Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:26][C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[N:3]=1)[O:10][CH2:9][C@H:8]([CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O)[O:7]3.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38]1>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C@H:37]1[CH2:41][CH2:40][C@H:39]([NH:42][CH2:14][C@H:8]2[CH2:9][O:10][C:11]3[CH:12]=[CH:13][C:4]4[N:3]=[C:2]([CH3:1])[O:26][C:5]=4[C:6]=3[O:7]2)[CH2:38]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: NC1CCC(c2c[nH]c3ccc(F)cc23)C1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)O[C@@H](CN[C@H]1CC[C@H](c2c[nH]c4ccc(F)cc24)C1)CO3
Temperature: 77.5 °C
Yield: 34.6 %

Procedure:
Toluene-4-sulfonic acid (8R)-2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclo-penta[a]naphthlen-8-ylmethyl ester (0.46 g, 1.2 mmole) and 3-(5-fluoro-1H-indol-3-yl)-cyclopentylamine (0.27 g, 1.2 mmole) were combined in 8 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen for 5 hours. After cooling to room temperature, the reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel (CH2Cl2 then 1% MeOH/CH2Cl2) afforded 0.175 g of the title compound as an off-white solid: m.p. 79-82° C.; MS (ESI) m/z 422 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:9](=[NH:10])[S:8][N:7]([C:11]([CH3:15])([CH3:14])[CH2:12][F:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(N(CC)CC)C>C1COCC1>[CH2:1]([C:5]1=[CH:6][N:7]([C:11]([CH3:14])([CH3:15])[CH2:12][F:13])[S:8]/[C:9]/1=[N:10]\[C:20](=[O:21])[C:19]1[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:18]=1[O:17][CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)CF)sc1=N
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1cn(C(C)(C)CF)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC
Temperature: 60 °C
Reaction time: 14 h
Yield: 8.7 %

Procedure:
To a solution of Example 152C (0.46 g, 2.0 mmol) in THF (10 mL) were added 2-methoxy-5-(trifluoromethyl)benzoyl chloride (0.52 g, 2.2 mmol, JRD Fluorochemicals Ltd) and triethylamine (0.84 mL, 6.0 mmol). After stirring at 60° C. for 14 hr, the reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in dichloromethane) to afford 75 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.22-1.46 (m, 2 H), 1.65 (s, 2 H), 1.65 (s, 6 H), 2.63-2.83 (m, 2 H), 3.89 (s, 3 H), 4.60 (d, J=47.1 Hz, 2 H), 7.31 (d, J=8.8 Hz, 1 H), 7.80 (dd, J=8.6, 2.5 Hz, 1 H), 8.10 (d, J=2.4 Hz, 1 H), 8.63 (s, 1 H); MS (ESI+) m/z 433 (M+H)+; Anal. Calculated C20H24F4N2O2S: C, 55.54; H, 5.59; N, 6.48. Found: C, 55.75; H, 5.23; N, 6.43.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[CH:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH:41]1([NH2:44])[CH2:43][CH2:42]1>>[CH:41]1([NH:44][C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:30])=[O:31])[CH:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)=[O:7])[CH2:43][CH2:42]1
Reactant: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: NC1CC1
Product: C[C@H]1COCCN1c1cc(-c2cc(F)ccc2S(C)(=O)=O)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1

Procedure:
Method as for example 58 using (S)-phenyl(4-(4-(5-fluoro-2-(methylsulfonyl)phenyl)-6-(3-methylmorpholino)pyrimidin-2-yl)phenyl)carbamate (intermediate 34) and cyclopropyl amine as starting materials. The solvent removed in vacuo and the crude material purified by prep HPLC at low pH to yield the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5]CCCCCCCCCC(O)=O.[C:20]1(=[O:33])[O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CC(CC)C[Mg]Br.C([Mg]Br)(CC)C>>[CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([OH:32])=[O:33]
Reactant: O=C1CCCCCCCCCCCO1
Reactant: CCC(C)CCCCCCCCCCCCC(=O)O
Agent: CCC(C)C[Mg]Br
Agent: CCC(C)[Mg]Br
Product: CCC(C)CCCCCCCCCCCCCCC(=O)O
Yield: 84 %

Procedure:
16-Methyloctadecanoic acid was synthesized by the same operation, except that in the step (a) of the synthesis process for 14-methylhexadecanoic acid described above, 12-dodecanolide was changed to 15-pentadodecanolide, and in the step (b), 2-methylbutylmagnesium bromide was changed to sec-butylmagnesium bromide. Thus, 16-methyloctadecanoic add was obtained from 15-pentadodecanolide at a total yield of 84%. The purity was 95%.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].O.[C:11]1(C)C=CC(S(O)(=O)=O)=C[CH:12]=1.C(OCC)(OCC)(OCC)C>C(OCCCCCCCC)(=O)C1C(=CC=CC=1)C(OCCCCCCCC)=O>[CH3:11][C:12]12[O:7][CH2:6][C:3]([CH2:8][OH:9])([CH2:4][O:5]1)[CH2:2][O:1]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(CO)(CO)CO
Agent: CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC
Agent: CCOC(C)(OCC)OCC
Solvent: O
Product: CC12OCC(CO)(CO1)CO2
Temperature: 120 °C
Reaction time: 22 h
Yield: 83 %

Procedure:
Pentaerythritol (60 g, 440.7 mmol) was added to a stirring solution of dioctyl phthalate (100 mL) containing trace p-toluene sulfonic acid monohydrate, and heated to 120° C. After triethyl orthoacetate (71.685 g, 81 mL, 441.87 mmol) was added in one portion the reaction was equipped with a distillation apparatus and stirred for 22 h. Upon return, 64 mL of ethanol had distilled (83% of the theoretical amount). TEA (40 drops) was added, stirred for 10 minutes, heated to 160° C. The TEA and remaining ethanol were removed under vacuum. After changing the distillation glassware, the final product, a white solid, was isolated by vacuum distillation at 185° C. and recrystallized using benzene. Yield: 83%, 58.64 g. 1H NMR (CDCl3; 500 MHz) δ ppm: 1.453 (s, 3H, CH3), 1.58 (t, 1H, OH), 3.454 (d, 2H, CCH2OH), and 4.015 (s, 6H, OCH2C). 13C NMR (CDCl3; 125.8 MHz) δ ppm: 23.53 (CH3), 35.71 (CH2CCH2), 61.50 (CCH2OH), 69.41 (OCH2C), and 108.67 (OCCH3). ESI-MS (m/z): 161.06 (161.07 calc'd for C7H12O4 [M+H]+). Elemental analysis calc'd (found) for C7H12O4: C, 52.49 (51.58); H, 7.55 (7.67).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N+:34]([O-])=O)[CH2:24][CH:23]2[OH:37])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].[H][H]>CO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH2:34])[CH2:24][CH:23]2[OH:37])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccccc3[N+](=O)[O-])CC2O)CCCCC1)c1cc2ccccc2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Yield: 98.7 %

Procedure:
4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-nitrophenyl)piperidin-3-ol (7.0 g) obtained in Step 1 was dissolved in 30 ml of methanol. The solution was stirred with 10%-palladium catalyst overnight under 30 psi hydrogen atmosphere, and then filtered and concentrated to give 6.5 g of titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH2:38](I)[CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:38][CH3:39])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: CCI
Product: CCOc1cc2c(cc1OC)CCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with ethyl iodide
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc([C@H](C)c2nccn2C(=O)OCC(C)C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the compound of Example 58 (1.00 g, 5.0 mmol) and triethylamine (0.77 ml, 5.5 mmol) in anhydrous dichloromethane (10 ml) was added dropwise isobutyl chloroformate (2.60 ml, 20 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate (10 ml) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (10 ml) and the combined organic layers were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][N:6]=1.O>C(#N)C>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][NH:3][CH:1]=[CH2:2])=[CH:9][CH:10]=1
Reactant: CCN
Reactant: ClCc1ccc(Cl)nc1
Solvent: O
Solvent: CC#N
Product: C=CNCc1ccc(Cl)nc1

Procedure:
To a solution of aqueous ethylamine, an appropriate amount of acetonitrile is, added. Then 2-chloro-5-(chloromethyl)pyridine in acetonitrile is added dropwise in ice bath. The reaction is monitored by TLC. After completion, the mixture is added large amount of water, extracted by DCM, dried, filtered and evaporated to obtain N-((6-chloropyridin-3-yl)methyl)ethenamine as oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:8]([NH:9][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCc1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
To a stirred solution of 2-phenylethylamine (2 g, 16.5 mmol) in 105 ml DMF at room temperature was added Et3N (2.75 ml, 19.8 mmol). This mixture was stirred for 5 min, and then benzenesulfonyl chloride (2.3 ml, 18.1 mmol) was added at this temperature. The reaction was stirred for 2.5 h, and then, the mixture was evaporated to dryness and the crude was chromatographically purified over SiO2 using Hexane/AcOEt 60/40 as the eluant, yielding 3.12 g (72%) of the desired product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].C(O)(=O)C.[CH:31]1([CH:34]=O)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:31]1([CH2:34][NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:33][CH2:32]1
Reactant: O=CC1CC1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1NCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 378.6 %

Procedure:
cis-N-(2-Amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) (200 mg, 0.05 mmol) was dissolved in 10 mL methanol. Acetic acid (0.156 mg, 2.6 mmol) and cyclopropanecarboxaldehyde (73 mg, 1 mmol) were added and the reaction mixture was stirred 1 h at room temperature. Sodium triacetoxyborohydride (221 mg, 1 mmol) was added at stirring was continued at room temperature overnight. The mixture was extracted with 2N sodium carbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Crystallization with diisopropylether and a small amount of dichloromethane yielded cis-N-[2-(cyclopropylmethyl-amino)-cyclohexyl]-2-methoxy-4,6-bis-trifluoromethyl-benzamide as a white solid (83 mg, 36%), MS: m/e=439.3 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11]I.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[C:9]#[N:10]
Reactant: CI
Reactant: N#CCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.9 g (96.41 mmol) of (2-bromophenyl)-acetonitrile and 31.41 g (221.74 mmol) of methyl iodide are dissolved in 150 ml of N,N-dimethylformamide. At 0° C., 8.87 g (221.74 mmol) of sodium hydride (as 60% suspension in oil) is added in portions, and the batch is stirred overnight at room temperature. The reaction mixture is poured into ice water and worked up as usual. Since the compound that is isolated after chromatography (20.9 g) still contains 2-(2-bromophenyl)-propionitrile in addition to the desired product, the entire amount is reacted another time with the same amounts of reagent. This reaction also yields only material that still contains mono-methyl compound. After another alkylation with 15 g of methyl iodide and 4.45 g of sodium hydride in 150 ml of N,N-dimethylformamide, 18.57 g of the desired compound is isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][CH:9]=2)[CH:3]=1.[ClH:18].C(=O)([O-])O.[Na+].O1CCO[CH2:26][CH2:25]1>CN(C)C=O.ICC>[ClH:18].[ClH:18].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[NH:17])[S:16][CH2:25][CH3:26])=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Cc1ccnc(-c2ccc(NC(N)=S)cc2)c1
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCSC(=N)Nc1ccc(-c2cc(C)ccn2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a suspension of N-(4-(4-methylpyridin-2-yl)phenyl)thiourea (186 mg) in N,N-dimethylformamide(4 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.383 ml) and iodoethane (0.306 ml), and the mixture was stirred at 50° C. for 2.5 hours. After cooling, the mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml). The precipitate was collected by filtration and recrystallized from ethanol-ethyl acetate to give N-(4-(4-methylpyridin-2-yl)phenyl)-S-ethylisothiourea dihydrochloride (162 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.C(O)(=O)C.[Br:16]Br>O>[Br:16][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: CCC(=O)c1ccc(Br)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
Dissolving 5.0 g (23 mmol) of 4′-bromopropiophenon into 50 milliliter of acetic acid, and adding 3.7 g (23 mmol) of bromine while cooling with ice, stirred at the temperature of 10° C. for 3 hours. After the color of bromine disappeared, adding water and an extraction was carried out using dichloro-methane. Washing the organic layer with water, it was dried with the use of sodium sulfate. The solvent was removed by distillation and the resultant crystals were washed with hexane thereby obtaining 4.3 g of 2,4′-dibromopropiophenon (yield: 63%).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12]CC)=O.Cl[CH2:20][C:21]([NH2:23])=[O:22]>C(O)C>[O:12]=[C:10]1[CH:9]([C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH2:20][C:21](=[O:22])[NH:23]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: NC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CC(=O)NC1=O
Reaction time: 20 h
Yield: 65.4 %

Procedure:
To a solution of 20% sodium ethoxide-ethanol solution (34.0 g) diluted with ethanol (40 ml) was added a solution of diethyl malonate (16.0 g) in ethanol (40 ml) dropwise over 30 minutes in ice-cooling. After stirring in ice-cooling for additional 30 minutes, thereto was added 2-chloroacetamide (4.7 g) in one portion and the mixture was stirred in ice-cooling for 30 minutes and then at room temperature for 20 hours. The white solid precipitated was collected by filtering and washed with a small amount of ethanol. This white solid was dissolved in water (300 ml) and this resulting aqueous solution was acidified with conc. hydrochloric acid and extracted with dichloromethane (50 ml) three times. The extract was dried over magnesium sulfate, filtered and concentrated to give a yellow oil. This was purified by a flash column chromatography (n-hexane:ethyl acetate=2:1→1:1) to give ethyl 2,5-dioxopyrrolidine-3-carboxylate (5.63 g, 66%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.[Br:18]N1C(=O)CCC1=O.O>O1CCCC1>[Br:18][C:10]1[NH:11][C:5]2[CH:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:3][N:2]([CH3:1])[CH2:8][CH2:7][C:6]=2[CH:9]=1
Reactant: CN1CCc2cc[nH]c2C(c2ccccc2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2cc(Br)[nH]c2C(c2ccccc2)C1
Reaction time: 0.67 h

Procedure:
A solution of 1,4,5,6,7,8-hexahydro-6-methyl-8-phenylpyrrolo[2,3-d]azepine (0.238 g) in tetrahydrofuran (30 ml) was cooled to -70° C. N-Bromosuccinimide (0.188 g) in tetrahydrofuran (3 ml) was added dropwise over 10 minutes, allowing the temperature to reach -10° C. over 40 minutes. Water was added and the product was extracted into ethyl acetate. The extracts were washed with water, dried and evaporated to give the title product as a solid, m.p. 132°-133° C. (acetonitrile).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([F:15])[CH:14]=1)[NH:11][C:10]1[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]2=1.[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN(C=O)C.O>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:11]1[C:10]2[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]=2[C:4]2[C:12]1=[C:13]([F:15])[CH:14]=[C:2]([F:1])[CH:3]=2
Reactant: O=C(O)CC1CCCc2c1[nH]c1c(F)cc(F)cc21
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CC1CCCc2c1n(Cc1ccccc1Cl)c1c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
A solution of 200 mg of 6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid from Example 34 step II in 8 cc of DMF was added portionwise 40 mg of sodium hydride. The resulting mixture was stirred for 30 minutes at room temperature and 185 mg of o-chloro-benzyl bromide was then added. After stirring overnight at room temperature, the resulting mixture was diluted with water and washed with ether. The aqueous layer was acidified with (1N) HCl and extracted with ether. The ethereal layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified on preparative plates (silica gel) eluting with CHCl3 :MeOH:NH4OH (8:4:1) to yield 98 mg of pure title product. m.p. 197°-198° C.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=O)C1C=CC=CC=1.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:47]([O:46][C:44]([N:41]1[CH2:42][CH2:43][CH:38]([N:37]2[CH2:17][CH2:16][C@@H:15]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:22][C:21]=3[Cl:35])[C:14]2=[O:36])[CH2:39][CH2:40]1)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Yield: 58 %

Procedure:
Treat a solution of (R)-4-((R)-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (Preparation 10) (4.0 g, 7.6 mmol) and 4-Amino-1N-Boc-piperidine (1.5 g, 7.6 mmol) in CH2Cl2 (100 mL) with acetic acid (0.4 mL, 7.6 mmol) and stir the reaction 1 hr at room temperature. Treat the reaction with sodium triacetoxyborohydride (3.2 g, 15 mmol) and stir overnight at room temperature. Quench the reaction with water and separate the organic layer. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 2.35 g (58%) of desired product. MS (m/e): 555 (M+Na+).
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.[Si]([O:35][CH2:36][CH2:37][CH:38]=O)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:38][CH2:37][CH2:36][OH:35])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out starting from 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrobromide and 3-(tert-butyldimethylsilanyloxy)propionaldehyde. The protecting group is cleaved off as already described by means of a 1M TBAF/THF solution. The product was purified by means of reversed-phase chromatography. The fractions were extracted under basic conditions, dried, filtered and evaporated.
Reaction SMILES: O=[O+][O-].[C:4]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][CH:19]=C)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C[OH:22].C(Cl)Cl.[BH4-].[Na+]>CCOC(C)=O>[C:4]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][CH2:18][CH2:19][OH:22])[CH2:15][CH2:16]1)([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: CO
Reactant: C=CCOC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCCO)CC1
Reaction time: 0.08 h

Procedure:
Ozone was bubbled into a solution of 21-3 (1.5 g, 6.4 mmol) in 2:1 CH3OH/CH2Cl2 (102 mL) at -78° C. After 5 min no starting material remained so oxygen was bubbled through the solution for 15 min to remove excess ozone. NaBH4 (1.7 g, 45 mmol) was added and the cooling bath removed. After 1 h the reaction mixture was concentrated. The residue was diluted with H2O (30 mL) and then extracted with CHCl3 (300 mL). The organic phase was washed with brine (30 mL), dried (MgSO4), and concentrated. Flash chromatography (silica, EtOAc) gave 21-4 as a nearly colorless oil. Rf 0.42 (silica, EtOAc).