Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
To a cooled (-65° C.) solution of DMSO (1.42 ml; 20 mmol) in CH2Cl2 (30 ml) was added oxalyl chloride (0.87 ml; 10 mmol). The resulting suspension was stirred for an additional 15 minutes at -65° C., whereupon the product of Step A (2.17 g; 10 mmol) dissolved in 5 ml of CH2Cl2 was added portionwise and the reaction was stirred for an additional 15 minutes at that temperature. Triethylamine (5.56 ml; 40 mmol) was then added dropwise, and the solution was allowed to warm to room temperature, whereupon the reaction was stirred for an additional 1.5 hours. The reaction was quenched with H2O and extracted several times with EtOAc. The combined organic phase was washed with 10% aqueous citric acid, H2O, saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 25% EtOAc-hexanes. The fractions containing pure material were combined and concentrated in vacuo to afford 1.87 g of the title compound as a yellow oil.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.[CH3:16]I.O>CN(C)C=O>[CH3:16][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:13]([CH:14]=[O:15])[C:4]1=[O:3]
Reactant: CI
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C=O)cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Sodium hydride (55% w/w suspension in oil; 0.268 g) was added portionwise to a stirred suspension of 1,2-dihydro-2-oxoquinoline-3-carbaldehyde (1 g) in dimethylformamide (10 ml) which had been cooled in an ice bath. The mixture was allowed to warm to ambient temperature and was then heated to 60° C. for 1 hour. The mixture was recooled in an ice bath and methyl iodide (0.41 ml) was added. Dimethylformamide (50 ml) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water (50 ml) and extracted with methylene chloride (3×50 ml). The combined extracts were washed with water (50 ml) and evaporated. The residue was triturated under diethyl ether to give 1,2-dihydro-1-methyl-2-oxoquinoline-3-carbaldehyde as a pale yellow solid (0.81 g, 74%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:14]([OH:16])=O.[CH3:17][CH:18]([NH:20][C:21]1[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1)[CH3:19]>>[CH3:19][CH:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([C:14]([C:2]2[NH:3][C:4]3[CH:5]=[CH:6][C:7]4[C:8]([C:9]=3[CH:1]=2)=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:16])[CH2:31][CH2:32]1)[CH3:17]
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Reactant: O=C(O)c1cc2c(ccc3ccccc32)[nH]1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3c(ccc4ccccc43)[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with benz[e]indole-2-carboxylic acid (PREPARATION 116, 0.5 g) and 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (PREPARATION 8, 0.52 g), the title compound is obtained, m.p. 228°-231°.
Reaction SMILES: [CH:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21](=O)[CH:22]([CH3:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(C)C=O
Reactant: c1ccc(N2CCNCC2)c(C2CCCCCCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)CN1CCN(c2ccccc2C2CCCCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
To a solution of the 1-(2-cyclooctylphenyl)piperazine (7 mg, 0.0257 mmol) produced in Example (46d) in tetrahydrofuran (1 mL) were added isobutyraldehyde (2.4 mg, 0.0334 mmol), sodium triacetoxyborohydride (7.1 mg, 0.0334 mmol) and acetic acid (0.0028 mL, 0.0448 mmol), followed by stirring for 17 hours and 10 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The organic layers was concentrated to produce a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 4.3 mg of 1-(2-cyclooctylphenyl)-4-isobutylpiperazine as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 171 mg, 0.62 mmol) and (S)-tert-butyl 3-aminopiperidine-1-carboxylate (125 mg, 0.62 mmol) in DMF (4 mL) was added DIPEA (0.326 mL, 1.87 mmol). The mixture was heated at 80° C. for 18 h then cooled to rt. Water (16 mL) was added and the resulting suspension was stirred for 1 h. The solids were filtered, rinsed with water (2×), and then dried to afford the crude product which was purified via silica gel chromatography (10% to 50% ethyl acetate in hexanes) to afford the title compound (175 mg, 64% yield) as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.89 (br s, 1H), 8.26 (s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.00 (br m, 2H), 4.18 (s, 1H), 3.68 (m, 1H), 3.35 (m, 3H), 1.99 (m, 1H), 1.70 M, 1H), 1.57 (m, 1H), 1.23 br s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][S:5]([CH2:8][CH:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])(=[O:7])=[O:6]>C(O)C.[Pd]>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][S:5]([CH2:8][CH:9]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10]([OH:12])=[O:11])(=[O:7])=[O:6]
Reactant: CN(C)CCS(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCS(=O)(=O)CC(Cc1ccccc1)C(=O)O
Yield: 91.9 %

Procedure:
The title compound of Step 12 (150 mg, 0.4 mmol) was debenzylated in ethanol with 5 psi H2 at room temperature for 1.5 hours using 4% Pd/C catalyst. After filtering, the solvent was stripped off to give the title compound as white powder (110 mg, 70% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal. calcd. for C14H21NO4S: C, 56.16; H, 7.07; N, 4.68. Found: C, 55.88; H, 6.99; N, 4.35.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:10](Br)[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6]1)(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[CH2:6][N:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH:9]=[CH:10]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)N1CCC(Br)C(OC(C)=O)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC=CC(OC(C)=O)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
A mixture of Compound 239A (371 mmol) and DBU (92 g, 604 mmol) was heated to 90-110° C. for 30 min. After cooling to room temperature, the mixture was diluted with toluene and stirred for an additional 30 min. The precipitate was removed by filtration and rinsed with toluene. Combined filtrates were washed with 1.0 N HCl, water and dried over anhydrous anhydrous MgSO4. Concentration in vacuo afforded 67.56 g (yield: 85.4%) of 239B as an oil. 1H-NMR (400 MHz, CDCl3): 6.00 (bs, 1H), 5.90 (bs, 1H), 5.20 (m, 1H), 4.20 (q, J=7.08, 2H), 4.19 (m, 1H), 3.85 (m, 1H), 3.80 (m, 1H), 3.55 (m, 1H), 2.08 (s, 3H), 1.28 (t, J=7.08, 3H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:21]([Cl:29])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6]1)(=[O:3])N.C(Cl)(=O)C(Cl)=[O:33].N1C(C)=CC=CC=1C.[C:45]([Si:49]([CH3:60])([CH3:59])OCCN1C=CC(N)=N1)([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.CO>[C:45]([Si:49]([CH3:60])([CH3:59])[O:3][CH2:1][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[C:21]([Cl:29])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][O:33][CH2:16][CH2:15]2)=[N:6]1)([CH3:48])([CH3:47])[CH3:46]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(N)=O)n2)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (prepared as in PCT WO 2003/095438 A1, Example 20, 144 mg, 0.41 mmol) was dissolved in methylene chloride (4 mL) and N,N-dimethylfomamide (three drops) at 25° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 0.21 mL, 0.43 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was cooled to 0° C. and 2,6-lutidine (100 μL, 0.83 mmol) was added to the flask and it was stirred for 15 min. To this was then added a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 100 mg, 0.41 mmol) in methylene chloride (2 mL) and the reaction was allowed to warm up to 25° C. and stirred for 1 h. After this time the reaction was diluted with a small amount of methanol in methylene chloride and washed with aqueous 1 N hydrochloric acid solution and then a saturated aqueous brine solution/water reaction (1/1). Flash chromatography using Biotage system (40S column, Silica gel, 50% ethyl acetate/hexanes) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (158 mg, 67%) as an off-white foam: ES-HRMS m/e calcd for C26H40N3O5SSiCl (M+H)+ 570.2219, observed 570.2210; 1H NMR (400 MHz, DMSO-d6) δ ppm −0.08 (s, 6H, 2×SiCH3), 0.78 (s, 9H, 3×CH3), 1.13-1.27 (m, 2H, CH2), 1.29-1.43 (m, 1H, CH of CH2), 1.50-1.71 (m, 3H, CH of CH2 and CH2), 2.01-2.12 (m, 1H, CH), 3.20 (m, 2H, OCH2), 3.34 (s, 3H, SO2CH3), 3.76-3.88 (m, 4 H, OCH2 and SiOCH2), 3.97-4.10 (m, 3H, CH and NCH2), 6.42 (d, J=2.3 Hz, 1H, Ar), 7.53 (d, J=2.3 Hz, 1H, Ar), 7.60 (dd, Jo=8.2 Hz, Jm=1.6 Hz, 1H, Ar), 7.71 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.81 (s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[O:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].O>C1COCC1>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([O:5][C:4](=[O:14])[C:3]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])=[C:2]2[O:1][C:32](=[O:33])[O:34][CH2:35][CH3:36])[CH2:7][CH2:8]1
Reactant: CCOC(=O)Cl
Reactant: CON1CCC2(CC1)OC(=O)C(c1c(C)cc(C)cc1C)=C2O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)OC12CCN(OC)CC2
Reaction time: 0.5 h

Procedure:
To a solution of crude (ca 50% purity) 4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1-oxa-8-aza-spiro[4.5]dec-3-en-2-one (1.0 g, 3.15 mmol), triethylamine (0.8 ml, 0.57 g, 5.67 mmol) in 6 ml THF at 0° C. under argon was added ethyl chloroformate (0.36 ml, 0.41 g, 3.78 mmol) dropwise. The suspension became immediately quite thick. It was diluted with additional 2 ml THF while stirring was continued at 0° C. for 30 minutes. The reaction mixture was poured into cold water (0° C.) and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude product (brown oil) was purified by column chromatography on silica gel (ethyl acetate/cyclohexane 1:1). Yield: 220 mg of carbonic acid ethyl ester 8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1-oxa-8-aza-spiro[4.5]dec-3-en-4-yl ester (title compound P1.5) as a white solid.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:17]([NH2:20])(=[S:19])[CH3:18]>C(O)C>[CH3:18][C:17]1[S:19][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:20]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)c1ccc(C)cc1
Solvent: CCO
Product: CCOC(=O)c1sc(C)nc1-c1ccc(C)cc1
Yield: 40.9 %

Procedure:
A solution of 4.4 g of ethyl 2-bromo-3-(4-methylphenyl)-3-oxopropanoate in 30 ml of anhydrous ethanol is added with 1.4 g of thioacetamide and the mixture is refluxed for 4 hours. The solvent is evaporated and the residue is dissolved in H2O and alkalinized to pH 10 with 10% NaOH, extracted 2 times with ether and the organic phase is washed with brine, dried and evaporated to dryness under reduced pressure. The residue is purified by F.C. (eluent 90:10 hexane:ethyl acetate) and 1.65 g of a light yellow solid are obtained (41% yield). 1H NMR (CDCl3), δ: 1.28 (t, 3 H), 2.39 (s, 3 H), 2.73 (s, 3 H), 4.26 (q, 2 H), 7.23 (d, 2 H), 7.62 (d, 2 H).
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])#[N:2].[CH3:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>>[C:1]([N:3]=[C:4]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[CH3:17])[CH2:5][CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:7])#[N:2]
Reactant: Cc1ccccc1CN
Reactant: CCOC(CC(C)c1ccccc1)=NC#N
Product: Cc1ccccc1CNC(CC(C)c1ccccc1)=NC#N
Temperature: 25 °C

Procedure:
A mixture of Example 52C (0.1 g, 0.44 mmol) and 2-methylbenzylamine (0.2 mL) was heated to 90° C. for 2.5 hours. The mixture was cooled down to room temperature and purified by flash chromatography (eluting with 35% ethyl acetate/hexanes) to give the title compound as a white solid. MS (ESI/NH3) m/z 292 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.24-1.26 (d, 3H) 2.17 (s, 3H) 2.79-2.82 (d, 2H) 3.38-3.40 (m, 1H) 4.25-4.29 (m, 2H) 7.08-7.32 (m, 9H) 9.01 (t, 1H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[O:3][C:2]=1S.S(Cl)(Cl)=O.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:2]2[O:3][C:4]3[C:9]([N:1]=2)=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Sc1nc2cccnc2o1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3cccnc3o2)CC1
Temperature: 60 °C
Yield: 19.1 %

Procedure:
To oxazolo[5,4-b]pyridine-2-thiol (1.0 g, 6.57 mmol, 1.0 equiv) was added thionyl chloride (14.1 g, 8.6 mL, 118.3 mmol, 18.0 equiv) and anhydrous DMF (0.56 g, 0.56 mL, 7.23 mmol, 1.1 equiv) and the reaction mixture heated to reflux for 30 min. The solvent was removed under reduced pressure and the crude oil azeotroped twice with xylene to remove excess thionyl chloride. To the crude reaction product was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.97 g, 9.86 mmol, 1.5 equiv) in anhydrous DMF (5 mL) and the solution heated to 60° C. for 18 h. The solution was concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with ethyl acetate/hexane (1:1) to give 0.40 g (19%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.34 (s, 9H), 1.26-1.40 (m, 2H), 1.84-1.92 (m, 2H), 2.82-2.95 (m, 2H), 3.67-3.76 (m, 1H), 3.82-3.84 (m, 2H), 7.13 (t, J=7.0 Hz, 1H), 7.52 (dd, J=7.0 Hz, J=1.8 Hz, 1H), 7.79 (dd, J=7.0 Hz, J=1.8 Hz, 1H), 8.23 (d, J=7.6 Hz, 1H).
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:28])[C@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C@H:17]1[C:25](Cl)=[O:26].N1C=CC=CC=1.Cl>C1C=CC=CC=1>[CH3:15][C:16]1([CH3:28])[C@H:18]([CH:19]=[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C@H:17]1[C:25]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:26]
Reactant: CC1(C)[C@H](C=C2CCCC2)[C@H]1C(=O)Cl
Reactant: OCc1cnc(Oc2ccccc2)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C=C2CCCC2)[C@H]1C(=O)OCc1cnc(Oc2ccccc2)s1
Temperature: 20 °C
Reaction time: 20 h
Yield: 52.7 %

Procedure:
2.74 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of 2 g of (1R,3R) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylic acid chloride [described in French Pat. No. 74405 published under No. 1,505,423] in 30 ml of benzene and 0.81 ml of pyridine was added dropwise thereto. The mixture was stirred at 20° C. for 20 hours and was poured into dilute aqueous hydrochloric acid. The decanted aqueous phase was extracted with ether and the combined organic phases were dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 1.9 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3R) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylate meltingat 67° C.
Reaction SMILES: [CH3:1][N:2](C)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[S:23])=[CH:17][C:16]=2[F:34])[CH:6]=1)=[O:4].NC[CH2:38][N:39]([CH3:47])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43]>>[F:34][C:16]1[CH:17]=[C:18]([NH:21][C:22]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[S:23])[CH:19]=[CH:20][C:15]=1[O:14][C:11]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:6]=[C:5]([C:3]([NH:2][CH2:1][CH2:38][N:39]([CH3:47])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:4])[S:13][C:12]=12
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: CN(C)C(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Product: CN(CCNC(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1)C(=O)OC(C)(C)C

Procedure:
Following the procedures described above for the synthesis of compound 8a (Example 1, scheme 1) but replacing dimethyl amine with tert-butyl 2-aminoethyl(methyl)carbamate, title compound 138 was obtained (13%). LRMS (M+1) 638.2 (100%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.[CH:16](I)([CH3:18])[CH3:17].O>CN(C=O)C>[CH:16]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1)([CH3:18])[CH3:17]
Reactant: CC(C)I
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C(C)C)c2ccccc12
Reaction time: 7 h
Yield: 77.8 %

Procedure:
In DMF (8.0 ml) was suspended sodium hydride (60% in oil, 275.2 mg, 6.881 mmol). To the resulting suspension was added methyl indole-3-carboxylate (401.8 mg, 2.294 mmol) at 0° C. under stirring. After stirring for further 45 minutes at the same temperature, isopropyl iodide (0.34 ml, 3.440 mmol) was added to the reaction mixture. Stirring was then conducted for 1.5 hours at 0° C. and for 7 hours at room temperature. Water was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate. The extract was washed successively with 1N HCl and saturated saline, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (3:1, v/v) eluate fractions, methyl 1-isopropylindole-3-carboxylate (387.6 mg, 78%) was obtained as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Li][C:12]([CH3:15])(C)[CH3:13].CCCCC.C1C[O:24]CC1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH2:13][C@H:12]([OH:24])[CH3:15])[CH:7]=1
Reactant: COc1ccc(F)cc1Br
Reactant: [Li]C(C)(C)C
Reactant: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(F)cc1C[C@@H](C)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A solution of 2-bromo-4-fluoro-1-methoxybenzene (2.0 g, 9.75 mmol) in 20 mL of anhydrous THF was cooled to −78° C. Then 1.7M solution of t-BuLi in pentane (13.0 mL, 22.1 mmol) was added dropwise. The mixture was stirred at −78° C. for 10 min, then R-(+)-propylene oxide (670 mg, 11.55 mmol) was added and the mixture was allowed to warm to 0° C. overnight. The mixture was quenched with 2 mL of sat. NH4Cl and then conc. HCl was added dropwise to pH 8. The mixture was extracted with EtOAc (2×20 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9) to give (2R)-1-(5-fluoro-2-methoxyphenyl)propan-2-ol (531 mg, 30%). 1H NMR (300 MHz, CDCl3): δ 6.88 (m, 2H), 6.78 (m, 1H), 4.06 (m, 1H), 3.81 (s, 3H), 2.66-2.84 (m, 2H), 1.92 (d, J=3.96 Hz, 1H), 1.22 (d, J=6.21 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]([NH:12][C@H:13]1[C:16](=[O:17])[NH:15][C@H:14]1[CH2:18][I:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:31]([O:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])[CH:32]=[O:33]>O1CCCC1.CCCCCC.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:10]([NH:12][C@H:13]1[C:16](=[O:17])[N:15]([CH:32]([OH:33])[C:31]([O:35][CH:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:34])[C@H:14]1[CH2:18][I:19])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N[C@H]1C(=O)N[C@H]1CI)c1ccccc1
Reactant: O=CC(=O)OC(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC(C(=O)N[C@H]1C(=O)N(C(O)C(=O)OC(c2ccccc2)c2ccccc2)[C@H]1CI)c1ccccc1

Procedure:
A suspension of 1.02 g (2.21 mmol) of product from Example 21 in 22 ml of dry tetrahydrofuran is stirred under argon with cooling to -78° and 1.24 ml (2.44 mmol) of a 1.97M n-butyllithium in hexane solution is added. The mixture is stirred for 30 minutes at -78° while 0.66 g (2.75 mmol) of benzhydryl glyoxylate in 20 ml of toluene is dried by distilling off 12 ml of the toluene. The remaining solution is added to the reaction mixture. The resulting mixture is stirred at -78° for 1 hour and then is warmed in an ice bath to 0° for 10 minutes. The reaction is quenched by pouring into cold aqueous NaH2PO4. The mixture is extracted with ethyl acetate and the combined extracts are washed with saline. The dried solution is evaporated and the residue is taken up in carbon tetrachloride and then hexane is added to precipitate the product, 15 g (97%).