Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>O1CCCC1>[C:1]1([S:7][C:8]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH2:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCl)Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(Sc1ccccc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
To a solution of 30 g (86.5 mmoles) of 2-chloro-1-(p-chlorophenylsulfonyl)ethyl phenyl sulfide in 100 ml of tetrahydrofuran was added 12.2 ml (8.88 g, 87.8 mmoles) of triethylamine. After two hours the reaction mixture was filtered to remove triethylamine hydrochloride. The filtrate was evaporated down under reduced pressure, first at 15 mm and finally at 0.01 mm (25° C.), to give a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)=[N:9][C:10]=2[C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](O)(=[O:36])[C:33]#[C:34][CH3:35]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:36])[C:33]#[C:34][CH3:35])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:25][CH:26]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Cc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4)n4ccnc(N)c34)cc2)c1
Reactant: CC#CC(=O)O
Product: CC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3cc(C)ccn3)cc2)c2c(N)nccn12
Yield: 27.2 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-methylpyridin-2-yl)benzamide (intermediate 7) and 2-butynoic acid, to afford the title compound (6.3 mg, 27.2%). Data: UPLC (C) Rt: 1.56 min; m/z 480.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18].[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:21](=[O:23])[CH3:22])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[O:16][C:17]([F:18])([F:20])[F:19]
Reactant: Cc1ccc(Oc2ccc(N)cn2)cc1OC(F)(F)F
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccc(C)c(OC(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-[4-methyl-3-(trifluoromethoxy)phenoxy]pyridin-3-amine (Intermediate 31, 475 mg, 1.67 mmol) and TEA (0.28 mL) in 5 mL of dry DCM under nitrogen at 0° C., acetyl chloride (0.13 mL) dissolved in 2 mL of dry DCM was added drop wise. The ice bath was then removed and the resulting solution was allowed to stir at room temperature for 30 minutes until complete conversion. Water was added and phases were separated. The organic phase was then washed with an aqueous 15% solution of NaHCO3, dried over Na2SO4, filtered and concentrated to give the title compound (502 mg) as yellow oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:10]=[C:9]2[CH:23]=O.[OH2:25].[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>>[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:10]=[C:9]2/[CH:23]=[CH:27]/[C:28]([O:29][CH2:30][CH3:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cccc(F)c32)cc1
Reactant: O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/c1cn(S(=O)(=O)c2ccc(C)cc2)c2c(F)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a suspension of sodium hydride (ca 60%, 240 mg, 6.3 mmol) in THF (10 mL) was added dropwise a solution of triethyl phosphonoacetate (1.33 g, 5.9 mmol) in THF (5 mL) at 0° C. After stirring at room temperature for 0.5 hour, a solution of 7-fluoro-1-tos yl-1H-indole-3-carbaldehyde (J. Med. Chem., 48 (19), 6023-6034 (2005)) (1.10 g, 3.48 mmol) in THF (5 mL) was added to the mixture at 0° C. The resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for 19 hours. The mixture was poured into water, extracted with dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo. The residual solid was washed with ethyl acetate to give 864 mg (65% yield) of the title compound as a white solid:
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[NH3:18]>C(O)C>[NH2:18][CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@H]2CO2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@H](O)CN)CC1
Reaction time: 12 h

Procedure:
Tert-butyl 4-[[(2S)-oxiran-2-yl]methyl]piperazine-1-carboxylate 20a (9.20 g, 38 mmol) was dissolved in 60 mL of ethanol followed by the addition of 50 mL of aqueous ammonia. The reaction solution was stirred for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound tert-butyl 4-[(2R)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 20b (9 g, as a white solid), which was used in the next step without further furification.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[NH2:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.C(O)C>O.[OH-].[Na+]>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[NH:11]
Reactant: NCc1cccs1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N=C(NCc1cccs1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydriodide and 3.39 g. of 2-(aminomethyl)thiophene in 25 ml. of absolute ethanol is heated under reflux for 16 hours, diluted with water and excess 10N sodium hydroxide is added. After standing, crystallization occurs, and filtration gives 3.50 g. of nearly colorless crystals. Recrystallization from aqueous ethanol gives the desired product as colorless crystals, m.p. 135°-137° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.C([Mg])(C)C.CN([CH:16]=[O:17])C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:16]=[O:17])=[N:6][CH:7]=1
Reactant: Brc1ccc(I)nc1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)cn1
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 5-bromo-2-iodopyridine (14.2 g, 50 mmol) in dry THF (160 mL) was added dropwise isopropylmagnesium (30 mL, 60 mmol) at −20 degrees Celsius under N2. After addition, the reaction mixture was stirred for about 2 h at the same temperature, and then DMF (5.11 g, 70 mmol) was added while keeping the temperature under 0 degrees Celsius. The reaction temperature was allowed to rise to rt and stirred for 1 hour, quenched with saturated ammonium chloride (10 ml), and then the solution pH was adjusted to 7-8 with 2.0 M HCl. The solvent was removed and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain 8.5 g (90%) of a yellow solid product which was used directly in the next step without further purification. MS: calc'd 186 (MH+), exp 186 (MH+).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-])=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]>CO.[Pd]>[NH2:13][C:8]1[C:9]([NH:11][CH3:12])=[N:10][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:6][CH:7]=1
Reactant: CNc1nc(OC(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1nc(OC(C)C)ccc1N

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 2.38 9 of 6-isopropoxy-2-methylamino-3-nitropyridine (prepared as described in Preparation 100) were hydrogenated in 50 ml of methanol in the presence of 0.50 g of 10 % w/w palladium-on-charcoal. After working up the product as described in Example 6, 2.00 g of the title compound having Rf=0.62 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent) were obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[NH:20][C:21]([O:23]C1C=CC(Cl)=CC=1)=O.CCN(C(C)C)C(C)C.[CH3:41][S:42]([NH:45][NH2:46])(=[O:44])=[O:43]>O1CCOCC1>[CH3:15][N:13]1[CH:14]=[C:10]([C:8]2[CH:9]=[C:4]3[C:5](=[CH:6][C:7]=2[C:16]([F:19])([F:18])[F:17])[NH:20][C:21](=[O:23])[N:46]([NH:45][S:42]([CH3:41])(=[O:44])=[O:43])[C:3]3=[O:2])[N:11]=[N:12]1
Reactant: COC(=O)c1cc(-c2cn(C)nn2)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)NN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)nn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
2-(4-Chloro-phenoxycarbonylamino)-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-4-trifluoromethyl-benzoic acid methyl ester (260 mg, 0.57 mmol) was dissolved in dioxane (15 mL). After addition of i-Pr2NEt (294 μL, 3 equiv) and CH3SO2NHNH2 (126 mg, 2 equiv), the solution was stirred for 2 h at 100° C. The solvent was removed in vacuo and the crude product was dried in vacuo for 2 h. DCM (5 mL) was then added and, after sonication, the solution was put in the freezer for 16 h. The resulting solid was filtered off, washed with DCM and dried to afford N-[6-(1-methyl-1H-[1,2,3]triazol-4-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (180 mg, 78%) as an off-white solid. (ESI-MS: m/z 446.5 [M+CH3CN+H]+, rt 3.71 min) 1H-NMR (DMSO-d6, 400 MHz) 8.33 (s, 1H), 8.28 (s, 1H), 7.64 (s, 1H), 4.13 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(NS(C)(=O)=O)cc1
Yield: 22.2 %

Procedure:
A solution of 22.63 g (0.25 mol) of acryloyl chloride in 250 ml of methylene chloride was added over a period of 35 minutes to a mixture of 46.81 g (0.25 mol) of N-(4-hydroxyphenyl)methanesulfonamide, 25.30 g (0.25 mol) of triethylamine and 750 ml of methylene chloride at 0° C. The resultant solution was stirred at reduced temperature for 2.17 hours, washed three times with water and dried over magnesium sulfate. Concentration of the solution in vacuo gave a solid which after two recrystallizations from benzene and drying gave 13.4 g (22.2 percent yield) of N-(4-acryloyloxyphenyl)methanesulfonamide; m.p.=136.5° to 139.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:15]3[C:11]([O:12][CH:13]=[CH:14]3)=[N:10][C:9]=2[C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.C(O)CCC.O.[NH2:31][NH2:32]>O.CCOC(C)=O>[NH:31]([C:2]1[N:7]=[N:6][C:5]([C:8]2[N:15]3[C:11]([O:12][CH:13]=[CH:14]3)=[N:10][C:9]=2[C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1)[NH2:32]
Reactant: Fc1cc(F)c(-c2nc3occn3c2-c2ccc(Cl)nn2)cc1F
Reactant: NN
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: NNc1ccc(-c2c(-c3cc(F)c(F)cc3F)nc3occn23)nn1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A flask was charged with 5-(6-chloropyridazin-3-yl)-6-(2,4,5-trifluorophenyl)imidazo[2,1-b]oxazole (0.25 g, 0.71 mmol; prepared using General Procedure H from 3,6-dichloropyridazine followed by General Procedure I from 5-iodo-6-(2,4,5-trifluorophenyl)imidazo[2,1-b]oxazole [Example #7, step C]) and n-butanol (2.0 mL) to give a tan suspension. Water (1.0 mL) was added, followed by hydrazine hydrate (0.42 mL, 8.6 mmol). The resulting mixture was heated at about 100° C. for about 20 h. To the cooled reaction mixture were added EtOAc and water and the layers were separated. The aqueous solution was extracted with EtOAc (2×50 mL) and the combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound (0.19 g, 77%): LC/MS (Table 1, Method b) Rt=1.58 min; MS m/z 347.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[O:18][CH:17]1[CH2:19][OH:20].N1C=CC=CC=1>C(O)C>[C:2]1([CH2:1][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:18])[CH2:19][OH:20])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: OCC1CO1
Solvent: CCO
Solvent: c1ccncc1
Product: OCC(O)COc1ccccc1OCc1ccccc1
Yield: 72.8 %

Procedure:
A solution of 49.6 g (0.248 mole) of 2-benzyloxyphenol, 22.2 g (0.3 mole) of glycidol, 2 ml of pyridine and 150 ml of absolute ethanol was heated at reflux overnight. The dark solution was concentrated to give an oil which gradually crystallized. The solid was purified by column chromatography on 1.2 kg of silica gel eluted with 0-25% acetone in benzene. Appropriate fractions were combined and concentrated to yield 49.5 g (73%) of the title compound as a white solid, mp 84°-85° C. (carbon tetrachloride) (lit.1 mp 81°-82.5° C.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][O:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][O:10][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=2[F:1])[C:6]#[N:7])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CBr)c1cccc(OCc2ccc(Cl)c(Cl)c2)c1
Reactant: N#Cc1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(F)c(OCC(=O)c2cccc(OCc3ccc(Cl)c(Cl)c3)c2)c1
Yield: 87.3 %

Procedure:
4-Fluoro-3-hydroxy-benzonitrile (7.3 g), 2-bromo-1-[3-(3,4-dichloro-benzyloxy)-phenyl]-ethanone (22 g), and potassium carbonate (24.3 g) were suspended together in 400 mL acetone with stirring. The mixture continued to stir for 8 hours, then was concentrated to dryness. The solid residue was taken up in 150 mL diethyl ether and 150 mL water and stirred 2 hours. The solid product was collected by filtration and washed with 100 mL diethyl ether two times and dried in vacuum, 20 g of desired product was obtained. 1H NMR (400 MHz, DMSO-d6): 7.80-7.85 (m, 1H), 7.77 (d, 1H), 7.67 (m, 1H), 7.57-7.64 (m, 2H), 7.44-7.54 (m, 4H), 7.34-7.36 (m, 1H), 5.77 (s, 2H), 5.21 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][CH2:17]Br)[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C([Mg]Cl)=C.Cl[CH:24]([Mg]Cl)[CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34].[Mg].ClCC(C)CCCC(C)CCCC(C)C>C1COCC1>[CH3:14][C:6]1[C:7]([OH:13])=[C:8]([CH3:12])[C:9]2[CH2:10][CH2:11][C@:2]([CH2:16][CH2:17][CH2:35][C@@H:33]([CH2:32][CH2:31][CH2:30][C@@H:29]([CH2:28][CH2:27][CH2:26][CH:25]([CH3:37])[CH3:24])[CH3:36])[CH3:34])([CH3:1])[O:3][C:4]=2[C:5]=1[CH3:15]
Reactant: CC(C)CCCC(C)CCCC(C)C(Cl)[Mg]Cl
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCBr)O2
Agent: C=C[Mg]Cl
Agent: CC(C)CCCC(C)CCCC(C)CCl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 1 h
Yield: 38 %

Procedure:
6.26 g (20 millimoles) of (2RS)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman were dissolved in 20 ml of absolute THF. 16.2 ml of a 1.5-molar solution of vinyl-magnesium chloride in THF were added to the above solution at -20° C. and the mixture was stirred for 1 hour at the same temperature. Thereafter, a solution of (2RS,6RS)-1-chloro-2,6,10-trimethylundecyl-magnesium chloride, which had been prepared by reacting a solution of 0.86 g (35.8 millimoles) of magnesium in 10 ml of absolute THF with a solution of 8.16 g (34 millimoles) of (2RS,6RS)-1-chloro-2,6,10-trimethyl-undecane in 10 ml of THF and stirring the mixture for 2 hours at +70° C. was added dropwise to the above solution at -20° C., followed by dropwise addition of 1.4 ml of an 0.5-molar solution of di-lithium tetrachlorocuprate in absolute THF. The reaction mixture was then stirred for 3 hours at -20° C. and 15 hours at room temperature. After it had been worked up by the method of Example 1c, 3.3 g of α-tocopherol were isolated by distillation at 210° C./0.2 mbar. This corresponds to a yield of 38% of theory.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:9][C:10]1[N:15]=[C:14]([CH2:16]Cl)[CH:13]=[CH:12][CH:11]=1.[O-]CC.[Na+]>>[CH3:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:15]=1
Reactant: Cc1cccc(CCl)n1
Reactant: Sc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cccc(CSc2ccccc2)n1

Procedure:
Following the method of Example 1A thiophenol is reacted with 6-methyl-2-picolyl chloride hydrochloride in the presence of sodium ethoxide to give 2-methyl-6-((phenylthio)methyl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10](O)=[O:11])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([NH2:33])=[O:32])[CH2:26]1.[Cl-].C(N=C=NCCC[NH+](C)C)C.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>CN(C=O)C.CO>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10]([N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([NH2:33])=[O:32])[CH2:26]3)=[O:11])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1
Reactant: NC(=O)C1CCCNC1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)O)c1
Agent: CCN=C=NCCC[NH+](C)C
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)N2CCCC(C(N)=O)C2)c1
Reaction time: 1 h

Procedure:
[5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]acetic acid (13 mg, 0.036 mmol) (see step 2 in Example 16), piperidine-3-carboxamide (4.6 mg, 0.036 mmol), 3-{[(ethylimino)methylene]amino}-N,N-dimethylpropan-1-aminium chloride (6.9 mg, 0.036 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (4.9 mg, 0.036 mmol), and triethylamine (0.005 mL, 0.036 mmol) were dissolved in DMF (0.5 mL). After 1 hour, the reaction mixture was diluted with aqueous MeOH (1 mL) and purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. Product fractions were lyophilized to yield the title product. 1H NMR (DMSO-d6) δ 7.84 (m, 1H), 7.77 (d, J=4.4 Hz, 1H), 7.76 (s, 2H), 7.58 (m, 1H), 7.51 (m, 1H), 7.44 (m, 1H), 7.36 (m, 1H), 7.02 (m, 1H), 6.84 (m, 1H), 5.97 (m, 2H), 5.93 (m, 1H), 5.87 (m, 0.5H), 5.83 (m, 0.25H), 4.29 (m, 2H), 3.80 (m, 4H), 3.40 (m, 1H), 3.10 (m, 1H), 2.95 (m, 1H), 2.65 (m, 1H), 2.20 (m, 1H), 1.90 (m, 2H), 1.70 (m, 4H), 1.40 (m, 1H). HRMS (M+1)=473.0867.
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:21])[C:15]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.Cl.ClCCl.CO>O.ClCCl.CO>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:37])([F:38])[C:26](=[O:36])[NH:27][CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:21])[C:15]([C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)C(=O)NCCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(N)c1=O)C(=O)C(F)(F)C(=O)NCCN1CCOCC1

Procedure:
2-[5-Benzyloxycarbonylamino-2-(4-fluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-N-[3,3-difluoro-1-isopropyl-2-oxo-3-[N-(2-morpholinoethyl)carbamoyl]propyl]acetamide. Using a procedure similar to that described in Example 1, except omitting the 10% hydrochloric acid wash, the ketone was prepared; chromatography solvent: dichloromethane:methanol (gradient, 96:4, 95:5); TLC: Rf =0.41, dichloromethane:methanol (95:5); MS: m/z=687(M+1). Analysis for C33H37F3N6O7.0.95 H2O: Calculated: C, 56;32; H, 5.57; N, 11.94; Found: C, 56.28; H, 5.63; N, 11.90.
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.O1C[CH2:26][CH2:25][CH2:24]1.CN(C)P(N(C)C)(N(C)C)=O>CN(C)P(N(C)C)(N(C)C)=O>[CH:5]1([CH2:6][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:21])([F:22])[F:9])=[CH:16][CH:15]=2)[C:18]([OH:20])=[O:19])[CH2:7][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-trifluoromethyl-phenyl)-acetic acid (693 mg, 3.4 mmol) in tetrahydrofuran/hexamethylphosphoramide (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 30 min. lodomethylcyclopentane (784 mg, 3.7 mmol) was then added in hexamethylphosphoramide (1 mL). The mixture was stirred at <78° C. for 4 h. The reaction was then warmed to 25° C and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The mixture was then poured into water (150 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (634.9 mg, 65%) as a white solid: mp 94-95° C.; EI-HRMS m/e calcd for C15H17F3O2 (M+) 309.1079, found 309.1072.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:35](I)[CH3:36].C(OC(C)C)(=O)C>O.CN(C)C=O>[CH2:35]([O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)[CH3:36]
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) prepared according to Example 2 in WO/2008/031567 is added to 2.55 g caesium carbonate. Dimethylformamide (4 ml) is then added. Ethyl iodide (0.55 ml) is then added and the mixture is stirred for 16 h at room temperature. Water (10 ml) and isopropyl acetate (10 ml) are added. The phases are separated. The aqueous phase is washed with isopropyl acetate (2×10 ml). The combined organic phases are washed with 20% aqueous sodium chloride solution (15 ml) and then dried (MgSO4). The mixture is concentrated under reduced pressure to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-a, R1=Boc, R2=H, R3=CO2Et). 1H NMR (CDCl3): 1.18 (3H), 1.27 (3H), 1.42 (9H), 1.49 (1H), 1.95 (1H), 2.62 (1H), 2.85 (2H), 3.94 (1H), 4.16 (2H), 4.36 (1H), 7.26 (2H), 7.35 (1H), 7.45 (2H), 7.55 (2H), 7.59 (2H).