Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:6].[C:13]([OH:17])(=O)[CH2:14][CH3:15].C(OC(=O)CC)(=O)CC.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[C:8]([CH:7]([C:5]#[N:6])[NH:1][C:13](=[O:17])[CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCC(=O)O
Reactant: O=N[O-]
Reactant: CCOC(=O)CC#N
Agent: CCC(=O)OC(=O)CC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C#N)NC(=O)CC
Reaction time: 1.5 h

Procedure:
To 16 g. sodium nitrite, 60 ml. water and 22.6 g. ethyl cyanoacetate cooled to approximately 5° C. was added 16 ml. propionic acid. After stirring the reaction mixture at 0°-5° C. for 1.5 hours, 200 g. ice and 50 ml. propionic anhydride were added. Finally, 70 g. sodium hydrosulfite was added in portions over a time period of from about 5 to about 10 minutes. Stirring was continued for one hour, and the precipitated solid was collected by filtration. The solids were then washed with 60 ml. hot acetone and recrystallized from ether-petroleum ether. The structure was verified by NMR. Yield 6.8 g.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:5]2[C:6](=[O:10])[C:7]=1[CH2:8][CH3:9].[CH3:16]C(C)=O.CI.[ClH:22]>C(O)C.O>[ClH:22].[CH3:16][N:3]1[CH:2]([CH3:1])[CH:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]2[CH:11]([CH3:15])[CH2:12][CH2:13][CH2:14][CH:4]12
Reactant: CCc1c(C)nc2cccc(C)n2c1=O
Reactant: CC(C)=O
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CI
Product: CCC1C(=O)N2C(C)CCCC2N(C)C1C
Reaction time: 24 h
Yield: 41 %

Procedure:
0.01 moles of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido(1,2-a)pyrimidine are dissolved in 20 ml. of acetone, 0.03 moles of methyl iodide are added and the mixture is kept in a bomb tube at 150° C. for 24 hours. The solution is evaporated to dryness, the residue is dissolved in 15 ml. of methanol and a solution of 0.05 moles of sodium tetrahydroborate(III) in 10 ml. of water is added. After 4 hours the methanol is distilled off and the aqueous phase is extracted with three 20-ml. portions of chloroform. The organic phase is dried, evaporated and added to the oily substance obtained are 10 ml. of ethanol saturated with hydrochloric acid. 1,2,6-trimethyl-3-ethyl-1,2,3,6,7,8,9,9a-octahydro-4-oxo-4H-pyrido(1,2-a)pyrimidine hydrochloride is obtained, while crystallizes when triturated with ether. The product obtained after recrystallization from a mixture of acetone and ether sublimates over 206° C. Yield: 41%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].Br[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=1)[C:16]#[N:17]>>[NH2:6][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: C#Cc1cccc(N)c1
Product: N#Cc1cncc(C#Cc2cccc(N)c2)c1
Yield: 37.6 %

Procedure:
Prepare according to the general procedure outlined in EXAMPLE 30 using 3-ethynylaniline (1.0 g, 8.5 mmol) and 5-bromonicotinonitrile (1.56 g, 8.54 mmol) to give the title compound (0.7 g, 38%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]12[CH2:34][C:30]([CH2:35]O)([CH2:31][CH2:32][CH2:33]1)[CH2:29][CH2:28][CH2:27]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:26]12[CH2:34][C:30]([CH2:35][O:7][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=3[O:12][CH3:13])([CH2:31][CH2:32][CH2:33]1)[CH2:29][CH2:28][CH2:27]2
Reactant: OCC12CCCN(CCC1)C2
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)OCC12CCCN(CCC1)C2
Reaction time: 1 h
Yield: 57.3 %

Procedure:
A solution of 4-amino-5-chloro-2-methoxybenzoic acid (2.02 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.70 g, 10.5 mmol), stirred for one hour, then degassed with a stream of nitrogen over 10 minutes. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.3.1]nonane-5-methanol (1.71 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (10.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The above prepared suspension was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated in vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little 2-propanol and saturated aqueous sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo and recrystallized from acetonitrile (2 crops) to afford 1.94 g (57%) of pale yellow solid; mp 152.5°-154.5° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)([C:17]([OH:19])=O)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)([C:17]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:19])[CH2:13][CH2:12]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)N
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)O)(C2CCCCC2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)C1(C2CCCCC2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
4-Cyclohexyl-1,4-piperidinedicarboxylic acid 1-(phenylmethyl) ester (8-4) (2.50 g, 7.24 mmol) was dissolved in 36 mL of methylene chloride and cooled at 0° C. in an ice-water bath. Oxalyl chloride (2.0 M solution in CH2Cl2, 3.98 mL, 7.96 mmol) was then added dropwise followed by the addition of 1-2 drops of DMF. This mixture was stirred at 0° C. for 2 h and then concentrated with toluene. The residue was dissolved in 36 mL of methylene chloride and cooled at 0° C. in an ice-water bath. tert-Butylamine (2.28 mL, 21.7 mmol) was then added dropwise, and the reaction mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred at room temperature overnight. The resulting mixture was diluted with methylene chloride, washed with brine, dried over MgSO4, filtered, and concentrated to give 2.92 g of title compound 8-5 as a solid. LCMS (ESI): m/z 401 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([Li])CCC.CCCCCC.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][CH:39]=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]([OH:43])[CH2:1][C:2]2[N:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:4]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)=[CH:40][CH:39]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(CC(O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a cold (−70° C.) solution of 2-methyl-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylic acid, tert-butyl ester (253) (3.36 g, 10.0 mmol) in THF is added 1.6M n-butyl lithium in hexane (6.9 mL, 11.0 mmol), and the mixture is stirred for 1 h at −70° C. To the reaction mixture is added 4-fluorobenzaldehyde (1.18 mL, 11.0 mmol), and the mixture is stirred for 1 h at −70° C. and 1 h at RT. To the reaction mixture is added ammonium chloride solution, EtOAc, and the organic layer is separated, and washed with brine, dried (MgSO4), and filtered. The filtrate is rotary evaporated, and the residue purified by chromatography on silica gel; elution with dichloromethane:EtOAc (9:1) gives 2.11 g of the product 256. 1H NMR (CDCl3) δ 7.60-7.45 (m, 2 H), 7.15-6.90 (m, 10 H), 6.85-6.60 (m, 2 H), 5.70-5.20 (m, 4 H), 3.60-3.10 (m, 2 H), 1.18 (s, 9 H); MS: m/z 461 (M++1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:26]([O-])([N+]([O-])=O)=[O:27]>>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(Cc1ccccc1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(Cc1ccccc1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 68.4 %

Procedure:
3.8 g of 1-(2-chloroethyl)-3-benzyl-3-(D-galactopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-benzyl-3-(D-galactopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([Sn](CCCC)(CCCC)CCCC)[N:9]=[N:8]1.Br[C:41]1[C:46]([C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])=[O:48])=[CH:45][CH:44]=[CH:43][N:42]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:35][C:34]([F:37])([F:36])[C:32]1[CH:31]=[C:5]([CH:4]=[C:3]([C:2]([F:39])([F:1])[F:38])[CH:33]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([C:41]2[C:46]([C:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[Cl:55])=[O:48])=[CH:45][CH:44]=[CH:43][N:42]=2)[N:9]=[N:8]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Reactant: O=C(c1ccccc1Cl)c1cccnc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 113 °C

Procedure:
Combine 4-[3-(3,5-bistrifluoromethylbenzyl)-5-tributylstannanyl-3H-[1,2,3]triazol-4-yl]-pyridine (489 g, 740 mmol) and toluene (1 L), add (2-bromopyridin-3-yl)-(2-chlorophenyl)-methanone (240 g, 810 mmol) in toluene (500 mL). Next, add tris(dibenzylideneacetone)dipalladium (16.95 g, 18.5 mmol) and toluene (300 mL). Add tri-2-furylphosphine (17.35 g, 74 mmol) in toluene (200 mL) and heat the reaction mixture to reflux (113° C.). Upon completion of the reaction, remove the solvent by rotary evaporation and purify the crude product by flash column chromatography (dichloromethane/ethyl acetate gradient). Treat the material with activated charcoal in ethyl acetate, wash with 5% aqueous trithiocyanuric acid trisodium salt solution, and recrystallize (ethyl acetate/hexane) to give the title compound. MS(IS) 588 (M+1). TLC (3% MeOH/CH2Cl2) Rf=0.17. 1H NMR (400 MHz, CDCl3): 5.46 (s, 2H); 7.19 (m, 5H); 7.36 (dd, 1H, J=4.9, 7.8); 7.45 (s, 2H); 7.59 (m, 1H); 7.83 (s, 1H); 7.93 (dd, 1H, J=1.5, 7.8); 8.56 (dd, 1H, J=1.5, 4.9); 8.70 (d, 2H, J=5.9).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([CH3:14])[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)[N:3]=1.[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[NH4+:3].[CH3:36][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34](=[O:35])[O:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([N:4]3[C:5]([CH3:14])=[C:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:2]([CH3:1])=[N:3]3)=[CH:20][CH:19]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Cc1ccc(-c2c(C)nn(-c3ccc(CCO)cc3)c2C)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2c(C)nn(-c3ccc(CCOC(=O)NS(=O)(=O)c4ccc(C)cc4)cc3)c2C)cc1
Product: [NH4+]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 2-{4-[3,5-dimethyl-4-(4-methylphenyl)-1H-pyrazol-1-yl]phenyl}ethanol (step 1, 0.88 mmol) in dichloromethane (10 ml) was added p-toluenesulfonyl isocyanate (221 mg, 1.06 mmol). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture washed with water and the organic phase was dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with toluene/ethanol (10:1) and SCX eluting with 2 M NH3 methanol solution to afford 155 mg (35%) of the title compound as white solids: MS (ESI) m/z 545 [M+H]+, 543 [M−H]−, 1H-NMR [DMSO-d6 (dimethyl-d6 sulfoxide)]δ 7.48 (2H, d, J=8.1 Hz), 7.32-7.20 (4H, m), 7.27-7.10 (4H, m), 7.07-7.04 (2H, d, J=8.1 Hz), 3.80 (2H, t, J=6.8 Hz), 2.69 (2H, t, J=6.8 Hz), 2.23 (3H, s), 2.19 (3H, s), 2.14 (3H, s), 2.09 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:26]=[CH:27][C:7]=1[CH2:6]2)=[O:4].[C:35](=O)([O-])[O-:36].[Cs+].[Cs+]>CO.O>[CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21]([O:36][CH3:35])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:26]=[CH:27][C:7]=1[CH2:6]2)=[O:4]
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(OC)nc1)C2
Yield: 94.2 %

Procedure:
A solution of (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid methyl ester (0.3 g) in methanol (10 mL) was treated with cesium carbonate (0.98 g) and water (0.5 mL) for 20 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, the combined organic extracts dried over sodium sulfate and the residue concentrated under reduced pressure to provide a white foam (0.28 g). LCMS (Method G): 499.1 (M+H)+, Retention time 3.77 minutes.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:21])([CH:19]=[CH2:20])[CH3:18])[CH3:13])[CH3:8])[CH3:3].CC(CCC[C@H](CCC[C@H:33]([CH2:35][CH2:36][CH2:37]/[C:38](=[CH:40]/[CH2:41][OH:42])/[CH3:39])C)C)C.[Al].B(F)(F)F.[CH3:48]COCC>[Pd].C(O)(=O)C.C(OCC)(=O)C>[CH3:48][C:40]1[C:41]([OH:42])=[C:35]([CH3:33])[C:36]2[CH2:20][CH2:19][C@:17]([CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])([CH3:18])[O:21][C:37]=2[C:38]=1[CH3:39]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CCOCC
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Pd]
Agent: FB(F)F
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2

Procedure:
The reaction of isophytol or phytol with TMHQ is well known. One method that has been employed with phytol is described in Japan Kokai No. 73 48,472 [Chem. Abstr. 79, 105067m (1973)]. It was discovered that a similar method could also be applied successfully in condensation of TMHQ with dehydrophytol. Essentially, 2.5 grams TMHQ and 0.1 gram aluminum powder were placed in a flask to which was added 35 mls. of ethyl acetate containing 1 ml. of boron trifluoride etherate. While stirring, 4 grams of dehydrophytol was added slowly and the mixture was refluxed for 4 hours at 80°. This gave 5.0 grams of crude dehydrotocopherol (dehydro-Vitamin E) after work-up and removal of unreacted starting materials. A portion of the dehydrotocopherol obtained (1.0 gram) was conveniently hydrogenated in 30 mls. glacial acetic acid containing 0.5 gram of 5% Pd on BaSO4. Shaking for 8 hours under 52 psig H2 pressure and ambient temperature provided 1.0 gram of crude α-tocopherol (Vitamin E). The present invention has been described with reference to the use of beta-myrcene to produce chloromyrcene (3-chloro-6-methylene-2-methylocta-1,7-diene) which is then coupled with 3,7-dimethyloctyl magnesium chloride. The invention is equally applicable to the use of alpha-myrcene, or alpha- or beta-ocimene.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[N:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH:26]=[N:25][C:24]([NH:27][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:23]2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(Cn2cnc(N)n2)cc1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1ccc(Cn2cnc(Nc3ccc(-n4cnc(C)c4)c(C#N)c3)n2)cc1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-methyl-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid (Yield=50%). MS ISP (m/e): 370.1 (100) [(M+H)+].
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:9][CH:8]=[C:7]([C:10]2[N:11]([CH3:18])[N:12]=[CH:13][C:14]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.[C:36]([O:40][C:41]([NH:43][C:44]1[S:48][C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[F:55])=[N:46][C:45]=1[C:56]([OH:58])=O)=[O:42])([CH3:39])([CH3:38])[CH3:37].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.[F:85][P-](F)(F)(F)(F)F>CO.C(Cl)Cl.[Pd]>[C:36]([O:40][C:41]([NH:43][C:44]1[S:48][C:47]([C:49]2[C:54]([F:85])=[CH:53][CH:52]=[CH:51][C:50]=2[F:55])=[N:46][C:45]=1[C:56]([NH:15][C:14]1[CH:13]=[N:12][N:11]([CH3:18])[C:10]=1[CH:7]1[CH2:6][CH2:5][CH:4]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]([O:2][CH3:1])[CH2:9][CH2:8]1)=[O:58])=[O:42])([CH3:37])([CH3:38])[CH3:39]
Reactant: F[P-](F)(F)(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: COC1CC=C(c2c([N+](=O)[O-])cnn2C)CCC1NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC1CCC(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CCC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl N-(−2-methoxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cyclohept-4-en-1-yl)carbamate (180 mg, 0.49 mmol) in MeOH (30 mL) was passed through the H-Cube® (full H2, 70° C., flow rate: 1 mL/min, 30 mm 20% Pd/C cartridge). The solvent was removed under reduced pressure to give a colourless oil. To a solution of this oil in DCM (30 mL) was added DIPEA (2.00 mL, 11.48 mmol) and 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid (171 mg, 0.50 mmol) followed by PyBOP (596 mg, 1.15 mmol) and the mixture was stirred at room temperature for 16 hr. The reaction was quenched with water (20 mL) and extracted with DCM (80 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel chromatography (70-80% EtOAc/isohexane) gave tert-butyl N-(5-(4-((5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl)amino)-2-methyl-pyrazol-3-yl]-2-methoxy-cycloheptyl]carbamate as a mixture of four diastereomers as an off-white solid (175 mg, 54% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.39 and 10.36 (2s, 1H), 8.69 and 8.62 (2s, 1H), 8.32-8.28 and 8.21-8.14 (2 m, 1H), 7.85 and 7.75 (2s, 1H), 7.43-7.36 (m, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.25-7.17 (m, 1H), 5.19 and 5.08 (2d, J=8.8 Hz, 1H), 3.84 (s, 3H), 3.78-3.54 (m, 2H), 3.37 and 3.27 (2s, 3H), 3.11-2.94 (m, 1H), 2.32-1.30 (m, 8H), 1.55 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=O)[CH2:12]Br)[NH:8][N:7]=1)=[O:5])[CH3:2].[C:15]([NH2:18])(=[S:17])[CH3:16]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:18]=[C:15]([CH3:16])[S:17][CH:12]=2)[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)CBr)[nH]n1
Reactant: CC(N)=S
Solvent: CCO
Product: CCOC(=O)c1cc(-c2csc(C)n2)[nH]n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of 5-(2-bromoacetyl)pyrazole-3-carboxylic acid ethyl ester (5.30 g), thioacetamide (1.60 g), and ethanol (100 ml) was stirred at 60° C. for 30 minutes and concentrated. The residue was dissolved in 50 ml of 2N HCl solution, and washed with ethyl ether (2×50 ml). The aqueous solution was separated and neutralized with solid NaHCO3. The mixture was then extracted with ethyl acetate (233 100 ml). The ethyl acetate solution was dried over sodium sulfate and concentrated to afford 3.46 g of 5-(2-methylthiazol-4-yl)pyrazole-3-carboxylic acid ethyl ester as pale yellow solids, mp 141-142° C. NMR: 1.41 (t, 3H), 2.78 (s, 3H, thiazolyl methyl), 4.42 (q, 2H), 7.15 (s, 1H, thiazolyl H), 7.47 (s, 1H, 4-pyrazolyl H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]([C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[CH2:25][CH2:24][N:23]2[C:34]([C@H:36]2[CH2:39][C@H:38]([CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[CH2:37]2)=[O:35])=[O:21])[CH:12]=[CH:13][C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>O.C(#N)C>[F:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]([C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[CH2:25][CH2:24][N:23]2[C:34]([C@H:36]2[CH2:39][C@H:38]([CH2:40][C:41]([OH:43])=[O:42])[CH2:37]2)=[O:35])=[O:21])[CH:12]=[CH:13][C:14]=1[Si:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)O)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cooled TFA (2.0 mL) was added to tert-butyl 2-(trans-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (90 mg, 0.16 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was neutralized with ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→90% ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (29.8 mg, 0.058 mmol, 36.7%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]#[N:16])=[CH:10][CH:9]=2)=[O:5])C.C(O)C.[OH-].[K+].Cl>O>[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)#[N:16]
Reactant: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc2[nH]c(C(=O)O)cc2c1

Procedure:
5-Cyano-1H-indole-2-carboxylic acid ethyl ester (1.71 g, 8.0 mmol) was added to a solution of ethanol (10 mL) and potassium hydroxide (2 g) and the resulting mixture heated at reflux for 1 hour. Water was added to dissolve the precipitate, and 6N HCl was added to bring the pH to 1. The mixture was cooled in an ice bath, filtered, and the resulting colorless solid washed with cold water and dried (1.51 g). A portion (1.4 g) was suspended in hot acetic acid (40 mL) and cooled giving a solid which was filtered, washed with cold ethyl acetate and dried: Yield 980 mg 70%; HPLC (60/40) 3.09 minutes (97%).