Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:51])[NH:4][C@@H:5]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:6](=[O:46])[NH:7][C@@H:8]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:36][CH:35]=1)[C@@H:9]([OH:32])[CH2:10][C@H:11]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:12][C:13](=[O:24])[C@H:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[NH:15][C:16](=[O:19])[O:17][CH3:18].[CH3:52][S:53][CH3:54].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:25]([C@H:11]([NH:12][C:13]([C@@H:14]([NH:15][C:16](=[O:19])[O:17][CH3:18])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:10][C@H:9]([O:32][CH2:52][S:53][CH3:54])[C@@H:8]([NH:7][C:6](=[O:46])[C@H:5]([C:47]([CH3:50])([CH3:49])[CH3:48])[NH:4][C:3]([O:2][CH3:1])=[O:51])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:38][CH:39]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Reactant: CSC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](OCSC)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of the compound of Example 25 (0.125 g, 0.178 mmol) and methyl sulfide (0.405 mL, 5.48 mmol) in acetonitrile (0.75 mL) at 0° C. was added benzoyl peroxide (0.63 g, 2.60 mmol), and the mixture was stirred at 0° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (0.104 g, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2(O)[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:19].[Na+].[Na+].S(=O)(=O)(O)O.O>C(OCC)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9](=[O:19])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)C=CC(O)(Cc2ccc(Cl)cc2)CC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)=CC1=O
Reaction time: 0.67 h
Yield: 189.6 %

Procedure:
A solution of the 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-2-en-1-ol (368 g, 1.47 mol) obtained in (a) in 40/60 petroleum (40 ml) was added in a steady stream to a solution of sodium dichromate (217 g, 0.74 mol) in dilute sulphuric acid (250 g, 2.6 mol 98% sulphuric acid in 1.5 liters of water). The reaction mixture was then held at a temperature between 10° and 30° C. and stirred for 40 minutes. Water (500 ml) and diethyl ether (700 ml) were added and the aqueous layer extracted twice with diethyl ether (2×700 ml). The organic phases were then combined and backwashed with saturated sodium bicarbonate solution (1×500 ml) and water (1×500 ml). The solvent was then flashed off to give 349 g crude 1-(4-chlorobenzyl)-4,4-dimethylcyclohex -1-en-3-one as a beige coloured granular solid. Trituration in petrol gave a pure sample of the desired product, m.pt. 87°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[OH:14][CH2:15][C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17][OH:18]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([O:14][CH2:15][C:16]([CH2:21][O:22][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=1[O:2][CH3:1])([CH2:19][O:20][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=1[O:2][CH3:1])[CH2:17][O:18][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=1[O:2][CH3:1])=[O:6]
Reactant: OCC(CO)(CO)CO
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Product: COc1ccc(C(=O)OCC(COC(=O)c2ccc(OC)cc2OC)(COC(=O)c2ccc(OC)cc2OC)COC(=O)c2ccc(OC)cc2OC)c(OC)c1
Yield: 78 %

Procedure:
Using the procedure of Eample I, 2,4-dimethoxybenzoyl chloride was allowed to react with pentaerythritol in the molar ratio of 4:1. The reaction gave a 78% yield of white crystalline product having a melting point of 125°-126.5° C. and the infrared spectrum was a consistent with the expected tetraester with no hydroxyl band and an ester carbonyl band at 5.85μ (s).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:6]=[CH:5][C:4]=1[N+:26]([O-])=O.C(OCC)(=O)C>C(O)(=O)C.[Zn]>[CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][C:11]=2[CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:6]=[CH:5][C:4]=1[NH2:26]
Reactant: CNc1cc(Oc2ccc(C(F)(F)F)cc2Cn2cncn2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNc1cc(Oc2ccc(C(F)(F)F)cc2Cn2cncn2)ccc1N

Procedure:
N-Methyl-2-nitro-5-[2-(1H-1,2,4-triazol-1-ylmethyl)-4-(trifluoromethyl)phenoxy]aniline (1.0 g) from Example 63 was dissolved in acetic acid (10 ml), followed by gradual addition of zinc powder (830 mg) at room temperature. After the addition, ethyl acetate was added to filter off insoluble matetials, and to the filtrate was added saturated sodium hydrogen carbonate solution carefully for separation. The organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, 2-methylamino-4-[2-(1H-1,2,4-triazol-1-ylmethyl)-4-(trifluoromethyl)phenoxy]aniline was obtained as the crude product (920 mg).
Reaction SMILES: C[C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](O)=O)[CH:18]=[CH:19][CH:20]=1>>[CH3:2][C:3]1[C:4](=[O:5])[CH:6]2[CH:11]([C:12](=[O:13])[C:22]=1[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Br:14])[CH:16]=1)[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Product: CC1=C(Cc2cccc(Br)c2)C(=O)C2C=CC=CC2C1=O
Yield: 52 %

Procedure:
As starting materials for the coupling reaction menadione and 3-bromophenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:1, UV), 328 mg (0.96 mmol, 52% yield) of P_TM99 were isolated as yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)=[O:2].[C:24](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH:1]([C:3]1[CH:7]=[C:6]([N:8]([CH3:24])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(NS(=O)(=O)c2ccccc2)n(-c2ccccc2)n1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cc(C=O)nn1-c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of N-(3-formyl-1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide (331 mg) in N,N-dimethylformamide (5 mL) were added potassium carbonate (182 mg) and iodomethane (215 mg) at room temperature. After stirring at room temperature for 1 hr, the mixture was further stirred at 80° C. for 1 hr, and allowed to cool to room temperature. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:1→3:1) to give the title compound as a pale-yellow amorphous (yield 297 mg, yield 86%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([N:10]=[C:11]2[N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]3[CH:13]([CH3:20])[O:12]2)=[C:4]([F:21])[CH:3]=1.Br.[OH-].[Na+]>>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:10]=[C:11]2[N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]3[CH:13]([CH3:20])[O:12]2)=[C:4]([F:21])[CH:3]=1
Reactant: COc1cc(N=C2OC(C)C3CCCCN23)c(F)cc1Cl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: CC1OC(=Nc2cc(O)c(Cl)cc2F)N2CCCCC12

Procedure:
14.4 g 3-(4-Chloro-2-fluoro-5-methoxyphenylimino)-1-methylhexahydro-3H-oxazolo[3,4-a]pyridine was heated under reflux with 25 ml 48% hydrobromic acid for 5 hours. After cooling it was neutralised with 40% caustic soda and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate, concentrated and the residue recrystallised from petroleum ether.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO.C(Cl)(Cl)Cl>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:16]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2ccc(-c3ccccc3)nc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc(-c3ccccc3)nc2-c2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
The 2-(4-benzyloxyphenyl)-3-(4-methoxyphenyl)-6-phenylpyridine (3.5 g, 7.9 mmol) and ammonium formate (2.5 g, 40 mmol) were stirred in 150 mL of EtOH, then 5% Pd/ C (1.4 g, 0.6 mmol Pd) was added and the reaction mixture was stirred at 60 ° C. for 1 h. The TLC (MeOH/ CHCl3, 1:9) indicated a small amount of the starting material remained, so more ammonium formate (0.3 g, 5 mmol) was added and reaction mixture stirred at 60° C. for 0.5 h, which consumed the remaining starting material. After cooling, the reaction mixture was filtered and the filter pad washed with 50 mL of EtOH, then 50 mL of EtOAc. The filtrates were combined and concentrated, then redissolved in 150 mL of EtOAc, washed with brine, dried (Na2SO4), concentrated, and the residue triturated with Et2O/ pet. ether to give 2.5 g (90% yield) of white solid: mp 200°-202° C.; 1H NMR (CDCl3) d 3.85 (s, 3H, OCH3), 5.07 (s, 1H, ArOH), 6.71-6.90 (m, 4H, ArH), 7.17-7.20 (d, 2H, J=8 Hz, ArH), 7.38-7.54 (m, 5H, ArH), 7.75 (s, 2H, ArH), 8.13-8.16 (d, 2H, J=9 Hz, ArH); MS(FD) 354(M+). Anal. Calcd for C24H19 NO2 : C, 81.56; H, 5.42; N, 3.96. Found: C, 81.50; H, 5.61; N, 3.99.
Reaction SMILES: [O-]CC.[Na+].Cl.[CH:6]([NH2:8])=[NH:7].C(O[C:12](=[O:24])[CH:13]([C:22]#[N:23])[CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])C>C(O)C>[NH2:23][C:22]1[N:7]=[CH:6][NH:8][C:12](=[O:24])[C:13]=1[CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: CCOC(=O)C(C#N)CC(OCC)OCC
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(Cc1c(N)nc[nH]c1=O)OCC
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 45.2 mmol of sodium ethoxide (made in situ from sodium and absolute ethanol) in 40 mL of absolute ethanol was added formamidine hydrochloride (1.74 g, 21.5 mmol) and 2-cyano-4,4-diethoxy-butyric acid ethyl ester (2.47 g, 11 mmol, literature reference: Davoll, J., J. Chem. Soc. 131-138 (1960)). The mixture was refluxed for 6 hours, cooled to room temperature and filtered. The solid was washed with hot acetonitrile. The filtrate was neutralized with acetic acid to pH 6.5 and then evaporated to half of the volume. Ethyl acetate (50 mL) was added to the resultant filtrate. The precipitate was filtered, washed with EtOAc to give 1.6 g (66%) of 6-amino-5-(2,2-diethoxy-ethyl)-3H-pyrimidin-4-one as a white solid which was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, br, 1H, NH), 7.68 (s, 1H), 6.07 (s, br, 2H, NH2), 4.54 (t, J=6.0 Hz, 1H, CH(OCH2CH3)2), 3.53-5.62 (m, 2H, CH(OCH2CH3)2), 3.31-3.49 (m, 2H, CH(OCH2CH3)2), 2.50 (m, 2H, CH2), and 1.05 (t, J=6.93 Hz, 6H, CH(OCH2CH3)2).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][CH2:23][CH2:24]O)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][CH2:23][CH2:24][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1ccccc1OCc1coc(/C=C/c2ccccc2)n1
Reactant: c1nc[nH]n1
Product: C(=C/c1nc(COc2ccccc2CCCn2cncn2)co1)\c1ccccc1
Yield: 54 %

Procedure:
In substantially the same manner as in Working Example 1, 3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with 1,2,4-triazole to give 1-[3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole. The yield was 54%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 72-73° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[Al](C)C.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[N:16]1[C:21]2[N:22]=[C:23]([NH:34][CH2:35][C:36]([O:38]C)=O)[N:24]=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH3:33])[C:20]=2[CH:19]=[CH:18][C:17]1=[O:40]>>[F:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[C:10]=1[N:16]1[C:21]2[N:22]=[C:23]([NH:34][CH2:35][C:36]([N:2]([CH3:3])[CH3:1])=[O:38])[N:24]=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH3:33])[C:20]=2[CH:19]=[CH:18][C:17]1=[O:40]
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CNC
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 54.5 %

Procedure:
Following the general procedure outlined in Example 193, dimethylamine (1.1 mL, 2.2 mmol), trimethylaluminum (1.1 mL, 2.2 mmol) and the product of Example 190 (100 mg, 0.22 mmol) were reacted to give the desired product 56 mg (54%). LC-MS: 468.2 (MH+, m/z), 2.00 (Rt, min).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:37]=[C:38]([C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1)[CH3:39]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6](/[CH:37]=[C:38](/[C:40]3[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=3)\[CH3:39])[C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Reactant: CC(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(OC(F)(F)F)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Methyl-8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (135 mg, 0.5 mmol) was dissolved in DMF. Copper (I) iodide (9.5 mg, 0.05 mmol), L-proline (11.5 mg, 0.1 mmol) and potassium phosphate (414 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)pyridine (116 mg, 0.55 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 90° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-7% MeOH-DCM. Yield: 12 mg. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.82 (d, 2H), 8.30 (d, 2H), 7.78 (s, 1H), 7.50 (s, 1H), 7.38 (d, 1H), 7.22 (d, 1H), 4.70 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:22]1(C)C=CC=C[CH:23]=1>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>[Cl:15][C:4]1[CH:3]=[C:2]([CH:22]=[CH2:23])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Cl
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+]
Product: C=Cc1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Yield: 46 %

Procedure:
To a stirred solution of tert-butyl 4-bromo-2-chlorobenzoate (1.6 g, 5.50 mmol) in toluene (20 mL) was added tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4; (0.31 mg, 0.27 mmol), K2CO3 (2.27 g, 16.5 mmol) and vinylboronic anhydride pyridine complex (2.0 g, 8.3 mmol) and the reaction mixture was heated to reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 5-6% EtOAc in n-hexane) afforded the title compound as a liquid (0.6 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.1 Hz, 1H), 7.44 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz, 1H), 5.85 (d, J=17.6 Hz, 1H), 5.40 (d, J=10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 238.95 ([M+H]+); IR (thin film) 2931, 1725, 1134 cm−1.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[CH:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[C:4]2[C:5]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)=[C:6]([Br:26])[NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1cccc2[nH]cc(-c3ccc(Cl)cc3)c12
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1cccc2[nH]c(Br)c(-c3ccc(Cl)cc3)c12
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of the indole of Step 6 (650 mg, 2.4 mmol) in CCl4 (15 mL) was added NBS (465 mg, 2.6 mmol). The reaction mixture was heated to 50° C. and stirred for 15 minutes. The resulting suspension was filtered on a SiO2 pad eluted with 50% EtOAc in hexanes and concentrated. The title compound was obtained in a quantitative yield as a brownish solid foam used as such.
Reaction SMILES: I[C:2]1[C:3]([CH3:12])=[N:4][N:5]([CH2:7][C@H:8]([OH:11])[CH2:9][OH:10])[CH:6]=1.IC1C=NN(C[C@H](O)CO)C=1C.C1COCC1.C([Mg]Cl)(C)C.CO[B:37]1[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1.[NH4+].[Cl-]>>[CH3:12][C:3]1[C:2]([B:37]2[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]2)=[CH:6][N:5]([CH2:7][C@H:8]([OH:11])[CH2:9][OH:10])[N:4]=1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1nn(C[C@H](O)CO)cc1I
Agent: CC(C)[Mg]Cl
Agent: Cc1c(I)cnn1C[C@H](O)CO
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nn(C[C@H](O)CO)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-(4-iodo-3-methylpyrazol-1-yl)-propane-1,2-diol (20.0 mg, 0.0709 mmol) and (S)-3-(4-Iodo-5-methylpyrazol-1-yl)-propane-1,2-diol (20.0 mg, 0.0709 mmol) in THF (1 mL, 10 mmol) was added 2 M isopropylmagnesium chloride in THF (0.18 mL, 0.36 mmol) at 0° C., and the reaction was allowed to warm to rt over 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.070 mL, 0.43 mmol) was then added, and the mixture was stirred at rt for 30 min. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil. It was used in the Suzuki coupling without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:40])[O:36][CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:40])[O:36][CH:37]([CH3:38])[CH3:39])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCCC1
Product: CC(C)OC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4Cl)CCCCC3)CC2)c1

Procedure:
Example 147 was prepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: ESMS m/e: 558.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.CCN(CC)CC.Cl.[CH3:38][NH:39][O:40][CH3:41]>C1COCC1>[CH3:41][O:40][N:39]([CH3:38])[C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 127.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.15 g, 25.6 mmol) in THF (100 mL) was added DCC (7.11 g, 34.5 mmol), Et3N (5.18 g, 51.2 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.3 mmol), the reaction was stirred at RT for about 16 hr. Concentrated under reduced pressure to remove solvent, the residue was portioned between EA (100 mL) and water (50 mL), the aqueous was further extracted with EA (50 mL×3). The combined organic phases were washed with brine (20 mL), concentrated under reduced pressure to remove solvent, then purified by column chromatography on silica gel (200-300 mesh, CH2Cl2/MeOH=20/1) to give the crude product (˜8.0 g) as a colorless oil. MS (ESI) m/e [M+23]+ 266.9, [M−55]+ 189.0.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][O:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[O:6][C:5]([CH2:7][O:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: COCc1oc(Br)cc1C(=O)OC
Reactant: OB(O)c1ccc(F)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COCc1oc(-c2ccc(F)cc2)cc1C(=O)OC
Yield: 90.5 %

Procedure:
A mixture of methyl 5-bromo-2-(methoxymethyl)furan-3-carboxylate (2.5 g), 4-fluorophenylboronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (14 mL) and 1,2-dimethoxyethane (30 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 25% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.4 g, 91%) as a white crystal.