Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:21][OH:22])[CH:3]([NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:23][CH:24]([CH2:44]O)[CH:25](NC(C1NC2C(C=1)=CC=CC=2)=O)C1C=CC=CC=1.COC1C=CC(C(O)=O)=CC=1.C(Cl)(=O)C(Cl)=O.NC(C1C=CC=CC=1)C(O)CO>C(N(CC)CC)C>[CH:2]([O:23][CH:24]([CH3:25])[CH3:44])([CH3:21])[CH3:3].[OH:1][CH:2]([CH2:21][OH:22])[CH:3]([NH:10][C:11](=[O:20])[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NC(c1ccccc1)C(O)CO)c1cc2ccccc2[nH]1
Agent: COc1ccc(C(=O)NC(c2ccccc2)C(O)CO)cc1
Agent: COc1ccc(C(=O)O)cc1
Agent: NC(c1ccccc1)C(O)CO
Solvent: CCN(CC)CC
Product: CC(C)OC(C)C

Procedure:
N-[(1RS, 2RS)-2,3-Dihydroxy-1-phenylpropyl]-4-methoxybenzamide may be prepared in the following manner: working as in Example 8 for the preparation of N-[(1RS, 2RS)-2,3-dihydroxy-1-phenylpropyl]-2-indolecarboxamide, but starting with 4-methoxybenzoic acid (3.7 g), oxalyl dichloride (2.26 cc), (2RS, 3RS)-3-amino-3-phenyl-1,2-propanediol (3.7 g) and triethylamine (9.26 cc) and after the precipitate is washed with distilled water and then with diisopropyl ether, N-[(1RS, 2RS)-2,3dihydroxy-1-phenylpropyl]-4-methoxybenzamide (5.5 g), m.p. 178° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([CH2:32][O:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[N:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:75]1([NH:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[C:82]([Cl:86])[C:81]=2[Cl:87])[CH2:77][CH2:76]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([CH2:32][O:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:38])[CH3:39])=[N:29][CH:28]=3)=[C:13]2[C:24](=[O:25])[N:78]([CH:75]2[CH2:76][CH2:77]2)[CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[C:82]([Cl:86])[C:81]=2[Cl:87])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cnc(COCCO[Si](C)(C)C(C)(C)C)s3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Reactant: Clc1cccc(CNC2CC2)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CC(c3cnc(COCCO[Si](C)(C)C(C)(C)C)s3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Reaction time: 168 h
Yield: 12.1 %

Procedure:
To a stirred sol. of compound D8 (0.38 g, 0.594 mmol) in CH2Cl2 (3.0 mL) were added EDC.HCl (0.285 g, 1.49 mmol), HOBt (0.109 g, 0.713 mmol), DMAP (2.0 mg, 0.15 mmol) and DIPEA (0.467 mL, 2.67 mmol). After 15 min cyclopropyl-(2,3-dichloro-benzyl)amine (0.257 g, 1.19 mmol) was added and stirring was continued for 7 days. Every day cyclopropyl-(2,3-dichlorobenzyl)amine (prepared by reductive amination from 2,3-dichlorobenzaldehyde and cyclopropylamine, 0.128 g, 0.59 mmol) was added. The reaction mixture was partitioned between aq. 1M HCl and CH2Cl2, and the phases were separated, washed with aq. sat. NaHCO3, dried over MgSO4, filtered, and the solvents were removed in vacuo. Purification of the crude by FC (heptane/EtOAc 7/3→1/1) yielded the title product (60 mg, 12%) as a yellow oil. LC-MS: tR=1.28 min, ES+: 837.48.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[CH3:56][C@H:57]1[CH2:62][NH:61][C@H:60]([CH3:63])[CH2:59][N:58]1[CH2:64][C:65]1[S:66][C:67]2[CH:73]=[CH:72][C:71]([C:74]([F:77])([F:76])[F:75])=[CH:70][C:68]=2[N:69]=1>CN(C=O)C.CCOC(C)=O>[CH3:63][C@@H:60]1[CH2:59][N:58]([CH2:64][C:65]2[S:66][C:67]3[CH:73]=[CH:72][C:71]([C:74]([F:77])([F:75])[F:76])=[CH:70][C:68]=3[N:69]=2)[C@@H:57]([CH3:56])[CH2:62][N:61]1[C:19](=[O:21])[CH2:18][O:17][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:24])([F:25])[F:23])[CH:6]=2)[CH2:12][CH2:13]1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: C[C@@H]1CN(Cc2nc3cc(C(F)(F)F)ccc3s2)[C@@H](C)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: C[C@@H]1CN(Cc2nc3cc(C(F)(F)F)ccc3s2)[C@@H](C)CN1C(=O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a solution of [4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetic acid (172 mg, 0.476 mmol, 2 eq.) in DMF (5 ml) was added EDAC hydrochloride (68 mg, 0.36 mmol, 1.5 eq.), HOBt (55 mg, 0.36 mmol, 1.5 eq.) and 4-methylmorpholine (0.13 ml, 1.2 mmol, 5 eq.). The resulting solution was stirred for 30 min then 2-((2S,5R)-2,5-dimethyl-piperazin-1-ylmethyl)-5-trifluoromethyl-benzothiazole hydrochloride (87 mg, 0.24 mmol, 1 eq.) was added. The solution was stirred overnight at room temperature and diluted with EtOAc (25 ml) and washed with water (25 ml), saturated aqueous lithium chloride (25 ml) and brine (25 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column with Heptanes—EtOAc to afford 1-[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone as a yellow solid (86.1 mg, 53.7%). (CI, m/z): [M+H]+ 674; 1H NMR (400 MHz, CDCl3) δ 1.02-1.53 (m, 10H), 2.18 (br s, 4H), 2.47 (d, J=11.7 Hz, 1H), 2.99 (d, J=8.8 Hz, 1H), 3.23 (br s, 1H), 3.31-3.53 (m, 2H), 3.85-4.13 (m, 4H), 4.20 (br s, 3H), 4.46 (d, J=7.6 Hz, 1H), 6.64 (dd, J=9.1, 2.5 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 8.01 (t, J=8.3 Hz, 2H), 8.21 (s, 1H).
Reaction SMILES: [O:1]=[C:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.Cl.[CH3:17][O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)[C@H](C)N
Reactant: CCCCCC(=O)CCCCCC(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCC(=O)CCCCCC(=O)N[C@@H](C)C(=O)OC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
7-oxododecanoic acid (1000 mg, 4.67 mmoles) and L-alanine methyl ester hydrochloride (656 mg, 4.7 mmoles) were dissolved in N,N-dimethylformamide (5 ml). The solution was cooled to 0° C. and diphenylphosphoryl azide (1300 mg, 4.72 mmoles) and triethylamine (950 mg, 0.95 mmoles) were added thereto. The reaction mixture was stirred for 1 hour on an ice bath and for 24 hours at room temperature. The resulting suspension was diluted with ethyl acetate (30 ml) and washed successively with citric acid (0.52M; 3×5 ml), water (3×5 ml), saturated NaCl solution (3×5 ml), saturated NaHCO3 solution (3×5 ml), water (3×5 ml) and saturated NaCl solution (3×5 ml). The organic phase was dried with MgSO4 and filtered, the filtrate was evaporated and the compound was precipitated from n-hexane/diethyl ether.
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33]>ClCCl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:18][CH2:17]3)=[CH:22][CH:23]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)COC(=O)Cl
Reactant: c1cc(-n2cnnn2)ccc1OCC[C@@H]1C[C@@H]1C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-((1R,2S)-2-(2-(4-(1H-Tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine (Step A, Example 1; 100 mg, 0.319 mmol) and triethylamine (97 mg, 0.96 mmol) were dissolved in dichloromethane (5 mL). Isobutyl chloroformate (52 mg, 0.38 mmol) was added. The mixture was stirred at RT for 30 min and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (12 g RediSep, eluted with dichloromethane/methanol, 199:1, 500 mL). The product containing fractions were combined and concentrated under reduced pressure. The compound was further purified by prep-HPLC (SunFire C18 OBD, 10 μm, 50×150 mm, 118 mL/min, acetonitrile/water 10:90 to 90:10 at 25 min, total run 30 min) provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 4.20-4.10 (m, 4H), 3.86 (d, J=6.6 Hz, 2H), 2.85-2.60 (m, 2H), 2.25-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.70 (m, 2H), 1.60-1.45 (m, 1H), 1.40-1.25 (m, 2H), 1.10-0.90 (m, 2H), 0.94 (d, J=6.7 Hz, 6H), 0.80-0.65 (m, 2H), −0.09 (q, J=5.2 Hz, 1H). MS (ESI) m/z 414 [M+H]+. GPR119 Human EC50:1.6 nM
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22]Cl)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[Na+].[C:25]1([S:31]([O-:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.O1CCOCC1.C>CO.C(OCC)(=O)C.CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCl
Reactant: O=S([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCS(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 21.6 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, a 2:1 mixture of N′-[2-butyl-1H-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-yl]-N,N-dimethylimidoformamide and 2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.3 g), benzenesulfinic acid sodium salt (1.67 g, 10.11 mmol), and anhydrous dimethyl formamide (15 mL) under a nitrogen atmosphere. The resulting solution was heated to 100° C. to give a homogeneous solution that was maintained at 100° C. for 90 hours at which time the starting materials were completely consumed. The solution was cooled and then partitioned between chloroform and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a dark yellow gum. The material was dissolved in methanol (20 mL) and a 4 M solution of hydrochloric acid in dioxane (3.02 mL, 12.1 mmol). The light orange solution was stirred at ambient temperature for 12 hours at which time the reaction was judged to be complete. The volatiles were removed under reduced pressure to give a light yellow gum. The material was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with chloroform (1×). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow solid. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to give an off-white solid. The solid (0.63 g) was dissolved in ethyl acetate (50 mL) and brought to reflux. Activated charcoal (0.6 g) was added and the resulting-mixture was heated at reflux for 5 minutes. The charcoal was removed by filtration through fluted paper to provide a colorless solution. The solution was concentrated under reduced pressure to give a solid that was recrystallized from ethyl acetate and hexanes to provide 2-butyl-1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.37 g, 0.85 mmol) as a white fluffy solid, m.p. 179–180° C. Analysis. Calculated for C24H28N4O2S: % C 66.03; % H, 6.46; % N, 12.83. Found % C 65.88; % H, 6.49; % N, 12.76.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2S[C:15]([C:19](O)=O)=[C:16](C)[N:17]=2)N=N1)C1C=CC=CC=1.[F:22][C:23]1[CH:43]=[CH:42][C:26]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]3[S:34][C:35]([C:39]([OH:41])=O)=[C:36]([CH3:38])[N:37]=3)[N:30]=[N:29]2)=[CH:25][CH:24]=1.N1C=CC=C(CN)C=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]3[S:34][C:35]([C:39]([NH:8][CH2:12][C:11]4[CH:13]=[N:17][CH:16]=[CH:15][CH:19]=4)=[O:41])=[C:36]([CH3:38])[N:37]=3)[N:30]=[N:29]2)=[CH:42][CH:43]=1
Reactant: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Reactant: Cc1nc(-c2cn(Cc3ccc(F)cc3)nn2)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(-c2cn(Cc3ccc(F)cc3)nn2)sc1C(=O)NCc1cccnc1
Yield: 64 %

Procedure:
Following the procedure as described in Example 4, making variations as necessary to replace 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 64% yield: mp 212-213° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.54 (br s, 1H), 8.46 (br s, 1H), 7.95 (s, 1H), 7.72-7.69 (m, 1H), 7.34-7.18 (m, 3H), 7.09-6.97 (m, 2H), 6.85 (t, J=5.6 Hz, 1H), 5.49 (s, 2H), 4.58 (d, J=5.6 Hz, 2H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.1, 161.9, 157.9, 157.2, 149.2, 148.9, 142.9, 135.8, 133.9, 130.3, 129.6, 129.5, 124.1, 121.5, 116.4, 53.9, 41.6, 17.3; MS (ES+) m/z 409.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[CH2:31]([Mg]Br)[CH:32]=[CH2:33].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)([OH:12])[CH2:33][CH:32]=[CH2:31])=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Br
Reactant: O=C(CCCc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(O)(CCCc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
To a solution of ketone from Example 25, Step 1 (1.5 g, 3.61 mmol) in dry THF (15 mL) at 0° C. was added a 1M solution of allyl magnesium bromide (4.3 mL, 4.3 mmol). The reaction mixture was stirred for 45 minutes at 0° C., at which point saturated NH4Cl solution (15 mL) was added, and the product was extracted with EtOAc. The organic layer was washed with water and brine, and was then evaporated to dryness. Purification by flash chromatography (gradient of 1:20, 1:10, 1:5 EtOAc/hexane) gave a pale yellow syrup which was triturated with 1:4 ether/hexane to give the title compound as a white solid, m.p.=87°-88° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][Si](C(C)(C)C)(C)C)=[C:7](Br)[CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:60]([C:62]([OH:95])([CH2:93][CH3:94])/[CH:63]=[CH:64]/[C:65]1[CH:70]=[CH:69][C:68]([C:71]([CH2:90][CH3:91])([C:74]2[CH:79]=[CH:78][C:77](B3OC(C)(C)C(C)(C)O3)=[C:76]([CH3:89])[CH:75]=2)[CH2:72][CH3:73])=[CH:67][C:66]=1[CH3:92])[CH3:61].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:6]=[C:7]([C:77]2[CH:78]=[CH:79][C:74]([C:71]([CH2:72][CH3:73])([C:68]3[CH:69]=[CH:70][C:65]([CH:64]=[CH:63][C:62]([CH2:93][CH3:94])([OH:95])[CH2:60][CH3:61])=[C:66]([CH3:92])[CH:67]=3)[CH2:90][CH3:91])=[CH:75][C:76]=2[CH3:89])[C:8]([OH:13])=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Reactant: COC(=O)Cc1cc(Br)c(O[Si](C)(C)C(C)(C)C)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)(C=Cc1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)OC)cc(OC)c3O)c(C)c2)cc1C)CC
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
[3-Bromo-4-(t-butyldimethyl-silanyloxy)-5-methoxy-phenyl]-acetic acid methyl ester (Example 178-(2); 68 mg, 0.176 mmol), palladium acetate (2.7 mg, 0.012 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (9.9 mg, 0.024 mmol), potassium phosphate (75 mg, 0.351 mmol) and water (0.2 mL) were added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 28; 57.2 mg, 0.117 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (33.6 mg, 51%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]1([OH:17])[C:16]2[CH2:15][CH:14]=[CH:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.S(OC)(OC)(=O)=O>C(O)C>[CH3:1][O:17][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]=[CH:13][CH2:12]2
Reactant: Oc1cccc2c1CC=CC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COS(=O)(=O)OC
Product: COc1cccc2c1CC=CC2
Temperature: 40 °C
Yield: 92.5 %

Procedure:
Add powdered potassium carbonate (193.1 g, 1.397 mol) to a solution of commercially available 5,8-dihydronaphthalen-1-ol [68.08 g, 90% potency based on 1H-NMR, 0.4657 mol, from Societa Italiana Medicinala Scandicci, s.r.l., Reggello (Firenze), Italy] in ethanol (700 mL). Cool the solution to 0° C. with ice water and add dimethyl sulfate (88.1 g, 66.1 mL, 0.699 mol) dropwise, maintaining the temperature between 5° C. and 10° C. Heat the reaction mixture to 40° C. until TLC shows the absence of starting material (about 2 hr). Filter off the solids by vacuum filtration and concentrate. Dilute the residual brown oil with diethyl ether (500 mL), wash with 10% aqueous ammonium hydroxide (500 mL), water (500 mL), brine (500 mL), dry (sodium sulfate) and concentrate to give the crude product as a brown oil (73 g). Purify the crude product by short path distillation under vacuum (bp 120-130° C./5 Torr) to give the title compound as a clear oil (69.0 g, 92.5% potency corrected) (contains some 1,2,3,4-tetrahydro-5-methoxynaphthalene as an impurity).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(Cl)cc5)n4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(-c2ccc(Cl)cc2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 4 h
Yield: 94.4 %

Procedure:
Ethyl 6-chloro-7-(4-(6-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (50 mg, 0.089 mmol) was diluted with THF (1 mL) followed by the addition of 1 N aq. NaOH (444 μL, 0.44 mmol) and ethanol (500 μL). After stirring for 4 hours, the reaction was diluted with ethyl acetate and 1N aq. HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 6-chloro-7-(4-(6-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (45 mg, 0.084 mmol, 95% yield). MS (ESI, positive) m/z=535.3.
Reaction SMILES: C([Zn]CC)C.[CH:6]1([C:9]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:10]=2)[CH2:8][CH2:7]1.[Br:27][CH2:28][C:29]([C:31](Br)(Br)[Br:32])=[O:30]>CCCCCC.C1(C)C=CC=CC=1.CCOC(C)=O>[Br:27][CH:28]1[C:29](=[O:30])[CH:31]([Br:32])[CH:10]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]1[CH:13]=[C:9]2[CH:6]1[CH2:7][CH2:8]1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1ccc(C2CC2)c1
Reactant: O=C(CBr)C(Br)(Br)Br
Agent: CC[Zn]CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1C(Br)C2C=C(C3CC3)C(C1Br)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.9 %

Procedure:
Diethyl zinc (18.1 mL, 18.1 mmol of a 1M solution in hexane) was added to a solution of 3-cyclopropyl-1-(4-(trifluoromethyl)phenylsulfonyl)-1H-pyrrole (3.18 g, 10.1 mmol) and tetrabromoacetone (7.53 g, 20.1 mmol) in toluene at −10° C. The reaction mixture was stirred at room temperature for 17 h and was subsequently diluted with EtOAc and washed with saturated aqueous Na2CO3. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/EtOAc, 9/1 to 7/3, v/v) to give compound 115 (3.31 g, 6.25 mmol, 62%). MS (ESI) 530.0 (M+H).
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[CH2:3][CH2:2]1.[CH3:13][C@@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1.[BH4-].[Na+].C(Cl)Cl.CO>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:13][C@H:14]1[NH:15][CH2:16][CH2:17][N:18]([CH:4]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][CH2:1][CH2:2][CH2:3]2)[CH2:19]1
Reactant: C[C@@H]1CNCCN1
Reactant: O=C1CCCCc2ccccc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1CN(C2CCCCc3ccccc32)CCN1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 70.2 %

Procedure:
A mixture of 1-benzosuberone (0.803 ml, 5.01 mmol), (R)-2-methylpiperazine (1.505 g, 15 mmol) in titanium (4+) isopropoxide (4.399 ml, 15 mmol) was heated at 80° C. overnight. After cooling to RT, the reaction mixture was diluted with 30 mL of MeOH and sodium borohydride (0.529 ml, 15 mmol) was slowly added. After stirring at rt for 20 min, the solvent was evaporated to dryness. The residue was redissolved in 50 mL of EtOAc and to this solution was added 10 g of NaHCO3 and 0.5 mL of water to generate a white slurry. After stirring at rt for 2 h, the mixture was filtered with the help of excess EtOAc and the filtrate was evaporated to dryness. Column chromatography (SiO2, DCM/MeOH=100:5 to 100:10 to 100:15 to 100:20) gave (3R)-3-methyl-1-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)piperazine (860 mg, 70% yield) as an off white gum.