Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]4)[CH:12]=3)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[C:26](#[N:29])[CH:27]=[CH2:28]>>[C:26]([CH2:27][CH2:28][N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:21])[CH2:15][CH:16]1[CH3:20])#[N:29]
Reactant: C=CC#N
Reactant: CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Product: CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1CCC#N
Yield: 75.4 %

Procedure:
Analogously to Example 9, 3.45 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-methyl-1-piperazinyl)-3-quinolinecarboxylic acid (Example B) are reacted with 4.5 g of acrylonitrile to give 3 g of 7-[4-(2-cyanoethyl)-3-methyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 203°-206° C.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Br.Br[C:8]1[S:9][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][N:12]=1.C(N(CC)CC)C>C(O)C>[CH:1]1([CH2:4][NH:5][C:8]2[S:9][C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: Brc1nnc(-c2cccnc2)s1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1cncc(-c2nnc(NCC3CC3)s2)c1
Temperature: 125 °C
Yield: 26.4 %

Procedure:
A suspension of cyclopropylmethanamine (0.528 g, 0.743 mmol), 2-bromo-5-(3-pyridyl)-1,3,4-thiadiazole hydrobromide (0.2 g, 0.619 mmol) and triethylamine (0.3 ml, 2.16 mmol) in ethanol (20 mL) was heated to 125° C. for 42 minutes in a microwave reaction vessel, cooled to room temperature, concentrated under reduced pressure and resuspended in 2:1 saturated aqueous sodium bicarbonate:ethyl acetate (100 mL). The suspension was shaken vigorously and the organic extract collected and washed with water (50 mL) and brine (30 mL) before drying over magnesium sulfate. The solution was concentrated under reduced pressure and purified by silica column chromatography, eluting with a gradient of methanol in ethyl acetate. The slower eluting fraction was concentrated under reduced pressure to afford the title compound as a yellow solid (38 mg, 26%): mp 162-165° C.; IR (ATR) 1573(s), 1549(s), 1464(m), 1063(m) cm−1; 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=1.6 Hz, 1H), 8.63 (dd, J=4.8, 1.6 Hz, 1H), 8.18 (ddd, J=8.0, 2.2, 1.7 Hz, 1H), 7.38 (ddd, J=8.0, 4.8, 0.7 Hz, 1H), 5.68 (s, 1H), 3.29 (d, J=7.1 Hz, 2H), 1.26-1.09 (m, 1H), 0.72-0.53 (m, 2H), 0.42-0.25 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 170.01, 154.19, 150.61, 147.94, 133.64, 127.47, 123.76, 52.20, 10.76, 3.73; ESIMS m/z 231.8 ([M−H]−).
Reaction SMILES: Cl[NH:2][C:3](=[NH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S-:12][C:13]#[N:14].[K+]>CO.C(OCC)(=O)C>[CH2:4]([C:3]1[N:11]=[C:13]([NH2:14])[S:12][N:2]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N=C(Cc1ccccc1)NCl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nc(Cc2ccccc2)ns1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
N-Chloro-2-phenyl-acetamidine (154 mg, 0.92 mmol) was dissolved in methanol (4.6 mL) and cooled to 0° C. then potassium thiocyanate (89 mg, 0.92 mmol) was added and it was stirred for 1 h. The mixture was diluted with ethyl acetate (50 mL), stirred for 5 min and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford 3-benzyl-[1,2,4]thiadiazol-5-ylamine (93 mg, 53%) as an off-white solid: H1-NMR (400 MHz, CDCl3) δ=4.02 (2H, s), 5.94 (2H, br), 7.28 (5H, m).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:15][C:16]([OH:18])=[O:17])=[CH:10][C:4]=2[O:3]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (53.7 mmol) 2,2-difluoro-benzo[1,3]dioxole-5-carbaldehyde, 6.24 g (60.0 mmol) malonic acid, 0.46 g (5.40 mmol) piperidine and 40 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 100 g ice and 30 ml 6N HCl. The precipitate was isolated, washed with water and dried. Yield: 8.60 g (70%) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl) -acrylic acid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:14]1[C:18]([CH:19]=O)=[CH:17][N:16]=[CH:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:14]1[C:18]([CH2:19][N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[CH:17][N:16]=[CH:15]1
Reactant: O=Cc1cncs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cncs2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.1 %

Procedure:
N-Boc-piperazine (0.900 g, 4.86 mmol, 1.1 eq) was dissolved in 1,2-DCE (12 mL). To this solution, 5-thiazolecarboxaldehyde (0.500 g, 4.42 mmol, 1 eq) in 1,2-DCE (2 mL) was added followed by the portionwise addition of sodium triacetoxyborohydride (1.310 g, 6.19 mmol, 1.4 eq). The reaction mixture was stirred at room temperature for 17 h and then washed with a saturated aqueous solution of NaHCO3. The organic layer was dried (MgSO4), the solvent removed in vacuo and the crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound as a light yellow oil (0.640 g, 51%); 1H-NMR (500 MHz, CDCl3): δ 1.46 (s, 9H, C(CH3)3), 2.43 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 3.44 (t, J=5.0 Hz, 4H, piperazine N(CH2)2), 3.77 (s, 2H, NCH2), 7.72 (s, 1H, thiazole 4-H), 8.76 (s, 1H, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=2.04 min—284 [(M+H)+, 100%].
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:8])([CH3:7])[CH:5]1[C:9]([OH:11])=[O:10].[OH-].[Na+].Cl>>[CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:7])([CH3:8])[C@@H:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=CC1C(C(=O)O)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
62 g. of chrysanthemic acid (consisting of 18% cis and 82% trans isomer) prepared as described in Example (3a) and enriched in the trans isomer were dissolved at 70°-75° C. in 70 ml. of a 20% aqueous sodium hydroxide solution, cooled to room temperature and set aside overnight. The precipitated crystals were filtered by thorough suction and dissolved in 330 ml. of water, 240 ml. of petroleum ether (b.p. 40° C.) were added to the solution of the sodium salt obtained and the mixture was acidified to pH 1 by concentrated hydrochloric acid while stirring. The organic phase was separated and the aqueous solution was again extracted with 75 ml. of petroleum ether. After combination, the organic solution was washed with 3×100 ml. of water, dried over anhydrous sodium sulphate, then evaporated to one-fourth its volume. The obtained solution was slowly cooled to 25° C. and stirred at this temperature for one hour. After filtering out a little amount of the crystals rich in the cis isomer, the mother liquor was further cooled to -10° C. and the precipitated crystals were separated. Thus 23.1 g. of dl-trans-chrysanthemic acid were obtained with a purity of 99.8% which was resolved according to the Example (3b).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:27]>>[F:24][C:17]1[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:27])=[O:2])=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cc(F)c(F)cc2F)cc1
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2cc(F)c(F)cc2F)cc1
Yield: 52 %

Procedure:
Prepared in analogy to example 3 from N-[4-(2,4,5-trifluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=52%. Colorless solid. MS: m/e=339.2 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:21]2[N:25]=[CH:24][CH:23]=[N:22]2)=[C:6]([CH:20]=1)[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][O:11][CH:10]1[C:15](OCC)=[O:16])=[O:8].[Li+].[BH4-].O>C1COCC1>[OH:16][CH2:15][CH:10]1[N:9]([C:7]([C:6]2[CH:20]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:21]2[N:25]=[CH:24][CH:23]=[N:22]2)=[O:8])[CH2:14][CH2:13][CH2:12][O:11]1
Reactant: CCOC(=O)C1OCCCN1C(=O)c1cc(C)ccc1-n1nccn1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCCOC2CO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-ethyl 3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,3-oxazinane-2-carboxylate obtained in Reference Example 3 (0.50 g, 1.5 mmol) in THF (5 mL), a solution of LiBH4 in THF (0.97 mL, 2.9 mmol) was added and stirred for 2 hours at room temperature. Water was added to the reaction mixture, followed by extraction with CHCl3. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane/EtOAc=88/12 to 0/100) to obtain the title compound (0.34 g) (colorless oil).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[C:16]([F:18])[C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][N:28]=3)[CH2:23][CH2:22]2)=[O:20])=[C:14]([F:35])[CH:13]=1>>[F:18][C:16]1[CH:17]=[C:12]([N:5]2[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]2(=[O:10])=[O:9])[CH:13]=[C:14]([F:35])[C:15]=1[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][N:28]=2)[CH2:25][CH2:26]1)=[O:20]
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4[C@H](C(C)C)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 7.3 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (320 mg) described in Preparation Example 6 and (4-bromo-2,6-difluorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (410 mg) described in Preparation Example 111 and by the reaction and treatment in the same manner as in Example 4, the title compound (36 mg) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[CH2:10]([SH:13])[CH2:11][SH:12].C(N(CC)CC)C>CN(C=O)C>[SH:12][CH2:11][CH2:10][S:13][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: SCCS
Reactant: CC1(CCl)COC(=O)N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(CSCCS)COC(=O)N1
Temperature: 90 °C

Procedure:
To a solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (1.85 g, 12.4 mmol) in DMF (5 ml) was added 1,2-ethanedithiol (10.0 ml, 119 mmol). Triethylamine (2.0 ml, 14 mmol) was added, and the solution heated to 90° C. for 2 h, then cooled to RT and concentrated in vacuo. Purification of the residue by flash chromatography (30%→80% EtOAc in hexanes) afforded a mixture of the title compound and various EDT disulfide adducts which was used without further purification. ESI/APCI expected for C7H13NO2S2: 207.04. Found: 208 (MH+), 300 (MH++EDT), 414 (MNa++2 EDT).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:32]1[CH:31]=[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([F:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:35]=[C:34]([CH3:36])[N:33]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(F)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-fluoro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M220) (291 mg, 0.533 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (169 mg, 74%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21](P(=O)(OCC)OCC)[Cl:22])=[CH:17][CH:16]=1.C[O-].[Na+]>CN(C)C=O>[C:8]1([C:6]2[S:7][C:3]([CH:1]=[C:21]([Cl:22])[C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)=[CH:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(-c2ccccc2)s1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClC(=Cc1ccc(-c2ccccc2)s1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
A solution of 1.3 grams (0.007 mole) of 5-formyl-2-phenylthiophene and 2.0 grams (0.007 mole) of diethyl (4-chlorophenyl)chloromethylphosphonate in 30 mL of dimethylformamide was stirred, and 0.5 gram (0.009 mole) of sodium methoxide was added. The reaction mixture was stirred at ambient temperature for 18 hours, and then was quenched with an aqueous solution saturated with ammonium chloride. The reaction mixture was cooled and filtered to collect a solid. The solid was dried to yield 2.0 grams of 1-(5-phenylthien-2-yl)-2-chloro-2-(4-chlorophenyl)ethene. The intermediate ethene, 1.2 grams (0.004 mole), was treated with 0.6 gram (0.005 mole) of potassium tert-butoxide in 20 mL of tetrahydrofuran. The reaction mixture was heated under reflux for four hours and then was allowed to cool to ambient temperature during a 16 hour period. An excess of aqueous 1.2N hydrochloric acid was slowly added to the reaction mixture, followed by an excess of an aqueous solution saturated with ammonium chloride. The reaction mixture was cooled, and a solid was collected by filtration. The solid was dried to yield 1.1 grams of 1-(5 -phenylthien-2-yl)-2-(4-chlorophenyl)ethyne; m.p. 141°-145° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:37]1[CH2:42][CH2:41][CH:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1>C(O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:37]4[CH2:42][CH2:41][CH:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]4)[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2cccc(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-[(1-methylethyl)oxy]benzonitrile (D73) (120 mg), acetic acid (0.036 mL) and sodium acetate (52.3 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (200 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (169 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-{[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-4-piperidinecarboxylate (D84) (165 mg). The crude product was used for next step without further purification. MS (ES): C30H35N3O3S requires 517. found 518.3 (M+H+).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:20]1[CH2:30][CH2:29][C@@H:28]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21]1>C(Cl)Cl>[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:20]1[CH2:30][CH2:29][C@@H:28]([O:31][Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:34])[CH3:35])[C:23]2=[N+:24]([O-:9])[CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21]1
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2cccnc21)(C(C)C)C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2ccc[n+]([O-])c21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
mCPBA (1.239 g, 5.53 mmol) was added to the CH2Cl2 (30 mL) solution of (6R,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (2.17 g, 5.03 mmol) at rt. The reaction was stirred at room temperature overnight. The solvent was removed via vacuum. The product was purified by flash column eluted with ethyl acetate in hexane from 0 to 50% to 85%. The product was obtained by flushing the column with 85% ethyl acetate in hexane (1.572 g, 69%). MS (ESI)[M+H+]=448.21; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.14 (br. s., 1H) 6.94-7.11 (m, 2H) 6.84-6.92 (m, 2H) 6.66-6.72 (m, 1H) 6.42 (t, J=4.28 Hz, 1H) 4.04 (dd, J=14.73, 4.41 Hz, 1H) 3.73-3.88 (m, 1H) 2.96 (dd, J=14.48, 5.41 Hz, 1H) 2.50 (d, J=5.79 Hz, 1H) 2.13-2.25 (m, 2H) 1.80-1.94 (m, 1H) 1.18-1.32 (m, 3H) 1.09 (d, J=7.55 Hz, 9H) 1.00 (d, J=7.55 Hz, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](C2OC(C3N=C4C=CC(C#N)=CN4C=3)=CC=2)=[CH:5][CH:4]=1)#[N:2].Br[C:26]1[CH:27]=[C:28]([CH3:43])[C:29]2[N:30]([CH:32]=[C:33]([C:35]3[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=3)[N:34]=2)[CH:31]=1>>[C:39]([C:38]1[CH:41]=[CH:42][C:35]([C:33]2[N:34]=[C:29]3[C:28]([CH3:43])=[CH:27][C:26]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)=[CH:31][N:30]3[CH:32]=2)=[CH:36][CH:37]=1)#[N:40]
Reactant: N#Cc1ccc(-c2ccc(-c3cn4cc(C#N)ccc4n3)o2)cc1
Reactant: Cc1cc(Br)cn2cc(-c3ccc(C#N)cc3)nc12
Product: Cc1cc(-c2ccc(C#N)cc2)cn2cc(-c3ccc(C#N)cc3)nc12
Yield: 73 %

Procedure:
The same procedure described for 4a was used starting with 20. Yield 73%, mp 283-285° C. 1H NMR (DMSO-d6); δ 2.60 (s, 3H), 7.53 (s, 1H), 7.85-7.93 (m, 6H), 8.17 (d, J=8.4 Hz, 2H), 8.53 (s, 1H), 8.87 (s, 1H). 13C NMR; δ 144.9, 142.5, 141.1, 138.1, 132.6, 132.4, 127.0, 126.6, 126.0, 123.6, 123.3, 122.9, 118.6, 118.4, 111.9, 110.0, 109.7, 16.3. MS (m/z, rel.int.); 335 (M++1, 100), 310 (30), 279 (20), 234 (40).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:42])[CH:14]([OH:41])[CH:15]([CH3:40])[C:16](=[N:38][OH:39])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:43].[Na].Cl.[N+](=[CH2:48])=[N-]>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:42])[CH:14]([OH:41])[CH:15]([CH3:40])[C:16](=[N:38][OH:39])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:4]([C:5]([O:7][CH3:48])=[O:6])[C:3]=1[OH:43]
Reactant: C=[N+]=[N-]
Reactant: CCC(C(=NO)C(C)C(O)C(C)CCc1ccc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Product: CCC(C(=NO)C(C)C(O)C(C)CCc1ccc(C)c(O)c1C(=O)OC)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
A solution of 3.55 g of (-)-3-methyl-6-{7-ethyl-4-hydroxy-6-hydroxyimino-3,5-dimethyl-7-[5-ethyl-3-methyl-5-(5-ethyl-5hydroxy-6-methyl-2tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}salicylic acid, sodium salt in 100 ml methylene chloride was treated with 1N HCl. The solvent layer was separated, washed with water and concentrated under reduced pressure to a solid. A portion (1.3 g) of the solid, equal to 2.15 millimole, was dissolved in ether and treated with 4.25 millimole of an ethereal solution of diazomethane. At the end of one hour the solvent was removed at reduced pressure leaving an oil which upon standing under a high vacuum solidified to yield 3-methyl-6-{7-ethyl-4-hydroxy-6-hydroxyimino-3,5-dimethyl-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl} salicylic acid, methyl ester, isomer A; [α]D25 +5.77° (1.03, CH3OH).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32](O)=[O:33])=[O:15])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:45])=O>ClCCl>[Cl:45][C:32]([C:31]1[CH:35]=[CH:36][N:37]=[C:29]([C:18]2[CH:19]=[C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]=[CH:22][C:17]=2[NH:16][C:14]([C:13]2[CH:12]=[C:11]([CH:40]=[CH:39][CH:38]=2)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])=[O:15])[CH:30]=1)=[O:33]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)Cl)ccn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 112.2 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid (170 mg, 0.30 mmol, 1.00 equiv) in dichloromethane (10 mL), and oxalyl dichloride (112 mg, 0.88 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated under vacuum to yield 200 mg of crude product a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[C:20]([OH:25])[CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>CC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[C:20]([O:25][CH2:32][CH3:33])[CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=C1CCc2c(O)cccc2N1C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc2c1CCC(=O)N2C1CCN(Cc2ccccc2)CC1
Reaction time: 6.5 h

Procedure:
1-(1-Benzyl-4-piperidinyl)-5-hydroxy-3,4-dihydrocarbostyril (500 mg) is dissolved in acetone (20 ml) and thereto are added potassium carbonate (246 mg) and ethyl iodide (0.18 ml). The mixture is refluxed with stirring for 6.5 hours. After the reaction, the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. Dichloromethane is added to the resulting residue and the mixture is washed with 5% aqueous sodium hydroxide solution and then dried with magnesium sulfate. The solvent is evaporated and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=50:1) to give 1-(1-benzyl-4-piperidinyl)-5-ethoxy-3,4-dihydrocarbostyril (0.27 g).