dihydro-3,3-dimethyl-7-phenylsulfonyl-4(1H)-quinolinone in pyridine. After stirring overnight at room temperature, the liquid reaction mixture was extracted with chloroform with the system acidified with hydrochloric acid. After the extract was dried over magnesium sulfate, chloroform was distilled off. The residue was dissolved in dimethylformamide, and 91 mg of sodium hydride were added to the solution under chilling with ice water to stir the resultant mixture at room temperature for 30 minutes. After completion of the reaction, ice water was added to the liquid reaction mixture, which was then extracted with diethyl ether. After the extract was dried over magnesium sulfate, diethyl ether was distilled off, and the residue was purified by column chromatography on silica gel to obtain 249 mg (yield: 41%) of the title compound as yellow crystals.