Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.CCO.O>[Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: C[C@H]1O[C@@H](n2c(Br)nc3ccc(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
A mixture of 0.44 g (1 mmol) of 2-bromo-6-chloro-1-(2,3-di-O-acetyl-5-deoxy-β-D-ribofuranosyl)-1H-benzimidazole and 0.17 g (1.6 mmol) of sodium carbonate in 8 mL of MeOH, 8 mL of EtOH and 2 mL of water was stirred at room temperature for 6 h. The reaction mixture was concentrated and redissolved in 50 mL of EtOAc. After 2 washings with saturated brine, the EtOAc solution was dried over MgSO4. Solvent removal resulted in a crude product which was flash column chromatographed on silica gel with EtOAc/hexane (1:1) to give 0.24 g (69%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ1.4 (d, 3H, CH3), 3.8-3.9 (m, 1H, CH), 3.9-4 (m, 1H, CH), 4.45 (q, 1H, CH), 5.21 (d 1H, OH), 5.45 (d, 1H, OH), 5.8 (d, 1H, CH), 7.3 (d, 1H, aromatic), 7.6 (s,1H, aromatic), 7.62 (d, 1H, aromatic).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]12[O:32][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]2>>[OH:32][C@@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[O:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Reactant: C1CCC2OC2C1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O[C@@H]4CCCC[C@H]4O)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 31 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and cyclohexene oxide instead of 1-oxaspiro[2.4]heptane.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.C([O:22][CH2:23][CH:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31]2[C:36]([NH2:37])=[CH:35][N:34]=[C:33]3[CH:38]=[CH:39][S:40][C:32]=23)[CH2:26][O:25]1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)C.O.CO>[OH:22][CH2:23][CH:24]1[O:25][CH2:26][C@@H:27]([N:30]2[C:31]3=[C:32]4[S:40][CH:39]=[CH:38][C:33]4=[N:34][CH:35]=[C:36]3[N:37]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:28][CH2:29]1
Reactant: C[C@@H](O)C(N)=O
Reactant: CC(=O)OCC1CC[C@H](Nc2c(N)cnc3ccsc23)CO1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCC(CO)OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (131 mg, 1.47 mmol) and triethyloxonium tetrafluoroborate (263 mg, 1.38 mmol) in THF (2 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.85 mL) and added to a suspension of {(5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methyl acetate (145 mg, 0.451 mmol) in ethanol (3.1 mL). The mixture was stirred at 80° C. for 1 h. The reaction was cooled to room temperature and diluted with water (1.0 mL). Lithium hydroxide (32.4 mg, 1.35 mmol) was added, and the mixture was stirred for 2 h. The reaction mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as white solid (95 mg, 63%). LCMS calculated for C16H20N3O3S (M+H)+: m/z=334.1. Found: 334.0.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][CH2:7][C@@H:8]([N:11]1[C:16](=[O:17])[CH2:15][NH:14][C:13]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[N:21][C:12]1=2)[CH2:9][OH:10])([CH3:4])[CH3:3]>C(Cl)Cl.O=[Mn]=O>[CH3:4][C:2]([Si:5]([CH3:24])([CH3:25])[O:6][CH2:7][C@@H:8]([N:11]1[C:16](=[O:17])[CH:15]=[N:14][C:13]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[N:21][C:12]1=2)[CH2:9][OH:10])([CH3:1])[CH3:3]
Reactant: COc1ccc2c(n1)N([C@@H](CO)CO[Si](C)(C)C(C)(C)C)C(=O)CN2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n([C@@H](CO)CO[Si](C)(C)C(C)(C)C)c2n1
Yield: 92.2 %

Procedure:
A solution of 4-[(1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-(hydroxymethyl)ethyl]-6-(methyloxy)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (494.1 g, 1.34 mol) and MnO2 (584.4 g, 6.72 mol) in DCM (18 L) was stirred at room temperature for 1 h. The mixture was filtered through celite and the filtrate was evaporated to give a purple/white solid. The crude was purified by column chromatography and mixtures of heptane and EtOAc as eluent to give of 451.6 g (66%) of 4-[(1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-(hydroxymethyl)ethyl]-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2([CH2:35][C:36]([NH2:38])=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C:29]2([CH2:35][C:36]([NH2:38])=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[N:14]([CH3:16])[CH3:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(NC3(CC(N)=O)CCCCC3)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide in an analogous manner to Example 61e. Product isolated as a pale yellow foam (0.064 g, 51%). MP: 90-107° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 7.92 (s, 1H), 7.87 (s, 1H), 7.17 (s, 1H), 6.65 (s, 1H), 5.43 (br s, 1H), 5.25 (s, 1H), 5.07 (br s, 1H), 3.85 (s, 3H), 3.29 (s, 2H), 3.14 (s, 3H), 2.98 (s, 3H), 2.92-2.86 (m, 6H), 2.72-2.67 (m, 4H), 2.38 (m, 2H), 1.70-1.58 (m, 5H), 1.50-1.40 (m, 3H). MS: 544.27 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)CCO.BrC1C=C([CH2:18][CH2:19][O:20][CH:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:39][CH3:40])[CH:31]=3)[NH:26][C:25]([CH3:42])([CH3:41])[CH:24]=2)[CH3:22])C=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC(N1C2C(=CC(C3C=CC=CC=3OC)=CC=2)C(C(OS(C)(=O)=O)C)=CC1(C)C)=O)(C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:8]=[CH:9][C:10]=1[CH2:18][CH2:19][O:20][CH:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[CH:31]=2)[NH:26][C:25]([CH3:42])([CH3:41])[CH:24]=1)[CH3:22]
Reactant: OCCc1cccc(Br)c1
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)OCCc1cccc(Br)c1)=CC(C)(C)N2
Agent: COc1ccccc1-c1ccc2c(c1)C(C(C)OS(C)(=O)=O)=CC(C)(C)N2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc2c(c1)C(C(C)OCCc1ccccc1Br)=CC(C)(C)N2

Procedure:
4-{1-[2-(3-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 3-Bromophenethyl alcohol (37 μL) was treated with 277 μL of 1 M solution of sodium bis(trimethylsilyl)amide in THF and 86 mg of 4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester to give alkylated product, which was deprotected to yield 13.6 mg of the title compound as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Br)cc1C(=O)O
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
Methyl 5-bromo-2-methylbenzoate (see Japanese Unexamined Patent Publication No. 9-263549) (16.12 g) was dissolved in methanol (100 ml), and thereto was added 10% aqueous sodium hydroxide solution (50 ml). The mixture was stirred at 50° C. for 40 minutes. Under ice-cooling, the mixture was adjusted to pH 1 by addition of 10% aqueous hydrochloric acid solution, and diluted with water. Precipitated powder was collected by filtration, and dried to give 5-bromo-2-methylbenzoic acid (14.1 g). ESI-Mass m/Z 213/215 (M−H). (2) The above 5-bromo-2-methylbenzoic acid (10.0 g) was suspended in dichloromethane (100 ml), and thereto were added oxalyl chloride (8.1 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-methylbenzoyl chloride. This benzoyl chloride was dissolved in dichloromethane (200 ml), and thereto was added N,O-dimethylhydroxylamine hydrochloride (12.3 g). To the mixture was added dropwise triethylamine (20 ml) at 0° C., and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and washed successively with water, 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.25 g) as oil. APCI-Mass m/Z 258/260 (M+H). (3) A solution of the above N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.2 g) in tetrahydrofuran (100 ml) was cooled to −78° C. under argon atmosphere. To the mixture was added dropwise diisobutyl aluminum hydride (1.0 M toluene solution, 75 ml), and the mixture was stirred at the same temperature for one hour. 10% aqueous hydrochloric acid solution (50 ml) was added thereto, and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate twice, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was solidified to give 5-bromo-2-methylbenzaldehyde (8.73 g). APCI-Mass m/Z 213/215 (M+H+MeOH—H2O).
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[N:12][C:13]2[C:14]([C:4]=1[OH:20])=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=2)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 100 °C
Yield: 97.6 %

Procedure:
The solid 2-[(4-bromo-phenylamino)-methylene]-malonic acid diethyl ester (157 g, 458.8 mmol) was added to a hot diphenyl ether (260 g) and the mixture was heated to reflux for 5 h to afford a brown suspension. Then, the mixture was cooled to 100° C. and diluted with ethanol (˜200 mL). This suspension was refluxed for 10 min and then cooled to room temperature. The solids were collected by filtration and washed with diethyl ether. After drying in air, 132.59 g (97.6% yield) of 6-bromo-4-hydroxy-quinoline-3-carboxylic acid ethyl ester was isolated as a white solid: EI-HRMS m/e calcd for C8H6N2O (M+) 146.0480, found 146.0478.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:23]3[C:22]([F:28])=[CH:21][C:20]([CH2:19][CH2:18][C:17]([OH:29])=[O:16])=[CH:25][C:24]=3[F:26])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCC1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: O=C(O)CCc1cc(F)c(OCc2cccnc2SC2CCC2)c(F)c1
Yield: 81.6 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.113 mmol) obtained in Step C of Preparation Example 23 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (26 mg, 0.113 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (35 mg, 82%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:19])([CH3:18])[C:7](=[O:17])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][C:6]([CH3:19])([CH3:18])[C:7](=[O:17])[CH:8]([Br:20])[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)(C)C(=O)COc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
56.9 g (0.2 mol) of 4-acetoxy-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one were dissolved in 350 ml of carbon tetrachloride. 10.3 g (0.2 mol) of bromine were added dropwise, at room temperature, in such a way that the bromine was steadily consumed. Thereafter, the mixture was stirred for 30 minutes at room temperature. After distilling off the solvent in vacuo, 4-acetoxy-1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one was obtained quantitatively and could be directly reacted further. ##STR11##
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCOC(=O)CCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1nccn1-c1ccc(F)cc1[N+](=O)[O-]
Yield: 47.8 %

Procedure:
1,4-Difluoro-2-nitrobenzene 239 mg, ethyl 3-(1H-imidazol-2-yl)propanoate 252 mg, potassium carbonate 415 mg and N,N-dimethylacetamide 10 mL were heated at 100° C. for 64 hours. The reaction liquid was diluted with ethyl acetate and filtered. The filtrate was condensed under reduced pressure and subjected to silica gel chromatography (ethyl acetate) to provide 220 mg of the title compound.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]([C:60]2[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=2)[C:57](O)=[O:58])=[CH:52][CH:51]=1>>[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([CH:56]([C:60]2[CH:61]=[CH:62][C:63]([Cl:66])=[CH:64][CH:65]=2)[C:57]([C:16]2[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)=[O:58])=[CH:54][CH:55]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with bis(4-chlorophenyl)acetic acid, mp 175°-176° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][N:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:13]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][N:3]=1)#[N:14]
Reactant: CN(C)C=O
Reactant: Brc1ccc(C2OCCO2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(C2OCCO2)cn1
Temperature: 80 °C
Yield: 74 %

Procedure:
2-Bromo-5-(1,3-dioxolan-2-yl)pyridine (895 mg, 3.89 mmol), zinc cyanide (1.14 g, 5.83 mmol) and tetrakis(triphenylphosphine)palladium (899 mg, 0.778 mmol) were dissolved in N,N-dimethylformaldehyde (30 ml) and the mixture was heated to reflux at 80° C. under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated, water was added thereto, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate=7/3) to give 2-cyano-5-(1,3-dioxolan-2-yl)pyridine (506 mg, yield: 74%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)[CH3:30]>>[CH2:29]([C:31]1[CH:36]=[CH:35][C:34]([C:12]2[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:33][CH:32]=1)[CH3:30]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2c3c(nn2C(C)C)CCNCC3)cc1
Yield: 100 %

Procedure:
The title compound (134 mg) was prepared as in Example 177, Steps C and D, using 202 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 212 mg of 4-ethylphenylboronic acid. MS (ESI): exact mass calculated for C18H25N3, 283.20; found, m/z 284.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44 (d, J=7.7 Hz, 2H), 7.31 (d, J=7.7 Hz, 2H), 4.52 (m, 1H), 3.50-3.48 (m, 2H), 3.36-3.34 (m, 2H), 2.85-2.83 (m, 2H), 2.75 (q, J=7.7 Hz, 2H), 1.47 (d, J=6.6 Hz, 6H), 1.29 (t, J=7.7 Hz, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15](=[NH:17])[NH2:16])=[N:7]1.[CH3:22][O:23][C:24](=[O:33])[C:25](=[CH:30]OC)[C:26](OC)=[O:27].C[O-].[Na+:36]>CO>[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[N:16]=[C:26]([O-:27])[C:25]([C:24]([O:23][CH3:22])=[O:33])=[CH:30][N:17]=2)=[N:7]1.[Na+:36]
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ccccc12
Reactant: COC=C(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1[O-]

Procedure:
2.5 g of 1-(2-fluorobenzyl)-1H-indazole-3-carboximidamide hydrochloride (1:1) (1-2-3×HCl, 8.20 mmol, 1 eq.), 1.43 g of dimethyl(methoxymethylidene)propanedioate (8.20 mmol, 1 eq.) and 50 ml of methanol and 443 mg of sodium methanolate were stirred under nitrogen atmosphere at 60° C. bath temperature for 24 hours. The clear yellowish solution turned into a suspension which was filtered off. The crystals were washed with cold methanol to yield 1.64 g (4.1 mmol, 50%) of the analytically pure target compound.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:16][C:17]1([CH3:24])[O:22][CH2:21][C:20](=O)[CH2:19][O:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl.CCOCC>[CH3:16][C:17]1([CH3:24])[O:22][CH2:21][CH:20]([NH:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:19][O:18]1
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: CC1(C)OCC(=O)CO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCCCc1ccc(NC2COC(C)(C)OC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a mixture of 4-n-octylaniline (0.205 g; 1 mmol) and 2,2-dimethyl-1,3-dioxan-5-one (Helvetica Chimica Acta, 2003, 86, 2467; 0.13 g; 1 mmol) and NaBH(OAc)3 in 1,2 dichloroethane (3.5 ml), AcOH (0.06 ml; 1 mmol) was added and the mixture was stirred for 2 h at room temperature under N2, diluted to 20 ml with Et2O and washed with 1N NaOH, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified crystallization from hexane to give the title compound (0.2 g; 63%) as a colourless solid. 1H-NMR (CDCl3) 6.97 (d, 2H, J=8.4 Hz); 6.54 (d, 2H, J=8.4 Hz); 4.1 (dd, broad s, 3H, J=4.2, 11.9 Hz); 3.74 (dd, 2H, J=4.2, 11.9 Hz); 3.4 (m, 1H); 2.47 (t, 2H, J=7.91 Hz); 1.55 (m, 2H+H2O); 1.46 (s, 3H); 1.43 (s, 3H); 1.25 (m, 10H); 0.86 (m, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:42])([CH3:41])[C@H:13]3[C@:30]([CH3:33])([CH2:31][CH:32]=2)[C@@H:29]2[C@:16]([CH3:40])([C@@:17]4([CH3:39])[C:26](=[CH:27][CH2:28]2)[C@H:25]2[C@:20]([C:36]([OH:38])=[O:37])([CH2:21][CH2:22][C@@H:23]([CH3:35])[C@@H:24]2[CH3:34])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1.CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:42])([CH3:41])[C@H:13]3[C@:30]([CH3:33])([CH2:31][CH:32]=2)[C@@H:29]2[C@:16]([CH3:40])([C@@:17]4([CH3:39])[C:26](=[CH:27][CH2:28]2)[C@H:25]2[C@:20]([C:36]([OH:38])=[O:37])([CH2:21][CH2:22][C@@H:23]([CH3:35])[C@@H:24]2[CH3:34])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC=C5[C@@H]6[C@@H](C)[C@H](C)CC[C@]6(C(=O)O)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Temperature: 65 °C
Yield: 61 %

Procedure:
Saponification of the intermediates A6 was conducted as followed: to a solution of (1S,2R,4aS,6aS,6bR,8aR,12aS,12bR,14bS)-10-(4-(methoxycarbonyl)phenyl)-1,2,6a,6b,9,9,12a-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropicene-4-a-carboxylic acid (intermediate A6) (20 mg, 0.035 mmol) in a mixture of dioxane (1 mL) and methanol (0.5 mL) was added a 1N solution of NaOH (0.5 mL, 0.5 mmol). The mixture was warmed to 65° C. for 2 h. The crude product was further purified by preparative HPLC(YMC Combiprep ODS 30×50 mm S5 column) eluted with gradient mixture of MeOH/water/TFA. The desired fractions were combined, evaporated to afford the title compound (12 mg, 61%).
Reaction SMILES: C1(C[O:8][C:9](=[O:46])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=[C:12]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:11]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[CH2:28]([O:27][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:13]=1)[C:9]([OH:46])=[O:8])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)O)c1
Yield: 94.3 %

Procedure:
A mixture of 14.6 g of 3-(octadecyloxy)-5-(3-phenoxypropoxy) benzoic acid phenylmethyl ester and 3 g of 10% palladium on carbon in 200 ml THF and 20 ml ethyl acetate was shaken in a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to a solid which was recrystallized from ether-hexane to give 11.8 g (95% yield, mp 79°-81°) of 3-(octadecyloxy) -5-(3-phenoxypropoxy)benzoic acid.