Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[C:19]([C:21](=[O:31])[NH:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:24])[CH:18]=[CH:17][C:16]=3[S:32][C:33]3[CH:38]=[CH:37][C:36]([NH:39]C(=O)OC(C)(C)C)=[CH:35][CH:34]=3)=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(Cl)Cl.FC(F)(F)C(O)=O>>[NH2:39][C:36]1[CH:35]=[CH:34][C:33]([S:32][C:16]2[CH:17]=[CH:18][C:19]([C:21]([NH:22][C@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH3:24])=[O:31])=[CH:20][C:15]=2[NH:14][C:8]2[C:7]3[C:12](=[CH:13][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[N:11]=[CH:10][N:9]=2)=[CH:38][CH:37]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(N)cc3)ncnc2c1
Yield: 72.5 %

Procedure:
The product of Example 91G (36 mg, 0.0568 mmol) was treated with 1:1 v/v methylene chloride/trifluoroacetic acid (3 mL) at room temperature for one hour then concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (50 mL), washed with saturated aqueous sodium hydrogencarbonate (25 mL), water (25 mL), and brine (25 mL) then dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel flash chromatography eluting with 3:97 methanol/methylene chloride afforded the title compound as a white solid (22 mg, 0.0412 mmol, 73%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31 (d, J=6.99 Hz, 6 H) 1.45 (d, J=7.35 Hz, 3 H) 3.01-3.20 (m, 1 H) 5.07-5.26 (m, 1 H) 5.57 (s, 2 H) 6.61 (d, J=8.46 Hz, 2 H) 6.83 (d, J=8.46 Hz, 1 H) 7.11 (d, J=8.82 Hz, 2 H) 7.17-7.43 (m, 5 H) 7.54-7.64 (m, 2 H) 7.69 (dd, J=8.46, 1.10 Hz, 1 H) 7.89 (d, J=1.47 Hz, 1 H) 8.43 (t, J=4.23 Hz, 2 H) 8.74 (d, J=7.72 Hz, 1 H) 9.88 (s, 1 H); MS (ESI+) m/z 534 (M+H)+, 1067 (2M+H)+; MS (ESI−) m/z 532 (M−H)−.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH3:24])=[O:22].[OH-].[K+].Cl.[C:29]([O-])([O-])=O.[K+].[K+].C(I)C>CO.CN(C=O)C.O>[F:25][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH2:24][CH3:29])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OC)c1NC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OC)c1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A mixture of 4.1 g (0.011 mol) of product of Example 76, 0.62 g (0.011 mol) of KOH and 5 ml of H2O in 50 ml of methanol was stirred at room temperature overnight. The reaction mixture was poured into 250 ml of H2O containing 50 ml of concentrated HCl, extracted with ether, dried (MgSO4) and concentrated in vacuo to 3.76 g of yellow oil. This oil, 1.52 g (0.011 mol) of K2CO3 and 0.88 ml (0.011 mol) of ethyl iodide in 30 ml of DMF was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ether, dried (MgSO4) and concentrated in vacuo to 3.64 g of yellow oil. Kugelrohr distillation at 53 Pa, pot temperature 103° C., afforded 2.98 g (70.5%) of product as a light yellow oil which solidified; mp 37°-39° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCOCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (47.08 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified via flash silica gel chromatography (5% MeOH/CHCl3) providing the title compound in 18% yield (25 mg, 0.043 mmol).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:20]([CH2:21][CH3:22])[CH:19]([CH3:23])[CH:18]([CH2:24][O:25][Si](C)(C)C)[CH2:17][C:16]2([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:33][CH:32]=2)O)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.Cl[Ti](Cl)(Cl)Cl>[CH2:21]([CH:20]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[C:16]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)=[CH:35][CH:36]=2)[CH2:17][CH:18]([CH2:24][OH:25])[CH:19]1[CH3:23])[CH3:22]
Reactant: CCC1C(C)C(CO[Si](C)(C)C)CC(O)(c2ccc(OCCN3CCCCC3)cc2)C1c1ccc(OCc2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC1C(c2ccc(O)cc2)=C(c2ccc(OCCN3CCCCC3)cc2)CC(CO)C1C

Procedure:
To a solution of 2-(4-benzyloxy-phenyl)-3-ethyl-4-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5-trimethylsilanyloxy methyl-cyclohexanol in DCM (1 mL) was added TiCl4 (0.033 mL, 3 eq.) and the mixture stirred until reaction was done. The reaction mixture was diluted with ethyl acetate (10 mL), and washed with 5% NaHCO3 aqueous solution, then brine. The crude products was purified on HPLC to yield 4-{6-ethyl-4-hydroxymethyl-5-methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-cyclohex-1-enyl}-phenol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH:8]([CH3:14])[C:9]([O:11]CC)=O)=[N:3][CH:2]=1.Cl.Cl.[NH:18]1[CH2:23][CH2:22][CH2:21][N:20]=[C:19]1[NH2:24]>>[CH3:14][C:8]1[C:9](=[O:11])[N:18]2[CH2:23][CH2:22][CH2:21][NH:20][C:19]2=[N:24][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][N:3]=1
Reactant: CCOC(=O)C(C)C(=O)c1ccncn1
Reactant: NC1=NCCCN1
Agent: Cl
Product: Cc1c(-c2ccncn2)nc2n(c1=O)CCCN2

Procedure:
A mixture of 10.72 g (51.48 mmol) of ethyl 3-(4-pyrimidinyl)-2-methyl-3-oxopropionate, (prepared by analogy to the method described in patent DE 2705641 and U.S. Pat. No. 4,110,450) 6.98 g (51.48 mmol) of 1,4,5,6-tetrahydro-2-pyrimidinamine dihydrochloride
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:51]([O:55][C:56]([N:58]1[C:66]2[C:61](=[CH:62][CH:63]=[C:64]([CH2:67]O)[CH:65]=2)[CH:60]=[CH:59]1)=[O:57])([CH3:54])([CH3:53])[CH3:52].C(N(CC)CC)C>ClCCl>[C:51]([O:55][C:56]([N:58]1[C:66]2[C:61](=[CH:62][CH:63]=[C:64]([CH2:67][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:16][CH3:17])=[CH:14][CH:13]=3)[CH:65]=2)[CH:60]=[CH:59]1)=[O:57])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(CO)cc21
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(C(=O)OC(C)(C)C)c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
To 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (472 mg, 2 mmol, 2 eq) was added polymer-bound triphenyl-phosphine (667 mg, 2 mmol, 2 eq) and dichloromethane (10 mL). The mixture was placed under nitrogen, cooled in an ice bath, diisopropyl azodicarboxylate (0.394 mL, 2 mmol, 2 eq) was added drop-wise, stirred for 1.5 hr. A solution of 6-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (247 mg, 1 mmol, 1 eq) and triethylamine (0.279 mL, 2 mmol, 2 eq) in dichloromethane (2 mL) was added drop to portion wise and the reaction allowed to warm to room temperature overnight (20 hr). The reaction was filtered over Celite, adsorbed onto silica gel, and purified by flash chromatography with a gradient from 1-15% ethyl acetate in hexanes to yield 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic acid tert-butyl ester white/clear solid (288 mg, 62%). LC-MS (ES) calculated for C27H25F2NO2, 465.2; found m/z 466 [M+H]+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:34][C:35]1[C:40]([CH2:41][OH:42])=[CH:39][CH:38]=[CH:37][N:36]=1.[CH:43]1([C:48]2[CH:53]=[CH:52][C:51](O)=[CH:50][CH:49]=2)[CH2:47][CH2:46][CH2:45][CH2:44]1>C1COCC1>[CH:43]1([C:48]2[CH:49]=[CH:50][C:51]([O:42][CH2:41][C:40]3[C:35]([NH2:34])=[N:36][CH:37]=[CH:38][CH:39]=3)=[CH:52][CH:53]=2)[CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: Nc1ncccc1CO
Reactant: Oc1ccc(C2CCCC2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncccc1COc1ccc(C2CCCC2)cc1
Reaction time: 20 h
Yield: 8.5 %

Procedure:
Diisopropylazodicarboxylate (0.714 mL) was added to a solution of triphenylphosphine (951 mg), (2-aminopyridin-3-yl)methanol (300 mg) and 4-cyclopentylphenol (392 mg) in THF (dry) (20 mL) at room temperature and the mixture was stirred for 20 hr. Volatiles were removed in vacuo with silica-gel. The silica-supported mixture was purified by column chromatography (1st; NH-silica gel, eluted with EtOAc in hexane, 2nd; silica gel, eluted with EtOAc in hexane) to give the title compound (55.4 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]C)=[O:32])[C:29]2([CH3:36])[CH3:35])=[C:4]([F:39])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[F:47]>>[CH3:35][C:29]1([CH3:36])[C@H:28]([C:8]2[N:7]([CH2:6][C:5]3[CH:37]=[CH:38][C:2]([C:44]4[CH:43]=[CH:42][C:41]([F:40])=[C:46]([F:47])[CH:45]=4)=[CH:3][C:4]=3[F:39])[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=2)[C@@H:30]1[C:31]([OH:33])=[O:32]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2F)C1(C)C
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccc(F)c(F)c3)cc2F)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 97 using racemic methyl cis-3-[1-(4-bromo-2-fluorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]-2,2-dimethylcyclopropanecarboxylate and (3,4-difluorophenyl)boronic acid in Step A. MS (ESI): mass calcd. for C36H28F3N3O3, 607.21; m/z found, 608.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J=8.5, 1H), 8.11 (d, J=8.5, 1H), 7.83 (d, J=8.2, 1H), 7.76-7.72 (m, 1H), 7.68 (d, J=8.5, 1H), 7.58-7.54 (m, 1H), 7.35-7.20 (m, 7H), 7.14-7.11 (m, 1H), 6.93-6.88 (m, 1H), 5.46 (d, J=17, 1H), 5.43 (s, 2H), 5.41 (d, J=17, 1H), 2.34 (d, J=8.2, 1H), 2.13 (d, J=8.2, 1H), 1.31 (s, 3H), 1.05 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[S:4][C:5]([CH3:14])([CH3:13])[CH:6]2[C:10]([OH:12])=[O:11].[Na].[CH3:16][C:17]1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(O)=O.C(Br)C.Cl>C(OCC)(=O)C.O.CN(C)C=O>[NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[S:4][C:5]([CH3:14])([CH3:13])[CH:6]2[C:10]([O:12][CH2:16][CH3:17])=[O:11]
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCBr
Product: CCOC(=O)C1N2C(=O)C(N)C2SC1(C)C
Reaction time: 0.25 h

Procedure:
6-Amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, sodium salt, hereinafter referred to as 6-APA, sodium salt, (5.0 mmole) is added to 50 ml of dimethylformamide at room temperature. After stirring for 15 minutes, 5.5 mmole of ethyl bromide is added. This mixture is stirred for 2 to 3 hours after which it is diluted with ethyl acetate and water. The pH is adjusted to about 6.5 to 7.0 by the addition of hydrochloric acid and the organic phase is separated from the aqueous phase. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [H-].[Na+].C(O)C.[C:6]([CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])([O:8][CH2:9][CH3:10])=[O:7].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br)([O-:20])=[O:19]>O>[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][C:11]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)C1CCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(Cc2ccccc2[N+](=O)[O-])CCCNC1=O
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 2.45 g) was added to ethanol (100 ml), to which was added 3-carboethoxy-2-piperidone (10.0 g). The reaction mixture was stirred for 15 minutes, to which was added 2-nitrobenzyl bromide (13.2 g) at room temperature. The reaction mixture was stirred at 60° C. for 3 hours. Water was added to the reaction mixture, which was concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the entitled compound (14.6 g).
Reaction SMILES: Cl[CH:2]([C:7](=O)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[NH2:11][C:12]([NH2:14])=[S:13]>C(O)C>[NH2:14][C:12]1[S:13][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:7]([CH2:8][CH3:9])[N:11]=1
Reactant: NC(N)=S
Reactant: CCC(=O)C(Cl)C(=O)OC
Solvent: CCO
Product: CCc1nc(N)sc1C(=O)OC
Yield: 94.7 %

Procedure:
Methyl 2-chloro-3-oxo-pentanoate obtained in Example (22a) (1.91 g, 11.57 mmol) was dissolved in ethanol (50 mL). Thiourea (0.77 g, 10.09 mmol) was added, and the mixture was heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was washed with hexane/ethyl acetate: 5/1 to obtain 1.78 g of the title compound as a pale yellow solid (95%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[C:11]([OH:13])=O.[NH2:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[Cl:17][C:15]1[CH:14]=[C:10]([CH:9]=[C:8]([Cl:7])[CH:16]=1)[C:11]([NH:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:13]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 1 h

Procedure:
2.0 mL of methylene chloride, 2.7 μL of N,N-dimethylformamide and 0.061 mL of oxalyl chloride were sequentially added to 0.13 g of 3,5-dichlorobenzoic acid at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 3.0 mL of methylene chloride and 0.45 mL of triethylamine containing 60 mg of tert-butyl 2-amino-4-phenethylbenzoate at room temperature and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(3,5-dichlorobenzamido)-4-phenethylbenzoate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(OCC)(=O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:18][C:17]3[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(F)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 160 °C
Yield: 46.1 %

Procedure:
To 2.0 g of 4,7-dichloroquinoline was added 2.24 g of 4-fluoroaniline, and the mixture was heated with stirring to 160° C. After a few minutes at this temperature, the mixture smoked and the melt solidified. The solid was allowed to cool and was then dissolved in ethyl acetate and washed to remove the aniline. The organic layer was dried over MgSO4 and then solvent was removed using reduced pressure. The residue was recrystallized in heptane to yield 1.27 g of 7-chloro-N-(4-fluorophenyl)-4-quinolinamine. M.P. 214°-16° C. (46.1% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:30]O.Cl>CO.O.C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C@H:10]2[CH2:9][C@@H:8]([C:6]3[O:7][NH:30][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:21][CH:22]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](CCc2ccc(F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CCc1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate (3.15 g, 8.30 mmol) was dissolved in MeOH (30 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.332 g, 8.30 mmol) dissolved in water (3.00 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.509 mL, 8.30 mmol) was added. The resulting solution was stirred at −40° C. for 3 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (42.9 mL, 257.36 mmol) and the mixture was stirred at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated. The compound (split into 4 runs) was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-fluorophenethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.9 g, 66%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.53-2.14 (m, 6H), 2.46-2.64 (m, 2H), 2.98-3.07 (m, 1H), 3.12-3.24 (m, 1H), 3.70 (s, 3H), 3.87-3.99 (m, 1H), 4.05-4.16 (m, 1H), 5.72 (s, 1H), 6.85-6.94 (m, 2H), 7.04-7.11 (m, 2H). MS m/z 349 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][C:5](/[CH:6]=[CH:7]/N(C)C)=[C:4]([N+:14]([O-])=O)[CH:3]=1.C[O:18][C:19]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1C(Cl)=O)=[O:20]>>[Cl:13][C:12]1[CH:11]=[C:5]2[C:4](=[CH:3][C:2]=1[Cl:1])[NH:14][C:7]([C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[C:19]([OH:20])=[O:18])=[CH:6]2
Reactant: CN(C)/C=C/c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccccc1C(=O)Cl
Product: O=C(O)c1ccccc1-c1cc2cc(Cl)c(Cl)cc2[nH]1

Procedure:
Starting from trans-4,5-dichloro-2-nitro-β-dimethylaminostyrene and 2-(methoxycarbonyl)benzoyl chloride and following successively the procedures of Descriptions 2, 3 and 4 afforded the title compound as a light brown solid which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])=[C:6]2[O:25][CH2:26][O:27][C:5]2=[C:4](I)[CH:3]=1.[CH2:29]([O:32][CH3:33])[C:30]#[CH:31].C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:23]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([C:31]#[C:30][CH2:29][O:32][CH3:33])=[C:5]3[O:27][CH2:26][O:25][C:6]=13)=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)#[N:24]
Reactant: COc1cc2ncc(C#N)c(Nc3c(Cl)cc(I)c4c3OCO4)c2cc1OC
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COCC#Cc1cc(Cl)c(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c2c1OCO2
Temperature: 25 °C

Procedure:
A mixture of 4-(6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline (0.25 g), methyl 2-propynyl ether (0.09 ml), N,N-diisopropylamine (0.154 ml), bis(triphenylphosphine)palladium(II) dichloride (0.069 g), cuprous iodide (0.028 g) and ethyl acetate (10 ml) was stirred and heated to reflux for 12 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulphate and evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained the title compound as an oil (0.138 g); NMR Spectrum: (DMSOd6) 3.42 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.38 (s, 2H), 6.17 (s, 2H), 7.13 (s, 1H), 7.36 (s, 1H), 7.92 (s, 1H), 8.39 (s, 1H), 9.42 (br s, 1H); Mass Spectrum: M+H+ 452.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10]O)=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][Cl:14])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ncccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1ncccc1CCl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The 2-isopropyl-3-hydroxymethylpyridine (240 mg, 1.59 mmol) was dissolved in CH2Cl2 (15 mL) and cooled under nitrogen to 0° C. and thionyl chloride (1.0 mL) was slowly added and the reaction was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 and saturated sodium bicarbonate. The organic layer was dried with MgSO4, filtered and the solvent removed under reduced pressure to give the desired 2-isopropyl-3-chloromethylpyridine. The 2-isopropyl-3-chloromethylpyridine (65 mg, 0.383 mmol) was dissolved in CHCl3 (10 mL) and cooled under nitrogen to 0° C. and m-chloroperbenzoic acid (55%, 150 mg) was added in small portions. The reaction was stirred for 2 hours. The solution was extracted with saturated aqueous sodium bicarbonate (2×5 mL). The organic phase was dried with MgSO4, filtered, and the solvent removed under reduced pressure. The residue was chromatographed on silica gel packed in 99:1 CH2Cl2 :MeOH and eluted with same. The appropriate fractions were combined and the solvent removed under reduced pressure to give the desired 2-isopropyl-3-chloromethylpyridine-N-oxide.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)=[CH2:19])=[CH:5][CH:4]=1>CCOC(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[CH2:19])=[CH:7][CH:8]=1
Reactant: C=C(c1ccc(OC)cc1)c1c(-c2ccc(OC)cc2)sc2ccccc12
Solvent: CCOC(C)=O
Product: C=C(c1ccc(O)cc1)c1c(-c2ccc(O)cc2)sc2ccccc12
Yield: 67 %

Procedure:
By essentially following the procedure detailed in Example 5, Part B, the title compound was prepared from methyl 4-[1-[2-(4-methoxyphenyl)benzo[b]thiophen-3-yl]ethenyl]phenyl ether (Part A) in 67% yield as a yellow solid following radial chromatography (SiO2; gradient of 20-40% EtOAc in hexanes).