Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[Mg].Br[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](C#N)([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[NH4+].[Cl-]>C(OCC)C.C1COCC1.CCOC(C)=O.CCCCCC>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][C:20]([N:23]([CH3:25])[CH3:24])([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Brc1cccs1
Reactant: CN(C)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)C1(c2cccs2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
A little iodine was added to a mixture of 5.6 g (3 eq) magnesium and 20 ml dry diethyl ether, followed over a period of 10 min by 5 g 2-bromothiophene, and the mixture was stirred for a further 10 min. Once the reaction had started, 33.5 g (2.6 eq) 2-bromothiophene dissolved in 80 ml diethyl ether were added dropwise and the mixture was stirred for a period of 2 h at room temperature. The Grignard reagent prepared in the preceding step was added dropwise to a solution of 20 g (1 eq) tert-butyloxycarbonyl-4-cyano-4-(dimethylamino)-piperidine dissolved in 200 ml THF and stirred overnight at room temperature. The reaction course was monitored by thin-layer chromatography (50% EtOAc/hexane). Once the conversion was complete, the reaction solution was cooled to 0° C., mixed with saturated NH4Cl solution, extracted with ethyl acetate (3×100 ml) and the combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (Alox neutral; 30% EtOAc/hexane). 6.1 g (25%) of product were obtained in the form of a white solid.
Reaction SMILES: C1(C)C=CC=C(C2OC=NC=2C(NC2C=NN(CC[O:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=O)=[O:24])C=2)=O)C=1.[OH:34][CH2:35][CH2:36][N:37]1[C:41]([CH3:42])=[C:40]([NH:43][C:44]([C:46]2[N:47]=[CH:48][O:49][C:50]=2[C:51]2[CH:52]=[C:53]([CH3:57])[CH:54]=[CH:55][CH:56]=2)=[O:45])[C:39]([CH3:58])=[N:38]1>>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([O:34][CH2:35][CH2:36][N:37]2[C:41]([CH3:42])=[C:40]([NH:43][C:44]([C:46]3[N:47]=[CH:48][O:49][C:50]=3[C:51]3[CH:52]=[C:53]([CH3:57])[CH:54]=[CH:55][CH:56]=3)=[O:45])[C:39]([CH3:58])=[N:38]2)(=[O:24])=[O:22])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)cc1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2c(C)nn(CCO)c2C)c1
Product: Cc1ccc(S(=O)(=O)OCCn2nc(C)c(NC(=O)c3ncoc3-c3cccc(C)c3)c2C)cc1

Procedure:
The title compound was synthesized according to above mentioned procedure for 2-(4-(5-(m-tolyl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)ethyl-4-methylbenzenesulfonate, starting from N-(1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide. LC-MS conditions A: tR=0.93 min, [M+H]+=467.46.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:36])[CH3:33]
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCN=C=O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 25 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and ethyl isocyanate (Aldrich), to give 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid ethylamide. HRMS, observed: 399.2143; Calcd for (M+H)+: 399.2139.
Reaction SMILES: C[Si]([Cl:5])(C)C.[OH-].[CH:7]1([Sn+:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH:20]1([Sn:13]([Cl:5])([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: C1CCC([Sn+](C2CCCCC2)C2CCCCC2)CC1
Reactant: C[Si](C)(C)Cl
Agent: [OH-]
Product: Cl[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1

Procedure:
In a 500 mL three-necked flask, trimethylsilyl chloride (170 g, 109 mmol) was added to tricyclohexyltin hydroxide (80 g, 133 mmol) and heated at reflux during 18 hours. After distillation of trimethylsilyl chloride in excess and hexamethyldisiloxane under reduced pressure, the crude product was recrystallized in petroleum ether. White needles were obtained (39.82 g, 79.6 mmol).
Reaction SMILES: [NH:1]([C:32](OC(C)(C)C)=[O:33])[C@H:2]([C:20]([N:22]1[CH2:31][CH2:30][CH2:29][C@H:23]1[C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[NH:39]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:40](C(O)=O)[CH2:41][CH:42]([CH3:44])[CH3:43].CS(O)(=O)=O.N(C(OC(C)(C)C)=O)[C@@H](C(O)=O)CC(C)C.C1C=C2N=NN(O)C2=CC=1.O.N[C@H](C(N[C@H](C(N1CCC[C@H]1C(NCC)=O)=O)CCCNC(=N)NS(C1C=CC(C)=CC=1)(=O)=O)=O)CC(C)C.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[NH:39]([C:48]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:49])[C@H:40]([C:32]([NH:1][C@H:2]([C:20]([N:22]1[CH2:31][CH2:30][CH2:29][C@H:23]1[C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10])=[O:33])[CH2:41][CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@@H](N)CC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Boc-Leu-Arg(Ts)-Pro-NHEt was prepared from Boc-Arg(Ts)-Pro-NHEt obtained in Example 1 and Boc-Leu by the same procedure as Example 1. To a solution composed of the compound (0.969 g) and dichloromethane (10 ml), methanesulfonic acid (0.78 g) was added at room temperature, and the resulting mixture was stirred at room temperature for 4 hours, thereby the Boc group was removed (reaction conversion ratio: 100.0%). After the reaction, triethylamine in an amount of the same molar equivalent as that of the added methanesulfonic acid was added thereto, and the resulting mixture was stirred for 15 minutes. After Boc-D-Leu (0.40 g) and HOBt monohydrate (0.33 g) were added to the thus obtained dichloromethane solution of Leu-Arg(Ts)-Pro-NHEt, the reaction solution was cooled with ice. Then, EDC hydrochloride (0.42 g) was added thereto, and the resulting mixture was stirred for 1 hour. Subsequently, the temperature of the mixture was raised to room temperature and the mixture was stirred for 15 hours, thereby performing a condensation reaction (reaction conversion ratio: 100.0%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:16]C1C=CC=C(C(OO)=O)C=1>ClCCl>[Cl:16][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=2)[N:1]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc2ncccc2c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2nc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.8 g (29 mmol) of ethyl quinoline-6-carboxylate was stirred in 80 ml of dichloromethane. 6.2 g of m-chloroperbenzoic acid was added to the obtained mixture under cooling with ice, and they were stirred at room temperature overnight. The mixture was washed with 10% aqueous sodium sulfite solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated. 70 ml of dichloromethane and 35 ml of phosphoryl chloride were added to the residue, and they were stirred at 50° C. overnight. The solvent was evaporated, and the residue was treated with dichloromethane as the extracting solvent by an ordinary method. After the purification by the silica gel chromatography (ethyl acetate/hexane), the title compound was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:14][S:15][CH3:16])[C:6]=1F)(=[O:4])=[O:3].[CH3:18][O:19][CH2:20][CH2:21][NH2:22].Cl>O>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:14][S:15][CH3:16])[C:6]=1[NH:22][CH2:21][CH2:20][O:19][CH3:18])(=[O:4])=[O:3]
Reactant: CSCc1c(C(=O)O)ccc(S(C)(=O)=O)c1F
Reactant: COCCN
Agent: Cl
Solvent: O
Product: COCCNc1c(S(C)(=O)=O)ccc(C(=O)O)c1CSC

Procedure:
2 g (7.2 mmol) of 4-methylsulfonyl-3-fluoro-2-methylthiomethylbenzoic acid were refluxed in 20 g (0.266 mol) of a 60% strength 2-methoxyethylamine solution in water for four days. The cold solution was acidified with concentrated HCl to a pH of 1 and extracted with EE. The organic solution was dried with MgSO4 and concentrated to completion. This gives a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[N:10][S:11](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:14]>ClC(Cl)C>[Cl:14][C:9]1[C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[S:11][N:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cccc2c1C=NS2=O
Solvent: CC(Cl)Cl
Product: COc1cccc2snc(Cl)c12
Yield: 60 %

Procedure:
The 4-methoxy benzisothiazolone (0.065 mole) was dissolved in 200 mL of dichloroethane and PCl5 (1.05 mole equiv.) was added neat. The reaction was refluxed-monitored by tlc. An additional 0.25 mole equiv. and 2×0.10 mole equiv. of PCl5 was added after 1 hour, 21/2 hours, and 3 hours before the reaction was judged complete by tlc. The reaction was cooled and the solvent and excess reagent removed by house vacuum distillation. The residue was flash chromatographed (30% CH2Cl2 /70% hexane) affording the 3-chloro-4-methoxy-1,2-benzisothiazole in 60% yield.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([NH2:11])[C:5]=2[S:4][CH:3]=1.[CH3:13][NH:14][S:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16]>>[NH2:11][C:10]1[C:5]2[S:4][CH:3]=[C:2]([C:20]3[CH:19]=[C:18]([S:15]([NH:14][CH3:13])(=[O:16])=[O:17])[CH:23]=[CH:22][CH:21]=3)[C:6]=2[N:7]=[C:8]([Cl:12])[N:9]=1
Reactant: Nc1nc(Cl)nc2c(Br)csc12
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Product: CNS(=O)(=O)c1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Yield: 71.2 %

Procedure:
The target compound (480 mg, 71% yield) was prepared in the same manner as Step 1 of Example 11 using 7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine (500 mg, 1.90 mmol) and 3-(N-methylsulfamoyl)phenylboronic acid (409 mg, 1.90 mmol).
Reaction SMILES: [C:1]1([C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O.[N+:29]([O-])([OH:31])=[O:30]>>[N+:29]([C:3]1[CH:2]=[C:1]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]=1[C:7]([O:9][CH3:10])=[O:8])([O-:31])=[O:30]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: COC(=O)c1ccc(C(=O)OC)c([N+](=O)[O-])c1

Procedure:
Czech Patent Specification No. 138,287 discloses a process for preparing 1-nitrobenzene-2-methoxycarbonyl-5-carboxylic acid. In this process, dimethyl benzene-1,4-dicarboxylate is nitrated in fuming sulfuric acid by means of a mixed acid of 20% strength oleum and 98% strength nitric acid; the dimethyl 1-nitrobenzene-2,5-dicarboxylate obtained is then first isolated and subsequently partially hydrolyzed by means of a large excess of 70% strength aqueous sulfuric acid. 1-Nitrobenzene-2-methoxycarbonyl-5-carboxylic acid precipitated in the acidic medium is then dissolved by means of sodium carbonate and reprecipitated by means of hydrochloric acid. In carrying out this process in industry, it suffers from the disadvantage that the waste water is very heavily polluted. The process moreover requires an additional isolating step as well as a purification operation, and it is impossible to prevent explosive dimethyl ether from forming from the methyl alcohol resulting in the hydrolysis of the ester group.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([NH:13]C(=NC)SC)#[N:12]>>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[CH2:5][S:4][CH2:3][CH2:2][NH:1][C:11]([NH2:13])=[NH:12]
Reactant: NCCSCc1nccs1
Reactant: CN=C(NC#N)SC
Product: N=C(N)NCCSCc1nccs1

Procedure:
Reaction of [(2-aminoethyl)thiomethyl]thiazole (from the dihydrobromide 20.2 g) with N-cyano-N',S-dimethylisothiourea (7.75 g) by a procedure similar to that described in Example 75, afforded N-cyano-N'-methyl-N"-[(2-(2-thiazolylmethylthio)ethyl]guanidine, m.p. 120°-122.5°, following chromatography on silica gel with alcohol.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:20][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[Li+].[OH-].Cl>O1CCOCC1.O>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[N:12]1[C:11]2[C@@H:10]3[CH2:20][C@@H:9]3[CH2:8][C:7]=2[C:6]([C:4]([OH:5])=[O:3])=[N:13]1
Reactant: CCOC(=O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of (1aR,5aR)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (150 mg, 0.56 mmol) in dioxane (2 mL) was added 1 N LiOH (1.1 mL, 1.11 mmol). The reaction was stirred for 1 h at 80° C., and cooled to room temperature. The reaction was acidified to pH 2 with 4 N HCl and diluted with H2O to form precipitate. The resulting precipitate was collected by filtration, rinsed with water, and then dried to give the title compound as a white solid (100 mg). LCMS m/z=243.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.43 (td, J=4.5 and 3.4 Hz, 1H), 1.26 (td, J=7.7 and 4.4 Hz, 1H), 2.26-2.33 (m, 1H), 2.70-2.79 (m, 2H), 2.89 (dd, J=16.6 and 6.3 Hz, 1H), 8.60 (dd, J=2.6 and 1.5 Hz, 1H), 8.67 (d, J=2.6 Hz, 1H), 9.17 (d, J=1.4 Hz, 1H), 13.01 (s, 1H).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH2:16]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH3:13])#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: CC(C)(C)CN
Solvent: CO
Product: CC(C)(C)CN=C(NC#N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), 2,2-dimethylpropylamine (0.30 g, 3.4 mmol) was added, and the resulting mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from dichloromethane-diethyl ether to give the title compound (0.63 g, 2.9 mmol, yield: 94%) as colorless needles.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)(=O)=O)=CC=1>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Reactant: O=C(N[C@@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: O=C(N[C@@H]1CCN(CCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(R)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide and 2-(4-fluorophenyl)ethyl p-toluenesulfonate were reacted under the same conditions as in Example 1 to give (R)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: [Mg].[C:2]([O:6][CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9]I)([CH3:5])([CH3:4])[CH3:3].[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[C:28](=[O:32])[CH2:29][CH2:30][CH:31]=1)([O:18][CH2:19][CH3:20])=[O:17].[Cl-].[NH4+]>C(OCC)C.O>[C:2]([O:6][CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][C@@H:31]1[C@@H:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:28](=[O:32])[CH2:29][CH2:30]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCCCCCC1=CCCC1=O
Reactant: CCCCCC(CCI)OC(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OC(C)(C)C
Yield: 85 %

Procedure:
To a Grignard solution, prepared from 5.05 g. of magnesium and 65.8 g. of 3-(tert-butoxy)-1-iodooctane in 150 ml. of diethyl ether under nitrogen atmosphere, is added 4.0 g. of copper iodide-tri-n-butylphosphine complex followed by dropwise addition of 49 g. of 2-(6-carbethoxyhexyl)cyclopent-2-en-1-one [Hardegger et al., Helv. Chim. Acta 50, 2501 (1967)] and the resulting mixture is stirred for 18 hours. Saturated ammonium chloride (110 ml.) is added followed by 100 ml. of water and 100 ml. of diethyl ether. Unreacted magnesium is removed by filtration. The ethereal layer is washed successively with aqueous sodium thiosulfate solution, ammonium chloride solution, and water, dried over magnesium sulfate and taken to dryness to give an oil. Distillation at 0.05 mm. (bath 100°-185° C.) give 45.4 g. of material containing unreacted starting material and 30 g. (85% yield based on non-recovered starting material; see below) of residue which contains the desired product. This material is chromatographed on silica gel. The product is eluted with diethyl ether to give 25.2 g. (71% based on recovered starting material) of a syrup; this material has no significant ultraviolet absorption; λthe maxKBr 5.74, 7.20, 7.35, 8.35 μ; nmr 2H quartet δ 4.09 (OCH2 of ester), 1H broad singlet 3.57 (carbinolic proton), 5H overlapping multiplets 2.0-2.4 (protons next to C-O), 3H triplet 1.22 (CH3 of ethyl), 9H singlet 1.17 (CH3 's to t-butyl) and 3H triplet 0.9 (terminal methyl); mass spectrum: m/c 424.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]=[C:6](Cl)[C:7]([F:10])([F:9])[F:8].Cl[C:17](=[CH2:20])[C:18]#[N:19].C(N(CC)CC)C.C(OCC)(=O)C.CCCCCCC>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]1[NH:5][C:6]([C:7]([F:10])([F:9])[F:8])=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: FC(F)(F)C(Cl)=NCc1ccccc1Cl
Reactant: C=C(Cl)C#N
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccccc1Cl
Reaction time: 3 h
Yield: 80.5 %

Procedure:
A solution of N-(o-chlorobenzyl)-2,2,2-trifluoroacetimidoyl chloride (10.0 g, 0.039 mol) and 2-chloroacrylonitrile (4.1 g, 0.047 mol) in N,N-dimethylformamide is cooled to 5° C. and treated with a solution of triethylamine (12.0 mL, 0.086 mol) in N,N-dimethylformamide (10 mL). When the addition is one-quarter complete, the cooling bath is removed and the reaction mixture is treated with the remaining triethylamine solution, stirred for three hours, diluted with water and extracted with methylene chloride. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil. Flash chromatography of the oil using silica gel and a 1:6 ethyl acetate/heptane solution gives an oil. Crystallization of the oil from heptane gives the title product as a solid (8.5 g, mp 151°-152.5° C.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[O-]CC.[K+]>O1CCCC1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2]>[OH:3][CH:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1cccnc1
Agent: [Ru+2]
Agent: CC[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1cccnc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Tris(triphenylphosphine)ruthenium(II) chloride (3.8 mg, 4 μmol, 1 mol %) and a chiral ligand (M=Ru, R=t-Bu, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in tetrahydrofuran (3 mL) under nitrogen atmosphere, and then heated and stirred for 2 h at 65° C. After the mixture was cooled to room temperature, 3-acetylpyridine (0.4 mmol), tetrahydrofuran (2 mL) and a solution of potassium ethoxide in ethanol (0.1 mL, 0.2M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 6 h under H2 (50 atm) at 25° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/1). Accordingly, pure 3-(1-hydroxyethyl)pyridine was obtained and the ee value (ee=93%) was measured by GC analysis.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)=[CH:4][CH:3]=1.[F:25][CH:26]([F:52])[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:51])([F:50])[N:34]2[CH2:38][CH2:37][N:36]([C:39]3[CH:40]=[C:41]([CH:46]=[CH:47][N:48]=3)[C:42]([O:44]C)=O)[C:35]2=[O:49])=[CH:29][CH:28]=1.FC1C=CC(CN)=CC=1>>[F:52][CH:26]([F:25])[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:50])([F:51])[N:34]2[CH2:38][CH2:37][N:36]([C:39]3[CH:40]=[C:41]([CH:46]=[CH:47][N:48]=3)[C:42]([NH:7][CH2:6][C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=3)=[O:44])[C:35]2=[O:49])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccnc(N2CCN(C(F)(F)c3ccc(C(F)F)cc3)C2=O)c1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(C(F)(F)c3ccc(C(F)F)cc3)C2=O)c1
Yield: 41 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-((4-(difluoromethyl)phenyl)difluoromethyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with 4-fluorobenzylamine, 2-(3-((4-(difluoromethyl)phenyl)-difluoromethyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)isonicotinamide was obtained as a colorless solid in 41% yield: mp 173-175° C.; 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=5.1 Hz, 1H), 8.25 (s, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.60 (d, J=7.8 Hz, 2H), 7.47 (dd, J=5.1, 0.9 Hz, 1H), 7.25-7.21 (m, 2H), 6.99-6.90 (m, 2H), 6.86-6.42 (m, 2H), 4.50 (d, J=5.7 Hz, 2H), 4.18 (t, J=7.8 Hz, 2H), 3.89 (t, J=7.8 Hz, 2H); MS (ES+) m/z 490.9 (M+1).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:34]1([CH2:40][CH2:41][S:42][CH:43]([C:47](O)=[O:48])[C:44](O)=[O:45])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[OH:48][C:47]1[CH:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])=[CH:15][CH:14]=2)[O:18][C:44](=[O:45])[C:43]=1[S:42][CH2:41][CH2:40][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(S(=O)(=O)c3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(phenylsulfonyl)acetophenone (2.50 g, 9.61 mmol), lithium bis(trimethylsilyl)amide (2.41 g, 14.42 mmol), chlorotrimethylsilane (1.83 mL, 14.42 mmol), THF (96 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 194-195° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 3.01 (t, 2 H), 6.87 (s, 1 H), 7.19 (m, 5 H), 7.68 (m, 3 H), 8.04 (m, 6 H), 12.05 (bs, 1 H).