Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:32])([CH3:31])[CH2:12][C@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:14]([OH:22])[C:15]#[C:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.[Pt]>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:31])([CH3:32])[CH2:12][C@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:14]([OH:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#CC(O)[C@H](CC(C)(C)CCOCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(O)[C@H](CC(C)(C)CCOCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A solution of 5.85 g of ethyl 9-benzyloxy-5(S)-tert-butoxycarbonylamino-4(R,S)-hydroxy-7,7-dimethyl-non-2-inoate in 100 ml of tetrahydrofuran is hydrogenated in the presence of 1.2 g of platinum-on-charcoal (5% of Pt; a further 1.2 g of catalyst are added after 24 h) at room temperature under normal pressure for 33 h. Filtration of the reaction mixture over Hyflo® and concentration of the filtrate gives the crude title compound as a yellow oil: Rf (B)=0.32; FAB-MS: (M+H)+ =452.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.Br[CH:21]([CH2:25]Br)[C:22]([NH2:24])=[O:23].C(N(CC)CC)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:21]([C:22]([NH2:24])=[O:23])[CH2:25]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NCCNCc2ccccc2)c1
Reactant: NC(=O)C(Br)CBr
Solvent: CCN(CC)CC
Product: COc1cccc(N2CCN(Cc3ccccc3)C(C(N)=O)C2)c1

Procedure:
In a manner similar to Preparation 1, react N-(3-methoxyphenyl)-N'-(phenylmethyl)-1,2-ethanediamine (16 g, 63 mmol) with 2,3-dibromopropanamide (29 g, 126 mmol) and triethylamine (25 g, 0.25 mol) to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[Na].Cl.[C:7]([O:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)(=[O:9])[NH2:8]>CO>[ClH:1].[C:7]([O:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:3](=[NH:4])[CH2:2][Cl:1])[CH2:12]1)(=[O:9])[NH2:8]
Reactant: N#CCCl
Reactant: NC(=O)O[C@@H]1CCNC1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(CCl)N1CC[C@@H](OC(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.646 ml of chloroacetonitrile was added to a solution of 23 mg of metallic sodium in 8 ml of absolute methanol, the mixture was stirred for about 60 minutes at room temperature, 1.70 g of (3R)-3-carbamoyloxypyrrolidine hydrochloride were then added, and the mixture was stirred for a further 3 hours. After completion of the reaction, a small amount of insoluble material was filtered off and the solvent was stripped off from the filtrate. Ether was added to the residue, and the precipitated crystals were collected by filtration and washed with ether, giving 2.20 g of 2-[(3R)-3-carbamoyloxypyrrolidin-1-yl]-2-iminoethylchloride hydrochloride.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][C:24]([NH2:28])=[CH:25][C:26]=3[CH2:27][C@H:16]12)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][C:24]([NH:28][C:1](=[O:3])[CH3:2])=[CH:25][C:26]=3[CH2:27][C@H:16]12)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2c3ccc(N)cc3C[C@@H]21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (50 μL) is added to a solution of cis-7-amino-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridine-1-carboxylic acid tert-butyl ester (140 mg) and triethylamine (70 μL) in dichloromethane (3 mL) at room temperature. The solution is stirred for 1 h at room temperature and then aqueous NaHCO3 solution is added. The mixture is stirred vigorously for 20 min and then extracted with dichloromethane. The combined extract is concentrated and the residue is chromatographed (cyclohexane/ethyl acetate 7:3→1:9) to give the title compound. Yield: 100 mg (62% of theory); LC (method 1): tR=3.60 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[C:24]([CH3:30])([CH3:29])[CH2:23]1>C1COCC1>[OH:28][C@@H:25]1[CH2:26][CH2:27][C@H:22]([NH:21][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:23][C:24]1([CH3:30])[CH3:29]
Reactant: CC1(C)CC(N)CCC1O
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.0 equiv.) and DIEA (3.0 equiv) in THF (0.05 M) was added 4-amino-2,2-dimethylcyclohexanol (peak 1, obtained above) (1.2 equiv.). The mixture was stirred at 50° C. overnight. After reaction completion, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (82% yield) as a white solid. MS (ESI) m/z 293.1 [M+H]+. The single crystal X-ray diffraction studies were carried out on a Bruker Kappa APEX-II CCD diffractometer equipped with Mo Kα radiation (λ=0.71073 Å). Crystals of the subject compound were grown by vapor diffusion of pentane into an isopropanol solution. A 0.215×0.183×0.055 mm colorless plate was mounted on a cryoloop with paratone oil. Data were collected in a nitrogen gas stream at 90 (2) K using φ and ω scans. Crystal-to-detector distance was 60 mm and exposure time was 5 seconds per frame using a scan width of 0.5°. Data collection was 99.9% complete to 25.00° in θ. A total of 45590 reflections were collected covering the indices, −53<=h<=56, −14<=k<=13, −23<=l<=27. 21888 reflections were found to be symmetry independent, with a Rint of 0.0549. Indexing and unit cell refinement indicated a C-centered, monoclinic lattice. The space group was found to be C2. The data were integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by direct methods (SHELXS) produced a complete phasing model consistent with the proposed structure.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:12][C@H:10]1[CH2:9][C@H:8]([NH2:7])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Tert-butyl(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)carbamate (Intermediate 10) (720 mg, 2.262 mmol) was dissolved in dichloromethane (30 mL) and treated with trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 15 minutes then evaporated to dryness under reduced pressure and further dried under high vacuum. 2 N Hydrochloric acid (50 mL) and diethyl ether (100 mL) were added and the phases mixed and separated. The organic was discarded. The aqueous layer was saturated with sodium chloride and the pH adjusted to >10 using 5N sodium hydroxide. Ethyl acetate (200 mL) was added and the phases mixed and separated. The aqueous was extracted with ethyl acetate one more time (200 mL) and the combined organic layers dried with magnesium sulfate before evaporating to dryness under reduced pressure. The crude trans-N-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (459 mg, 2.10 mmol, 92.4% yield) was used without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:16][CH2:15][C:9]2([O:13][N:12]=[C:11]([CH3:14])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>CO.O>[CH3:14][C:11]1[CH2:10][C:9]2([CH2:15][CH2:16][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[O:13][N:12]=1
Reactant: CCOC(=O)C1CCC2(CC1)CC(C)=NO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=NOC2(CCC(C(=O)O)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-methyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid ethyl ester (570 mg, 2.5 mmol) in MeOH (15 ml) and lithium hydroxide monohydrate (284 mg, 3.8 mmol) in H2O (3 ml) was stirred overnight at RT.
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[Na+].[I-].Cl.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:2][C:3]#[C:4][CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]3)=[CH:9][CH:8]=2)[CH2:31][CH2:30]1
Reactant: O=C1CCc2ccc(OCC#CCCl)cc2N1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=C1CCc2ccc(OCC#CCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
A mixture of intermediate 50 (200 mg, 0.8 mmol) and NaI (240 mg, 1.6 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 41 (320 mg, 1.2 mmol) and anhydrous K2CO3 (442 mg, 3.2 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=50:1) to give 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-ynyloxy)-3,4-dihydroquinolin-2(1H)-one (compound 27) (280 mg, 79%). 1H NMR (300 MHz, CDCl3): δ 7.85 (s, 1H), 7.20-7.13 (m, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.97 (dd, J=3.0 Hz, 6.6 Hz, 1H), 4.73 (s, 2H), 3.42 (s, 2H), 3.10 (s, 4H), 2.93-2.88 (m, 2H), 2.75 (s, 4H), 2.64-2.59 (m, 2H), 2.06 (s, 1H), 1.70 (s, 2H), 1.29-1.24 (m, 1H). HPLC: 99%, RT 2.403 min. MS (ESI) m/z 444.1 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCNC(=O)CCCCO
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCNCCCCCO
Temperature: 25 °C
Yield: 85.2 %

Procedure:
Part B. To a solution of lithium aluminum hydride (6.7 g, 0.176 mol) in dry tetrahydrofuran (300 mL), a solution of N-heptyl-5-hydroxypentanamide (19.0 g, 0.088 mol) in dry tetrahydrofuran (100 mL) under a nitrogen atmosphere was added dropwise. The reaction mixture was heated to reflux for 18 hours, allowed to cool to room temperature and was poured slowly into a stirred mixture of 10% aqueous sodium sulfate (400 mL) and ice (200 mL). The resulting slurry was filtered through a bed of Celite® and the filtrate was extracted with ethyl acetate (2×500 mL). The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and concentrated to give a viscous yellow oil. The product was crystallized from hexane to give N-(5-hydroxypentyl)-N-heptylamine (15.2 g, 0.075 mol) as a white powder, mp 47°-48°. 1H NMR (CDCl3) δ3.63 (t,2H,J=8.4 Hz), 2.63 (quartet,4H,J=8.3 Hz), 2.39 (bs,2H), 1.66-1.24 (m,16H), 0.91 (t,3H,J=6.6 Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:4][CH2:3]1.[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](O)=[C:29]([F:34])[CH:28]=1)=[O:26]>>[F:34][C:29]1[CH:28]=[C:27]([C:25](=[O:26])[CH3:24])[CH:32]=[CH:31][C:30]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])[CH2:6][CH2:7]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Reactant: CC(=O)c1ccc(O)c(F)c1
Product: CC(=O)c1ccc(OC2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Yield: 21 %

Procedure:
Prepared in analogy to Example 4 from (4-hydroxy-piperidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 3(a)) and 3-fluoro-4-hydroxyacetophenone. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 21%). MS (m/e): 478.4 (M+H+, 100%).
Reaction SMILES: [N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:13]1([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]2[CH2:23][C:22](=O)[CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO>C(O)(=O)C>[N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH:22]3[CH2:23][N:20]([CH:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(C1CCNCC1)N1CCC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)N1CCC1
Temperature: 120 °C
Yield: 67.4 %

Procedure:
To a mixture of 4-(azetidin-1-ylcarbonyl)piperidine (0.34 g, 2.0 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.37 g, 1.6 mmol), methanol (5 mL) and acetic acid (0.1 mL) was added (polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.61 g). The reaction mixture was heated for 10 min at 120° C. using microwave single node heating and then filtered through a phase separator. The solvent was removed by evaporation and the product was purified by chromatography on silica gel (methanol-methylene chloride, 5:95). There was obtained 0.42 g (70%) of 4-(azetidin-1-ylcarbonyl)-1-[1-(diphenylmethyl)azetidin-3-yl]piperidine as a colorless foam. 1H NMR (500 MHz, CDCl3): 1.6-1.7 (m, 2H), 1.7-1.8 (m, 4H), 2.0-2.1 (m, 1H), 2.2 (qn, 2H), 2.7-2.8 (m, 2H), 2.8-3.0 (m, 3H), 3.4 (t, 2H), 4.0 (t, 2H), 4.1 (t, 2H), 4.4 (s, 1H), 7.1-7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 390 (M+1)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=O.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>>[CH3:14][C:15]1[N:19]2[CH2:2][CH2:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)[C:18]2=[CH:17][N:16]=1
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1ccc(C2=CCCn3c2cnc3C)cc1

Procedure:
Combine 50 g (0.25 mol) of 4-chloro-4'-methylbutyrophenone with 124 g (1.5 mol) of 2-methylimidazole and heat to 175° C. for 70 hr. Crystallize from ether to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][CH2:25][CH2:24][NH:23][C:22]=2[CH:27]=1)=[O:17]>ClCCl.N1C=CC=CC=1>[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][CH2:25][CH2:24][N:23]([S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:12][CH3:13])(=[O:10])=[O:9])[C:22]=2[CH:27]=1)=[O:17]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)NCCO2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-methoxy-benzenesulfonyl chloride (4.7 g, 19.7 mmol, 1.05 equiv.) in dichloromethane (60 mL) and pyridine (25 mL) was added a solution of 3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester (3.6 g, 18.8 mmol, 1 equiv.) in dichloro-methane (60 mL). The mixture was stirred at room temperature overnight then the solvent was removed. The residue was purified by flash chromatography to yield 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester as a pink solid, 7.12 g (95%), MS (ISP): m/e=398.0 (M+H+.); δH (300 MHz; CDCl3) 8.24 (1H, s), 8.07 (1H, s), 7.72 (1H, dd), 7.48 (1H, dd), 6.91 (1H, d), 6.89 (1H, d), 4.10 (2H, m), 3.91 (2H, m), 3.88 (3H, s), 3.63 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:17]([O:18][CH2:19][O:20][CH3:21])=[CH:16][CH:15]=[CH:14][C:13]=2[O:22][CH3:23])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:24][S:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:17]([O:18][CH2:19][O:20][CH3:21])=[CH:16][CH:15]=[CH:14][C:13]=2[O:22][CH3:23])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:27])=[O:26]
Reactant: COCOc1cccc(OC)c1-c1ccc(N)cc1C(=O)OC
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COCOc1cccc(OC)c1-c1ccc(NS(C)(=O)=O)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Example 32B (10 g, 34.8 mmol), in pyridine (50 mL) at room temperature was treated with methanesulfonyl chloride (2.7 mL, 34.8 mmol), stirred at room temperature for 16 hours, and concentrated. The concentrate was treated with ethyl acetate (100 mL), and the resulting solution was washed with 2N HCl, dried (Na2SO4), filtered, and concentrated. The concentrate was recrystallized from ethanol to provide the desired product. MS (ESI(−)Q1MS) m/z 394 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH2:23][CH2:24][CH2:25][CH3:26])[C:18]([O:20]CC)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>C(O)C>[C:12]([C:9]1[CH:8]=[C:7]([S:16][CH:17]([CH2:23][CH2:24][CH2:25][CH3:26])[C:18]([OH:20])=[O:19])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O

Procedure:
The ethyl 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoate product (75 grams; 0.195 mole) obtained in Example 2 was dispersed in 300 ml. of 95% ethanol and 500 ml. of 5N potassium hydroxide added thereto. The resulting reaction mixture was heated on a steam bath at the boiling point under gentle reflux for about 90 minutes with occasional stirring. Following the heating period, the reaction mixture was poured into 2000 ml. of 5% HCl with vigorous stirring. The white precipitate formed upon acidification was obtained by filtration and washed with water. Recrystallization (twice) of the precipitate from a methylene chloride-hexane mixture gave the desired 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid compound having a melting point of 140°-142° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([N:19]([CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)[CH3:20])=[O:18])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([NH:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([N:19]([CH3:20])[CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[O:18])=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1ccc(N)nc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(/C=C/C(=O)N(C)Cc2cn(C)c3ccccc23)cn1
Reaction time: 48 h
Yield: 44.5 %

Procedure:
Acetic anhydride (0.12 mL, 1.24 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (0.10 g, 0.31 mmole) and sodium bicarbonate (0.13 g, 1.55 mmole) in THF (20 mL) at RT, and the reaction was heated at reflux under nitrogen. After 48 hr, the reaction was concentrated in vacuo and the residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (ethyl acetate) gave the title compound (50 mg. 45%) as a white solid: MS (ES) m/e 363 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([CH3:14])=[C:12]([S:15](Cl)(=[O:17])=[O:16])[C:11]([CH3:19])=[N:10]1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:36][CH3:37])=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=2)[CH:26]=1>ClCCl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:36][CH3:37])=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C@H:33]([NH:35][S:15]([C:12]3[C:11]([CH3:19])=[N:10][N:9]([CH3:8])[C:13]=3[CH3:14])(=[O:17])=[O:16])[CH3:34])=[CH:29][CH:28]=2)[CH:26]=1
Reactant: COc1ccc(F)cc1-c1ccc([C@@H](C)N)cc1
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2c(C)nn(C)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
Palladium acetate (56 mg, 0.25 mmol) was added to a mixture of 5-fluoro-2-methoxyphenylboronic acid (850 mg, 5.0 mmol) and (R)-1-(4-bromophenyl)ethylamine (500 mg, 2.5 mmol) in water (20 ml). This mixture was heated for 5 min at 200° C. in a Smithcreator microwave oven and then diluted with methanol (200 ml). The mixture was purified on a SCX column (20 g) using 2M ammonia in methanol to elute the intermediate amine. Evaporation of solvents under reduced pressure gave (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine as a gum (580 mg, 2.37 mmol, 96.6%). Triethylamine (41.1 μl, 0.295 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (20.5 mg, 0.0984 mmol) were added to a solution of (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20 mg, 0.082 mmol) in dichloromethane (1 ml) and the resulting solution shaken at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution (500 μl), the dichloromethane layer separated, dried over magnesium sulfate and the solvent evaporated. Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (13.8 mg, 0.033 mmol, 40%): 1H NMR (400 MHz, CDCl3): δ7.37, 7.14 (a/b, 4H), 7.02-6.87 (m, 3H), 4.68 (m, 1H), 4.48 (t, 1H), 3.78 (s, 3H), 3.55 (s, 3H), 2.35 (s, 3H), 2.22 (s, 3H), 1.50 (d, 3H) ppm; MS (ESI) m/z: 417 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:13]([NH:16][NH2:17])(=O)[CH3:14]>C(O)CCC.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:13]([CH3:14])=[N:16][N:17]=[C:7]1[CH2:6][CH2:5]2
Reactant: CC(=O)NN
Reactant: S=C1CCc2cc(Br)ccc2N1
Solvent: CCCCO
Solvent: O
Product: Cc1nnc2n1-c1ccc(Br)cc1CC2
Temperature: 140 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 6-bromo-3,4-dihydroquinoline-2(1H)-thione (74-4; 1.0 g, 0.004 mol) in n-butanol (20 mL) was added acetic hydrazide (1.19 g, 0.016 mol) at room temperature. Reaction mass was allowed to stir at 140° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the crude compound. Crude compound was purified by silica gel column chromatography to obtain title compound. MS (M+2): 266.0.
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:6])[CH2:4][CH3:5].FC(F)(F)S(O[C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH:25]3[CH2:30][CH2:29][Si:28]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(C4C=CC=CC=4)[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)(=O)=O>>[CH2:37]([Si@H:28]1[CH2:27][CH2:26][C@H:25]([C@H:22]2[CH2:21][CH2:20][C@H:19]([C:16]3[CH:15]=[CH:14][C:13]([CH2:2][C@@H:3]([CH3:6])[CH2:4][CH3:5])=[CH:18][CH:17]=3)[CH2:24][CH2:23]2)[CH2:30][CH2:29]1)[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CC2)CC1
Reactant: CC[C@H](C)CBr
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C[C@@H](C)CC)cc3)CC2)CC1

Procedure:
The general procedure of Example 18 was repeated using (S)-1-bromo-2-methylbutane and (4-(trans-4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)cyclohexyl)phenyl) trifluoromethanesulfonate, thereby obtaining the intended compound.