Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][C:10]=2[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:37][C:38]([NH:40][CH3:41])=[O:39]>CC#N.CCOC(C)=O>[NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][C:10]=2[N:20]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:7])=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CNC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2cccs2)cc1NC(=O)c1ccc(N)cc1

Procedure:
To a solution of tert-butyl [2-[(4-aminobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate (mg, mmol) in CH3CN was added K2CO3 and 2-chloro-N-methylacetamide. The reaction was allowed to stir at reflux overnight. The crude reaction mixture was diluted with EtOAc (20 mL) and then washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (10-100% MeCN/H2O with 0.05% TFA). The appropriate fractions were combined and concentrated in vacuo and gave the desired tert-butyl [2-[(4-aminobenzoyl)amino]-4-(2-thienyl)phenyl][2-(methylamino)-2-oxoethyl]carbamate which was confirmed by MS: cal'd 481.2 (MH+), exp 481.2 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>CO.C(N(CC)CC)C>[OH:19][CH2:18][CH2:17][CH2:16][NH:15][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: NCCCO
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCCCO
Temperature: 50 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
To a solution of methyl 2-chloro-3-nitrobenzoate (100 g, 0.463 mol) in methanol (800 mL) and triethylamine (129 mL) was added 3-amino-1-propanol (52.2 g, 0.696 mol), and the mixture was stirred at 50° C. for 6 hr. The mixture was concentrated and the residue was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50% ethyl acetate/n-hexane mixture (short column). The filtrate was concentrated in vacuo to give the title compound as a brown oil (86.6 g, 0.341 mol, 74%).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:18][CH:19]=C)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]=[O+][O-]>C(Cl)Cl>[CH2:1]([O:8][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:18][CH:19]=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[O+][O-]
Reactant: C=CCC(Cc1ccccc1C)OCc1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1CC(CC=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(2-(benzyloxy)pent-4-enyl)-2-methylbenzene (5.0 g, 18.72 mmol) in DCM (100 ml) was passed O3 gas at −78° C. for 3 h. The reaction mixture was quenched with TEA (5 ml) at −78° C., and stirred for room temperature for 5 h. The title compound was purified by separation methods A and E. (Yield 2.0 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O>[CH2:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 36.8 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]phenylamine (60 mg, 0.26 mmol) was dissolved in dichloroethane and the solution was added with benzaldehyde (28 μL, 0.28 mmol), sodium triacetoxyborohydride (81 mg, 0.38 mmol) and acetic acid (15 mL, 0.25 mmol), followed by stirring at room temperature for 13 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. A crude product was purified by silica gel chromatography [ethyl acetate/hexane=1/8 to 1/1] and further crystallized from ethyl acetate to obtain Compound 26 (31.1 mg, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:17][C:18]1C=CC(CC(O)=O)=C[CH:19]=1.C(Cl)(=O)C>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1)(=[O:17])[CH3:19]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=C(O)C1(c2ccc(O)cc2)CCCCC1
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C2(C(=O)O)CCCCC2)cc1
Reaction time: 0.25 h
Yield: 23.6 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)cyclohexanecarboxylic acid (10) (1.264 g crude material, obtained from 1.000 g (6.57 mmol) of 9) in pyridine (5 ml) under argon atmosphere at 0° C. acetyl chloride (0.541 g, 7.61 mmol) slowly (ca. over 10 minutes) was added and the mixture was stirred for 15 minutes at this temperature. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 3 hours, then the content was poured into ice water (30 ml) and the pH of the medium was brought to 1-2 by adding conc.HCl. The mixture was extracted with ethyl acetate (2×40 ml), the organic extract was washed successively with water (30 ml), brine (15 ml), and dried (Na2SO4). The solvent was evaporated, the residue was dissolved in toluene and chromatographed on silica gel (100 g) with petroleum ether-dioxane-acetic acid (8:2:0.1) as eluent affording the title compound (0.406 g, 23.5% based on 9) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 1.06-1.98 (8H, m); 2.28 (3H, s); 2.30-2.63 (2H, m); 7.09 (2H, d, J=8.6 Hz); 7.46 (2H, d, J=8.6 Hz); 10.49 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].Cl>CN(C=O)C>[CH2:12]([O:19][C:9]1[C:8]([F:11])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1cc(F)c(F)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution of 5.0 g of 3,4,5-trifluorobenzonitrile and 4.5 g of benzyl alcohol in 25 ml of DMF was added 1.5 g of 60% sodium hydride (oily) at 0° C. The mixture was stirred at room temperature for 4 hours. Then, dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.0 g of 4-benzyloxy-3,5-difluorobenzonitrile represented by the formula:
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CC=CC=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCCC(C)CCCC(C)CCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCC(C)CCCC(C)CCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 27 g (0.11 mol) of 5,9,13-trimethyl-1-tetradecanol and 10 g (0.13 mol) of pyridine in 200 ml of dry methylene chloride was added dropwise to a solution of 22.1 g (0.12 mol) of p-toluenesulfonyl chloride in 100 ml of dry methylene chloride under ice cooling. After the dropwise addition, the mixture was agitated at room temperature overnight, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated under reduced pressure to obtain 34.4 g of (5,9,13-trimethyltetradecyl)tosylate. Under a nitrogen gas stream, 25.8 g (0.21 mol) of erythritol was dissolved in 200 ml of dry DMF, and 4.2 g (0.11 mol) of 60% NaH was added in several batches under ice cooling. After the addition, the resultant was agitated at room temperature for 1 hour, and then was heated to 50° C. A half amount of (5,9,13-trimethyltetradecyl)tosylate obtained above (17.2 g) was added dropwise thereto, and was washed with 55 ml of DMF. The resultant was heated to 80° C. and then agitated for 4 hours, the resulting reaction solution was concentrated under reduced pressure, 500 ml of ether was added to the residual solution to perform extractive dissolution twice, the product was washed twice with saturated saline, and then it was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated, and purified by silica gel column chromatography to obtain 2.3 g of 1-O-(5,9,13-trimethyltetradecyl)erythritol having the following properties. As a result of HPLC analysis of the obtained product, the purity of 1-O-(5,9,13-trimethyltetradecyl)erythritol was 76.9% and that of 2-O-(5,9,13-trimethyltetradecyl)erythritol was 23.1%. The results of NMR analysis are as shown below.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)n(-c2ccccc2)n1
Yield: 80 %

Procedure:
0.37 g of ethyl 3-methyl-1-phenyl-1H-5-pyrazolecarboxylate was dissolved in 10 ml ethanol, and 1 ml of 5N sodium hydroxide was added, followed by heating under reflux for 1 hour. The reaction solution was ice-cooled and neutralized with 2N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 0.26 g of 3-methyl-1-phenyl-1H-5-pyrazolecarboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[CH:6]=1)=[O:4].[CH3:16][O:17][C:18](=[O:24])[CH2:19][CH2:20][C:21]([O-:23])=[O:22].[Na+]>CC(C)=O>[C:21]([O:23][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[CH:6]=1)=[O:4])(=[O:22])[CH2:20][CH2:19][C:18]([O:17][CH3:16])=[O:24]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: O=C(CBr)c1cc(Cl)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CCC(=O)OCC(=O)c1cc(Cl)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A stirred suspension of 2-bromo-1-(3-chloro-5-(trifluoromethyl)phenyl)ethanone (Reference Example 34, 1.05 g, 3.48 mmol) and sodium 4-methoxy-4-oxobutanoate (0.805 g, 5.22 mmol) in acetone (50.0 mL) was heated at reflux overnight. After that time the reaction mixture was cooled to room temperature and adsorbed onto silica gel (4.30 g). The residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 4:1) to provide 2-(3-chloro-5-(trifluoromethyl)phenyl)-2-oxoethyl methyl succinate (1.12 g, 91%) as a pale yellow oil.
Reaction SMILES: NC1C=CC(CO)=CC=1Cl.Cl[Si](C(C)(C)C)(C)C.N1C=CN=C1.[Si:24]([O:31][CH2:32][C:33]1[C:39](OC)=[CH:38][C:36]([NH2:37])=[C:35]([Cl:42])[CH:34]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C>[Si:24]([O:31][CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[C:35]([Cl:42])[CH:34]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: COc1cc(N)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: Nc1ccc(CO)cc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(N)c(Cl)c1

Procedure:
Obtained as a light orange oil (87%) starting from (4-Amino-3-chlorophenyl)methanol (intermediate 45; 2.72 g, 0.016 mol), 4.94 g (0.033 mmol) of cloro(tertbutyl)-dimethylsilane and 3.35 g (0.049 mol) of imidazole in 68 ml DMF and following the experimental procedure as described for intermediate 39.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([C:29]#[C:30][Si](C)(C)C)=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+]>CO.O>[F:36][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][C:27]([C:29]#[CH:30])=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(C#C[Si](C)(C)C)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccn2c(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3C)cnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridine-3-carboxamide (52) (50 mg, 0.1 mmol) was dissolved in MeOH (1 mL) and K2CO3(42 mg, 0.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL). The resulting precipitate was filtered and dried to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-ethynylimidazo[1,2-a]pyridine-3-carboxamide (53). MS m/z 434.1 (M+1)+.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH2:49])[CH:47]=2)[N:42]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)[N:41]=1>CN(C=O)C>[NH:33]1[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N:31]=[C:32]1[C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH:49][C:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:11])[CH2:7][CH2:6]3)=[O:10])[CH:47]=2)[N:42]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)[N:41]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: O=C(O)C1CCC(F)(F)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
4,4-Difluorocyclohexanecarboxylic acid (8 mg, 0.048 mmol), HOBt (9 mg, 0.066 mmol), EDC (13 mg, 0.068 mmol) and sodium bicarbonate (4 mg, 0.047 mmol) was added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (15 mg, 0.045 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (10 mg). 1H NMR (400 MHz, CD3OD): δ 8.51 (s, 1H), 7.74 (m, 2H), 7.66 (m, 2H), 7.28 (m, 2H), 5.92 (d, 1H, J=8.8 Hz), 4.01 (m, 1H), 3.84 (m, 1H), 2.66 (m, 1H), 2.54-2.44 (m, 2H), 2.17 (m, 3H), 2.01-1.70 (m, 9H).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:28]1[C:33]([CH:34]=O)=[CH:32][C:31]2[O:36][CH2:37][O:38][C:30]=2[CH:29]=1>C1COCC1>[CH:34]([C:33]1[CH:28]=[CH:29][C:30]2[O:38][CH2:37][O:36][C:31]=2[CH:32]=1)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)OCO2
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
t-BuOK (7.77 g, 69.3 mmol) was added portions to a suspension of compound methyltriphenylphosphonium iodide (28.0 g, 68.3 mmol) in dry THF (250 mL) over 10 min at 0° C. The resulting yellow suspension was stirred for 20 min at this temperature. A solution of piperonal (8.0 g, 53.3 mmol) in dry THF (25 mL) was added dropwise to the above suspension and the mixture was stirred for 1 h at 0° C. The reaction mixture was concentrated and the residue was purified by column chromatograph (petroleum ether) to provide compound 5-vinylbenzo[d][1,3]dioxole (7.4 g, 94%) as colorless liquid. 1H-NMR (DMSO-d6): δ 5.09 (d, 1H, J=11.2 Hz), 5.68 (d, 1H, J=18 Hz), 6.00 (s, 2H), 6.63 (1, 1H, J1=11.2 Hz, J2=18 Hz), 6.85 (m, 2H), 7.11 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1.C(OCC)(=O)C>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(Nc2ccccc2Oc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A −78° C. solution of Example 1C (236 mg, 1.0 mmol) and 2-phenoxyaniline (370 mg, 2.0 mmol) in THF (10 mL) was treated with 1M lithium hexamethyldisilazide in THF (4 mL, 4.0 mmol), warmed to room temperature over 4 hours, diluted with ethyl acetate (50 mL), washed sequentially with 1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10-30% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 384 (M−H)−.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:19][C:20]2[CH:21]=[C:22]3[C:31](=[CH:32][C:33]=2[C:34]([F:37])([F:36])[F:35])[O:30][CH2:29][C:28]2[N:23]3[CH:24]([CH3:47])[C:25](=[O:46])[N:26](COCC[Si](C)(C)C)[N:27]=2)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:1]([N:14]1[CH2:15][C:16]([NH:19][C:20]2[CH:21]=[C:22]3[C:31](=[CH:32][C:33]=2[C:34]([F:37])([F:36])[F:35])[O:30][CH2:29][C:28]2[N:23]3[CH:24]([CH3:47])[C:25](=[O:46])[NH:26][N:27]=2)([CH3:18])[CH2:17]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A solution of 6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.020 g, 0.034 mmol) in DCM (0.5 mL) and TFA (0.25 mL) was stirred at ambient temperature for 1 h. The solvent was removed in vacuo. The residue was dissolved in THF (0.5 mL) and aqueous ammonium hydroxide solution (25%, 0.25 mL) was added. The mixture was stirred for additional 2 h at ambient temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo to give crude 6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-4-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a yellow solid (0.015 g, 84%), which was used in next step directly. LC/MS (Table 1, Method 2) Rt=0.997 min.; MS m/z: 536 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7].[BH4-].[Na+]>CO>[CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:22])([F:23])[F:21])[C:16]([F:17])([F:18])[F:19])=[CH:11][CH:10]=1)[CH2:3][CH:4]([OH:8])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(=O)CN(C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC(O)CN(C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a solution of 1-(methyl{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]phenyl}amino)-pentan-2-one (52 mg, 0.15 mmol) in methanol (3 mL) at −78° C. was added sodium borohydride (17 mg, 0.44 mmol). The reaction mixture was allowed to warm to ambient temperature over 4 hours. The reaction mixture was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded the title compound as a colorless oil (40 mg, 74%). 1H NMR (CDCl3) δ 7.51 (d, 2H), 6.80 (d, 2H), 3.96 (m, 1H), 3.32 (s, 1H), 3.30 (dq, 2H), 3.03 (s, 3H), 1.39-1.52 (m, 4H), 0.96 (t, 3H). 13C NMR (CDCl3) δ 151.0, 127.4, 116.8, 112.1, 69.4, 60.0, 39.3, 36.8, 18.9, 14.1. MS (ES+) m/z 360 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH3:10])([O-:9])=[O:8].Cl[C:12]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1.Cl>CS(C)=O>[Cl:18][C:17]1[C:12]([CH2:10][N+:7]([O-:9])=[O:8])=[N:13][CH:14]=[C:15]([Cl:19])[CH:16]=1
Reactant: C[N+](=O)[O-]
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])Cc1ncc(Cl)cc1Cl
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To 30.74 g of potassium tert-butoxide in 100 ml of dimethylsulfoxide, 16.72 g of nitromethane was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 1 hour. Then, the reaction mixture was cooled with ice again, and to the reaction mixture, 25.00 g of 2,3,5-trichloropyridine in 100 ml of dimethylsulfoxide was added dropwise with stirring, and after the addition, the mixture was stirred at 70° C. for another 6 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, poured into 200 ml of 10% aqueous hydrochloric acid with stirring under cooling with ice and extracted with ethyl acetate (200 ml×1). The resulting organic layer was washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 10:90) as the eluent to obtain 10.10 g of the desired product as a pale yellow oil.