Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[CH3:11][C:12]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:14]([S:15][CH:9](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:13]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:12]=1[CH3:11]
Reactant: Cc1ccc(CS)c(C)c1
Reactant: C#Cc1ccc(C)cc1C
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2C)c2ccc(C)cc2C)c2ccc(C)cc2C)c(C)c1

Procedure:
A solution of 2,4-dimethylphenylacetylene (0.02 mol) and 2,4-dimethylbenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-dimethylstyryl-2,4-dimethylbenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:17]([CH2:19][C:20](OCC)=O)#N.ClC1C=CC=CC=1C=O.[N+](C(C)C)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:19]1([CH3:20])[CH3:17])#[N:2]
Reactant: CCOC(=O)/C(C#N)=C/c1ccccc1Cl
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: O=Cc1ccccc1Cl
Agent: [K+]
Solvent: CC(C)[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(c2ccccc2Cl)C1(C)C
Yield: 88 %

Procedure:
A mixture of 640 mg (2.7 mmoles) of (E)-ethyl 2-cyano-3-(o-chlorophenyl)-2-propenoate (6) (prepared from ethyl cyanoacetate and o-chlorobenzaldehyde using the procedure described in Example I for an analogous cyanoester), 0.25 mL (2.78 mmoles) of 2-nitropropane, 357 mg (2.6 mmoles) of anhydrous potassium carbonate, and 4.0 mL of absolute ethyl alcohol was heated at reflux for 3 hours. The product was isolated as described in the procedure of Example VIII, affording 664 mg (88% yield) of cyclopropanoid cyanoester 12, stereochemically homogeneous as shown by NMR analysis: δ3.22 (singlet, cyclopropyl H); bp: 122°-155° C. (bath temperature, 0.08 mm).
Reaction SMILES: Br[CH:2]([C:4]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:3].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:21]([CH:2]([C:4]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:3])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(Br)c1nn2ccccc2c1-c1cc(F)cc(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1nn2ccccc2c1-c1cc(F)cc(F)c1
Yield: 72.1 %

Procedure:
2-(1-Bromoethyl)-3-(3,5-difluorophenyl)pyrazolo[1,5-a]pyridine (0.63 g, 1.9 mmol) and sodium azide (0.12 g, 1.9 mmol) were stirred in N,N-dimethylformamide (20 mL) for 1 hour at 20° C. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, concentrated and purified on silica gel with ethyl acetate in hexanes (0-35%) to give the desired compound (0.41 g, 73%). LCMS for C15H12F2N5 (M+H)+: m/z=299.9. 1H NMR (300 MHz, DMSO-d6): δ 8.80 (m, 1H), 7.72 (m, 1H), 7.38 (m, 1H), 7.22 (m, 3H), 7.02 (m, 1H), 4.92 (m, 1H), 1.62 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:11]([C@H:13]1[CH2:18][C@H:17]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH3:16])[C@H:14]1[O:32][C:33](=[O:36])[CH2:34]Br)[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH2:21][CH2:20]3)[CH3:12].CN(C=O)C>CC(C)=O>[CH2:11]([C@H:13]1[CH2:18][C@H:17]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH3:16])[C@H:14]1[O:32][C:33](=[O:36])[CH2:34][O:5][C:4](=[O:6])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH2:21][CH2:20]3)[CH3:12]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CC(C)(C)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CC(C)(C)C
Yield: 61 %

Procedure:
In 10 ml of acetone is dissolved 1.16 g of 3,3-dimethylbutyric acid, and 5.0 ml of 2N-NaOH is added, followed by addition of 1.15 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 20 ml of DMF. The mixture is refluxed for 5 hours, and thereafter treated in the same manner as Example 26. The reaction mixture is chromatographed on a silica gel column. Following passage of 200 ml of n-hexanediisopropyl ether (3:7), elution is carried out with a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.76 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]([F:20])=[C:18]2[C:13]([C:14]([CH3:21])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[C:22]([O:24]C)=[O:23].[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]([F:20])=[C:18]2[C:13]([C:14]([CH3:21])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)c1cc2c(C)ncnc2c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution of methyl 7-(2-fluoro-4-iodophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylate (205 mg, 0.48 mmol) in a mixture of THF (10 ml) and H2O (5 ml) was added a solution of LiOH (57 mg, 2.4 mmol) in H2O (2.4 ml). After stirring at room temperature for 4 h, the reaction was concentrated, acidified with 1 M. HCl solution, and extracted with EtOAc (2×20 ml). The organic solution was dried over MgSO4 and concentrated to give 190 mg (96%) the title compound as an orange solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[CH3:19][C:20]1[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=1[CH:22]=[N+:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:22]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=2[CH3:19])=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: Cc1ccccc1C=[N+]1CCCC1
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccccc2C)N2CCCC2)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and 1-(2-methyl-benzylidene)-pyrrolidinium chloride
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH3:22]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:20])[C:17](=[CH2:22])[CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: CNC
Reactant: CCCC(=O)c1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(CC)C(=O)c1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A mixture of 2-(2,3-dichloro-4-butyrylphenoxy)-2-methylpropionic acid (10 g, 0.031 mole), dimethylamine hydrochloride (15 g, 0.18 mole), paraformaldehyde (3 g, 0.10 equiv.) and acetic acid (0.6 ml) was stirred and heated on a steam bath for two hours. N,N-dimethylformamide (30 ml) was added and stirring and heating was continued for another two hours. The mixture was poured into ice water which was then extracted with ether. The ether extract was washed with water, then brine and finally dried over MgSO4. The ether was evaporated in vacuo and the residue recrystallized from cyclohexane to give 6.3 g 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]-2-methylpropionic acid, m.p. 88°-89° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 10 °C

Procedure:
A mixture of 14.7 g of 5-methoxy-1H-indole, 30.7 g of the monohydrate of 4-piperidone hydrochloride and 150 ml of 2 N methanolic potassium hydroxide solution was refluxed under an inert atmosphere for 81/2 hours and was then cooled. 300 ml of water were added to the mixture which caused crystallization and the mixture was cooled to 10° C. and filtered. The recovered product was empasted 3 times with water, twice with ethanol and twice with ether. The product was dried at 20° C. under reduced pressure to obtain 18.25 g of 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in the form of a clear yellow powder melting at 183° C.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH3:28][CH:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=2)[C:11]([NH:35][CH:32]2[CH2:33][CH2:34][CH:29]([CH3:28])[CH2:30][CH2:31]2)=[O:12])=[CH:26][CH:27]=1)#[N:2]
Reactant: CC1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 105.5 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.5 g (1.26 mmol) and 4-methylcyclohexylamine (0.143 g, 1.26 mmol) were used to afford 0.6 g of the required product. Percentage purity (LCMS): 84.6%, (M+1)=451.1+1.
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([C:50]([F:53])([F:52])[F:51])=[CH:6][C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]3[C@H:22]4[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]4[C@H:20]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH:38]6[CH2:40][CH2:39]6)[C:31]=5[CH:30]=[CH:29]4)[CH2:19]3)[N:9]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]=2[CH:49]=1.[BH3-][C:55]#N.[Na+]>CO.C1COCC1>[Cl:3][C:4]1[C:5]([C:50]([F:53])([F:51])[F:52])=[CH:6][C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:17][C@@H:18]3[C@H:22]4[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]4[C@H:20]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH:38]6[CH2:39][CH2:40]6)[C:31]=5[CH:30]=[CH:29]4)[CH2:19]3)[CH3:55])[N:9]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]=2[CH:49]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CNCCCCc3nc4cc(C(F)(F)F)c(Cl)cc4n3COCC[Si](C)(C)C)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCCCc1nc2cc(C(F)(F)F)c(Cl)cc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 1 h
Yield: 62 %

Procedure:
37% aq. Formaldehyde (54.07 uL, 0.722 mmol, 2 eq) was added to a solution of 7-[(3aS,4R,6R,6aR)-6-[({4-[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butyl}amino)methyl]-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (270 mg, 0.361 mmol, 1 eq) in MeOH:THF (1:1, 10 ml) at RT and stirred. NaCNBH3 was then added portionwise and continued stirring for 1 h. LCMS at 1 hr showed the reaction to be complete. The solvent was then removed in vacuo. The residue was dissolved in DCM (30 ml) and washed with water (30 ml) before drying over Na2SO4, filtering and evaporated. Purification by preparative TLC, eluting three times with MeOH:DCM (6:94) gave the desired product as a colorless oil (200 mg, 62%): MS (ESI+) for C37H51ClF3N7O3Si m/z 762.30 [M+H]+; HPLC purity 86% (ret. time, 1.75 min).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:18])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=2.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:18][N:4]1[C:5]2=[N:6][C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:9]=[C:10]2[N:11]=[C:3]1[CH2:2][O:1][C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2ccc(-c3ccccc3)nc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(-c3ccccc3)nc21
Yield: 62.9 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 2-hydroxymethyl-3-methyl-5-phenylimidazo[5,4-b]pyridine (prepared as described in Preparation 110), 0.97 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.57 ml of tributylphosphine, 0.53 g of 1,1'-(azodicarbonyl) dipiperidine and 50 ml of benzene were used. After working up the product as described in Preparation 4, the resulting crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.9 g of the title compound having Rf=0.26 (on silica gel thin layer chromatography using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH:7]([P:18](=[O:27])([O:23][CH2:24][CH:25]=[CH2:26])[O:19][CH2:20][CH:21]=[CH2:22])[P:8](=[O:17])([O:13][CH2:14][CH:15]=[CH2:16])[O:9][CH2:10][CH:11]=[CH2:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:36][CH2:37][C:38](Br)=[O:39]>C(Cl)Cl>[Br:36][CH2:37][C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([P:18](=[O:27])([O:23][CH2:24][CH:25]=[CH2:26])[O:19][CH2:20][CH:21]=[CH2:22])[P:8](=[O:17])([O:13][CH2:14][CH:15]=[CH2:16])[O:9][CH2:10][CH:11]=[CH2:12])=[CH:28][CH:29]=1)=[O:39]
Reactant: C=CCOP(=O)(OCC=C)C(Cc1ccc(N)cc1)P(=O)(OCC=C)OCC=C
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOP(=O)(OCC=C)C(Cc1ccc(NC(=O)CBr)cc1)P(=O)(OCC=C)OCC=C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 75.9 %

Procedure:
To a solution of aminobenzyl bisphosphonate 27 (180 mg, 0.41 mmol) in CH2Cl2 (5 mL) at 0° C. was added pyridine (49 μL, 0.61 mmol) followed by bromoacetylbromide (35 μL, 0.41 mmol). The reaction mixture was stirred at 0° C. for 30 min and at room temperature for another 2.5 h. The reaction mixture was diluted with CH2Cl2, washed with aqueous 1N HCl solution, saturated NaHCO3 solution, and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using a gradient of 0-10% MeOH in CH2Cl2 as eluant to provide bromide 28 as a clear yellow oil (175 mg, 3.11×10−4 mol, 76%). 1H NMR (400 MHz, CDCl3) δ 2.72 (tt, J=23.9, 6.2 Hz, 1H), 3.26 (dt, J=16.3, 6.1 Hz, 2H), 4.02 (s, 2H), 4.48-4.62 (m, 8H), 5.20-5.24 (m, 4H), 5.29-5.35 (m, 4H), 5.83-5.94 (m, 4H), 7.25-7.28 (m, 2H), 7.42-7.46 (m, 2H), 8.11 (bs, 1H).
Reaction SMILES: [N:1]1([C:10]([O-])=[O:11])C2C(=CC=CC=2)CC1.CCCCCCCCCCS[C:24]1[C:29](=O)[CH2:28][C:27](C)(C)[C@@:26]([OH:41])(/C=C/C(/C)=C\C(O)=O)[C:25]=1C>>[C:10](=[O:11])([O:41][C:26]1[CH:25]=[CH:24][CH:29]=[CH:28][CH:27]=1)[NH2:1]
Reactant: O=C([O-])N1CCc2ccccc21
Reactant: CCCCCCCCCCSC1=C(C)[C@](O)(/C=C/C(C)=C\C(=O)O)C(C)(C)CC1=O
Product: NC(=O)Oc1ccccc1
Yield: 88 %

Procedure:
tert-Butyl-2-(1-(4-dimethylamino)phenyl)-1H-imidazole-2-carbonyl)indoline-1-carboxylate (white solid) represented by the following formula (as10) was obtained in the same manner as in Example 1-15, except that tert-butyl-2-(3-oxo-3-(1-(4-dimethylamino)phenyl)-1H-imidazol-2-yl)propyl)phenyl carbamate (an10) obtained in Synthesis Example 14 was used as a substrate in an amount of 21.7 mg (0.05 mmol), the compound represented by the general formula (25) wherein R5 is the functional group F was used as a quaternary ammonium salt in an amount of 6.4 mg (0.005 mmol), and the reaction time was changed to 5 hours. The yield was 88%, and the enantioselectivity determined by HPLC measurement (chiral column: “DAICEL CHIRALPAK IA”, eluant: hexane/ethanol (=10/1), flow rate: 1 mL/min, t1=16 min, t2=24 min) was 78% ee (see Table 1-5). The analysis data for the resulting compound (as10) is shown below.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][CH:11]([CH2:31]OS(C)(=O)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:38]#[N:39].[K+].O>CS(C)=O>[CH2:1]([O:8][C:9](=[O:37])[NH:10][CH:11]([CH2:31][C:38]#[N:39])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cc(CC(COS(C)(=O)=O)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(CC(CC#N)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
To a solution of 2-(4-benzyloxy-3-t-butylphenyl)-1-methanesulfonyloxymethylethylcarbamic acid benzyl ester 1.93 g, 4.23 mmol) in DMSO (11 ml), potassium cyanide (827 mg, 12.7 mmol) was added and heated at 70° C. After stirring for 4 hours, the mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:1), giving the titled compound (1.42 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N:9]([O-])=[O:10].[Na+]>>[CH3:1][C:2]1[C:3](=[O:8])[CH:4]=[CH:5][C:6](=[N:9][OH:10])[CH:7]=1
Reactant: O=N[O-]
Reactant: Cc1ccccc1O
Agent: [Na+]
Product: CC1=CC(=NO)C=CC1=O

Procedure:
2-Methyl-1,4-benzoquinone-4-oxime was prepared by reaction of 2-methylphenol with sodium nitrite under acidic conditions by the method described by T. Ishikawa et al. in J. Org. Chem. 1996, 61, page 2778.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][N:25]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[N:25][C:24]([O:23][CH3:22])=[N:29][CH:28]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cn1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-Methoxy-5-pyrimidine boronic acid. MS (M+H) 385.2
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1(C)C=CC=CC=1>[CH2:29]([O:28][C:26]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)=[O:27])[CH3:30]
Reactant: N#Cc1ccc2[nH]cc(CC3CCN(Cc4ccccc4)C3)c2c1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(Cc2c[nH]c3ccc(C#N)cc23)C1
Yield: 79 %

Procedure:
A mixture containing 41 mmol of the compound of Example 14 and 209 mmol of ethyl chloroformate in 400 ml of toluene is brought to reflux for two hours. After evaporation of the solvent, the expected product is obtained by purification of the residue by chromatography on a silica column, using a dichloromethane/methanol/aqueous ammonia (98/2/0.2) mixture as solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[CH3:36]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][C:18]3[N:19]([CH3:36])[CH:20]=[C:21]([CH2:25][C:26]4[CH:31]=[N:30][CH:29]=[N:28][CH:27]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: O=c1nc(SCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(Cc2cncnc2)c(=O)nc1SCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]thio}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (75 mg, 0.145 mmol) and DIPEA (0.08 mL, 0.458 mmol) in DCM (2 ml) was added MeI (0.014 mL, 0.217 mmol). The solution was stirred at room temperature overnight. Purification via MDAP then afforded the title compound (13 mg, 16.88% yield). LCMS: rt=3.45 min, [M+H+]=533
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[N:32]([C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)[CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). (1R,2S)-2-(3-Methyl-butylamino)-cyclopentanecarboxylic acid ethyl ester (0.068 g, 0.3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.315 mmol). Then N-methylmorpholine (0.064 g, 0.63 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 7 h. The solution was poured into a 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, (1R,2S)-2-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.3 mmol), as a light yellow oil, which was used directly for next step. LC-MS (ESI) calcd for C23H34N4O7S2 542.19, found 543.3 [M+H+].