Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16](=[O:30])[C@@H:17]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]([C:31]([NH:33][C@:34]1([C:39]([O:41]CC)=[O:40])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:32])[CH2:9]2.O.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16](=[O:30])[C@@H:17]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]([C:31]([NH:33][C@:34]1([C:39]([OH:41])=[O:40])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:32])[CH2:9]2
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1Cc2cc(Oc3cccc(Cl)c3)ccc2CN1C(=O)[C@@H](Nc1ccc(F)cc1)C(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)C1Cc2cc(Oc3cccc(Cl)c3)ccc2CN1C(=O)[C@@H](Nc1ccc(F)cc1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
The crude (1R,2S)-ethyl 1-(6-(3-chlorophenoxy)-2-((S)-2-(4-fluorophenylamino)-3,3-dimethylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-2-vinylcyclopropanecarboxylate (130 mg, 0.20 mmol) was dissolved in 1.0 mL of a mixture of THF:MeOH:H2O (2:1:1). Lithium hydroxide monohydrate (0.050 g, 1.2 mmol) was added and reaction stirred at rt overnight. The reaction was then concentrated under vacuum and quenched with 5 mL of 1 N HCl. The product precipitated and could be filtered off giving an off-white powder (110 mg). It was directly used in the next step without further purification. MS m/e 619 (M−−H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@@H:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.P(Br)(Br)[Br:19].Br>>[Br:19][C@@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: BrP(Br)Br
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Br
Product: C[C@@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 20.5 °C
Reaction time: 0.5 h
Yield: 187.8 %

Procedure:
Under argon atmosphere, (S)-[3,5-bis(trifluoromethyl)phenyl]ethanol (1) (300 g, 1.16 mol, 96% ee) was added dropwise with phosphorous tribromide (157.3 g, 0.58 mol) at a temperature lower than 20° C. on a water bath, and the mixture was stirred at 19 to 22° C. for 30 minutes. The reaction mixture was cooled, and added dropwise with hydrogen bromide (30% solution in acetic acid, 228 mL, 1.16 mol) at a temperature lower than 0° C., and the mixture was stirred at 13 to 15° C. for 16 hours. The reaction mixture was poured into ice water, and the mixture was extracted with n-hexane (3 L×2). The organic layers were combined, successively washed with saturated aqueous sodium hydrogencarbonate (3 L), and saturated brine (3 L), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure (90 to 100 mmHg) to obtain 389.2 g of a crude product. The resulting crude product was purified by column chromatography (silica gel: 900 g, developing solvent: n-hexane) to obtain 349.8 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (2) as colorless oil (yield: 93.8%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[C:21](Cl)(=[O:23])[CH3:22].Cl>C(=S)=S>[C:21]([C:12]1[CH:13]=[CH:14][C:9]2[S:8][C:7]3[CH:15]=[CH:16][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=3[C:10]=2[CH:11]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc2sc3ccccc3c2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2sc3ccc(C(C)=O)cc3c2c1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
To a solution of 45.3 g of 2-dibenzothienyl methyl ketone in one liter of carbon disulfide was added 106 g of anhydrous aluminum chloride. To this was added 17.3 g of acetyl chloride over 8 minutes. This mixture was refluxed for 3 hours and then poured into a mixture of 2 liters of crushed ice and 400 ml of concentrated hydrochloride acid. This mixture was stirred until the green color had changed to pale tan, then the solid was collected washed with water and air dried. This solid was collected, washed with water and air dried. This solid was dissolved in 2 liters of hot acetontride, filtered, concentrated to about one liter and allowed to crystallize, giving 39.0 g of the desired product as tan crystals, mp 207°-210° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CN1C(=O)CCC1>[NH:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[NH:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=c1c(CNc2nc3ccccc3[nH]2)cn(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 115 °C

Procedure:
A mixture of 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (40 mg, 0.140 mmol), N,N-diisopropylethylamine (74.0 mg, 100 μL, 0.570 mmol) and 2-chlorobenzimidazole (29 mg, 0.186 mmol) in NMP (500 μL) was heated at 115° C. in a sealed tube overnight. After this time, very little desired product was observed via LC/MS. Additional 2-chlorobenzimidazole (30 mg, 0.196 mmol), N,N-diisopropylethylamine (74.0 mg, 100 μL, 0.570 mmol), and NMP (0.2 mL) were added, and the reaction mixture was transferred to a small microwave tube. The mixture was heated via microwave irradiation at 180° C. for 2 hr. The reaction mixture was concentrated under a stream of nitrogen, and the crude product was purified by preparative reverse-phase HPLC. The product 3-[(1H-Benzoimidazol-2-ylamino)-methyl]-7-chloro-1-phenyl-1H-quinolin-4-one (4 mg, 6.8%) was obtained as an off-white solid. MS calcd. for C23H17ClN4O [(M+H)+] 401.1, obsd. 401.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:21])[C:5]2[N:6]=[CH:7][N:8]([C:19]=2[N:20]=1)[C@@H:9]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:10]1[O:11][CH3:12].[CH3:22]I>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([NH:21][CH3:22])[C:5]2[N:6]=[CH:7][N:8]([C:19]=2[N:20]=1)[C@@H:9]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:10]1[O:11][CH3:12]
Reactant: CI
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(C)nc21
Solvent: CN(C)C=O
Product: CNc1nc(C)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OC
Temperature: 100 °C
Reaction time: 0.58 h

Procedure:
1 g of 2,2'-O-dimethyladenosine (Compound 5) was dissolved in 5 ml of dimethylformamide, and 2 ml of methyl iodide was added thereto and the solution was stirred for 30 to 40 minutes. After the solvent was distilled off, 5 ml of 0.5N sodium hydroxide was added and the solution was heated for 75 minutes at 100° C. The solution was neutralized and desalted by hydrophobic column chromatography, and then recrystallized from methanol to give 2,N6,2'-O-trimethyladenosine (Compound 21).
Reaction SMILES: [N:1]1([C:7](=[O:23])[CH2:8][CH:9]([CH2:13][CH:14]2[CH2:16][CH:15]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:24][CH:25]([CH2:37][CH2:38][CH3:39])[C@@H:26]([C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1)[OH:27]>>[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[C:26]([C@@H:25]([NH:24][C:10](=[O:12])[CH:9]([CH2:13][CH:14]1[CH2:16][CH:15]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[O:23])[CH2:37][CH2:38][CH3:39])=[O:27]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CC1CC1c1ccccc1
Reactant: CCCC(N)[C@H](O)c1nc2ccccc2o1
Product: CCC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CC1CC1c1ccccc1)C(=O)c1nc2ccccc2o1

Procedure:
It is similarly prepared according to general procedure given for example 10 above but using 4-Morpholin-4-yl-4-oxo-2-(2-phenyl-cyclopropylmethyl)-butyric acid and (S)-2-Amino-1-benzoxazol-2-yl-pentan-1-ol.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[CH3:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[CH2:25][C:9]4([CH2:24][C:11]5([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]5)[CH2:10]4)[O:8][C:5]3=[CH:6][N:7]=2)=[CH:33][CH:32]=1)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3O1)C2

Procedure:
The title compound is prepared from 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] and 4-methylsulfonylmethyl-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted in a microwave oven at 140° C. LC (method 3): tR=0.95 min; Mass spectrum (ESI+): m/z=499 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:27][C:26]=1[F:38]>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:27][C:26]=1[F:38])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cc(OC2CCOCC2)ccc1Br
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOCC2)cc1F)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 4-(4-bromo-3-fluoro-phenoxy)-tetrahydro-pyran (Intermediate 31) in analogy to Example 1a): MS (ISP): 498.1 and 500.2 (M+H)+, 442.2 and 444.0 ((M-isobutene)+H)+ (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[CH:8]=[C:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2)=[O:6].C(N(C(C)C)CC)(C)C.[CH2:36]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]([C:48]2[CH:53]=[CH:52][C:51]([CH2:54][CH:55]([CH3:57])[CH3:56])=[CH:50][CH:49]=2)Cl)=[CH:42][CH:41]=1)[CH:37]([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:54]([C:51]1[CH:52]=[CH:53][C:48]([CH:46]([NH:1][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=2)[C:5]([C:7]2[CH:8]=[C:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)=[O:6])[C:43]2[CH:44]=[CH:45][C:40]([CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:41][CH:42]=2)=[CH:49][CH:50]=1)[CH:55]([CH3:57])[CH3:56]
Reactant: CCOC(=O)CCCc1cc(C(=O)c2cccc(N)c2)c2ccccn12
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCc1cc(C(=O)c2cccc(NC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)c2)c2ccccn12
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a stirred solution of ethyl 4-[1-(3-aminobenzoyl)indolizin-3-yl]butyrate (320 mg) in methylene chloride (10 ml) was added diisopropylethylamine (0.22 ml) and bis(4-isobutylphenyl)chloromethane (340 mg) in methylene chloride (5 ml) at room temperature. After stirring for 18 hours, the reaction mixture was evaporated and extracted with ether. The organic layers were washed with water and brine and dried over sodium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (methylene chloride:ethyl acetate=20:1) to give ethyl 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indolizin-3-yl]butyrate (279 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[C:20]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCCCCCCCCOC(=O)c1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)ccc1OCOC
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCOC(=O)c1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)ccc1O
Yield: 78.3 %

Procedure:
In 20 ml of ethanol was dissolved 340 mg of 2-(3,4-diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-methoxymethoxyphenyl)thiazole. Thereto was added 2 ml of 10% hydrochloric acid, and the mixture was refluxed for 20 minutes. The solvent was removed by distillation. To the residue were added 40 ml of dichloromethane and 20 ml of water, and phase separation was conducted. The organic layer was washed with 15 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was recrystallized from ethanol to obtain 245 mg of 2-(3,4-diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-hydroxyphenyl)thiazole as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]2[CH2:27][NH:28][CH2:29][C:22]=12>>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]2[CH2:27][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:29][C:22]=12
Reactant: c1cnc2c(c1)CNC2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3Cc4cccnc4C3)n2)c1

Procedure:
B48 was prepared following the general procedure reported for B10 using A1 and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride; yield: 92.2 mg (24%), dark amorphous solid. MS (ES) C17H17N7O2S requires: 383. found: 384 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 92.4 %

Procedure:
A mixture of ethyl 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]benzenepropanoate (1.85 g, 4.3 mmol), 3N sodium hydroxide solution (4.4 mL) and methanol (100 mL) was heated on a steam bath. After 20 minutes the mixture was concentrated, diluted with water and 1N hydrochloric acid solution to pH=1 and extracted with CH2Cl2. The combined extracts were dried over sodium sulfate and the solvent evaporated to leave a white solid. Recrystallization from a mixture of hexanes and CH2Cl2 gave 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]benzenepropanoic acid (1.58 g, 91%) mp 119°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=[C:9]2[S:18][CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)C.O.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]2[S:18][CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylate (10) (1 g, 2.44 mmol) in THF at 0° C. was added lithium aluminum hydride (1M in THF, 4.88 mL, 4.88 mmol). The reaction was stirred for 1 h at 0° C. and at room temperature for 1 h. The solution was diluted with diethyl ether, and water (0.1 mL), 2N NaOH (0.1 mL), water (0.3 mL) and magnesium sulfate were added. The reaction was filtered and washed with THF to obtain (1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazol-5-yl)methanol (28) as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CC(=O)OCC>>[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N:17]1[CH2:18][CH2:19][N:20]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:21][CH2:22]1
Reactant: ClCc1nc2cccnc2s1
Reactant: c1csc(N2CCNCC2)n1
Solvent: CCOC(C)=O
Product: c1cnc2sc(CN3CCN(c4nccs4)CC3)nc2c1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(1,3-thiazol-2-yl)piperazine (219 mg, 1.3 mmol), and D1 EA (340 μL, 2.1 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.71 (m, 4H) 3.46 (m, 4H) 4.06 (s, 2H) 6.86 (d, J=3.73 Hz, 1H) 7.17 (d, J=−3.73 Hz, 1H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H). (ESI) m/z 318 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[C:4]([F:13])[CH:3]=1.[Cu][C:15]#[N:16].[Cu](C#N)C#N>CC(N(C)C)=O>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[CH:3][C:4]=1[F:13]
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: N#C[Cu]
Agent: N#C[Cu]C#N
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(OC(F)(F)F)c(F)c1
Reaction time: 4 h

Procedure:
49 g 1-Bromo-3-fluoro-4-trifluoromethoxybenzene was stirred into 100 mL dimethylacetamide together with 20 g copper(I)cyanide at 140° C. overnight. Additional 10 g copper cyanide was added and heating was continued at 150° C. for 4 h. Further 12 g copper cyanide was added and stirring continued at 150° C. overnight. After cooling, the mixture was filtered through Celite/Cellulose and washed with ethyl acetate. The filtrate was added to ice water and filtered again through Celite/Cellulose. The filtrate was extracted with ethyl acetate (×3), dried over magnesium sulfate and concentrated to provide a brown oil which was distilled at 7 mbar and 60° C. to yield two product fractions with 23.5 g and 12 g (content 80%) yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:35][CH2:36][N:37]([S:40]([CH3:43])(=[O:41])=[O:42])[CH2:38][CH2:39]2)(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CS(=O)(=O)N1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CS(=O)(=O)N1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-4-(methylsulfonyl)piperazine. MS (ESI): mass calcd. for C21H22FN5O4S2, 491.11; m/z found, 492.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.23 (s, 1H), 8.13 (d, J=7.0, 1H), 7.97 (m, 1H), 7.77-7.71 (m, 1H), 7.67-7.61 (m, 1H), 7.46 (d, J=6.4, 1H), 7.39-7.32 (m, 2H), 3.03-2.94 (m, 8H), 2.78 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)C(Cl)=O)([O-:17])=[O:16]>N1C=CC=CC=1>[CH3:12][O:11][C:9]1[C:8]([O:13][CH3:14])=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:1][C:25]2[CH:24]=[CH:20][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:26]=2)[CH:10]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Solvent: c1ccncc1
Product: COc1cc(Nc2cccc([N+](=O)[O-])c2)c(C(N)=O)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 2-amino-4,5-dimethoxybenzamide (5.05 g, 25.7 mmole) and 3-nitro benzoyl chloride (5.2 g, 28.0 mmole) CHCl3 (120 ml) was added pyridine (50 ml) drop wise at RT. The reaction mixture was stirred at RT for 24 h. The solvent was removed in vacuo and residue was triturated with Et2O, filtered and dried under high vacuum to give 4,5-dimethoxy-2-(3-nitrophenyl)aminobenzamide, which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[CH:7]([C:9]([CH3:11])=[O:10])=[CH2:8]>>[C:9]([CH:7]1[CH2:8][CH2:5][C:4]([CH3:6])=[C:2]([CH3:1])[CH2:3]1)(=[O:10])[CH3:11]
Reactant: C=CC(C)=O
Reactant: C=C(C)C(=C)C
Product: CC(=O)C1CCC(C)=C(C)C1

Procedure:
The reaction between 2,3-dimethylbutadiene and methyl vinyl ketone was performed in substantially the same manner as in Example 45, except that each of the compounds synthesized in Examples 42 to 44 was individually used as the Lewis acid catalyst. The yields of the reaction product (i.e., 4-acetyl-1,2-dimethylcyclohexene) are shown in Table 1.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])O[C@@H]2CO)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].P([O-])([O-])([O-])=O>>[CH2:5]([OH:20])[C@H:6]1[O:7][C@H:9]([O:8][C@H:6]2[O:7][C@H:2]([CH2:1][OH:23])[C@@H:3]([OH:22])[C@H:4]([OH:21])[C@H:5]2[OH:20])[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]1[OH:17]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Product: OC[C@H]1O[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Five units each per 1 g of the substrates of purified extracellular trehalose phosphorylase and purified extracellular maltose phosphorylase produced in the same manners as in Examples 2 and 1 were added to 10 ml of 20% (W/V) solution of high maltose syrup (trade name; MC-95, Nihon Shokuhin Kako Co.,Ltd, Sugar composition; 2.5% of glucose, 95.2% of maltose, 0.8% of maltotriose and 1.5% of maltotetraose) containing 5 mM phosphate buffer (pH 6.0) and allowed to react as in Example 6. Trehalose formed was measured by the HPLC method described above and it was found to correspond to 54.3% of the weight of the used substrates.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.Br[CH2:15][C:16]([NH2:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:15][C:16](=[O:17])[NH2:18])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NCC(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-amino-1-N-Boc pyrrolidine (0.5 g, 2.68 mmol) and 2-bromo acetamide (0.44 g, 3.21 mmol) in DMF (6.0 mL) was added potassium carbonate (1.11 g, 8.04 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and re-dissolved in dichloromethane. Potassium carbonate was filtered off and filtrate was concentrated and purified using ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 1.50 (9H, s), 1.60–1.80 (2H, m), 2.10 (1H, m), 3.10–3.60 (6H, m), 5.65 (1H, br, s), 6.90 (1H, br, s). ESI-MS m/z: 367(M+1), UV retention time: 0.61 min.