Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH:26]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl.[NH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].[OH-].[Na+].C([O-])([O-])=O.[K+].[K+]>C(O)C.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CN
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CNCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (381 mg) and ethyl glycinate hydrochloride (223 mg) were added to a solution of NaOH (27 mg) in ethanol (20 mL), followed by addition of AcOH (3 mL). Under stirring NaBH3CN (50 mg) in ethanol (2 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight and then basified to pH 9 by K2CO3 solution. The mixture was concentrated and EtOAc (50 mL) was added. The organic layer was separated and washed with water and brine. After the solvent was evaporated off the residue was purified by Mass Directed AutoPrep to afford ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}glycinate (D73) (130 mg) as a yellow solid. δH (DMSO-d6, 400 MHz): 1.20 (3H, t), 1.38 (6H, d), 3.48 (2H, s), 4.03 (2H, s), 4.12 (2H, q), 4.88-4.94 (1H, m), 7.25 (1H, t), 7.44 (1H, d), 7.46 (1H, d), 7.96 (1H, t), 8.22 (1H, dd), 8.39 (1H, d), 11.00 (1H, s).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:5].CC([O-:26])(C)C.[K+]>CCOCC>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][CH:10]=[C:9]2[C@@H:7]2[CH2:8][C@H:6]2[C:4]([OH:5])=[O:26])=[CH:14][CH:15]=1
Reactant: COc1ccc2cccc([C@@H]3C[C@H]3C(=O)N(C)OC)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: COc1ccc2cccc([C@@H]3C[C@H]3C(=O)O)c2c1

Procedure:
6 g (21 mmol) of the compound obtained in Step G in 50 ml of anhydrous ether and 15.4 g of potassium tert-butylate are stirred for 2 days at room temperature. 3.2 g of a light brown solid are collected and reacted without purification.
Reaction SMILES: C(OC([NH:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.ClS([N:33]=[C:34]=[O:35])(=O)=O.O.Cl>C(Cl)Cl.CO.C(Cl)(Cl)Cl.CC(O)C>[ClH:21].[NH2:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:34](=[O:35])[NH2:33])[CH:23]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(COc1noc2ccc(Cl)cc12)c1cccc(O)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)O
Product: NC(=O)Oc1cccc(C(N)COc2noc3ccc(Cl)cc23)c1

Procedure:
To a solution of 0.40 g of 3-[2-tert-butoxycarbonylamino-2-(3-hydroxyphenyl)ethoxy]-5-chloro-1,2-benzoisoxazole in 10 ml of methylene chloride is added 0.20 g of chlorosulfonyl isocyanate at -30° C., and thereafter, the temperature is gradually elevated to 0° C., after which 5 ml of water is added and they are subjected to reaction at the same temperature for 30 minutes. The solvent is removed by distillation under reduced pressure, water and ethyl acetate are added to the residue obtained, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The oily product obtained is dissolved in 20 ml of methanol and 20 ml of chloroform, and 3.0 ml of a 2-propanol solution (6.5M) of hydrogen chloride is added at room temperature. They are subjected to reaction at the same temperature for 18 hours, after which the solvent is removed by distillation under reduced pressure. 2-Propanol is added to the residue obtained, and after stirring, the crystals precipitated are collected by filtration to obtain 0.3 g of colorless, crystalline 3-[2-amino-2-(3-carbamoyloxyphenyl)ethoxy]-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 232.0°-233.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH3:16])[C:12]1[N:8]([CH:9]=[C:10]([C:17]3[N:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[CH:19][N:18]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.C([Sn](CCCC)(CCCC)[C:30]([O:32][CH2:33][CH3:34])=[CH2:31])CCC.[Li+].[Cl-].[F-].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:33]([O:32][C:30]([C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH3:16])[C:12]1[N:8]([CH:9]=[C:10]([C:17]3[N:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[CH:19][N:18]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2)=[CH2:31])[CH3:34]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2c(cc1Br)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(OCC)c1cc2c(cc1C)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 70 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
A mixture of 12-bromo-13-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (1.0 g, 2.6 mmol), tributyl(1-ethoxyvinyl)stannane (1.2 mL), Pd(PPh3)4 (90 mg, 7.8 mmol), and LiCl (328 mg, 7.8 mmol) in dry THF (10 mL) was stirred at 70° C. for 48 h under nitrogen atmosphere. KF (100 mL, 0.16 M) was added and the mixture was further stirred at room temperature for 1 h. The solid was filtered off. The filtrate was concentrated to give the crude product, which was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to afford 12-(1-ethoxyethenyl)-13-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (660 mg, 68% yield). LCMS (ESI) m/z: 380.2 [M+H+].
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>C1COCC1>[N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:27][CH2:24][CH2:25][CH3:26])=[O:21])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CCCN
Reactant: CCOC(=O)CCCCCn1cnc2cnc3ccccc3c21
Solvent: C1CCOC1
Product: CCCNC(=O)CCCCCn1cnc2cnc3ccccc3c21
Yield: 95.9 %

Procedure:
A solution of ethyl 6-(1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (7.0 g, 22.5 mmol) and n-propylamine (11.1 mL, 135 mmol) in THF (10 mL) was heated at 100° C. for ten days in a sealed high-pressure vessel. Additional n-propylamine (20 mL) was added after three days and again after seven days. After ten days, the reaction was concentrated under reduced pressure to provide 7.0 g of 6-(1H-imidazo[4,5-c]quinolin-1-yl)-N-propylhexanamide.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([C:23]1[S:24][C:25]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])=[CH:26][N:27]=1)([CH3:22])[CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl[C:84]1[N:89]=[C:88]([C:90]([F:93])([F:92])[F:91])[CH:87]=[CH:86][N:85]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:1]([O:18][CH2:19][C:20]([C:23]1[S:24][C:25]([C:28]2[CH:29]=[C:30]([NH:31][C:84]3[N:89]=[C:88]([C:90]([F:93])([F:92])[F:91])[CH:87]=[CH:86][N:85]=3)[CH:32]=[CH:33][CH:34]=2)=[CH:26][N:27]=1)([CH3:22])[CH3:21])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cccc(N)c2)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a suspension of the product of Step 3 (393 mg, 0.807 mmol), cesium carbonate (526 mg; 1.62 mmol), XantPhos (70.1 mg, 0.121 mmol) and palladium(II) acetate (18 mg; 0.081 mmol) in dioxane (5 mL) was added the 2-chloro-4-(trifluoromethyl)pyrimidine (102 μL; 0.848 mmol). The reaction was stirred at 100° C. overnight. After dilution with ethyl acetate (100 mL), the mixture was filtered through celite and concentrated in vacuo. Purification by chromatography on silica gel (100:0 to 50:50, hexanes:ethyl acetate) provided 327 mg (0.517 mmol, 64%) of N-{3-[2-(1-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropan-2-yl)-1,3-thiazol-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine as an off-white foam.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:16]([O-:18])=O)[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1)#[N:2].[K+].N1C=CC=CC=1.O=S(Cl)Cl.[C:30]([Si:34]([CH3:56])([CH3:55])[O:35][CH2:36][C:37]([C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[C:42]([C:47]2[CH2:52][CH2:51][C:50]([CH3:54])([CH3:53])[CH2:49][CH:48]=2)[CH:41]=1)([CH3:39])[CH3:38])([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl.CCOC(C)=O>[C:30]([Si:34]([CH3:55])([CH3:56])[O:35][CH2:36][C:37]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:16]([C:5]2[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)=[O:18])=[C:42]([C:47]2[CH2:52][CH2:51][C:50]([CH3:54])([CH3:53])[CH2:49][CH:48]=2)[CH:41]=1)([CH3:39])[CH3:38])([CH3:33])([CH3:31])[CH3:32]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(C(C)(C)CO[Si](C)(C)C(C)(C)C)ccc2N)CC1
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1(C)CC=C(c2cc(C(C)(C)CO[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a mixture of potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 1.37 g, 4.49 mmol) and pyridine (363 μL, 4.49 mmol) in 15 mL of DCM at 0° C. was added SOCl2 (328 μL, 4.49 mmol). After stirring at 0° C. for 0.5 h under Ar, the resulting mixture was warmed to RT and added to a solution of 4-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-2-(4,4-dimethyl-cyclohex-1-enyl)-phenylamine (as prepared in the previous step, 1.45 g, 3.74 mmol) in 15 mL of DCM at 0° C. After stirring at 0° C. for 2 h under Ar, the reaction was warmed to RT. Treated with 100 mL of EtOAc, the mixture was washed with H2O (20 mL), 10% aqueous citric acid (20 mL), aqueous saturated NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (0-5% EtOAc/hexane) to afford the title compound (2.22 g, 93%) as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C35H56N4O3Si2, 637.4 (M+H). found 637.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[C:34](Cl)[N:33]=[N:32][C:31]=2[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:34]2[N:33]=[N:32][C:31]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:29][CH:28]=3)[CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OCC2CN(C(=O)OC(C)(C)C)C2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (1.5 mmol, 281 mg) in THF (4.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 1.5 mmol, 60 mg) was added and stirring continued for 10 min at room temperature, then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 1.0 mmol, 352 mg) was added. The resulting mixture was stirred at 50° C. for 1 hour, poured into water, and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give 3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-azetidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to give 6-(azetidin-3-ylmethoxy)-4-(4-benzyloxy-phenyl)-3-butyl-pyridazine dihydrochloride.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:13]=[C:12]([Cl:14])[C:9]([C:10]#[N:11])=[C:8]([Br:15])[C:7]=1[O:16][CH2:17][CH3:18])(=[O:5])[CH3:4].CO>>[Br:15][C:8]1[C:7]([O:16][CH2:17][CH3:18])=[C:6]([CH:3]([OH:5])[CH3:4])[CH:13]=[C:12]([Cl:14])[C:9]=1[C:10]#[N:11]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1c(C(C)O)cc(Cl)c(C#N)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Sodium tetrahydroborate (38 mg, 0.99 mmol) was added to a mixture of 4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile (200 mg, 0.7 mmol) in methanol (5 mL, 100 mmol) at 0° C. The reaction was stirred at room temperature for 1 hour, concentrated and partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give crude 2-bromo-6-chloro-3-ethoxy-4-(1-hydroxyethyl)benzonitrile as a clear oil (0.15 gm, 100%), LCMS calculated for C11H11BrClNO2(M+H)+: m/z=303.9, 305.9; found: 304.0, 305.9.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:11]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
Diphenylmethyl 3-methoxymethyl-7β-(2'-thienylacetamido)-ceph-3-em-4-carboxylate (2 g.,) was dissolved in a mixture of trifluoroacetic acid (8 ml) and anisole (2 ml) and after 5 minutes the reagents removed under reduced pressure. The resulting gum was dissolved in ethyl acetate and poured into 60°-80° petroleum and the product recovered by filtration. This material crystallised from ethyl acetate as colourless prisms, m.p. 153°-157° (decomp.), [α]D25 + 81.6°(c 1, tetrahydrofuran), λmax (ethanol) 237, 260 (Sh.) nm (ε 13,700 and 7,700 respectively), νmax (Nujol) 1780 (β-latham), 1720 (-COOH), 1690 and 1524 cm-1 (-CONH), N.M.R. 5,80 (-CH2OCH3), 6.70τ (-CH2OCH3), (Found: C, 49.2; H, 4.4; N, 7.5; S, 17.0. C15H16N2O5S2 requires: C, 48.9; H, 4.4; N, 7.6; S, 17.4%).
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([O:28][C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)[CH3:19])OCC[O:11]2)=[CH:6][CH:5]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO>[ClH:35].[ClH:1].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:11])[CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:26][CH2:27]2)[CH3:19])=[CH:8][CH:9]=1
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CCN1CCC(Oc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: CO
Product: CN(CCCC(=O)c1ccc(F)cc1)CCN1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
A solution of 8.94 g (17.7 mmol) of 1-{2-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylamino}ethyl}-4-(4-chlorophenoxy)piperidine dihydrochloride, 135 ml of methanol, and 55 ml of 3N HCl was heated at reflux for 3 hours under nitrogen. The mixture was allowed to cool to room temperature, poured into saturated sodium carbonate, extracted twice with ether and dried over potassium carbonate. Filtration followed by evaporation of the solvent provided an oil. The yield of a crude dihydrochloride was 6.71 g (81%). Recrystallization from ethanol provided 2.37 g (28%) of the desired ketone.
Reaction SMILES: Cl.[P:2]([C:6]1([C:15]([OH:17])=[O:16])[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH2:11][NH:12]2)=[CH:7]1)([OH:5])([OH:4])=[O:3]>O.O=[Pt]=O>[P:2]([C:6]1([C:15]([OH:17])=[O:16])[CH2:14][CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][NH:12]2)[CH2:7]1)([OH:4])([OH:5])=[O:3]
Reactant: O=C(O)C1(P(=O)(O)O)C=C2C=CCNC2=C1
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Product: O=C(O)C1(P(=O)(O)O)CC2CCCNC2C1

Procedure:
1.0 g of dihydro-6-phosphono-1-pyrindine-6-carboxylic acid hydrochloride (Example 31) in 50 ml of H2O with 0.5 g of PtO2 is hydrogenated on a Parr apparatus at 40 PSI and 50° for 3 days. The catalyst is filtered off, and the filtrate is taken to dryness under vacuum. The resulting solid is taken up in the minimum amount of water, and precipitated by slow addition of ethanol to give octahydro-6-phosphono-1-pyrindine-6-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=1[F:18])=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH2:7][NH:9][C:10]2[C:11]([F:18])=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=2[F:16])[CH:19]=1
Reactant: O=C(Nc1c(F)ccc(O)c1F)c1cc(Br)ccc1F
Solvent: C1CCOC1
Product: Oc1ccc(F)c(NCc2cc(Br)ccc2F)c1F
Temperature: 60 °C
Yield: 223.1 %

Procedure:
To a solution of 5-bromo-N-(2,6-difluoro-3-hydroxy-phenyl)-2-fluoro-benzamide (5.78 g, 7.1 mmol, 1.0 eq) in THF (100 mL) at 0° C. under N2 was added a solution of BH3 (1M in THF, 83.5 mL, 83.5 mmol, 5.0 eq) dropwise. The reaction mixture was heated at 60° C. overnight then cooled to room temperature and quenched with water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 30:1 to 20:1) to give the title compound as a brown oil (5.26 g, 94%).
Reaction SMILES: [CH:1]1([C:4](=O)[CH3:5])[CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:16])[O:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[O:9]1>>[CH:1]1([C:4](=[C:11]2[C:12](=[O:14])[O:13][C:8]([CH3:16])([CH3:7])[O:9][C:10]2=[O:15])[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(=O)C1CC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CC(=C1C(=O)OC(C)(C)OC1=O)C1CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 1 starting from 1-cyclopropylethanone (Alfa Aesar, Cat. #A13540) and 2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1.C(O)(=O)C>C1COCC1.C(OCC)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]([OH:19])[C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C#CC(O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 64.7 %

Procedure:
To a cooled (−78° C.) solution of ethyl propiolate (8.96 mL, 88.4 mmol) in THF (100 mL) was added n-butyllithium (37.5 mL of 2.37M solution in hexane, 88.9 mmol) dropwise over 70 minutes so as to maintain the internal temperature below −70° C. Additional THF (5 mL) was used to rinse the addition funnel. A solution of 4-chloro-2-nitrobenzaldehyde (14.88 g, 80.2 mmol) in THF (30 mL) was transferred to the addition funnel and added dropwise over 47 minutes to maintain the reaction temperature below −70° C. Additional THF (5 mL) was used to rinse the addition funnel. The solution was stirred for 90 minutes at −70° C. and was then warmed to −60° C. glacial acetic acid (18.3 mL, 316 mmol) was quickly added. The solution was allowed to warm to 10° C. over 60 minutes and poured into diethyl ether (900 mL). The resulting solution was washed with saturated aqueous sodium carbonate (2×450 mL) and saturated aqueous sodium chloride (1×450 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator. This product was purified by flash chromatography eluting with ethyl acetate:hexanes (90:10) to give the title compound as red oil (14.73 g, 64.8%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:35]=[C:36](\[C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:42][CH:41]=2)/[C:37]([OH:39])=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1>C(Cl)Cl>[CH:28]1(/[CH:35]=[C:36](\[C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:42][CH:41]=2)/[C:37]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A solution of triphenylphosphine (8.08 g, 30.8 mmol) in methylene chloride (100 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (5.48 g, 30.8 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-3-cycloheptyl-2-(4-(methanesulfonyl)-phenyl)-acrylic acid (4.97 g, 15.41 mmol) in methylene chloride (20 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (4.63 g, 46.23 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (250 mL) and a 1N aqueous hydrochloric acid solution (150 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×150 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×250 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 5/1 to 3/2 hexanes/ethyl acetate) afforded (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide (2.7 g, 43%) as an amorphous solid. This compound was dissolved in acetonitrile (˜55 mL) and stored overnight at 25° C. The solids were collected by filtration and washed with acetonitrile (5 mL) to obtain (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide (2.1 g, 33%) as a crystalline solid: mp 163-165° C.; EI-HRMS m/e calcd for C20H24N2O3S2 (M+) 404.1253, found 404.1251.