Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](Cl)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCOCC1
Yield: 85 %

Procedure:
The product from Example 10D (185 mg, 0.6 mmol), morpholine (0.058 ml, 0.65 mmol) and diisopropylethylamine (100 μl, 0.6 mmol) in 2 mL of dichloromethane were stirred at 20° C. for 18 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3/MeOH/NH4OH 9:1:0.1) to provide the title compound (85% yield).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH2:11])[C:8]([NH2:12])=[CH:7][CH:6]=1.[CH:13](O)=O>>[CH3:3][O:4][C:5]1[N:10]=[C:9]2[N:11]=[CH:13][NH:12][C:8]2=[CH:7][CH:6]=1
Reactant: O=CO
Reactant: COc1ccc(N)c(N)n1
Agent: Cl
Product: COc1ccc2[nH]cnc2n1

Procedure:
10.19 g of 6-methoxypyridine-2,3-diamine dihydrochloride were dissolved in 100 ml formic acid and stirred under reflux for 72 h. The formic acid was evaporated under vacuum and the residue was dried under vacuum at 95° C. to give crude 5-methoxy-1H-imidazo[4,5-b]pyridine (as hydrochloride and/or as formic acid salt and/or as free base) that was used for the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10]CC)=[O:9])=[C:4]([C:17]#[C:18][C:19]2[CH:24]=[C:23]([S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=2[CH3:31])[CH:3]=1.[OH-].[Na+].Cl>CCO.O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]([CH2:13][CH3:14])[C:8]([OH:10])=[O:9])=[C:4]([C:17]#[C:18][C:19]2[CH:24]=[C:23]([S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=2[CH3:31])[CH:3]=1
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OC(CC)C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OC(CC)C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
A solution of ethyl 2-(4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenoxy)butanoate (Intermediate 268; 100 mg; 0.11 mmol) in EtOH (1 ml) was treated with a 1M solution of sodium hydroxide in water (0.16 ml; 0.16 mmol). After stirring at 70° C. for 45 minutes, a 1 N solution of HCl in water (65 μl) was added, the solvents removed under reduced pressure and the residue purified by preparative HPLC to afford the title compound as a beige solid.
Reaction SMILES: [C-]#N.[K+].[C:4]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].[CH3:16][OH:17]>O>[C:4]([C:8]1[CH:15]=[CH:14][C:11]([C:16](=[O:17])[CH:12]([C:11]2[CH:10]=[CH:9][C:8]([C:4]([CH3:7])([CH3:5])[CH3:6])=[CH:15][CH:14]=2)[OH:13])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CO
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)C(O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 90 °C
Reaction time: 40 h

Procedure:
A solution of potassium cyanide (4.61 g, 70.89 mmol) in water (14 ml) is slowly added to a solution of 4-tert-butylbenzaldehyde (115 g, 708.9 mmol) in a methanol (300 ml)/water (40 ml) mixture. The mixture is stirred at 90° C. for 40 hours. After cooling, the methanol is concentrated under reduced pressure and the residue is taken up in dichloromethane and water. After three extractions with dichloromethane, the recombined organic phases are dried on magnesium sulfate, filtered and concentrated under reduced pressure. Pentane (approximately 800 ml) is then added, and the resulting precipitate is filtered, washed several times in pentane and dried to yield 55.23 g (49%, not optimized) of pure product in the form of a white solid. Analyses identical to the literature.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]1[O:13][CH2:4]1
Reactant: COc1ccccc1C=O
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: COc1ccccc1C1CO1

Procedure:
A mixture of 9.7 g of sodium hydride, 38 g of trimethylsulfonium iodide and 25.2 g (0.185 mol) of o-methoxybenzaldehyde is reacted to give o-methoxystyrene oxide.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[CH:37][CH:36]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
1-[1-(4-Fluoro-benzyl)-piperidin-4-yl]-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]-pyrimidine was prepared according to General Procedure H by the reaction 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 4-fluorobenzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.93-1.99 (m, 2H), 2.20-2.30 (m, 4H), 2.93-2.97 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.53 (s, 2H), 4.75-4.81 (m, 1H), 7.14-7.19 (m, 2H), 7.36-7.40 (m, 2H), 7.62-7.64 (m, 2H), 8.04-8.06 (m, 2H), 8.38 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=482.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([F:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:29]1>CS(C)=O.C(OCC)(=O)C.CCCCCC>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]2[CH2:42][CH2:41][N:40]([CH2:11][CH:12]3[O:26][C:16]4=[C:17]5[C:21](=[C:22]([F:24])[CH:23]=[C:15]4[O:14][CH2:13]3)[NH:20][C:19](=[O:25])[CH2:18]5)[CH2:39][CH2:38]2)=[CH:29]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(F)c4c(c3O2)CC(=O)N4)cc1
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1Cc2c(c(F)cc3c2OC(CN2CCC(c4c[nH]c5ccccc45)CC2)CO3)N1
Temperature: 25 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-fluoro-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.0 g, 2.5 mmole) and 4-(1H-indol-3-yl)piperidine (2.0 g, 10 mmole) are combined in 30 ml of dry DMSO and heated at 80°-90° C. for 4 hours under an argon atmosphere. After cooling to room temperature, the mixture is diluted with 500 ml of 1:1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate and with two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue is column chromatographed on silica gel using 0.5% methanol/CHCl3 as eluant to give the free base of the title compound. The product is crystallized from ethanol with the addition of one equivalent of fumaric acid to give the (S) enantiomer of the title compound as a fumarate salt.
Reaction SMILES: [N+](C1C2C(=O)C3C(=C([N+]([O-])=O)C=CC=3O)C(=O)C=2C(O)=CC=1)([O-])=O.[N+:25]([C:28]1[C:41]2[C:40](=[O:42])[C:39]3[C:34](=[C:35]([OH:46])[CH:36]=[CH:37][C:38]=3[N+:43]([O-])=O)[C:33](=[O:47])[C:32]=2[C:31]([OH:48])=[CH:30][CH:29]=1)([O-:27])=[O:26].C1(O)C=CC=CC=1>CO>[NH2:43][C:38]1[C:39]2[C:40](=[O:42])[C:41]3[C:32](=[C:31]([OH:48])[CH:30]=[CH:29][C:28]=3[N+:25]([O-:27])=[O:26])[C:33](=[O:47])[C:34]=2[C:35]([OH:46])=[CH:36][CH:37]=1
Reactant: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c([N+](=O)[O-])ccc(O)c21
Agent: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c(O)ccc([N+](=O)[O-])c21
Solvent: Oc1ccccc1
Solvent: CO
Product: Nc1ccc(O)c2c1C(=O)c1c([N+](=O)[O-])ccc(O)c1C2=O

Procedure:
16.5 parts of a mixture of 1,5-dinitro-4,8-dihydroxyanthraquinone and 1,8-dinitro-4,5-dihydroxyanthraquinone (about 1:1 parts) is heated with 50 parts of phenol for eight hours at 180° C while stirring. After cooling 100 parts by volume of methanol is added, the precipitate is suction filtered and the residue is washed with methanol and then with hot water. After drying 13 parts of a mixture of 1-amino-5-nitro-4,8-dihydroxyanthraquinone and 1-amino-8-nitro-4,5-dihydroxyanthraquinone is obtained; this is equivalent to 87% of the calculated yield.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][O-:25].[Na+]>CO>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([O:25][CH3:24])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: C[O-]
Reactant: C[Si](C)(C)CCOCn1cnc2c(-c3ccco3)nc(Cl)nc21
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2ccco2)c2ncn(COCC[Si](C)(C)C)c2n1
Yield: 67 %

Procedure:
A solution of 2-chloro-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine (0.35 g, 1.0 mmol) and sodium methoxide (60 mg, 1.1 mmol) in methanol (5 mL) was refluxed for 23 h, cooled, concentrated in vacuo and the resulting solid treated with water, acidified to pH 4 with acetic acid, extracted with EtOAc, dried (Na2SO4), concentrated in vacuo and purified by chromatography [SiO2; EtOAc:heptane (1:1)]to give the title compound (232 mg, 67%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]([OH:14])/[CH:11]=[CH:12]\[CH3:13].CC1C(C(O)/C=C\C)C(C)(C)CCC=1>>[CH3:1][C:2]1[CH:3]([C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13])[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=1
Reactant: C/C=C\C(O)C1=C(C)CCCC1(C)C
Agent: C/C=C\C(O)C1C(C)=CCCC1(C)C
Product: C/C=C/C(=O)C1C(C)=CCCC1(C)C

Procedure:
By replacing in the above procedure cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene by cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-2-cyclohexene, trans-2,6,6-trimethyl-1-crotonoyl-2-cyclohexene was obtained which had the following characteristics: NMR spectrum: δ=0.83 ppm (3 H, s); 0.92 ppm, (3 H, s); 1.55 ppm, (3 H, s broad); 1.89 ppm, (d of d, J=6.5 and 1.1 cps); 1.0-2.3 ppm (4 H, complex band); 2.77 ppm, (1 H, s broad); 5.52 ppm, (1 H, s broad); 6.18 ppm, (1 H, d of q, J=16 cps and 1.1 cps); 6.77 ppm, (1 H, d of q, J=16 cps and 6.5 cps).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@H:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@H:3]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CBr
Reactant: N[C@@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2ccccc21
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
In 700 ml of dimethylformamide is dissolved 54.8 g of trans-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. To this solution is added 8.8 g of 60% sodium hydride under ice-cooling. The reaction temperature is gradually elevated to room temperature, and the mixture is stirred for 1.5 hours. After the reaction mixture is again cooled to about 10° C., 100 ml of a dimethylformamide solution containing 25.5 ml of ethyl bromoacetate is added dropwise. After the reaction temperature is elevated again to room temperature, the mixture is stirred for 5 hours and then concentrated under reduced pressure. By adding ice-water and chloroform to the residue, the organic substance is extracted. After the chloroform layer is washed with water and dried, the solvent is distilled off under reduced pressure. By adding a mixed solution of isopropyl ether and isopropyl alcohol to the residue, the crystallization is effected. The resulting crystals are collected by filtration to give 37 g of ethyl trans-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([C:21](=[O:23])[CH3:22])[C:12]3[C@@H:24]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)[O:25][C:26]4([CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:42][Mg]Br>O1CCCC1.C1(C)C=CC=CC=1.O1CCCC1.C(OCC)C>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([C:21]([OH:23])([CH3:42])[CH3:22])[C:12]3[C@@H:24]([C:32]4[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=4)[O:25][C:26]4([CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C(C)(C)O)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
26 mg 1-((3R,9S)-9-(tert-butyldimethylsilyloxy)-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-4-yl)ethanone are dissolved in 2 ml tetrahydrofurane cooled to −10° C. and treated with 110 μl of a 1.4 M solution of methylmagnesium bromide in toluene/tetrahydrofurane 75:25. The mixture is warmed to room temperature and stirred for 12 hours. The mixture is diluted with diethylether, washed with saturated aqueous ammonium chloride and dried with magnesium sulphate. The solvents are evaporated in vacuo and the residue is directly used in the next step.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[NH:7][CH2:6][CH2:5][CH:4](C)[N:3]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[CH3:19].[OH-].[Li+].[CH2:23](O)C>>[O:1]=[S:2]1(=[O:20])[N:7]([CH3:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH3:19]
Reactant: CCO
Reactant: COC(=O)c1ccc(N2C(C)CCNS2(=O)=O)c(C)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(C(=O)O)ccc1N1CCCN(C)S1(=O)=O

Procedure:
Prepared analogously to Example 39d from methyl 4-(1,1-dioxo-3-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzoate and lithium hydroxide in ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:33]2[CH:37]=[N:36][N:35]=[N:34]2)=[C:22]([CH:32]=1)[CH2:23][NH:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CC#N.O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:33]2[CH:37]=[N:36][N:35]=[N:34]2)=[C:22]([CH:32]=1)[CH2:23][NH:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:14]([C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
The title compound was prepared from (2R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (52 mg, 0.23 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 70 mg, 0.23 mmol, 1.0 equiv), EDC (66 mg, 0.34 mmol, 1.5 equiv) and HOAt (16 mg, 0.11 mmol, 0.5 equiv) in DMF (500 μl) essentially according to the procedure described in Example 26, Step C. Reverse phase HPLC [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 9.16 (s, 1 H), 7.90 (br s, 1 H), 7.59 (s, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 7.24 (d, J =8.4 Hz, 1 H), 4.56 (br s, 1 H), 4.38 (br s, 1 H), 4.18–4.15 (m, 2 H), 3.80 (br s, 1 H), 3.58–3.52 (m, 3 H), 2.15–2.11 (m, 2 H), 2.05–1.98 (m, 2 H), 1.95–1.84 (m, 2 H), 1.70–1.68 (m, 2 H), 1.55 (br s, 2 H), 1.33 (s, 9 H). LCMS (M+H): 518.3.
Reaction SMILES: [C:1]1(=[CH:7][C:8](OCC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]1(=[CH:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C=C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC=C1CCCCC1
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl cyclohexylideneacetate (see route to this by Wadsworth and Emmons in Org. Synth. Coll. Vol 5 547) (3.00 g, 17.8 mmol) in dry ether (50 ml) under an atmosphere of nitrogen at 0° C. was added lithium aluminium hydride (407 mg, 10.7 mol) portionwise and the mixture stirred for 2 hours before quenching with dilute hydrochloric acid (2M; 20 ml). The mixture was filtered and the aqueous layer was separated and extracted further with ether (2×25 ml) and the combined ether layers washed with water (2×25 ml) and saturated sodium chloride solution (25 ml) and then dried over MgSO4. Filtration and evaporation of the solvent and distillation of the residue gave 2-cyclohexylidene ethanol (2.16 g, bp. 112° C. at 10 mmHg [Kugelrohr]).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1C=CC=CC=1CBr.[H-].[Na+]>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[CH2:26][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1cccc(F)c1-c1ccccc1CBr
Reactant: Fc1cccc(F)c1-c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1Cn1c(-c2c(F)cccc2F)nc2ccccc21
Yield: 4 %

Procedure:
2-(2,6-difluorophenyl)benzimidazole (Example 12) (2.00 g, 8.70 mmol) and 2,6-difluoro-α-bromo-toluene (25) (2.85 g, 160 M %), were dissolved in THF (20 mL). To this mixture, NaH (0.75 g, 215 M %) was added. After mixing for 2 hours, the reaction was quenched with MeOH and concentrated. The residue was redissolved in ethylacetate, and washed with NaHCO3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was recrystallized from ethylacetate/hexane (1:1) yielding white powders of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (2.62 g, 0.35 mmol, 85% yield. M.p. 145° C. 1H-NMR (300 MHz, CD2Cl2): δ 7.77 (m, 1H, H4), 7.54 (m, 1H, H4′), 7.49m, 1H, H7), 7.29 (m, 2H, H5,6), 7.24 (m, 1H, H4″), 7.08 (m, 2H, H3′, 5′), 5.82 (m, 2H, H3″, 5″), 5.30 (s, 2H, CH2PhF2).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]([CH2:21][C:22](=[O:24])[CH3:23])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(Oc2nc3ccccc3[nH]2)cc1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Cn1c(Oc2ccc(Br)cc2)nc2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of 2-(4-bromophenoxy)-1H-benzo[d]imidazole (5.72 g) in DMF (60 mL) was added NaH (60% in oil, 950 mg) at 0° C. After stirring for 5 min, chloroacetone (2.36 mL) was added to the mixture at 0° C. The mixture was stirred at room temperature for 5 h. The mixture was diluted with AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt in hexane) and recrystallized from THF/Et2O to give the title compound (3.47 g).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>CC1C=CC(C)=CC=1.CC1C=CC=C(C)C=1.CC1C(C)=CC=CC=1>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccc(C)cc1
Solvent: Cc1ccccc1C
Solvent: Cc1cccc(C)c1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 125 °C
Yield: 94.64 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in xylenen (70 mL) respectively and heated to 125° C. Then lithium bromide (0.15 g, 1.74 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.89 g, yield: 94.64%).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3]>CC1C=CC=CC=1C>[CH3:4][C:2]1[CH:3]=[CH:3][C:2]([C:4]([CH3:1])([CH3:2])[CH3:4])=[CH:1][C:1]=1[CH3:3]
Reactant: C=C(C)C
Solvent: Cc1ccccc1C
Product: Cc1ccc(C(C)(C)C)cc1C

Procedure:
At 190° C. o-xylene was alkylated with isobutylene to give 1,2-dimethyl-4-t-butylbenzene. The selectivity was 97% and conversion of the olefin 95%. The reaction was maintained for 48 hours without a decline in catalyst activity.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[H-].[Na+]>CC(N(C)C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccccc1CCCCc1ccccc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: c1ccc(CCCCc2ccccc2OCCN2CCOCC2)cc1
Yield: 76.5 %

Procedure:
Following a procedure similar to that described in Example 2, 340 mg of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3), 330 mg of 4-(2-chloroethyl)morpholine hydrochloride and 140 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 2, was purified by column chromatography through silica gel, using a 3:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 390 mg (yield 76%) of the title compound as a colorless oil.