Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH3:11][C:12]1([CH3:34])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:14][C:13]1=2>C1COCC1>[CH3:11][C:12]1([CH3:34])[CH2:21][CH:20]=[C:19]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:18]2[CH:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:14][C:13]1=2
Reactant: COC(=O)c1ccc2c(c1)C(OS(=O)(=O)C(F)(F)F)=CCC2(C)C
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(c1cccs1)=CCC2(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 329.0 mg (3.93 mmol) of thiophene in 2.0 mL THF at 0° C. was added 251.8 mg (3.93 mmol, 1.56 mL of 2.5 M solution in hexanes) of n-butyllithium. After stirring for 3 h at 0° C., a solution of 845.0 mg (6.28 mmol) of Zna2 in 5.0 mL THF was added and the resulting solution stirred for 30 minutes. This solution was added to a second flask containing 570.0 mg (1.57 mmol) of methyl 5,5-dimethyl-5,6-dihydro-8-(trifluoromethylsulfonyl)oxy-naphthalene-2-carboxylate (Compound E4) and 76.0 mg (0.063 mmol) of tetrakis(triphenyphosphine)palladium(0) in 4.0 mL THF, and the resulting solution was heated to 50° C. for 3 h. Upon cooling to room temperature the reaction was quenched by the addition of saturated aqueous NH4Cl. Extraction with EtOAc was followed by washing of the combined organic layers with H2O and saturated aqueous NaCl, and drying over MgSO4. The dry solution was concentrated under reduced pressure and the title compound was isolated from the residue as a yellow oil by column chromatography (5-10% EtOAc/hexanes).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>CN(C=O)C>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:2]([CH3:3])[CH3:1])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: Clc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(Cl)cc1

Procedure:
Referring to the problem (i), the present inventors have used safer and less expensive alkali metal hydroxide instead of sodium hydride; and they also found that dimethylamine resulting from the decomposition of DMF sometimes reacts with 4-chlorobenzyl bromide to give (4-chlorobenzyl)dimethylamine as a by-product and that a solvent containing dimethylsulfoxide can be used in place of DMF for avoiding the production of the (4-chlorobenzyl)dimethylamine to afford the vinyl imidazole derivatives (I) in high yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([N:25]([C:32]3[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:50]([Br:57])=[CH:49][CH:48]=1.C([O-])([O-])=O.[K+].[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.O>[Br:57][C:50]1[C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:47]([C:14]2[CH:13]=[C:12]([N:25]([C:32]3[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:11]=[C:10]([N:9]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:15]=2)=[CH:48][CH:49]=1
Reactant: Cc1cc(C)cc(N(c2ccccc2)c2cc(B3OC(C)(C)C(C)(C)O3)cc(N(c3ccccc3)c3cc(C)cc(C)c3)c2)c1
Reactant: Brc1ccc(Br)c2ccccc12
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: C1CCOC1
Solvent: O
Product: Cc1cc(C)cc(N(c2ccccc2)c2cc(-c3ccc(Br)c4ccccc34)cc(N(c3ccccc3)c3cc(C)cc(C)c3)c2)c1

Procedure:
13.74 g of a product (yield: 68%) was obtained in the same manner as described in the synthesis method of intermediate 2-3 except that N1,N3-bis(3,5-dimethylphenyl)-N1,N3-diphenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,3-diamine (17.84 g, 30 mmol), 1,4-dibromonaphthalene (9.44 g, 33 mmol), Pd(PPh3)4 (1.04 g, 0.9 mmol), K2CO3 (12.44 g, 90 mmol), THF (90 mL), and water (45 mL) were used.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:23]=1[NH2:24].Cl.N1C=CC=CC=1>C(OCCO)C.C(=O)(O)[O-].[Na+]>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:23]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1O
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2cc3c(Nc4cc(OC)c(Cl)cc4Cl)c(C#N)cnc3cc2cc1O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
A mixture of 0.7 g (2.46 mmol) of 4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.57 g (2.95 mmol) of 2,4-dichloro-5-methoxyaniline and 0.28 g (2.46 mmol) of pyridine hydrochloride in 7 mL of 2-ethoxyethanol is heated at 120° C. for 2 hours, then cooled to room temperature. The product mixture is diluted with saturated solution of sodium bicarbonate and stirred for 15 minutes. The resulting solid is collected by filtration, washed with water and dried. The crude product is purified by silica gel chromatography, utilizing a 98:2 to 90:10 gradient of methylene chloride/methanol to give 0.71 g of 4-(2,4-dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp, 238–240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([CH2:16][OH:17])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:13][CH:14]([CH2:16][O:17][C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=3)[CH2:15]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(CO)C1
Product: COC(=O)c1cc(Cl)cnc1N1CC(COc2cccc(F)c2)C1
Yield: 132 %

Procedure:
The title compound (D83) (D021/006/3) (66.2 mg) was prepared according to the experimental procedure described in Description 82 starting from methyl 5-chloro-2-(3-(hydroxymethyl)azetidin-1-yl)nicotinate (D65) (37 mg, 0.143 mmol) and 3-Fluorophenol (13 μl, 0.143 mmol).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35](OCC)=[O:36])=[CH:27][CH:26]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(C)(C)C.C1COCC1>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:3][C:2]([NH2:4])=[NH:1])=[O:36])=[CH:27][CH:26]=1)[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: N=C(N)N
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC(=N)N)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A solution of 3.64 g (61.69 mmol) of guanidine in 150 ml of tert-butanol was added to a solution of 20 g (41.23 mmol) of (1.1) in THF and the mixture was stirred at room temperature for 18 h. A further 4.5 g of guanidine in 150 ml of tert-butanol were then added, and the reaction solution was stirred at room temperature for 7 h, concentrated to about a half and stirred at room temperature for a further 18 h. The solvent was removed in vacuo and the residue was first filtered through basic Al2O3 using CH2Cl2/MeOH/H2O (95/5/0.5) and then chromatographed on silica gel by means of MPLC using CH2Cl2/MeOH/acetic acid (90/10/0.5). 8.6 g (42%) of (1.2) were obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([OH:32])[CH:25]=[C:26]2[O:30][CH:29]([CH3:31])[CH2:28][C:27]=12)=[O:21]>CN(C=O)C>[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([O:32][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:25]=[C:26]2[O:30][CH:29]([CH3:31])[CH2:28][C:27]=12)=[O:21]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(O)cc2c1CC(C)O2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Temperature: 120 °C
Yield: 54.9 %

Procedure:
4-Fluorophenyl methyl sulfone (307 mg, 1.76 mmol) and Cs2CO3 (1.15 g, 3.52 mmol) were added to a solution of 6-hydroxy-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (1e) (366 mg, 1.76 mmol) in DMF (8 mL). The mixture was heated to 120° C. for 1 hr, cooled to room temperature, quenched with H2O (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with H2O (2×80 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 40% EtOAc in hexanes to give a pale brown solid (350 mg, 55% yield). 1H NMR (400 MHz, CDCl3) δ 7.84-7.93 (m, 2 H) 7.18 (d, J=2.02 Hz, 1 H) 7.04-7.14 (m, 2 H) 6.67 (d, J=2.27 Hz, 1 H) 4.94-5.17 (m, 1 H) 3.89 (s, 3 H) 3.68 (dd, J=17.43, 8.84 Hz, 1 H) 3.13 (dd, J=17.43, 7.58 Hz, 1 H) 3.07 (s, 3 H) 1.51 (d, J=6.32 Hz, 3 H);); LCMS for C18H18O6S m/z 363.0 (M+H)+.
Reaction SMILES: C[O-].[Na+].[Si]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:40][S@@:41]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:42])([C:26]2[CH:31]=[C:30]([O:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])[CH:29]=[C:28]([F:39])[CH:27]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][C:13]=1[F:47])(C(C)(C)C)(C)C>>[F:47][C:13]1[CH:14]=[C:15]([C:18]([NH:40][S@@:41]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:42])([C:26]2[CH:31]=[C:30]([O:32][C:33]([F:37])([F:38])[CH:34]([F:35])[F:36])[CH:29]=[C:28]([F:39])[CH:27]=2)[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:17][C:12]=1[OH:11]
Reactant: CC(C)(C)[S@@](=O)NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(F)c1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)[S@@](=O)NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(O)c(F)c1
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
At room temperature a solution of NaOMe (5 mL, 0.5 M solution in MeOH) was added to the 4:1 diastereomeric mixture of (R)—N-(1-(4-(tert-butyldimethylsilyloxy)-3-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (801 mg, 1.22 mmol). The reaction mixture was stirred for 15 minutes, MeOH was removed then the residue dissolved in EtOAc (50 mL) and transferred to a separation funnel. HCl (20 mL, 1.0 N solution) was added and the EtOAc layer was separated. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated to yield (R)—N-(1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as a white foam (578 mg, 87% yield). LCMS: RT=1.987 min [M+H] 546.35 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[C:35]3[C:30](=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:33][CH:34]=3)[N:29]=[CH:28][C:27]=2[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:41])[CH:23]=[CH:24][CH:25]=1>C(#N)C>[C:40]([C:27]1[CH:28]=[N:29][C:30]2[C:35]([C:26]=1[C:22]1[CH:21]=[C:20]([NH:19][C:8](=[N:9][C:10]#[N:11])[O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:25]=[CH:24][CH:23]=1)=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:37])[F:38])(=[O:41])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: N#CN=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Oc1ccccc1
Yield: 46.6 %

Procedure:
A mixture of diphenyl cyanocarbonimidate (0.6 g, 2.52 mmol) and [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone (0.1 g, 0.26 mmol) in 30 mL of acetonitrile was refluxed for 3 days. Removal of solvent under reduced pressure gave a crude product that was purified by silica gel chromatography eluting with ethyl acetate/hexanes (5% to 30%) to give 65 mg (47%) of the title compound as an off-white solid. MS (ES) m/z 534.9.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:45])[CH2:30][CH2:31][N:32]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:45][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[S:40]([CH2:43][CH3:44])(=[O:42])=[O:41]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCS(=O)(=O)N(CCN(C)C)c1ccc(N)cc1
Product: CCS(=O)(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-ethylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C29H32N4O5S
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:28][N:29](C1C=CC=CN=1)C.C(=O)([O-])[O-].[K+].[K+].CN>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:29][CH3:28])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CN(C)c1ccccn1
Reactant: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCBr
Agent: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNCCOc1ccc(CC(=O)NCCCc2ccc(C)c(C)c2)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.10 g (0.23 mmol) of N-{3-(3,4-dimethylphenyl)propyl}-4-(2-bromoethoxy)-3-methoxyphenylacetamide obtained in step 1 of Example 2 and a catalytic amount of dimethylaminopyridine were dissolved in 50 ml of tetrahydrofuran and 0.048 g (0.35 mmol) of potassium carbonate was added thereto. Then, methylamine was passed through the mixture by bubbling at the temperature ranging from -10° to -20° C. The resultant mixture was stirred at a room temperature for 6 hours. After removing the solvent under a reduced pressure, the residue was subjected to silica gel column chromatography(eluent: ethyl acetate:hexane= 1:1) to obtain the title compound.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:22]I>O1CCCC1.O>[CH:15]1([CH:14]([CH3:22])[C:13]([O:12][CH3:11])=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)CC1CCCCC1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)C1CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
1.0 M of Lithium hexamethyldisilazide in tetrahydrofuran (2.2 mL, 2.2 mmol) was added to a solution of methylcyclohexylacetate (0.30 g, 1.9 mmol) (Aldrich, Cat. #209600) in tetrahydrofuran (7.0 mL) at −78° C. The mixture was stirred at −78° C. for 1 h., then methyl iodide (0.14 mL, 2.3 mmol) was added. The mixture was allowed to warm slowly to r.t., and stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-10%) to afford the desired product (0.30 g, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2OC(C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=[O:37])C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[O:13][C:14]=1[C:15]([OH:37])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C=O)o2)c1
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)o2)c1

Procedure:
3-Benzyloxy-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-4H-pyran-2-carboxylic acid (12-04) (1.6 g, crude) was synthesized as a white solid from N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (11-04) (1.8 g, 4.35 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.O>O1CCCC1>[O:15]=[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCCCC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)C(Cc1ccc(C#N)cc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
240 mg of sodium hydride as a suspension at 50% in oil were added to a solution of 0.81 g of 1-phenyl-2-hexanone of Step A of Example 7 in 20 ml of tetrahydrofuran and the mixture was stirred for 90 minutes at 40° C. Then, a solution of 900 mg of 4-(bromo-methyl)-benzonitrile in 10 ml of tetrahydrofuran was added and after stirring for 2 hours at ambient temperature, the reaction mixture was poured into water. Extraction was carried out with ethyl acetate and the extracts were washed with water, dried, and evaporated to dryness. The residue was chromatographed on silica (eluant: methylene chloride - hexane (1-1)) to obtain 1.1 g of the desired product melting at 70° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([N:13]1[CH:17]=[C:16]([CH2:18][C@@H:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:20]([NH2:22])=[O:21])[N:15]=[N:14]1)[CH2:8][CH2:7][CH2:6]2>ClCCCl.CC#N.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([N:13]1[CH:17]=[C:16]([CH2:18][C@@H:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[C:20]([NH2:22])=[O:21])[N:15]=[N:14]1)[CH2:8][CH2:7][CH2:6]2)=[O:1]
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(CO)ccc43)nn2)C(N)=O)cc1
Agent: O=[Mn]=O
Solvent: CC#N
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(C=O)ccc43)nn2)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-3-(1-((R)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylbenzenesulfonamido)propanamide (0.66 g, 1.4 mmol) in DCE/MeCN (1:1, 30 mL) was added MnO2. The reaction mixture was stirred overnight at RT. The solid was removed by filtration, and the filtrate was concentrated to give a tan solid. MS (m/z): 468.4 (m+H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:24]=[C:23]([C:25]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[C:22]([C:33]([F:36])([F:35])[F:34])=[CH:21][C:10]=2[C:11]([O:13]CC2C=CC=CC=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].O.Cl>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:24]=[C:23]([C:25]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:26])[C:22]([C:33]([F:36])([F:34])[F:35])=[CH:21][C:10]=2[C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(F)(F)F)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To a solution of phenylmethyl 2-[(phenylmethyl)oxy]-4-(1-piperidinylcarbonyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 57; 170 mg, 0.34 mmol) in tetrahydrofuran (4 ml) was added LiOH (24.55 mg, 1.03 mmol) and water (1 ml). The solution was heated at 45° C. for one hour then room temperature for 18 hours. 2M hydrochloric acid (0.51 ml, 1.03 mmol) was added and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (20 ml) and 2M HCl (10 ml). The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo to give the title compound. 139 mg.
Reaction SMILES: [CH3:1][N:2](C)[C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)[CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CNC>>[CH3:1][NH:2][C:3]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)[CH2:17]3)[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)=[O:38]
Reactant: CN(C)C(=O)c1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Agent: CNC
Product: CNC(=O)c1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was synthesized in similar fashion to N,N-dimethyl-4-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidin-1-yl)benzamide, substituting methylamine for dimethylamine, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.42-1.62 (m, 2H), 1.64-1.78 (m, 1H), 1.93-2.08 (m, 2H), 2.20-2.38 (m, 2H), 2.55-2.65 (m, 2H), 2.80-2.95 (m, 7H), 3.28-3.32 (m, 2H), 3.35 (s, 1H), 3.81-3.92 (m, 2H), 4.02 (s, 2H), 4.35-4.44 (m, 1H), 6.96 (d, J=9.0 Hz, 2H), 7.68 (t, J=7.5 Hz, 1H), 7.69 (d, J=8.7 Hz, 2H), 7.86 (d, J=8.1 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 8.21 (s, 1H). MS m/z: 532 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:22]([OH:27])[C:23]([F:26])([F:24])[F:25])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:28][CH:29]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC1Cc2ccccc2C1
Reactant: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)NC2Cc3ccccc3C2)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Temperature: 110 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
To a solution of 2,2,2-trichloroethyl 5-tert-butyl-2-methoxy-3-(2,2,2-trifluoro-1-hydroxyethyl)phenylcarbamate (0.150 g, 0.331 mmol) and 2-aminoindane (0.053 g, 0.398 mmol) in acetonitrile (1.0 mL), N,N-diisopropylethylamine (0.173 mL, 0.994 mmol) was added, and the mixture was stirred at 110° C. for 18 hours. The reaction mixture was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-60/40) to obtain 0.133 g of the captioned compound (92% yield).