Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[C:36](Cl)(=[O:38])[CH3:37]>>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:36](=[O:38])[CH3:37])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Reactant: CC(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NC(C)=O)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using the following starting materials: {4′-amino-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester and acetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9]2)=[CH:4][CH:3]=1>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccn(-c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccn(-c2ccc(F)cc2)c1

Procedure:
To an ethanol solution (2.6 mL) of 1-(4-fluorophenyl)-3-nitro-1H-pyrrole (131 mg, 0.635 mmol) synthesized in Reference Synthesis Example 248, palladium-activated carbon (13.1 mg) was added and the resultant mixture was stirred under hydrogen atmosphere at room temperature for 1 day. After completion of the reaction, the reaction solution was filtered with Celite and the filtrate was concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:34]3[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cc1
Yield: 66 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-cyanophenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (66%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH:10]([NH:15]C(=O)OC(C)(C)C)[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1)#[N:2].[ClH:24]>CO>[ClH:24].[NH2:15][CH:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(C#N)cc1)C(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(C)C(N)C(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
tert-Butyl 1-(4-chlorophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (Example 2a, 2.30 g, 7.06 mmol) and Zn(CN)2 (0.87 g, 7.4 mmol) were dissolved in DMF (20 mL) under N2 (g). Pd(PPh3)4 (0.86 g, 0.74 mmol) was added and the mixture was heated at 130° C. overnight. The mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The product was purified on a silica column (EtOAc:hexane 1:10) to give tert-butyl 1-(4-cyanophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (961 mg, 43%). tert-Butyl 1-(4-cyanophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (961 mg, 3.04 mmol) was dissolved in 1.25 M HCl in MeOH at 0° C. and the mixture was stirred at rt for 8 h. The solvent was removed and the residue dried in vacuo to give 4-(2-amino-3,3-dimethyl-butanoyl)-benzonitrile hydrochloride (110 mg, 93%).
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:33]1[CH2:38][CH2:37][C:36]([CH3:40])([CH3:39])[CH2:35][CH:34]=1>[Cu]I.CS(C)=O>[CH3:39][C:36]1([CH3:40])[CH2:37][CH2:38][C:33]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:18][CH:19]=2)=[CH:34][CH2:35]1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Reactant: CC1(C)CC=C(Br)CC1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CC1(C)CC=C(Oc2ccc(-c3cccnc3N)cc2)CC1
Temperature: 130 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 1-bromo-4,4-dimethylcyclohex-1-ene (609 mg) and DMSO (8 mL). The mixture was stirred at 130° C. under nitrogen for 16 hr. The insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc). Silica-gel was added to the filtrate and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (563 mg) as an off-white amorphous solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.[OH:23][C:24]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:23][C:24]2([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25]2)=[O:21])=[CH:15][CH:14]=1
Reactant: COC(=O)C1(O)CC1
Reactant: O=C(Cl)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Reaction time: 14 h
Yield: 77.9 %

Procedure:
To a stirred solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetyl chloride (2.0 g, 6.557 mmol) in DCM (50 mL) was added DMAP (1.4 g, 13.11 mmol) followed by methyl 1-hydroxycyclopropanecarboxylate (1.1 g, 9.836 mmol) under a nitrogen atmosphere at RT. The reaction mixture was stirred for 14 h and after complete consumption of the starting material (by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with a saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude methyl 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropanecarboxylate (2.0 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:6]=1[CH2:19]Br)[CH3:2].[CH3:22][O:23][C:24](=[O:37])[CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:6]=1[CH2:19][N:26]([CH2:25][C:24]([O:23][CH3:22])=[O:37])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)(=[O:29])=[O:28])[CH3:2]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1cccc(Oc2ccc(F)cc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Oc2ccc(F)cc2)c1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.1 %

Procedure:
A mixture of 2-bromomethyl-3-(4-fluoro-phenoxy)-benzoic acid ethyl ester (3.37 g, 9.57 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (2.33 g, 9.57 mmol), sodium iodide (2.15 g, 14.36 mmol) and potassium carbonate (1.98 g, 14.36 mmol) in anhydrous dimethylformamide (22 mL) was stirred at room temperature for 24 h before it was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexane to give the title compound as a yellow oil (2.67 g): MS: (+) m/z 538.13 (M+Na+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc(F)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Reaction time: 3 h
Yield: 84.5 %

Procedure:
A solution of 2-(4-fluorophenyl)ethanol(10.0 g, 71.3 mmol) in pyridine (100 mL) was stirred at −5° C. and treated with 4-toluenesulfonyl chloride (14.95 g, 78.4 mmol). After 3 hours, water (10 mL) was added slowly, followed by dilution with ice water and extraction with chloroform. The organic phase was washed with cold 0.5 M aqueous sulfuric acid, then with water, then with saturated aqueous sodium chloride, and was dried over sodium sulfate. Concentration under vacuum provided a pale orange oil containing residual pyridine. Further concentration under vacuum provided an oil (17.74 g) containing about 10% by weight of residual alcohol. A portion was purified by flash chromatography, eluting with 20% ethyl acetate in hexane, to provide a colorless oil. 1H NMR (300 MHz, CDCl3) δ7.70 (d, J=8 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 7.07 (m, 2H), 6.94 (t, J=9 Hz, 2H), 4.20 (t, J=7 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 2.45 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1.Br[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[C:41]([CH3:48])[CH:40]=2)=[O:37])[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CCO.C1(C)C=CC=CC=1.O.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>[CH:45]([C:42]1[CH:43]=[CH:44][C:39]([NH:38][C:36]([C:32]2[CH:31]=[C:30]([C:6]3[CH:5]=[N:4][C:3]([O:2][CH3:1])=[C:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:7]=3)[CH:35]=[CH:34][N:33]=2)=[O:37])=[CH:40][C:41]=1[CH3:48])([CH3:47])[CH3:46]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)OCc1ccccc1
Reactant: Cc1cc(NC(=O)c2cc(Br)ccn2)ccc1C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ncc(-c2ccnc(C(=O)Nc3ccc(C(C)C)c(C)c3)c2)cc1NC(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of benzyl (2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)carbamate (180 mg, 0.47 mmol) in EtOH (4 mL) and toluene (16 mL) was added 4-bromo-N-(4-isopropyl-3-methylphenyl)picolinamide (0.23 g, 0.70 mmol), Pd(PPh3)4 (5.4 mg, 0.046 mmol), and 2M K2CO3 in water (0.46 mL). The mixture was stirred at 100° C. overnight under nitrogen. After cooling to room temperature and evaporation of the solvent, the residue was purified by combi-flash (ISCO, 40 g silica, UV254, 3:1 pet ether/ethyl acetate) to afford benzyl (2′-((4-isopropyl-3-methylphenyl)carbamoyl)-6-methoxy-[3,4′-bipyridin]-5-yl)carbamate (216 mg, 90% yield) as a yellow solid: MS (ES) m/z 511 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]2[C:32]([C:33](O)=[O:34])=[C:31]([CH3:36])[N:30]=[C:27]2[S:28][CH:29]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:26]3[C:27]([S:28][CH:29]=[C:25]3[CH3:24])=[N:30][C:31]=2[CH3:36])=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1nc2scc(C)n2c1C(=O)O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3scc(C)n23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,6-Dimethyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=506.0.
Reaction SMILES: CS(OCC1C(C2C=CC(Cl)=CC=2)=CSC=1C(F)(F)F)(=O)=O.FC1C(F)=C(O)C=CC=1CCC(OCC)=O.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([CH2:55][O:56][C:57]3[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][C:65]([O:67]CC)=[O:66])=[C:59]([F:70])[C:58]=3[F:71])=[C:48]([C:51]([F:54])([F:53])[F:52])[S:49][CH:50]=2)=[CH:42][CH:41]=1>>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]2[C:47]([CH2:55][O:56][C:57]3[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][C:65]([OH:67])=[O:66])=[C:59]([F:70])[C:58]=3[F:71])=[C:48]([C:51]([F:54])([F:53])[F:52])[S:49][CH:50]=2)=[CH:44][CH:45]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c(F)c1F
Agent: CCOC(=O)CCc1ccc(O)c(F)c1F
Agent: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)csc1C(F)(F)F
Product: O=C(O)CCc1ccc(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of [4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.45 (m, 4H), 6.85 (t, J=6.5 Hz, 1H), 6.65 (t, J=6.5 Hz, 1H), 4.95 (s, 2H), 2.96 (t, J=8.0 Hz, 2H), 2.68 (t, J=8.0 Hz, 2H). LCMS (ESI, M/Z) for C21H14ClF5O3S: 476, 478.
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)#[C:2][CH3:3].[OH-].[Na+].O>CO>[C:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)#[C:2][CH3:3]
Reactant: CC#Cc1coc2ccc(C(=O)OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC#Cc1coc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
Methyl 3-prop-1-ynyl-1-benzofuran-5-carboxylate (388 mg, 1.81 mmol) is dissolved in 10 ml MeOH. The solution is treated with 2N NaOH (2.3 ml, 4.6 mmol) followed by 2 ml H2O and the reaction is stirred overnight at RT. The reaction is concentrated to dryness, the residue is dissolved in 9 ml H2O, and the pH is adjusted to 3 with 10% aqueous HCl. The precipitate is collected, washed with H2O, and is dried to afford 356 mg (98%) of 3-prop-1-ynyl-1-benzofuran-5-carboxylic acid as an off-white solid. HRMS (EI) calcd for C12H8O3: 200.0473, found 200.0476 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[CH:22]1([CH2:27][C:28](Cl)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH:22]1([CH2:27][C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=3[CH:14]=2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Reactant: O=C(Cl)CC1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1nc2cc(OC(=O)CC3CCCC3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole), 4-dimethylaminopyridine (100 mg., catalyst) and triethylamine (1.4 ml., 0.01 mole) in dimethylformamide (20 ml.) is added cyclopentaneacetyl chloride (1.6 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 2 hours, poured into ice water and excess hydrochloric acid and extracted into ether. The organic extract is washed with water and dried over magnesium sulfate. The ether is evaporated and the residue chromatographed on silica gel (130 g. 70-230 mesh) to give 2-sulfamoyl-5-benzothiazolyl cyclopentaneacetate.
Reaction SMILES: [CH3:1][C@@H:2]1[O:10][CH2:9][C@:5]2([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[NH:6][O:7][CH2:8][C@@H:4]2[CH2:3]1.N[C@]1(C2C=C(C=CC=2Cl)C#N)[C@H](CO)C[C@H](C)OC1>>[NH2:6][C@:5]1([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[C@H:4]([CH2:8][OH:7])[CH2:3][C@H:2]([CH3:1])[O:10][CH2:9]1
Reactant: C[C@H]1C[C@H]2CON[C@@]2(c2cccc(C#N)c2)CO1
Agent: C[C@H]1C[C@@H](CO)[C@](N)(c2cc(C#N)ccc2Cl)CO1
Product: C[C@H]1C[C@@H](CO)[C@](N)(c2cccc(C#N)c2)CO1

Procedure:
3-[(3aR,5S,7aS)-5-Methyltetrahydro-1H-pyrano[3,4-c][1,2]oxazol-7a(7H)-yl]benzonitrile (C21) was converted to the product using the method described for the synthesis of 3-[(3S,4R,6S)-3-amino-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]-4-chlorobenzonitrile (C18) in Example 6. The resulting product was used in the next step without further purification. Yield: 105 mg, 0.426 mmol, 60%. LCMS m/z 247.1 [M+H+].
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][OH:19])[N:17]=1)[CH2:10][CH2:11][CH3:12]>C(O)C.O>[CH2:9]([C:13]1[NH:17][C:16]([CH2:18][OH:19])=[C:15]([I:1])[N:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc(CO)c[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CCO
Product: CCCCc1nc(I)c(CO)[nH]1
Yield: 95 %

Procedure:
N-iodosuccinimide (148.75 g, 0.661 mol) was added to a stirred solution of 2-n-butyl-4-hydroxymethylimidazole (100.78 g, 0.652 mol) in 500 ml of absolute ethanol. After 20 minutes the solution was heated to 40°-45° C. for 45 minutes, diluted with 2.5 L of water, and chilled. The crystalline product which formed was collected by filtration, washed with water, and dried to give 1.74.5 g (95%) of crystals; mp 166°-166.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[S:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:29]3[CH2:30][CH2:31][S:26][CH2:27][CH2:28]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: O=C1CCSCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCSCC3)CC2)nc1
Temperature: 50 °C
Reaction time: 96 h
Yield: 40.1 %

Procedure:
5-Chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) was dissolved in 95:5 methanol-acetic acid (10 mL), followed by addition of tetrahydrothiopyran-4-one (1.46 g, 12.6 mmol) and sodium cyanoborohydride (5.0 mL of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, the mixture was concentrated in vacuo; and the residue was directly subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol provided 0.23 g (40%) of the title product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].C(N(C(C)C)CC)(C)C.[F:43][C:44]1[CH:67]=[CH:66][C:47]([CH2:48][N:49]2[C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=3[N:51]=[C:50]2[C:58]([CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[O:59])=[CH:46][CH:45]=1.ClC1C=CC=CC=1>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:63]2[CH2:64][CH2:65][CH:60]([C:58]([C:50]3[N:49]([CH2:48][C:47]4[CH:46]=[CH:45][C:44]([F:43])=[CH:67][CH:66]=4)[C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=4[N:51]=3)=[O:59])[CH2:61][CH2:62]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Clc1ccccc1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 14 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.50 g, 0.94 mmol), diisopropylethylamine (0.24 g, 1.9 mmol), 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidine (0.48 g, 1.41 mmol), and chlorobenzene (10 mL). Heat to reflux. After 14 hours, cool and partition the reaction mixture between ethyl acetate and water. Extract the organic layer with 5% sodium bicarbonate solution and a saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 10% methanol/ethyl acetate to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=O.N1CCCCC1.[CH2:19]([O:21][C:22](=[O:38])[CH2:23][C:24]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:25])[CH3:20]>C1C=CC=CC=1>[C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:24](=[O:25])/[C:23](/[C:22]([O:21][CH2:19][CH3:20])=[O:38])=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:32])([CH3:36])([CH3:37])[CH3:35]
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)/C(=C\c1ccc(CC(=O)O)cc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 33.6 %

Procedure:
To a solution of 4-formylphenylacetic acid (4.31 g, 26.3 mmol) in benzene (75 ml) and piperidine (0.95 ml, 9.5 mmol) was added tert-butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (8.1 g, 28.4 mmol). The solution was refluxed under a Dean-Stark trap for 8 h. The solvent was removed by rotary evaporation. The product was purified by silica gel column chromatography (silica gel/75% ethyl acetate in petroleum ether) giving A as an off-white solid (3.81 g, 34% yield). LCMS m/z 432 (MH)+.
Reaction SMILES: [CH2:1]1[CH2:19][O:18][CH:17]2[CH:3]([C@@H:4]([C@@H:15]([CH:20]=[CH:21][C:22](=[O:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:16]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:2]1>C(OCC)(=O)C.[Pd]>[CH2:1]1[CH2:19][O:18][CH:17]2[CH:3]([C@@H:4]([C@@H:15]([CH2:20][CH2:21][C:22](=[O:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])[CH2:16]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:2]1
Reactant: COC(=O)CCCCCC[C@H]1C2OCCOC2C[C@@H]1C=CC(=O)CCC=C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCC[C@H]1C2OCCOC2C[C@@H]1CCC(=O)CCC=C(C)C
Yield: 94 %

Procedure:
To the solution of 3.6 g of 9-ethylenedioxy-15-keto-19-methyl-prost-13,18-dienoic acid, methyl ester, in ethyl acetate (100 ml.) 0.18 g of Pd/C (5%) are added and the mixture is hydrogenated at room temperature under pressure. After absorption of the theoretical quantity of hydrogen the catalyzer is separated by filtration and the solvent evaporated in vacuo to yield 3.4 g of 9-ethylenedioxy-15-keto-19-methyl-prost-18-enoic acid, methyl ester.