Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH:9]([NH:21][CH3:22])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:24]1([C:34](Cl)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:23])[CH:9]([N:21]([CH3:22])[C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:35])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CNC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)c1cccc2ccccc12)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.9 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-2-(methylamino)-3-(4-(trifluoromethyl)phenyl)-1-propanol (150 mg, 0.46 mmol) in ethyl acetate (5 ml) were added 1-naphthoyl chloride (76 ml, 0.50 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 6 hrs. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the title compound (166 mg, 75%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[CH3:1][C:2]1[NH:7][C:6]([S:8][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(C)NC(=S)NC1c1cccc([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(SCc2ccccc2)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1,2,3,4-tetrahydro-6-methyl-4-(3-nitrophenyl)-2-thioxo-5-pyrimidinecarboxylic acid, ethyl ester (400 mg., 1.24 mmole), potassium carbonate (270 mg., 2.0 mmole) and benzyl bromide (240 mg., 1.4 mmole) in acetone (7.0 ml.) is stirred at room temperature overnight. The solid is filtered off and the filtrate is diluted with ethyl acetate. The solution is washed with water and brine, and is dried over anhydrous magnesium sulfate. Evaporation of the solvent provides a light yellow solid which is triturated with isopropyl ether and filtered off to give 370 mg. of product. This material is combined with product from another run (150 mg.) and recrystallized from isopropyl etherdichloromethane to give 1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2-[(phenylmethyl)thio]-5-pyrimidinecarboxylic acid, ethyl ester as light yellow crystals; m.p. 129°-130°. TLC (silica gel; ethyl acetate:hexane, 40:60) Rf =0.39.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:35][C@@H:36]([CH2:49][NH2:50])[CH2:37][O:38][C:39]1[C:47]2[NH:46][C:45](=[O:48])[NH:44][C:43]=2[CH:42]=[CH:41][CH:40]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:29][CH2:30][CH:31]([NH:50][CH2:49][C@H:36]([OH:35])[CH2:37][O:38][C:39]5[C:47]6[NH:46][C:45](=[O:48])[NH:44][C:43]=6[CH:42]=[CH:41][CH:40]=5)[CH2:32][CH2:33]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(NC4CCN(Cc5ccccc5)CC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1N=C(NC2CCN(Cc3ccccc3)CC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(which was obtained in Intermediate 21) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a pale yellowish solid; mp>165° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt, J=9.9 Hz, 2 H), 2.55-2.95 (m, 6 H), 3.47 (s, 2 H), 3.75-4.05 (m, 5 H), 4.87 (brs, 1 H), 6.57 (d, J=7.5 Hz, 1 H), 6.61 (d, J=8.1 Hz, 1 H), 6.84 (t, J=8.1 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.50 (m, 8 H), 9.46 (brs, 1 H), 10.57 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 341.6 ((M+2H)2+, 100%); 682.1 (MH+, 5%); HRMS Calcd. for C37H44N7O4S (MH+): 682.3176. Found: 682.3211.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][F:21]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:19][CH2:20][F:21]
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)c(OCCF)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Intermediate 16A (475 mg, 2.179 mmol) was dissolved in DMF (1 mL) and to this solution was added potassium carbonate (903 mg, 6.54 mmol) and 1-bromo-2-fluoroethane (415 mg, 3.27 mmol). The reaction mixture was stirred at 100° C. for 3 hours, cooled, diluted with water (20 mL) and then extracted with EtOAc (2×20 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Intermediate 16B was obtained as a pale yellow semi-solid (570 mg, 2.159 mmol, 99% yield). MS (ES): m/z=199.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.47-4.51 (m, 1 H) 4.55-4.59 (m, 1 H) 4.73-4.78 (m, 1 H) 4.85-4.91 (m, 1 H) 7.77-7.83 (m, 1 H) 7.91 (d, J=2.51 Hz, 1 H) 7.94 (d, J=8.53 Hz, 1 H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[CH:11]=[C:12]([N:16]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:17]2[O:21][C:20]([C:22]([N:24]([C:33]3[CH:34]=[N:35][C:36]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:37][CH:38]=3)[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:23])=[N:19][N:18]=2)[CH:13]=[CH:14][CH:15]=1.[C:53]1(B(O)O)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C=O)C.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:10]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:17]2[O:21][C:20]([C:22]([N:24]([C:33]3[CH:34]=[N:35][C:36]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:37][CH:38]=3)[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:23])=[N:19][N:18]=2)[CH:11]=1
Reactant: C[Si](C)(C)CCOCN(C(=O)c1nnc(N(COCC[Si](C)(C)C)c2cccc(I)c2)o1)c1ccc(N2CCOCC2)nc1
Reactant: OB(O)c1ccccc1
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: CN(C)C=O
Product: C[Si](C)(C)CCOCN(C(=O)c1nnc(N(COCC[Si](C)(C)C)c2cccc(-c3ccccc3)c2)o1)c1ccc(N2CCOCC2)nc1
Temperature: 80 °C
Yield: 84.8 %

Procedure:
Potassium phosphate (214 mg, 1.01 mmol) was added to 5-((3-iodophenyl){[2-(trimethylsilyl)ethoxy]methyl}amino)-N-(6-morpholin-4-ylpyridin-3-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}-1,3,4-oxadiazole-2-carboxamide (190 mg, 0.25 mmol) and phenylboronic acid (37 mg, 0.30 mmol) in DMF (3 mL) and the mixture was degassed. Tetrakis(triphenylphosphine)palladium (29 mg, 0.03 mmol) was added and the mixture was heated to 80° C. for 90 minutes. Phenylboronic acid (8 mg, 0.06 mmol) and tetrakis(triphenylphosphine)palladium (10 mg, 0.01 mmol) was added, the mixture degassed and heated to 80° C. for 240 minutes. The mixture was cooled, diluted with ether (60 mL) and washed with water (3×20 mL). The aqueous layers were re-extracted with ether (20 mL) and the organic layers were combined, dried and concentrated by evaporation. The residue was purified by chromatography, eluting with 0-20% ether/DCM to give the title compound (Intermediate 49, 149 mg, 84%) as a gum; 1H NMR δ 8.09 (1H, s), 7.83-7.66 (4H, m), 7.66-7.37 (6H, m), 6.86 (1H, d), 5.37 (2H, s), 5.19 (2H, s), 3.79-3.62 (8H, m), 3.55-3.49 (4H, m), 0.93 (4H, t), 0.06 (9H, s), 0.01 (9H, s).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([CH:21]=O)[CH:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OP([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])(OCC)=O)C>CN(C)C=O>[CH2:3]([N:10]1[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:13](/[CH:21]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:12]=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cnn(Cc2ccccc2)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnn(Cc2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 71 %

Procedure:
Sodium hydride (60%, oily, 1.28 g) was added to a mixture of 1-benzyl-5-phenyl-1H-pyrazole-4-carbaldehyde (7.00 g), ethyl diethylphosphonoacetate (6.59 g), and N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was poured into ice water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and ethyl(E)-3-(1-benzyl-5-phenyl-1H-pyrazol-4-yl)propenoate (6.30 g, yield: 71%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 62–63° C.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[N+:12]([C:15]1[CH:16]=[C:17]([CH:21]2[S:25][C:24](=[O:26])[NH:23][CH:22]2[C:27](O)=[O:28])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:27]([CH:22]1[CH:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[S:25][C:24](=[O:26])[NH:23]1)=[O:28])([O-:7])=[O:6]
Reactant: O=C1NC(C(=O)O)C(c2cccc([N+](=O)[O-])c2)S1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2cccc([N+](=O)[O-])c2)S1
Yield: 67.8 %

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 380 mg of N-(2-nitrooxyethyl)-amine nitrate and 500 mg of 5-(3-nitrophenyl)-2-oxothiazolidine-4-carboxylic acid, to obtain 450 mg of the title compound as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(F)cc2Oc2sc3ccccc3c21
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Oc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: O.[C:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[OH-].[K+].[CH3:10][N:11]([CH3:15])[CH2:12]CO>CO>[CH3:10][N:11]([CH2:15][CH2:4][O:3][C:2](=[O:7])[O:5][CH2:6][CH2:10][N:11]([CH3:15])[CH3:12])[CH3:12]
Reactant: COC(=O)OC
Reactant: CN(C)CCO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)CCOC(=O)OCCN(C)C
Temperature: 80 °C

Procedure:
Into a flask equipped with a reflux cooler, a water separator and a dropping funnel, there were charged 113.5 grams (1.25 moles) of dimethyl carbonate. The substance was heated to 80° C. A solution of 1.4 grams (0.025 moles) of potassium hydroxide in 225.0 grams (2.5 moles) of dimethylethanolamine was then added in drops over a period of 30 minutes. The methanol formed during the reaction was removed by azeotropic distillation using cyclohexane as an entraining agent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9](=[CH:15][C:16]2[O:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:5][CH:4]=1.[NH2:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>CCCCO.C1COCC1>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]2[N:24]=[C:25]3[NH:26][N:27]=[C:28]([CH3:30])[C:29]3=[C:15]([C:16]3[O:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=Cc1ccc(C)o1)C(=O)c1ccc(OC)cc1
Reactant: Cc1cc(N)n[nH]1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)nc2[nH]nc(C)c2c1-c1ccc(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
A mixture of 0.76 g (2.41 mmol) of ethyl 2-(4-methoxybenzoyl)-3-(5-methylfuran-2-yl)acrylate and of 0.23 g (2.41 mmol) of 3-amino-5-methyl-pyrazole is heated to 140° C. in 6 ml of n-BuOH for 24 h. The mixture is then cooled to room temperature and 0.55 g (2.4 mmol) of DDQ in 6 ml of THF is added. The mixture is stirred at room temperature for 1 h. The mixture is then poured onto a saturated solution of NaHCO3 then extracted with ethyl acetate. The organic phase is washed in a saturated solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated. The mixture is then purified using reverse-phase HPLC to yield 146 mg (15%) of ethyl 6-(4-methoxyphenyl)-3-methyl-4-(5-methylfuran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH:7]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(COc3ccccc3Cl)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ccccc1OCc1cccc(OCC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.7 %

Procedure:
A solution of 215 mg of 1-[(2-chlorophenoxy)methyl]-3-[[N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]benzene, as prepared in the preceding step, in methylene chloride (2 mL) was treated with 1.5 mL of 4 N HCl in dioxane. The reaction mixture was stirred at ambient temperature for 1 h, and then concentrated to provide 183 mg of the title compound as a colorless powder after repeated concentrations from diethyl ether/hexane/methanol. 1H-NMR (300 MHz, DMSO-d6) δ 8.51 (br s, 2 H), 7.45 (dd, 1 H, J=1.3, 7.9 Hz), 7.27-7.35 (m, 2 H), 7.21 (d, 1 H), 6.90-7.05 (m, 4 H), 5.18 (s, 2 H), 3.87 (d, 2 H), 2.90 (t, 2 H, J=10 Hz), 2.05 (m, 1 H), 1.91 (d, 2 H, J=13.8 Hz), and 1.5-1.54 (m, 2 H). Mass spectrum (MALDI-TOF; α-cyano-4-hydroxycinnamic acid matrix) calcd. for C19H22ClNO2 : 332.1 (M+H). Found: 332.0.
Reaction SMILES: C[C@H](CCCC(C)C)C[CH2:4][CH2:5][C@H:6]([CH2:8][CH2:9][CH2:10][C:11]([CH3:13])=[O:12])C.[O-]Cl.[Na+].CC(O)CCCCCC>C(O)(=O)C>[CH3:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:6][CH2:5][CH3:4]
Reactant: CC(=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Solvent: CCCCCCC(C)O
Product: CCCCCCC(C)=O
Yield: 95 %

Procedure:
Subsequent hydrogenation (H2 /Pd-C) yields the same saturated C-18 alcohol: ##STR22## Other methods used to oxidize 2° alcohol 9 to "phytone" include: (a) aqueous NaOCl (bleach) in acetic acid; such conditions give >95% yield of 2-octanone from 2-octanol. See: J. Org. Chem., 45, 2030 (1980).
Reaction SMILES: [OH:1][C@H:2]([CH3:15])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]([O:13]C)=[O:12])=[CH:5]1.[OH-].[Na+].Cl>O1CCOCC1.CO>[OH:1][C@H:2]([CH3:15])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]1
Reactant: COC(=O)c1ccc(=O)n(C[C@@H](C)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](O)Cn1cc(C(=O)O)ccc1=O
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A solution of (R)-methyl 1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (508 mg, 2.405 mmol) in 1,4-dioxane (12 mL) and MeOH (4.00 mL) was treated with aqueous sodium hydroxide, 5.0 M (0.962 mL, 4.81 mmol). The reaction was stirred at 23° C. After 20 h, the reaction was neutralized to pH=6.0 with 2 N HCl, and concentrated in vacuo. The residue was azeotroped with toluene (3×10 mL), suspended in a 1:1 MeOH:DCM solution (25 mL), and the white NaCl residue was removed by filtration. The filtrate was concentrated, affording (R)-1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid as a white solid. MS (ESI pos. ion) m/z: 198.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[C:16]([CH3:17])=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](O)[CH2:27][OH:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:19]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[C:11]([CH3:18])[C:12]([CH:13]2[O:28][CH2:27][CH2:26][O:14]2)=[CH:15][C:16]=1[CH3:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C1OCCO1
Temperature: 80 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a stirred solution of 4-dibenzylamino-2,5-dimethylbenzaldehyde (3.60 g, 10.9 mmol) in toluene (35.0 mL) under nitrogen was added 1,2-ethanediol (1.83 mL, 32.8 mmol) and p-toluenesulfonic acid (451 mg, 2.62 mmol). The reaction mixture was heated at 80° C. overnight. TLC (3:1 hexanes:EtOAc) showed a ˜50:50 mixture of product and starting material. Magnesium sulfate (1.32 g, 10.9 mmol) was added and stirring was continued for 6 h. The reaction mixture was then filtered and concentrated under reduced pressure to give title compound (3.19 g, 78% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[NH4+].[OH-]>Cl.C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[C:7]2[C:2](=[C:3]([OH:9])[CH:4]=1)[N:1]=[C:12]([CH3:13])[CH:11]=[CH:10]2
Reactant: Nc1ccc(F)cc1O
Reactant: C/C=C/C=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc2cc(F)cc(O)c2n1
Reaction time: 0.5 h

Procedure:
2-Amino-5-fluorophenol (13.0 g, 102 mmol) was dissolved in 6N HCl (78 mL) and heated to reflux. The solution was treated with (E)-but-2-enal (8.8 ml, 107 mmol) in 1 mL portions over 1 hour. The reaction was heated at reflux for 13 hours. The reaction mixture was cooled and adjusted to pH 8 with concentrated NH4OH. The reaction was diluted with ethyl acetate, stirred for 30 minutes then filtered through a nylon membrane (0.45 μM). The filtrate was separated and the aqueous was washed with ethyl acetate. The combined organics were washed with saturated NaHCO3, saturated NaCl, dried over Na2SO4 and concentrated in vacuo to a thick dark oil (19 g). MS APCI (+) m/z 178.1 (M+1) detected.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[CH3:34][C:35]1([OH:41])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.FC1C=CC(C(/N=C2\NC3C=CC(CN4CCN(S(C)(=O)=O)CC4)=CC=3N\2[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)=O)=CC=1>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][N:38]4[CH2:39][CH2:40][C:35]([OH:41])([CH3:34])[CH2:36][CH2:37]4)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:15][CH2:16][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: CC1(O)CCNCC1
Agent: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCN(S(C)(=O)=O)CC4)cc32)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C)(O)CC4)cc32)CC1

Procedure:
The title compound was prepared from (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide and 4-methylpiperidin-4-ol using a method analogous to that used in the preparation of (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide. The title compound was isolated as a white powder (37 mg, 30% yield). MS, m/z (C31H40FN5O3): calcd, 549.3. found, 549.9 [M+H]
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20](OS(C(F)(F)F)(=O)=O)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCOB1[C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1.C(=O)([O-])O.[Na+]>COCCOC.O.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:1]1([C:7]2[C:8]3[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(OS(=O)(=O)C(F)(F)F)cccc1-3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(-c2cccnc2)cccc1-3
Temperature: 90 °C
Yield: 82 %

Procedure:
To a suspension of methyl 12-cyclohexyl-4-trifluoromethanesulfonyloxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (130 mg, 0.248 mmol), 3-(1,3,2-dioxaborinan-2-yl)pyridine (53 mg, 0.323 mmol) and sodium hydrogen carbonate (62 mg, 0.744 mmol) in 1,2-dimethoxyethane (2 ml) and water (0.75 ml) was added tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol), and the mixture was heated at 90° C. for 3 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to give methyl 12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (92 mg, yield 82%).