Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CN1CCOCC1.[C:16]1(=[O:35])[N:20]([C@@H:21]([CH2:25][CH2:26][CH2:27][CH2:28]O)[C:22](O)=[O:23])[C:19](=[O:30])[C:18]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:17]12.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[C:19]1(=[O:30])[N:20]([C@@H:21]([CH2:25][CH2:26][CH2:27][CH3:28])[C:22]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:23])[C:16](=[O:35])[C:17]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:18]12
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCC[C@@H](C(=O)NCC(=O)OCC)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A slurry of glycine, ethyl ester, hydrochloride salt (2.718 g, 19.5 mmol.) in dimethylformamide (36 ml.) was treated with 4-methyl morpholine (2.60 ml., 2.39 g., 23.6 mmol.) and stirred at room temperature for 5 minutes. The mixture was then treated with (S)-2-phthalimido-6-hydroxyhexanoic acid (4.50 g., 16.2 mmol.) and hydroxybenzotriazole (2.225 g., 16.5 mmol.), cooled to 0° C., and then treated with ethyl-3-(3-dimethylamino)propyl carbodiimide, hydrochloride salt (3.438 g., 17.9 mmol.). After stirring at 0° C. for 1 hour and at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid and subsequently extracted three times with ethyl acetate. The pooled ethyl acetate extracts were washed in succession with water, saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 5.77 g. of title product as a colorless oil. TLC (ethyl acetate) Rf =0.34.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH2:10][OH:11])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:23][CH3:24])(=[O:22])[C:19]([CH3:21])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:21][C:19]1([C:18]([O:23][CH3:24])=[O:22])[O:9][CH2:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:10][O:11]1
Reactant: OCC(CO)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(C)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COC(=O)C1(C)OCC(c2ccccc2)(c2ccccc2)CO1
Yield: 22.4 %

Procedure:
A mixture of 22.8 g (0.1 M) of 2,2-diphenyl-1,3-propanediol and 100 g (0.98 M) of methyl pyruvate is brought to 70° C. in a 500 ml round-bottomed flask under a nitrogen atmosphere. 22.4 g (0.156 M) of P2O5 are added portionwise. An exothermic reaction takes place and the temperature rises to 98° C. The mixture is allowed to return to room temperature and is poured slowly into ice-cold water. This mixture is extracted with methylene chloride and the extracts are washed with sodium hydroxide and water. The extracts are concentrated and the residue is chromatographed by flash chromatography (70 CH2Cl2/50 cyclohexane eluent). The product is then recrystallized from 40 ml of diisopropyl ether. 7 g of a product of m.p. 116° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)CCC.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][CH:9]([CH3:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:42]2[S:43][CH:44]=[CH:45][CH:46]=2)[CH:3]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[OH:12]
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(O)(c1cccc(-c2cccs2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1-(3-Bromophenyl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.70 g) and a solution of tri-n-butyl(2-thienyl)tin (1.31 ml) in DMF (10 ml) were deaerated and tetrakis(triphenylphosphine)palladium(0) (110 mg) was added. The mixture was stirred under an argon atmosphere at 80° C. for 4 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed twice with water and then with saturated brine, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chomatography (eluent, hexane:ethyl acetate=6:1→3:1). Recrystallization from ethyl acetate-hexane gave the title compound (1.32 g) as colorless powder crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]1[NH:13][CH:14]=[CH:15][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]1[N:13]([S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH:14]=[CH:15][C:16]=1[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1[nH]ccc1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1c(C(=O)OC(C)(C)C)ccn1S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.08 h

Procedure:
(R)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)propyl)-1H-pyrrole-3-carboxylate (505b, 4.58 g, 14.12 mmol) was dissolved in THF (40 mL) under nitrogen and cooled in an ice bath. Sodium tert-butoxide (1M in THF, 14.12 mL, 14.12 mmol) was added and the mixture stirred for 5 min. Toluene-4-sulfonyl chloride (2.69 g, 14.12 mmol) was added to the solution and the mixture was stirred at 0° C. for 30 min. Water (50 mL), and EtOAc (50 mL) were added to the reaction mixture and the organic layer was washed with brine and dried over MgSO4, filtered and concentrated affording crude (R)-tert-butyl 2-(1-aminopropyl)-1-tosyl-1H-pyrrole-3-carboxylate (505c) as an orange viscous oil. m/z (ESI, +ve) 501.2 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].CCN(C(C)C)C(C)C.[NH2:21][C@@H:22]([CH3:25])[CH2:23][OH:24]>CC(O)C.CN(C1C=CN=CC=1)C>[Cl:8][C:6]1[C:5]([Cl:9])=[C:4]([NH:21][C@@H:22]([CH3:25])[CH2:23][OH:24])[C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: C[C@H](N)CO
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@@H](CO)Nc1c(Cl)c(Cl)nc(Cl)c1Cl
Yield: 52 %

Procedure:
To a solution of pentachloropyridine (30 g) in 2-propanol (300 ml) was added DIPEA (18 ml), DMAP (0.8 g) and (S)-(+)-2-amino-1-propanol (18 g), and the reaction mixture was heated under reflux for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was triturated with methanol and filtered to give the title compound as a white solid (18 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17](O)([CH2:18][C@@H:19]([O:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH2:20][C@@H:21]3[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.[C:45](=[O:50])([O:48]C)[O:46][CH3:47]>S(=O)(=O)(O)O>[CH3:44][C:2]1([CH3:1])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH2:20][C@@H:21]3[O:29][Si:30]([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:31])[CH3:32])=[CH:16][C@H:15]4[O:50][C:45]([O:46][CH3:47])=[O:48])[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1
Reactant: COC(=O)OC
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](OC(=O)N(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(=O)N(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12

Procedure:
In 10 ml of dimethyl carbonate was dissolved 350 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(tert-butyldimethylsilyl)oxy-3β-(N,N-dimethylcarbamoyl)oxypregn-6-en-5α-ol, followed by addition of one drop of concentrated sulfuric acid. The mixture was stirred in an atmosphere of argon gas under ice-cooling for 1 hour. The reaction mixture was then worked up in the same manner as Example 132 to give 95 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α -(tert-butyldimethylsilyl)oxy-3β-(N,N-dimethylcarbamoyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:35]2([CH3:36])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:30])[CH2:15][CH2:16][CH:17]([O:21][C:22](=[O:29])[C:23]2C=CC=CC=2)[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([O:38][C:39](=[O:46])[C:40]2C=CC=CC=2)[CH2:3]1.[CH2:47]([O:49]CC)[CH3:48]>>[C:47]([O:1][C@@H:2]1[C@@:35]2([CH3:36])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:30])[CH2:15][CH2:16][CH:17]([O:21][C:22](=[O:29])[CH3:23])[CH:18]([CH3:19])[CH3:20])[CH2:5][C@@H:4]([O:38][C:39](=[O:46])[CH3:40])[CH2:3]1)(=[O:49])[CH3:48].[CH3:30][C@@H:14]([C@@H:13]1[C@@:31]2([CH3:37])[CH2:32][CH2:33][CH2:34]/[C:9](=[CH:8]\[CH:7]=[C:6]3\[CH2:5][C@@H:4]([OH:38])[CH2:3][C@H:2]([OH:1])[C:35]\3=[CH2:36])/[C@@H:10]2[CH2:11][CH2:12]1)[CH2:15][CH2:16][CH:17]([OH:21])[CH:18]([CH3:19])[CH3:20]
Reactant: CCOCC
Reactant: CC(C)C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)OC(=O)c1ccccc1
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCC(O)C(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Product: CC(=O)OC(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C)C(C)C

Procedure:
20 mg of 1α-hydroxy-3β,24-dibenzoyloxycholesta-5,7-diene was dissolved in 500 ml. of diethyl ether. The solution was irradiated with ultraviolet rays, isomerized, and hydrolyzed in the same way as in Example 21, (B) to afford 1.9 mg of 1α,24-dihydroxycholecalciferol which showed the same properties as the product obtained in Example 20.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[C:16]([CH3:17])=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](O)[CH2:27][OH:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:19]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[C:11]([CH3:18])[C:12]([CH:13]2[O:28][CH2:27][CH2:26][O:14]2)=[CH:15][C:16]=1[CH3:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OCCO
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C1OCCO1
Temperature: 80 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a stirred solution of 4-dibenzylamino-2,5-dimethylbenzaldehyde (3.60 g, 10.9 mmol) in toluene (35.0 mL) under nitrogen was added 1,2-ethanediol (1.83 mL, 32.8 mmol) and p-toluenesulfonic acid (451 mg, 2.62 mmol). The reaction mixture was heated at 80° C. overnight. TLC (3:1 hexanes:EtOAc) showed a ˜50:50 mixture of product and starting material. Magnesium sulfate (1.32 g, 10.9 mmol) was added and stirring was continued for 6 h. The reaction mixture was then filtered and concentrated under reduced pressure to give title compound (3.19 g, 78% yield) as an oil.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH:3](C)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C-:11]#[N:12].[Na+]>>[C:11]([CH2:10][CH:2]([OH:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:12]
Reactant: [C-]#N
Reactant: CCOC(=O)C(C)C(C)O
Agent: [Na+]
Product: CCOC(=O)CC(O)CC#N

Procedure:
The recombinant E. coli HB101 (pNTS1G) obtained in Example 10 was inoculated in 100 ml of a 2×YT medium sterilized in a 500 ml Sakaguchi flask, and cultured with agitation at 37° C. for 13 hours. Glucose, 7.5 g, 3.2 mg of NADP, and then 4 g of ethyl 2-methyl-3-oxoacetate were added to 50 ml of the resultant culture. The culture was stirred at 30° C. while being adjusted at pH 6.5 with a 5 M sodium hydroxide solution to allow for reaction for 18 hours. After the reaction, the reaction solution was subjected to extraction using ethyl acetate, the solvent was removed under decompression, and the concentrate was purified by silica gel column chromatography, to obtain 3.5 g of ethyl 3-hydroxy-2-methylbutyrate. The optical purity of the ethyl 3-hydroxy-2-methylbutyrate was analyzed as follows and found to be 91.6% e.e. The analysis was performed in the following manner. The sample was reacted with sodium cyanide in demethyl sulfoxide at room temperature to obtain ethyl 4-cyano-3-hydroxybutyrate, which was then changed to a benzoic ester using benzoyl chloride under the presence of pyridine. The optical purity of the benzoic ester was measured by the HPLC method. 1H-NMR(CDCl3) δ (ppm): 1.17(3H,t), 1.22(2H,t), 1.28(3H,t), 2.46(1H,m), 2.82(1H,br), 3.90(1H,m), 4.18(2H,q).
Reaction SMILES: Cl[CH:2]([CH3:19])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[O:31][CH2:30][CH2:29][O:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-:39].[K+].[K+]>C(#N)C>[C:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]([N:35]2[CH2:36][CH2:37][CH:32]([C:27]3([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[O:31][CH2:30][CH2:29][O:28]3)[CH2:33][CH2:34]2)[CH3:19])=[CH:6][CH:7]=1)(=[O:39])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(Cl)C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(C2(C3CCNCC3)OCCO2)cc1
Agent: [K+]
Solvent: CC#N
Product: CC(C(=O)c1ccc(OC(=O)c2ccccc2)cc1)N1CCC(C2(c3ccc(F)cc3)OCCO2)CC1

Procedure:
A mixture of 10.99 g (0.04 mole) of 2-chloro-1-(4-benzyloxyphenyl)-1-propanone, 10.05 g (0.04 mole) of 2-(4-fluorophenyl)-2-(4-piperidyl)-1,3-dioxolane, 5.52 g of potassium carbonate and 150 ml of acetonitrile is heated under reflux for 4 h. Working as described in Example 4a, an oil is isolated which is used as it is in the following stage.
Reaction SMILES: C(OC(N1C=C([CH2:13][CH:14]([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])N=C1CCCC)=O)(C)(C)C>[Pd].CO.O>[CH2:32]1[O:31][C:28]2[CH:29]=[CH:30][C:25]([CH:14]([CH3:13])[C:15]([OH:17])=[O:16])=[CH:26][C:27]=2[O:33]1
Reactant: CCCCc1nc(CC(C(=O)OCc2ccccc2)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 188 %

Procedure:
The mixture of benzyl (2RS)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionate (2R:2S=1:4, 3.65 g) and 10% palladium on activated carbon (1.0 g) in methanol (50 ml) and water (5 ml) was shaken under hydrogen atmosphere (3 atmospheric pressure) at ambient temperature for 1 hour. The catalyst was filtered through a bed of celite and the filtrate was evaporated in vacuo. The residue was diluted with AcOEt (ethyl acetate) and the organic layer was washed with brine. Drying, filtering and removal of the solvents afforded (2RS)-3-(1-tert-butoxycarbonyl)-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionic acid (2R:2S=1:4) (2.63 g) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[N:24]=3)[N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:37]>>[ClH:37].[CH3:27][O:26][C:23]1[N:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[C:16]2[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][CH:12]=1
Reactant: COc1ccc2nccc(-c3ccc(CCNC(=O)OC(C)(C)C)cc3)c2n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2nccc(-c3ccc(CCN)cc3)c2n1
Product: Cl
Reaction time: 2 h

Procedure:
To a stirred solution of {2-[4-(6-methoxy[1,5]naphthyridin-4-yl)phenyl]ethyl}carbamic acid tert-butyl ester (0.67 g, 1.76 mmole) in dry CH2Cl2 (75 mL) at RT was added trifluoroacetic acid (50 mL). After 2 h, the reaction solution was concentrated under vacuum and the residue dissolved in 4M HCl in dioxane (5 mL) at RT. After 1 hr, the reaction contents were concentrated and dried under high vacuum to give the crude title compound as a tan solid which was used immediately in the proceeding reaction: LC-MS (ES) m/e 280 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]([CH3:19])[CH:6]=1)=[O:4].[CH:20]([N-:22][CH:23]=[O:24])=[O:21].[Na+]>C(#N)C>[CH:20]([N:22]([CH:23]=[O:24])[CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]([CH3:19])[CH:6]=1)=[O:4])=[O:21]
Reactant: O=C[N-]C=O
Reactant: Cn1cc(C(=O)CCl)cc1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(C(=O)CN(C=O)C=O)cc1C(=O)c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
A solution of 10 g (0.034 mole) of 2-chloro-1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-ethanone and 3.8 g (0.041 mole) sodium diformylamide in 80 mL acetonitrile was heated under reflux overnight under argon. An additional 2.0 g portion of sodium diformylamide was added and reflux was continued for 1.5 hrs. After evaporation of the solvent in vacuo the residue was passed through a flash column (silica gel, 3:1 hexane:acetone the 2:1 hexane:acetone) to give 6.18 g of a solid. mp 279-282° C. 260° C. decomp. mass spectrum (Cl—CH4) m/z=333 (M+1). NMR 300 MHz (CDCl3) d 9.0 (s, 2H); 7.8 (d, 2H); 7.55 (s, 1H); 7.45 (d, 2H); 7.1 (s, 1H); 4.85 (s, 2H); 4.1 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][C:4]21CCCC2.CB(Br)C.[OH-:24].[Na+]>ClCCl>[CH2:13]([N:11]1[CH2:10][CH2:9][C:4](=[O:24])[CH:3]([CH2:2][OH:1])[CH2:12]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: OCC1CN(Cc2ccccc2)CCC12CCCC2
Agent: CB(C)Br
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCN(Cc2ccccc2)CC1CO
Temperature: -78 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
A solution of 3.0 gm (11.4 mMol) 6-hydroxymethyl-8-benzyl-8-azaspiro[4,5]decane in 50 mL dichloromethane was cooled to −78° C. and then treated with 2.2 mL (22.8 mMol) dimethylboron bromide dropwise. After stirring at −78° C. for 4 hours, the reaction mixture was treated with 45 mL 1N sodium hydroxide and was allowed to warm to room temperature. The phases were separated and the aqueous phase was extracted well with dichloromethane. The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with dichloromethane containing from 0-5% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 1.1 gm (44%) 1-benzyl-3-hydroxymethyl-4-oxopiperidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[CH:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C#CCCCCCC.Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([C:42]34[CH2:51][CH:46]5[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]5)[CH2:43]3)[CH2:49]4)[CH:35]=2)=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:42]12([C:36]3[CH:35]=[C:34]([C:31]4[CH:32]=[CH:33][C:28]([C:17]#[C:16][C:8]5([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]5)=[CH:29][CH:30]=4)[CH:39]=[CH:38][C:37]=3[O:40][CH3:41])[CH2:49][CH:48]3[CH2:47][CH:46]([CH2:45][CH:44]([CH2:50]3)[CH2:43]1)[CH2:51]2
Reactant: COc1ccc(-c2ccc(Br)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: COc1ccc(-c2ccc(C#CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 35 %

Procedure:
When tert-butyl-5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step A was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 35% yield, as pale paste. 1H-NMR (CDCl3) 1.47 (s, 3H); 1.48 (s, 9H); 1.5 (s, 3H); 1.77 (broad s, 6H); 2.07 (broad s, 3H); 2.12 (s, 6H); 3.86 (s, 3H); 4.00 (d, 2H, J=11.38 Hz); 4.10 (d, 2H, J=11.45 Hz); 5.20 (s, 1H); 6.9 (d, 1H, J=8.46 Hz); 7.28-7.5 (s, 6H).
Reaction SMILES: Cl.[CH2:2]([N:6]1[C:10](CC#N)=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH3:5].O.[C:27]([O:30][CH2:31]C)(=[O:29])[CH3:28]>CO>[CH3:31][O:30][C:27](=[O:29])[CH2:28][C:10]1[N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:8][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(C)=O
Reactant: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CC#N
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CC(=O)OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Hydrogen chloride gas is bubbled into solution of (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile (187) (640 mg, 2.03 mmol) in methanol (30 mL) at 0° C. for 10 minutes, followed by stirring for 30 minutes. Water (0.0365 ml, 2.03 mmol) is then added and the reaction refluxed at 80° C. for 2 hours. The methanol is then removed in vacuo, the reaction crude is dissolved in ethyl acetate (100 mL), and the organic layer is washed with saturated sodium bicarbonate (1×100 mL), brine (1×100 mL), and dried over magnesium sulfate. The sample is filtered, concentrated and purified by flash chromatography on SiO2 using an eluent of 2:3 ethyl acetate:hexane to afford (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid methyl ester (188) as a colorless oil.
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].S([O:20][CH2:21][C:22]1([CH:28]=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(C)(=O)=O.C(N(CC)CC)C.Cl>COCCOCCOC>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[S:1][CH2:28][C:22]1([CH:21]=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccccc1S
Reactant: CS(=O)(=O)OCC1(C=O)CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: O=CC1(CSc2ccccc2C(=O)c2ccccc2)CCCCC1
Yield: 18.1 %

Procedure:
A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil. HCl and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme. This was purified by silica gel flush column (5% EtOAc:Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and mass spectra were consistent with the product.