Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:8]O.[C:10]1([CH:16]([CH3:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:19][C:20]([CH3:22])=[O:21]>>[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([O:21][O:8][C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:18])[CH3:17])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:22])[CH3:19]
Reactant: CC(C)c1ccccc1
Reactant: [O-]O
Reactant: CC(C)=O
Solvent: Oc1ccccc1
Product: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1

Procedure:
In an embodiment, a method for the production of phenol and acetone from a cumene hydroperoxide mixture comprises: a first stage and a second stage and at least two serially connected reactors, wherein the first stage comprises decomposition of a cumene hydroperoxide in the presence of a catalyst mixture to form phenol, acetone, and dicumyl peroxide mixture, and the second stage comprises formation of a phenol and acetone mixture from decomposition of the remainder of the cumene hydroperoxide and dicumyl peroxide formed in the first stage, wherein, the first stage further comprises: a) forming a catalyst mixture by combining sulfuric acid and phenol in a weight ratio of from 2:1 to 1:1000 in a catalyst formation reactor, b) holding the catalyst mixture in the catalyst formation reactor at a temperature of about 20 to 80° C. for about 1 to 600 minutes; and, c) adding the catalyst mixture to the cumene hydroperoxide mixture to form the phenol and acetone mixture. In an embodiment, the sulfuric acid is an aqueous sulfuric acid solution comprising at least 75 wt. % sulfuric acid. In another embodiment, the sulfuric acid is fuming sulfuric acid (oleum). In an embodiment, water is added in the second stage in an amount of up to 1% of the reaction mass. In another embodiment, the reaction temperature of the first stage is between 40 and 75° C., and in another embodiment, the reaction temperature of the second stage is between 90 and 140° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([OH:14])=O)[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].[CH2:30]([O:34]C(Cl)=O)C(C)C.C[N:39]1CC[O:42][CH2:41][CH2:40]1>CN(C)C=O.ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:39][CH2:40][C@H:41]([OH:42])[CH2:30][OH:34])=[O:14])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC[C@H](O)CO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.9 %

Procedure:
To a solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (0.3 g, 0.65 mmol) in dimethylformamide (3.0 mL) at −10° C. was added isobutylchloroformate (0.13 g, 0.92 mmol) followed by the addition of N-methylmorpholine (0.130 g, 1.28 mmol). The mixture was stirred for 10 min. under argon atmosphere. The reaction mixture was then stirred at room temperature for 30 min, cooled to 0° C., and added S-3-amino-1,2 propanediol (0.118 g, 1.3 mmol). The resulting mixture was stirred at room temperature for 1.5 h, concentrated in vacuo, and the residue was purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=538) were combined, and freeze-dried to give a white solid. This was dissolved in dichloromethane (20 mL), washed successively with 5% sodium bicarbonate (2×15 mL), water (2×20 mL), dried (Na2SO4), and concentrated to dryness to afford the racemic title compound (0.15 g, 43%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.89 (dd 1H, J=1.6 Hz, 8.0 Hz), 7.66 (d, 1H, J=1.6 Hz), 7.60 (m, 1H), 7.52 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.54 (abq, 2H), 3.77 (m, 1H), 3.51 (m,3H), 3.38 (m, 1H), 2.74 (s, 3H), and 2.11(s, 3H); ES-HRMS m/z 538.0782 (M+H calcd for C23H23N3O5F2Br requires 538.0784). 19F NMR(CD3OD/400 MHz) −111.85(m) and −115.91 (m).
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21]S(C)(=O)=O)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].[CH2:34]([N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[C:46]([CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])[CH:35]=[CH2:36]>>[CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21][N:51]1[CH2:52][CH2:53][CH:48]([C:46]([C:38]2[N:37]([CH2:34][CH:35]=[CH2:36])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[N:39]=2)=[O:47])[CH2:49][CH2:50]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: C=CCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N(C)CC(CCS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Product: C=CCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3cc(-n4cnnn4)ccc3OC)c3ccc(Cl)c(Cl)c3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide and 4-(1-allyl-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH:4]([CH3:6])[CH3:5].[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11](F)[CH:10]=1.Cl>O1CCCC1.O>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])[CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC(C)CCBr
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.6 %

Procedure:
To a mixture of magnesium (1.61 g) in tetrahydrofuran (10 ml) was added a solution of isoamyl bromide (5.0 g) in tetrahydrofuran (23 ml) dropwise at room temperature under nitrogen, and the mixture was refluxed for 0.5 hour and cooled to room temperature. The mixture was transferred via a syringe to a solution of 4-bromo-2-fluorobenzoic acid (2.5 g) in tetrahydrofuran (15 ml) at 4-10° C. The resulting mixture was stirred at room temperature for 16 hours. To the reaction mixture was added water (200 ml) dropwise with ice-cooling. The aqueous solution was acidified with 6N aqueous hydrochloride solution and extracted with ethyl acetate (150 ml×2). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=10/1) to give 4-bromo-2-(3-methylbutyl)benzoic acid (1.35 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:19]1[CH2:31][OH:32])=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl.Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:19]1[CH:31]=[O:32])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C1CO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C1C=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 99.4 %

Procedure:
A solution containing 2M oxalyl chloride in DCM (22 mL) in DCM (40 mL) was cooled to −78° C. A solution containing DMSO (3.2 mL, 45 mmol) in DCM (20 mL) was added in a dropwise fashion. After 45 min, alcohol 40 (9.5 g, 29 mmol) in DCM (50 mL) was added in a dropwise fashion. After 45 min, TEA (16 mL, 115 mmol) was added in a dropwise fashion. The reaction mixture was warmed and maintained at 0° C. for 15 min. The solution was diluted with 1M HCl, extracted with DCM, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 9.5 g (100%) of 41 as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ9.53 (d, J=29 Hz, 1H), 4.39-4.36 (m, 1H), 4.24 (m, rotomer, 0.5H), 3.93 (m, rotomer, 0.5H), 3.73-3.49 (m, 2H), 1.98-1.86 (m, 2H), 1.47 (s, minor rotomer), 1.41 (s, 9H), 0.88 (s, 9H), 0.09 (s, 6H), 0.07 (s, minor rotomer) ppm.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[N:4]1.[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[CH:7][N:3]([CH2:2][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[N:4]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)c1ncn(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cnc(C(F)(F)F)n1
Yield: 5.7 %

Procedure:
1.56 g of 1-(chloromethyl)-3-(trifluoromethyl)-1H-1,2,4-triazole and 1.38 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 25 ml of N,N-dimethylformamide. 2.35 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.15 g of {[3-(trifluoromethyl)-1H-1,2,4-triazole-1-yl]methyl}(3,3,3-trifluoropropyl)malononitrile (referred as the compound of the present invention (33), hereinafter) shown by below formula.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][CH2:40][O:41][C:42]2[CH:50]=[CH:49][C:45]([C:46](O)=O)=[CH:44][N:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][CH2:40][O:41][C:42]2[N:43]=[CH:44][C:45]([CH2:46][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:49][CH:50]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)nc1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)nc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 63.7 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 6-(2-azepan-1-ylethoxy)nicotinic acid hydrochloride (60 mg) according to an analogous synthetic method to Example 337 described below and purified by LC-MS, the title compound (26 mg) was obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:8][CH2:7][N:6]([C@H:9]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:10]([NH2:12])=[O:11])[C:5](=[O:24])[C@H:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:3]1.N(C(OC(C)(C)C)=O)[C@H:32]([C:39]([OH:41])=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH:49](C(OC(C)(C)C)=O)[C@H:50](C(O)=O)[CH2:51][CH:52](C)C>CC(O)=O>[CH3:1][C@@H:2]1[CH2:8][CH2:7][N:6]([C@H:9]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:10]([NH2:12])=[O:11])[C:5](=[O:24])[C@H:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]1[C:39](=[O:41])[CH2:32][C:33]1[CH:34]=[C:35]2[C:36](=[CH:37][CH:38]=1)[N:49]=[CH:50][CH:51]=[CH:52]2
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H]1CCN([C@H](Cc2cccc3ccccc23)C(N)=O)C(=O)[C@H](c2ccccc2)N1
Solvent: CC(=O)O
Product: C[C@@H]1CCN([C@H](Cc2cccc3ccccc23)C(N)=O)C(=O)[C@H](c2ccccc2)N1C(=O)Cc1ccc2ncccc2c1

Procedure:
The title compound is prepared by following the procedure of Example 1 but starting from (R)-2-[(3S,5R)-5-methyl-2-oxo-3-phenyl-[1,4]-diazepan-1-yl]-3-(naphthalen-1-yl)-propionamide and using Boc-α-D-Nal—OH in step a) instead of N-Boc-β-L-Nal—OH and Boc-L-Phg—OH in step d) instead of Boc-Leu—OH. MH+: 571 (ES+) αD20+187.6 (c=0.15 95% AcOH)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[B:17](OC)([O:20]C)[O:18]C.Cl>O1CCCC1.O.II>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([B:17]([OH:20])[OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
62 g (0.236 mol) of 3-benzyloxybromobenzene, 6.64 g (0.277 mol) of magnesium and 0.3 g of iodine are reacted in 800 ml of tetrahydrofuran at 60° C. for 2 hours to give the solution of the corresponding Grignard compound, which is subsequently added dropwise to a solution, cooled to 0° C. of 28.77 g (0.277 mol) of trimethyl borate in 300 ml of tetrahydrofuran. The mixture is stirred at 0° C. for 1 hour, 74 ml of 37% strength hydrochloric acid in 300 ml of water are added, and the reaction mixture is subsequently partitioned between water and ether. The organic phase is washed twice with water, dried over sodium sulfate, evaporated and recrystallized from hexane, giving 33.65 g of 3-benzyloxybenzeneboronic acid. ##STR13##
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1.[CH3:18][C:19]1([CH3:27])[CH2:25][C:24](=O)[O:23][C:21](=[O:22])[CH2:20]1>O1CCOCC1>[CH3:18][C:19]([CH3:27])([CH2:25][C:24]1[O:1][N:2]=[C:3]([CH2:4][CH2:5][CH2:6][C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][NH:10][C:9]=3[N:8]=2)[N:17]=1)[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: N/C(CCCc1ccc2c(n1)NCCC2)=N\O
Solvent: C1COCCO1
Product: CC(C)(CC(=O)O)Cc1nc(CCCc2ccc3c(n2)NCCC3)no1
Temperature: 100 °C

Procedure:
A stirred mixture of (1Z)-N′-hydroxy-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanimidamide (100 mg, WO 99/30709), 3,3-dimethylglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting mixture was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.12 (6H, s); 1.96 (2H, p); 2.14 (2H, p); 2.36 (2H, s); 2.80 (6H, m); 3.05 (2H, s); 3.50 (2H, t); 6.63 (1H, d); 7.57 (1H, d).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.C(Cl)Cl>[ClH:13].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([Cl:13])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cl
Product: O=C(Cl)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 20 g of picolinic acid, 200 ml of methylene chloride and 5 drops of dimethylformamide is added, dropwise, 30.93 g of oxalyl chloride. The reaction is stirred at room temperature for 18 hours and concentrated in vacuo to give the desired product as a black crystalline material.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]([CH3:20])=[C:10]2[C:21]#[N:22])=[C:5]([O:23][CH3:24])[CH:4]=1)#[N:2].FC(F)(F)S(O[CH2:31][CH3:32])(=O)=O.CO>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:31][CH3:32])[NH:12][C:11]([CH3:20])=[C:10]2[C:21]#[N:22])=[C:5]([O:23][CH3:24])[CH:4]=1)#[N:2]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: COc1cc(C#N)ccc1C1C(C#N)=C(C)Nc2cc[nH]c(=O)c21
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C#N)=C(C)N2
Reaction time: 0.17 h

Procedure:
505 mg (1.58 mmol) of 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile are suspended in THF (20 ml), and 1.9 ml (1.9 mmol) of N′″-(tert-butyl)-N,N′,N″-tris[tris(dimethylamino)phosphoranylidene]phosphorimide triamide (phosphazene base P4-t-Bu; 1 M in hexane) are added. Then 240 μl (1.9 mmol) of ethyl trifluoromethanesulfonate are added to the dark red solution. The decolorized solution is stirred for a further 10 min and then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 124 mg (21% of theory) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[C:21]([CH3:23])[N:20]=[C:19](Cl)[C:18]=4[CH3:25])[CH2:13][CH2:12]3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:26][CH2:27][C@@H:28]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].[F-].[Cs+]>COCCOC>[CH3:46][C:43]([O:42][C:40](=[O:41])[C@H:28]([CH2:27][NH:26][C:19]1[C:18]([CH3:25])=[C:17]([N:14]2[CH2:15][CH2:16][CH:11]([C:8]3[N:9]=[C:10]4[C:5]([CH2:4][CH2:3][CH2:2][NH:1]4)=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)[N:22]=[C:21]([CH3:23])[N:20]=1)[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])([CH3:44])[CH3:45]
Reactant: Cc1nc(Cl)c(C)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: Cc1nc(NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c(C)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1
Yield: 14.5 %

Procedure:
A mixture of 2.2 g (6.15 mmoles) of 6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-2,5-dimethyl-4-chloro-pyrimidine and 2.17 g (7.38 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), is heated under reflux for 24 hours in the presence of 1.31 g (8.61 mmoles) of caesium fluoride, 383 mg (0.615 mmoles) of (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 281 mg (0.307 mmoles) of tris-dibenzylideneacetone)dipalladium(o), in 55 ml of 1,2-dimethoxyethane. The reaction mixture is then returned to ambient temperature, 281 mg (0.307 mmoles) of tris-dibenzylideneacetone)dipalladium(o) is added, then the reaction mixture is taken to reflux for another 24 hours. After cooling down the solution is concentrated to dryness under reduced pressure (2 kPa) then taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under reduced pressure (2 kPa). The residue is chromatographed on alumina with a gradient of isopropyl ether/ethyl acetate (50/50)-dichloromethane (50-50). The fractions containing the expected product are combined for a second purification on silicagel with a gradient of ethyl acetate-heptane-methanol 50-50-0 to 90-0-10. 550 mg (Yield=15%) of expected product is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:30])[CH2:29][O:28]2)=[CH:23][CH:22]=1>CN(C=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:28])([CH3:29])[CH2:30][N:11]2[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]3[CH:3]=[C:2]([CH3:1])[CH:14]=[CH:13][C:12]2=3)=[CH:25][CH:26]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: CC1(c2ccc(F)cc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(F)cc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.8 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (150 mg, 0.66 mmol) was dissolved in DMF (2 mL), sodium hydride (79 mg, 1.98 mmol) was added and the mixture was stirred at RT for 5 min. 2-(4-Fluoro-phenyl)-2-methyl-oxirane (201 mg, 1.32 mmol) was added dropwise into the reaction mixture and stirred at RT for 18 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (2×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (neutral alumina) Eluent: −2% MeOH in DCM followed by chiral HPLC to obtain 77 mg of 2-(4-fluoro-phenyl)-1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-propan-2-ol. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.4 (m, 2H), 7.2 (m, 2H), 7.0 (m, 3H), 5.08 (t, 1H), 4.3 (d, 1H), 4.15 (d, 1H), 3.65 (m, 1H), 3.5 (m, 2H), 3.3 (m, 1H), 2.90 (m, 2H), 2.7 (m, 1H), 2.4 (s, 3H), 2.2 (m, 3H), 1.62 (s, 3H). Separation by chiral HPLC provided diastereomers II-121a-b.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[F:19][C:20]([F:27])([F:26])[C:21](=O)[CH2:22][S:23][CH3:24].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:21]([CH2:22][S:23][CH3:24])[C:20]([F:27])([F:26])[F:19])=[O:14])[CH3:2]
Reactant: CSCC(=O)C(F)(F)F
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(CSC)C(F)(F)F
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a 100 ml volume three-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (3.04 g) was placed at room temperature, and added dropwise a solution of 1,1,1-trifluoro-3-methylsulfanyl-2-propanone (7-0-2) (2.29 g) in toluene (27 g). After para-toluenesulfonic acid monohydrate (0.028 g) was added, the resulting mixture was stirred under reflux for 45 minutes, and cooled to room temperature. The reaction mixture was poured into water (30 ml), and extracted with ethyl acetate (50 ml) 2 times. The resulting organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (chloroform) to give 2.13 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(1,1,1-trifluoro-3-methylsulfanyl-2-propylidene)-1-methylhydrazine ((4-46)-(1)-39).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:57](=[O:58])[C@H:49]([CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[NH:48][C:46]([O:45][CH2:44][CH:42]1[C:43]2[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=2[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@H](Cc3ccccc3)NC(=O)OCC3c4ccccc4-c4ccccc43)ccn2)cc(OC)c1OC

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (973 mg) and N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine (871 mg) were treated in the same manner as in Preparation Example 9 to obtain the title compound.