Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[C:23]([CH3:34])[C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=1)=[O:19]>>[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[C:23]([CH3:34])[C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)[N:27]=1)=[O:19]
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CNC(=O)c1scc(C)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
The title compound was prepared in an analogous manner to the preparation of example 381 by combining 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide to yield an orange solid (11%). LCMS: m/z=485.08 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.05 (m, 2H), 7.65 (s, 1H), 7.45 (d, 1H, J=8.6 Hz), 7.29 (m, 1H), 7.01 (s, 1H), 6.75 (d, 1H, J=8.6 Hz), 6.11 (m, 1H), 3.52 (m, 3H), 2.93 (d, 3H, J=4.8 Hz), 2.35 (m, 2H), 2.06 (m, 2H), 1.31 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:5].[C:24](Cl)(Cl)=[O:25]>C1(C)C=CC=CC=1>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][CH:17]=2)[NH:1][C:24]1=[O:25]
Reactant: O=C(Cl)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)NCCc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)n1CCc1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a stirred solution of 2-amino-N-[2-(2,4-dichlorophenyl)ethyl]-4-nitrobenzamide (1.0 g, 2.82 mmol) in toluene (30 mL) was added a 1.9 M solution of phosgene in toluene (4.5 mL, 8.5 mmol). The reaction mixture was heated to 60° C. and stirred for 4 hours. The solvent was removed under reduced pressure and CH2Cl2 was added to the residue. The precipitate was collected via vacuum filtration and washed with CH2Cl2 to give the product (0.92 g, 86% yield) as a white solid. HPLC retention time: 3.28 min; Method A; LRMS (ESI) m/z 378 (M−1).
Reaction SMILES: [CH3:1][C:2]1([NH2:8])[CH2:7][O:6][CH2:5][O:4][CH2:3]1.[OH-].[Na+].O.[Br:12][CH:13]([CH2:17][Br:18])[C:14](Cl)=[O:15]>C(Cl)Cl>[CH3:1][C:2]1([NH:8][C:14](=[O:15])[CH:13]([Br:12])[CH2:17][Br:18])[CH2:7][O:6][CH2:5][O:4][CH2:3]1
Reactant: O=C(Cl)C(Br)CBr
Reactant: CC1(N)COCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1(NC(=O)C(Br)CBr)COCOC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Five and nine-tenths grams (g) (0.05 mole) of 5-methyl-5-amino-1,3-dioxane, 3.2 g (0.04 mole) of 50% sodium hydroxide, 8 milliliters (ml) of water and 55 ml of methylene chloride were combined in a reaction flask. The mixture was cooled to -10° C. Ten g (0.04 mole) of 2,3-dibromopropionyl chloride were added dropwise. The reaction mixture was stirred for 2 hours and then vacuum stripped. The product was recrystallized in ethanol/water. Yield was 8.7 g of 5-methyl-5-(2',3'-dibromopropionyl)amino-1,3-dioxane. m.p.=115°-119° C. Structure was confirmed by NMR spectroscopy.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](/[CH:41]=[CH:40]/[C:39]3[CH:45]=[CH:46][C:36]([F:35])=[CH:37][CH:38]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: OB(O)/C=C/c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(/C=C/c2ccc(F)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), (E)-4-fluorostyrylboronic acid (49.7 mg, 0.299 mmol) and PdCl2(PPh3)2 (42.0 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2.0 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-((E)-4-fluorostyryl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) at room temperature for 1 hour to remove the protecting groups. TFA was subsequently evaporated from the reaction mixture. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 20-50% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a light yellow solid (32 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (d, J=16.17 Hz, 1H), 2.00-2.21 (m, 1H), 3.55-3.71 (m, 2H), 3.79-3.93 (m, 2H), 3.93-4.10 (m, 1H), 4.33-4.46 (m, 2H), 4.54 (d, J=8.84 Hz, 1H), 7.15 (d, J=5.05 Hz, 1 H), 7.28 (t, J=8.84 Hz, 1H), 7.58-7.74 (m, 3H), 7.93 (br s, 3H), 8.15 (d, J=15.92 Hz, 1H), 8.51 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H20F2N4O2, 387. found, 387.
Reaction SMILES: [OH:1][C@H:2]([C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].Br[CH2:26][C:27]#[N:28]>CC#N>[C:27]([CH2:26][O:1][C@@H:2]([C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1)#[N:28]
Reactant: Cc1cccc([C@@H](O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc([C@H](OCC#N)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 3-((S)-hydroxy(m-tolyl)methyl)piperidine-1-carboxylate (30.5 g, 0.1 mol) in MeCN (300 mL), NaH (12 g, 0.3 mol) was added at 0° C. The mixture was stirred for 1 hr at rt. The mixture was cooled to −40° C., then bromoacetonitrile (35.7 g, 0.3 mol) was added in portions. The mixture was stirred for 0.5 hr at −20° C. continually. The reaction was quenched with sat. NH4Cl. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated. Crude (R)-tert-butyl 3-((R)-(cyanomethoxy)(m-tolyl)methyl)piperidine-1-carboxylate was used for the next step without purification.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH:12]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[CH2:13][CH3:14])=[CH:5][CH:4]=1.Br.[OH-].[NH4+]>O>[NH:18]1[CH:19]=[C:15]([CH:12]([CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([OH:2])[CH:11]=3)[CH2:7][CH2:8]2)[CH2:13][CH3:14])[N:16]=[CH:17]1
Reactant: CCC(c1c[nH]cn1)C1CCc2ccc(OC)cc21
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCC(c1c[nH]cn1)C1CCc2ccc(O)cc21

Procedure:
A stirred mixture of 4-[1-(6-methoxyindan-1-yl)-propyl]-1H-imidazole (174 mg) and 48% hydrobromic acid (9 ml) is heated under reflux for 50 minutes. The cooled reaction mixture is poured into water and is made basic with ammonium hydroxide solution. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated to dryness. The crude product is purified by flash chromatography using methylene chloride-methanol as eluent. The product is a mixture of two diastereomers (1:1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:10]1[O:18][CH:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[O:7]([CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][OH:18])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC(Oc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A mixture of phenol (28.2 g), NaOH (4.0 g) and water (15 ml) was heated on a boiling water bath until the mixture became homogeneous. Styrene oxide (12.0 g) was added dropwise over a period of 15 minutes and the mixture was heated with stirring on a boiling water bath for 1 hr. The mixture was poured into a solution of NaOH (12.0 g) in ice water (200 ml) and extracted with ether (50 ml) 2 times. The ether solution was dried over anhydrous sodium sulfate and the solvent distilled off to obtain a crystalline product. Recrystallization from methylene chloride-hexane gave white crystals (6.6 g) of 2-phenoxy-2-phenylethanol.
Reaction SMILES: Cl[N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:13][C:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)([CH3:17])[CH2:15][OH:16]>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].O>[CH3:17][C:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([N:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)([CH3:13])[CH2:15][OH:16]
Reactant: ClN1CCCCC1
Reactant: CC(C)(CO)Oc1ccc(-c2ccccc2)cc1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(C)(CO)Oc1ccc(-c2ccc(N3CCCCC3)cc2)cc1
Reaction time: 0.25 h

Procedure:
Under agitation, a solution of 12 g. of N-chloropiperidine in 15 ml. of concentrated sulfuric acid is added dropwise within 10 minutes to a mixture of 24.2 g. of 2-methyl-2-(4-phenylphenoxy)-propanol (obtainable from 4-hydroxy-diphenyl and 2-bromo-2-methylpropanol), 7 g. of iron(II) sulfate heptahydrate, 8 ml. of concentrated sulfuric acid, and 3 ml. of water. The mixture is agitated for 15 minutes at 20°, then poured on ice water, washed with ether, made alkaline with sodium hydroxide solution, and extracted with chloroform. From the extract, after evaporation, one obtains 2-methyl-2-[4-(4-piperidinophenyl)-phenoxy]-propanol, m.p. 158°-160°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:26]([Mg]Br)[CH3:27].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:26][CH3:27]
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cc(OC)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Under an argon atmosphere, 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (140 mg) was dissolved in tetrahydrofuran (2 ml), and the solution was then cooled to −78° C. A 0.96 M tetrahydrofuran solution (0.7 ml) of ethylmagnesium bromide was added dropwise thereto, and the mixture was stirred at −78° C. for one hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (74.5 mg, yield 49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([N:13]([CH2:18][CH2:19][C:20]([OH:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][C:22]([CH3:24])=[CH2:23])[C:14](=[O:17])OC)([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([N:13]2[CH2:18][CH2:19][C:20]([CH2:21][C:22]([CH3:24])=[CH2:23])([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:31][C:14]2=[O:17])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: C=C(C)CC(O)(CCN(C(=O)OC)C(C)(C)C#Cc1ccc(F)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)CC1(c2ccccc2)CCN(C(C)(C)C#Cc2ccc(F)cc2)C(=O)O1
Yield: 150.7 %

Procedure:
To a stirred solution of methyl 4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl(3-hydroxy-5-methyl-3-phenylhex-5-enyl)carbamate (35 mg, 0.03 mmol) in dry THF (2 mL) was added 60% NaH in oil (5 mg, 0.12 mmol). The mixture was heated at 60 C for 3 h, cooled, diluted with EtOAc (90 mL), washed with water (10 mL) and brine (10 mL), and dried over Na2SO4. Removal of the solvent left an oil (18 mg) which was purified by prep HPLC to afford 3-(4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (17.7 mg, 55%) as an oil. LC-MS Method 1 tR=2.22 min, m/z=392; 1H NMR (CDCl3) δ 1.63 (s, 3H), 1.66 (s, 3H), 1.81 (s, 3H), 2.24 (m, 1H), 2.37 (m, 1H), 2.58 (m, 2H), 3.06 (m, 1H), 3.64 (m, 1H), 4.64 (s, 1H), 4.83 (s, 1H), 6.98 (m, 2H), 7.25-7.40 (7H).
Reaction SMILES: Cl.[CH2:2]([CH:5]1[C:9](OC(=O)C)([CH3:10])[CH:8]=[CH:7][C:6]1=[O:15])[CH:3]=[CH2:4].[O:16]1CCOCC1>>[CH2:2]([C:5]1[C:6](=[O:15])[CH2:7][CH:8]([OH:16])[C:9]=1[CH3:10])[CH:3]=[CH2:4]
Reactant: C=CCC1C(=O)C=CC1(C)OC(C)=O
Reactant: C1COCCO1
Agent: Cl
Product: C=CCC1=C(C)C(O)CC1=O
Reaction time: 2 h

Procedure:
In the same flask as in Example 1, 10% aqueous hydrochloric acid (10 ml) and dioxane (10 ml) were charged, and 2-allyl-3-acetoxy-3-methyl-4-cyclopentenone (1.94 g) was dropwise added thereto in 2 hours while keeping the inner temperature at 0° to 10° C. After completion of the dropwise addition, the resultant mixture was stirred at the same temperature as above for 3 hours. The reaction mixture was subjected to post-treatment and purification as in Example 1 to give 1.37 g of 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone. Yield, 90%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:27]=1[N:35]=[C:36]=[O:37])([CH3:25])[CH3:24]>>[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:33])[CH3:34])[C:27]=1[NH:35][C:36](=[O:37])[N:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][CH:12]=1)([CH3:24])[CH3:25]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCc1ccc(NCc2ccc(N3CCOCC3)cc2)cc1
Product: CCc1ccc(N(Cc2ccc(N3CCOCC3)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using (4-ethylphenyl)(4-morpholinophenylmethyl)amine (0.63 g) and 2,6-diisopropylphenyl isocyanate (0.46 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-ethylphenyl)-N-(4-morpholinophenylmethyl)urea (0.45 g) was obtained. melting point: 159–161° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:7]=2[CH:15]=1.S(Cl)([Cl:19])(=O)=O>ClCCl>[Cl:19][C:15]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1cc2cc(OC)ccc2o1
Solvent: ClCCl
Product: COC(=O)c1cc2c(Cl)c(OC)ccc2o1
Temperature: 20 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
Methyl 5-methoxybenzofuran-2-carboxylate (5.22 g, 25.3 mmol) was dissolved in dichloromethane, and sulfuryl chloride (3.76 g, 27.9 mmol) was added at such rate to maintain a temperature of 20° C. After stirring for 5 h the solution was dripped slowly onto ice water (70 mL). The organic phase was then washed with water, aqueous saturated NaHCO3 and again with water. The layers were separated and the organic portion was passed through a phase separation cartridge and evaporated to afford a solid (5.81 g), which was taken through to the next step with no further purification.
Reaction SMILES: C([N:8]1[C:12]2[C:13]([O:19][CH3:20])=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=2[N:10]=[C:9]1[NH2:21])C1C=CC=CC=1>[Pd]>[NH2:21][C:9]1[NH:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([O:19][CH3:20])[C:12]=2[N:8]=1
Reactant: COc1ccc(OC)c2c1nc(N)n2Cc1ccccc1
Agent: [Pd]
Product: COc1ccc(OC)c2[nH]c(N)nc12

Procedure:
1-Benzyl-2-amino-4,7-dimethoxybenzimidazole (17.85 g, 0.06 mole) is hydrogenated in the presence of palladium on carbon catalyst (10%) at 50 psi for about twelve hours. After filtration the methanol is removed in vacuo and the residue dissolved in boiling water and treated with decolorizing charcoal. The suspension is filtered into 1N NaOH, giving a white precipitate of 2-amino-4,7-dimethoxybenzimidazole. The amorphous white powder melts at 251°-253° C.
Reaction SMILES: [CH3:1][C:2]([CH3:69])([CH3:68])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH:13]2[CH:14]([CH3:67])[CH2:15][CH2:16][CH:17]([O:59][Si](CC)(CC)CC)[CH2:18][C:19]([O:21][CH:22](/[C:27](/[CH3:58])=[CH:28]/[CH:29]=[CH:30]/[C:31]([CH3:57])([O:49][Si](CC)(CC)CC)[CH2:32][CH:33]3[O:48][CH:34]3[CH:35]([CH3:47])[CH:36]([O:39][Si](CC)(CC)CC)[CH2:37][CH3:38])[CH:23]([CH3:26])[CH:24]=[CH:25]2)=[O:20])=[O:11])[CH2:6][CH2:5]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:69][C:2]([CH3:1])([CH3:68])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH:13]2[CH:14]([CH3:67])[CH2:15][CH2:16][CH:17]([OH:59])[CH2:18][C:19]([O:21][CH:22](/[C:27](/[CH3:58])=[CH:28]/[CH:29]=[CH:30]/[C:31]([OH:49])([CH3:57])[CH2:32][CH:33]3[O:48][CH:34]3[CH:35]([CH3:47])[CH:36]([OH:39])[CH2:37][CH3:38])[CH:23]([CH3:26])[CH:24]=[CH:25]2)=[O:20])=[O:11])[CH2:6][CH2:5]1
Reactant: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(OC(=O)N2CCN(CC(C)(C)C)CC2)C=CC1C)O[Si](CC)(CC)CC
Agent: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)C(OC(=O)N2CCN(CC(C)(C)C)CC2)/C=C/C1C
Agent: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(OC(=O)N2CCN(CC(C)(C)C)CC2)/C=C/C1C)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)C(OC(=O)N2CCN(CC(C)(C)C)CC2)C=CC1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (8E,12E,14E)-7-((4-(2,2-dimethylpropyl)piperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (9.7 mg, 9.5 μmol) in tetrahydrofuran (1 mL) was cooled to 5° C. Tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran, 31 μL, 31 μmol) was added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate, and then the organic layer was washed with an aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel plate; methanol-methylene chloride, 1:49) to obtain the title compound (6.3 mg, 98%) as a colorless oil.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][C:20]=4[F:33])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][N:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[BH4-].[Na+].[Cl-].[NH4+]>CO.O1CCCC1>[F:33][C:20]1[CH:21]=[C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][C:15]1[C:16](=[O:17])[N:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([OH:4])[CH2:6][CH2:7]2)[C:12]2[N:13]([N:37]=[CH:38][N:39]=2)[C:14]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Temperature: 25 °C

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (347 g), 3M hydrochloric acid (1.4 L) and tetrahydrofuran (2.1 L) was stirred under reflux for 16 hr. The reaction mixture was cooled to room temperature, and extracted with ethyl acetate (2 L). The resulting aqueous layer was extracted with ethyl acetate (1 L). The combined extracts were successively washed with saturated aqueous sodium hydrogen carbonate (1 L) and brine (1 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was dissolved in methanol (650 mL) and tetrahydrofuran (960 mL), and the resulting solution was added to a suspension of sodium borohydride (37.3 g) in tetrahydrofuran (1.6 L) with the internal temperature maintained below 10° C. After stirring at the same temperature for 0.5 hr, saturated aqueous ammonium chloride solution (640 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The resulting residue was extracted with ethyl acetate (2 L). The organic layer was washed with saturated brine (1 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the title compound as a diastereomeric mixture. The diastereomeric mixture obtained was dissolved in ethyl acetate (940 mL) at 50° C. Hexane (1.6 L) was added to the solution, and the resulting mixture was stirred at the same temperature for 2 hr. Additional hexane (940 mL) was added to the mixture, which was cooled to room temperature and stirred for further 0.5 hr. The precipitate was collected by filtration to give the title compound as a white solid (233 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[NH:6]2.CC1C=CC(S(O[CH2:34][C@H:35]2[CH2:39][CH2:38][CH2:37][O:36]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[N:6]2[CH2:34][C@H:35]1[CH2:39][CH2:38][CH2:37][O:36]1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)CCO3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: BrCC1CCCCO1
Product: O=C1N(C[C@H]2CCCO2)c2cccc(Cl)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 4′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: mp 78-82° C.; 1H NMR (300 MHz, DMSO-d6) δ7.32-7.09 (m, 1H), 7.05-6.92 (m, 1H), 6.44 (s, 1H), 6.35 (s, 1H), 4.96 (dd, J=9.1, 1.1 Hz, 1H), 4.85 (d, J=9.1 Hz, 1H), 4.51 (t, J=8.7 Hz, 1H), 4.31-4.16 (m, 1H), 4.00-3.59 (m, 1H), 2.98 (t, J=8.6 Hz, 1H), 2.12-1.80 (m, 1H), 1.76-1.61 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ178.0 (2), 162.1 (2), 162.0, 144.7, 131.1 (2), 129.8 (2), 128.7 (2), 123.9, 119.4 (2), 118.4 (2), 117.5 (2), 108.1 (2), 92.9, 77.5, 76.9 (2), 72.3, 68.2 (2), 58.1 (2), 44.9 (2), 29.1 (2), 29.0 (2), 25.6 (2); MS (ES+) m/z 397.9 (M+1), 399.9 (M+1).