Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](C)(C)[CH3:10])=[C:6](O)[CH:7]=1.C1C=CC=CC=1.CC(C)([O-])C.[K+].BrC1C=CC(CC)=CC=1[N+]([O-])=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(Br)cc1O
Agent: CC(C)(C)[O-]
Agent: CCc1ccc(Br)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCc1ccc(Br)cc1

Procedure:
Employing the same general procedure as for the preparation of 5-bromo-2-tert-butyl-1-[(2′-amino-4′-methyl)phenoxy]benzene (Compound I), 781 mg (3.4 mmol) of 5-bromo-2-tert-butylphenol (Compound H) was converted into crude 5-bromo-2-tert-butyl-1-[4′-ethyl-2′-nitro)phenoxy]benzene using 611 mg (5.0 mmol) of potassium t-butoxide, 1.0 g (5.25 mmol) of cuprous iodide, 770 mg (˜2.78 mmol) of 1-bromo-4ethyl-2-nitrobenzene (˜80% purity, obtained from the nitration of 1-bromo-4-ethylbenzene) and 10 mL of pyridine. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) gave crude 5-bromo-2-tert-butyl-1-[(4′-methyl-2′-nitro)phenoxy]benzene as a yellow oil. 290 mg of this crude sample was converted into the title compound using a balloon filled with hydrogen, 31 mg of 10% Pd/C, 4 mL of acetonitrile and 1 mL of methanol. Purification by flash chromatography (silica, 2% ethyl acetate in hexane) gave the title compound as a yellow oil. PMR (CDCl3): δ 1.24 (3 H, t, J=7.5 Hz), 1.44 (9 H, s), 2.58 (2 H, q, J=7.5 Hz), 3.72 (2 H, br s), 6.57 (1 H, dd, J=2.1, 8.2 Hz), 6.68-6.74 (2 H, m), 6.81 (1 H, d, J=2.1 Hz), 7.09 (1 H, dd, J=2.1, 8.4 Hz), 7.22 (1 H, d, J=8.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[N:5][CH:6]=[CH:7][CH:8]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[S:27][C:28]([CH2:31][N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:29][CH:30]=2)=[CH:20][N:19]=1)([O-])=O>>[CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[S:27][C:28]([CH2:31][N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:29][CH:30]=3)=[CH:20][N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCN(CCCC)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)s1
Reactant: COc1cccnc1CCCCN
Product: CCCCN(CCCC)Cc1ccc(Cc2cnc(NCCCCc3ncccc3OC)[nH]c2=O)s1

Procedure:
Reaction of 4-(3-methoxypyridyl)butylamine with 2-nitroamino-5-(5-di-n-butylaminomethyl-2-thienylmethyl)-4-pyrimidone gives 2-[4-(3-methoxypyridyl)butylamino]-5-(5-di-n-butylaminomethyl-2-thienylmethyl)-4-pyrimidone.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][C:16]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:15]1=2)=O)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].B.C1COCC1.CO>C1COCC1>[CH2:1]([N:3]([CH2:11][CH2:12][N:14]1[CH2:19][CH2:18][O:17][C:16]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:15]1=2)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:7])[CH3:8])[CH3:2]
Reactant: CCN(CC(=O)N1CCOc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CCN1CCOc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A yellow solution of tert-butyl ethyl(2-(7-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-2-oxoethyl)carbamate (8.7 g, 23.8 mmol) in anhydrous THF (50 mL) under positive argon pressure was treated with borane-THF complex (1M in THF, 47.6 mL, 47.6 mmol) to give an orange solution. The mixture was refluxed for 20 minutes. It was then cooled in an ice bath and treated dropwise with MeOH (100 mL). The solution stirred for half an hour at room temperature, and the reaction was then concentrated. The residue was subjected to flash chromatography on silica gel using 1:9 EtOAc:hexanes to give an orange solid (7.5 g, 91%). 1H-NMR (DMSO-d6) δ 7.72 (dd, J=2.7, 9.0 Hz, 1H), 7.49-7.47 (m, 1H), 6.85-6.83 (m, 1H), 4.18 (t, J=4.2 Hz, 2H), 3.59-3.53 (m, 2H), 3.37-3.36 (m, 2H), 3.20-3.18 (m, 2H), 1.47 (s, 2H), 1.30 (br s, 9H), 1.02 (t, J=6.9 Hz, 3H); ESI-MS (m/z, %): 374 (MNa+, 86), 352 (MH+, 7.8), 296 (100), 252 (87).
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([OH:15])(=[O:14])[C:12]#[CH:13]>CC(C)=O>[CH2:1]([N:8]1[CH:13]=[C:12]([C:11]([OH:15])=[O:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CC(=O)O
Solvent: CC(C)=O
Product: O=C(O)c1cn(Cc2ccccc2)nn1
Temperature: 0 °C

Procedure:
To a solution of 84 milliliters (ml) of acetone and 35.8 grams (g) (269 mmoles) of benzyl azide, 19.3 g (276 mmoles) of propiolic acid was added by drop. The reaction mixture was stirred and heated to reflux overnight. After cooling to 0° C., 33.6 g (62%) of 1(2 or 3)-benzyl-1H-1,2,3-triazole-4-carboxylic acid precipitated from the reaction solution as white crystals. The structure was confirmed by nuclear magnetic resonance (n.m.r.) and infrared spectroscopy (I.R.).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18]Br>CN(C)C=O>[O:2]1[C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4][CH2:18][CH2:17][CH2:16]1
Reactant: BrCCCBr
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OCCCO2
Yield: 41.3 %

Procedure:
110 g of pyrocatechol, 276 g of potassium carbonate and 303 g of 1,3-dibromopropane were stirred at 120° C. for 48 hours in 800 ml of absolute dimethylformamide. The cooled suspension was filtered under suction, the residue was back-washed with ether and the filtrate was poured into 4 l of water. This was extracted with ether. The ether extract was washed twice with 3N sodium hydroxide and then neutral with water, dried over sodium sulfate and evaporated in vacuo. The residue (146.6 g) was distilled at 11 mm/118°-120° C. 61.9 g (41.2% of theory) of 3,4-dihydro-2H-1,5-benzodioxepine were obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C@@H:27]1[C@@H:31]([OH:32])[CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][C@@H:27]3[CH2:28][NH:29][CH2:30][C@H:31]3[OH:32])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: N[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Br)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H]3CNC[C@H]3O)c2c1

Procedure:
The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and benzyl (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.13-8.10 (d, J=7.6 Hz, 1 H), 8.06 (s, 1 H), 7.95-7.90 (d, J=7.2 Hz, 1 H), 7.78-7.70 (m, 2 H), 7.65-7.58 (m, 2 H), 6.16 (s, 1 H), 5.3 (q, J=1.2 Hz, 2 H), 4.65-4.40 (m, 2 H), 4.50-4.40 (m, 2 H), 4.12-3.95 (m, 1 H), 3.80-3.68 (m, 3 H), 3.60-3.50 (m, 1 H), 3.48-3.40 (d, J=7.2 Hz, 1 H), 2.47 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH2:42][CH3:43])=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH2:42][CH3:43])=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(C)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K31) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (346 mg, 85%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:27][CH:28]3[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]3)[CH:9]=[C:10]([N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[CH:42]1(B(O)O)[CH2:44][CH2:43]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCO>C1(C)C=CC=CC=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>[CH:42]1([C:2]2[N:6]3[N:7]=[C:8]([NH:27][CH:28]4[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]4)[CH:9]=[C:10]([N:11]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:5]3=[N:4][CH:3]=2)[CH2:44][CH2:43]1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(NC3CCC(NC(=O)OC(C)(C)C)CC3)nn3c(Br)cnc23)cc1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(CN(c2ccccc2)c2cc(NC3CCC(NC(=O)OC(C)(C)C)CC3)nn3c(C4CC4)cnc23)cc1
Temperature: 120 °C
Yield: 15.4 %

Procedure:
tert-Butyl 4-(3-bromo-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate (30 mg, 0.048 mmol) from (1a) and cyclopropylboronic acid (10 mg, 0.090 mmol) in toluene were purged with argon for 15 min, then aq. K3PO4 (2M, 0.06 mL), EtOH (0.04 mL) and tetrakis(triphenylphosphine)palladium(0) were added sequentially. The mixture was heated at 120° C. for 20 h. After cooling to room temperature, the mixture was partitioned between EtOAc (20 mL) and water (5 mL) and the organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by reverse phase preparative HPLC to provide tert-butyl 4-(3-cyclopropyl-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate as a cream colored oil (4.3 mg, 15%) LCMS [M+H]+ 583.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:23]([CH3:24])[C:14]2=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]2[N:12]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:23]([CH3:24])[C:14]2=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]2[N:12]=1)=[O:33])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cc(F)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1cc(F)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(2-ethylsulfanyl-4-fluorophenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.85 g) and chloroform (12 ml), 3-chloroperbenzoic acid (purity: not less than 65%, 0.81) was added under ice-cooling, heated to room temperature, and stirred for 30 minutes. Into the reaction mixture, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.33 g of 2-(2-ethylsulfinyl-4-fluorophenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 117) and 0.52 g of 2-(2-ethylsulfonyl4-fluorophenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 118).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCN1CCN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
A mixture of the compound from step 1 (1.8 g), Pd/C (5%, 0.3 g) and ethanol (150 ml) was stirred at ambient temperature under hydrogen (1 atm) for 16 h. The reaction mixture was filtered and the solvent was removed under vacuum to furnish the title compound as a light tan solid (1.52 g, 94.6%): MS (ESI) m/z 264 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.55 (t, J=7.2 Hz, 2H), 2.65 (t, J=4.8 Hz, 4H), 2.77 (t, J=7.2 Hz, 2H), 3.05 (br, 4H), 3.70 (s, 3H), 6.80-6.83 (m, 2H), 8.11-8.14 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)(=O)C>C(O)C.[Fe]>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]2[OH:1]
Reactant: CCOC(=O)c1nc2ccc([N+](=O)[O-])cc2c(O)c1C(=O)OCC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(N)cc2c(O)c1C(=O)OCC
Yield: 75.1 %

Procedure:
A stirred mixture of diethyl 4-hydroxy-6-nitroquinoline-2,3-dicarboxylate (4.4 g, 13 mM), powdered iron (6.6 g, 118 mM) and glacial acetic acid (18.5 g, 307 mM) in ethanol (80 mL) was refluxed for 20 hr under a nitrogen atmosphere. The reaction mixture was cooled and filtered and the filtrate was concentrated. The dark residue was chromatographed (eluant: methylene chloride/methanol; 98/2) over silical gel to provide (3.01 g, 75.3%) the title compound as light orange crystals, mp 219°-221° C.; MS(CI): 305 (M+H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[NH:21][CH2:20][CH2:19][CH2:18]2)=[O:11].[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH3:25][N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12][S:10]([C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:11])[CH2:18][CH2:19][CH2:20]1
Reactant: O=S(Cc1cccc2c1NCCC2)c1nc2ccccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCc2cccc(CS(=O)c3nc4ccccc4[nH]3)c21
Yield: 13.5 %

Procedure:
8-(2-Benzimidazolyl)sulfinylmethyl-1,2,3,4-tetrahydroquinoline (14.9 g) was dissolved in dimethyl formamide (150 ml). Sodium hydride (60% in oil, 2.2 g) was added thereto with stirring under ice-cooling, and the mixture was stirred for 30 minutes. Sequentially, methyl iodide (8.5 g) was added dropwise to the reaction mixture and the mixture was stirred for 5 hours at 70° to 80° C. After distilling off the solvent, the residue was poured into water and the mixture was extracted with chloroform. The residue obtained by distilling off the chloroform was purified by silica gel column chromatography and recrystallized from diethyl ether-n-hexane to give 1-methyl-8-(2-benzimidazolyl)sulfinylmethyl-1,2,3,4-tetrahydroquinoline (2.1 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:15][C@@H:5]2[O:6][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][C@@H:4]2[C@H:3]1/[CH:16]=[CH:17]/[C@@H:18]([OH:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CC([OH:32])C>[OH-].[K+].C([O-])(O)=O.[Na+]>[OH:1][C@@H:2]1[CH2:15][C@H:5]([OH:32])[C@H:4]([CH2:13]/[CH:12]=[CH:11]\[CH2:10][CH2:9][CH2:8][C:7]([OH:6])=[O:14])[C@H:3]1/[CH:16]=[CH:17]/[C@@H:18]([OH:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Reactant: CC(C)O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Product: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (6Z,8aR,9R,10R,11aS)-4,5,8,8a,9,10,11,11a-octahydro-10-hydroxy-9-((S,E)-3-hydroxy-5-phenylpent-1-enyl)cyclopenta[b]oxecin-2(3H)-one (2 g, 5.4 mmol) in 20 ml 2-propanol and 6.3 ml of 3 N potassium hydroxide aqueous solution in 50 mL round-bottom flask was refluxed and stirred for 2 hours. The mixture was cooled to room temperature and adjusted to a pH of 8.5 with 3 N hydrochloric acid aqueous solution. Subsequently, the 2-propanol was removed under reduced pressure and resulting mixture was diluted with 30 ml saturated NaHCO3 aqueous solution. The basic aqueous solution was extracted with 30 ml ethyl acetate twice and the aqueous layer was adjusted to a pH of 3 with 3 N hydrochloric acid aqueous solution. Then, the acidic aqueous layer was extracted with 50 ml ethyl acetate. The organic layer was dried over anhydrous MgSO4, the solid was filtered off and organic solvent was evaporated off under vacuum to obtain 2 g of the crude title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.N1C=CC=CC=1.O>C1COCC1>[CH:14]1([C:17]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)=[O:18])[CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(O)c1ccc(OCCO)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCOC(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To 3.7 g (20.3 mmol) of 4-(hydroxyethoxy)benzoic acid, 100 ml of dry THF and 5.3 g (50.75 mmol) of cyclopropylcarboxylic acid chloride, at 0°, is added 6.6 ml (81.2 mmol) of pyridine. The mixture is allowed to warm to RT and is stirred at RT for 6 days, after which it is filtered. The filtrate is stirred, at RT, with 0.7 ml (~40.6 mmol) of water for 6 days. Solvent is removed by rotoevaporation, and 150 ml of ethyl acetate, 150 ml of water and 40 ml of aqueous 3 N sulfuric acid are added to the residue. The aqueous layer is separated and extracted once with 50 ml of ethyl acetate. The combined organic layers are washed with water (100 ml), with aqueous saturated cupric sulfate (50 ml), again with water (100 ml) and with aqueous saturated sodium chloride (50 ml) and are then dried over calcium sulfate. Solvent is removed by rotoevaporation, and the crude product is washed with 20 ml hexane (3X) and dried to yield 4-(2-cyclopropylcarbonyloxyethoxy)benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH:7]([NH:10][C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:22](O)(=O)C>COC(OC)OC>[C:1]([O:5][C:6](=[O:21])[C@@H:7]([N:10]1[C:11](=[O:20])[C:12]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)[N:19]=[CH:22]1)[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)O
Reactant: CCC(NC(=O)c1cc(Cl)ccc1N)C(=O)OC(C)(C)C
Solvent: COC(OC)OC
Product: CC[C@@H](C(=O)OC(C)(C)C)n1cnc2ccc(Cl)cc2c1=O
Yield: 42 %

Procedure:
2-(2-amino-5-chloro-benzoylamino)-butyric acid-tert-butyl ester (2.82 g) was dissolved in trimethylorthoformate (50 ml). Acetic acid (10 ml) was added, and reaction mixture refluxed for 48 hours. After this time, the solvents were removed and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous layer was further extracted with ethyl acetate and the combined organic extracts washed with brine, dried (MgSO4) and concentrated under reduced pressure to give a yellow oil. This was purified by flash chromatography (20% EtOAc: Petroleum) to give the sub-title compound as an oil (1.23 g, 42% yield). 1H NMR (400 MHz, CDCl3) δ 8.25 (1H, s), 8.05 (1H, s), 7.7 (2H, m), 5.3 (1H, m), 2.3 (1H, m), 2.0 (1H, m), 1.5 (9H, s), 1.0 (3H, t) ppm.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][S:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:7].S(=O)(=O)(O)O.O>C(Cl)Cl>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([S:6]([CH3:5])(=[NH:1])=[O:7])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: CS(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 45 °C
Yield: 63 %

Procedure:
0.70 g (10.76 mmol) of sodium azide was added to 1.56 g (8.42 mmol) of 1-(methylsulfinyl)-4-nitrobenzene in 20 ml DCM. 2.3 ml concentrated sulfuric acid was slowly added to the mixture at 0° C. and it was then heated to 45° C. After 16 h the mixture was cooled to room temperature, and after adding water it was extracted with DCM. The aqueous phase was adjusted to pH 11 with 15% sodium hydroxide solution and extracted with DCM (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. 1.08 g (5.39 mmol; yield: 63%) of the product was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:18][CH3:19])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][C:9]2=[O:17])[CH:7]=1.[CH3:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1B(O)O.[F-].[Cs+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[CH:4][C:5]([CH2:18][CH3:19])=[C:6]([CH:8]3[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][C:9]3=[O:17])[CH:7]=2)=[C:21]([CH3:20])[CH:26]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: CCc1ccc(Br)cc1C1C(=O)CCC(C)(C)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2C)cc1C1C(=O)CCC(C)(C)C1=O
Temperature: 80 °C

Procedure:
A mixture of 2-(5-bromo-2-ethylphenyl)-4,4-dimethylcyclohexane-1,3-dione (0.194 g, 0.6 mmol), 2-methyl-4-chloro-phenylboronic acid (0.153 g, 0.9 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with dichloromethane 1:1) (80 mg, 0.098 mmol) and cesium fluoride (0.608 g, 4 mmol) are stirred together in 1,2-dimethoxyethane (4 ml) and the reaction mixture is heated at 80° C. overnight. The warm reaction mixture is filtered, washing the filter cake with 9:1 dichloromethane:methanol. The mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel to give 2-(4′-chloro-4-ethyl-2′-methylbiphen-3-yl)-4,4-dimethyl-cyclohexane-1,3-dione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccccc1)Nc1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Brc1cccc(NCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
To a solution of crude N-(3-bromophenyl)-2-phenylacetamide (3.02 g, 10.4 mmol) in dry tetrahydrofuran (25 mL) was added 1.0 N borane-tetrahydrofuran complex (1:1. 26 mL, 26.12 mmol) from an addition funnel at 0° C. The reaction was refluxed under nitrogen overnight. Reaction mixture was cooled to room temperature, treated with 2.0 N aqueous sodium hydroxide (30 mL) and then stirred for 20 min. The reaction was then cooled again at 0° C. and neutralized with 2.0 N aqueous hydrochloric acid (60 mL) and further stirred for 30 min. The aqueous layer was extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (20 mL), saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered, and concentrated to afford 3-Bromo-N-(2-phenylethyl)aniline (2.55 g, 85% yield) as brown oil with reasonable purity: 1H NMR (400 MHz, CDCl3): 7.30 (t, 2H), 7.20 (m, 3H), 6.95 (t, 1H), 6.78 (br d, 1H), 6.70 (t, 1H), 6.45 (dd, 1H), 3.62 (br s, 1H), 3.40 (m, 2H), 2.92 (t, 2H); MS (EI) for C14H12NOBr: 290 MH+).