Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:30]=3)=[O:24])[CH2:21][CH:22]=2)[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([CH:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([CH2:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:30]=3)=[O:24])[CH2:21][CH2:22]2)[CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c(C2=CCN(C(=O)c3cncc(CCc4ccccc4)c3)CC2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(F)c(C2CCN(C(=O)c3cncc(CCc4ccccc4)c3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of N-(tert-butoxycarbonyl)-4-fluoro-3-[1-(5-phenylethyl-pyridine-3-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-benzylamine in ethanol (12 ml) was treated with 10% palladium on carbon (75 mg) and the mixture was stirred at ambient temperature under an atmosphere of hydrogen for 72 hours. The reaction mixture was filtered through a short pad of hyflo and the filtrate was concentrated under vacuum to give N-(tert-butoxycarbonyl-4-fluoro-3-[1-(5-phenylethyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzylamine as colorless oil (85 mg). This material was dissolved in methanol (10 ml) and the solution was cooled to 0° C. and then saturated with hydrogen chloride gas. This mixture was stirred at ambient temperature for 4 hours and then concentrated to dryness under vacuum. The residue was triturated with a mixture of dichloromethane and diethyl ether to give 4-fluoro-3-[1-(5-phenylethyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzylamine di-hydrochloride as a white amorphous solid (50 mg). 1H NMR [(CD3)2SO, 500 MHz]: δ 8.60 (s, 1H), 8.58 (s, 1H), 7.83 (s, 1H), 7.60 (m, 1H), 7.38 (m, 1H), 7.20 (m, 6H), 4.61 (br m, 1H), 4.00 (m, 2H), 3.50 (br m, 1H), 3.20 (br m, 2H), 2.99 (m, 2H), 2.95 (m, 2H), 2.90 (br m, 1H), 1.82 (br m, 1H), 1.65 (br m, 3H). MS(EI): 418(M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[C:26]#[N:27]>>[C:26]([C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[CH2:23][O:21][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10]1)#[N:27]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2ccccc2C#N)C1

Procedure:
In an analogous manner to that described in Example 9 (a)-(c), by alkylating tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3 (b)] with 2-bromomethylbenzonitrile there was obtained tert-butyl (3RS,4RS)-3-(2-cyano-benzyloxy)-4-(4-fluoro-phenyl)-piperidine-1-carboxylate, reduction of which using borane-dimethyl sulphide complex gave tert-butyl (3RS,4RS)-3-(2-aminomethyl-benzyloxy)-4-(4-fluoro-phenyl)-piperidine-1-carboxylate. Subsequent acylation with pyridine-2-carboxylic acid in the presence of EDC yielded tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-(2-{[(pyridine-2-carbonyl)-amino]-methyl}-benzyloxy)-piperidine-1-carboxylate as a white solid.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:26])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:36]1[N:40]2[CH:41]=[C:42]([O:45][C@H:46]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C@@H:49]([NH2:56])[CH2:48][CH2:47]3)[CH:43]=[CH:44][C:39]2=[N:38][N:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:56][C@@H:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:46]([O:45][C:42]3[CH:43]=[CH:44][C:39]4[N:40]([C:36]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]5[CH3:29])=[N:37][N:38]=4)[CH:41]=3)[CH2:47][CH2:48]2)=[O:26])[N:8]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccnc(OCCO)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccnc(OCCO)c4)c4ccccc43)cn12
Temperature: 60 °C
Yield: 84.6 %

Procedure:
Intermediate 67d (74 mg, 0.16 mmol) and Intermediate B (62 mg, 0.16 mmol) were suspended in 1,4-dioxane (5 mL) and DIPEA (32 mg, 42 μL, 0.25 mmol) added and the reaction heated to 60° C. for 18 h. The reaction was cooled, concentrated in vacuo and subjected to FCC, eluting with 0-5% 2M NH3 in MeOH/DCM, to afford the title compound (92 mg, 83%). LCMS (Method 3) Rt 3.51 min, 680.4 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH3:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:9]
Reactant: Sc1ccccc1Br
Reactant: Cc1cc(Cl)ccc1I
Product: Cc1cc(Cl)ccc1Sc1ccccc1Br

Procedure:
Prepared from 4-chloro-1-iodo-2-methyl-benzene and 2-bromo-benzenethiol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1.[CH2:36]([O:43][CH2:44][CH2:45]I)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:43][CH2:44][CH2:45][O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: ICCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(CO)cc1)C2
Product: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(COCCOCc3ccccc3)cc1)C2

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (1RS,2RS,3RS,5SR)-3-(4-hydroxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate [Example 86 (eee)] with 2-(benzyloxy)-ethyl iodide [Helv.Chim.Acta Vol.71, (1988), 2039] there was obtained tert-butyl (1RS,2RS,3RS,5SR)-3-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate as a colourless oil; MS: 625 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:14][CH2:15][C@@H:16]([NH:19][C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: Fc1cc(F)cc(N[C@H]2CC[C@@H](Nc3ccnc4cc(Cl)ccc34)CC2)c1

Procedure:
A mixture of example 23A (30 mg, 0.11 mmol), 1-bromo-3,5-difluorobenzene (25 mg, 0.132 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (1.6 mg, 002 mmol) and sodium-tert-btoxide (14 mg, 0.132 mmol) was heated for 15 hours in ethyleneglycoldimethylether, concentrated and the residue was purified with high throughput HPLC system to provide the desired compound as its bis trifluoroacetic acid salt. MS (ESI(+)Q1MS m/z 388 (M+H)+); 1H NMR (300 MHz, DMSO-D6) δ ppm 8.91 (d, 1 H), 8.71 (d, 1 H), 8.55 (d, 1 H), 7.92 (d, 1 H), 7.80 (dd, 1 H), 7.01 (d, 1 H), 6.25 (m, 4 H), 3.86-4.10 (br.s, 1 H), 3.54 (br.s, 1 H), 3.54 (m, 8 H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:12]([O:19][C:20](=[O:23])[CH:21]=[CH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([O:19][C:20](=[O:23])[CH:21]=[CH:22][C:2]1[CH:3]=[N:4][C:5]([C:8](=[O:9])[NH:10][CH3:11])=[N:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNC(=O)c1ncc(Br)cn1
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CNC(=O)c1ncc(C=CC(=O)OCc2ccccc2)cn1
Temperature: 110 °C

Procedure:
To a solution of 5-bromo-N-methylpyrimidine-2-carboxamide (0.14 g, 0.64 mmol) in DMF (5 mL) was added acrylic acid benzyl ester (0.13 g, 0.78 mmol), Pd(OAc)2 (14.3 mg), tri-o-tolyl phosphine (49 mg, 0.16 mmol), tributyl amine (0.48 g, 2.59 mmol). The reaction mixture was heated in microwave oven at 110° C. for 1 h. The reaction mixture was cooled to room temperature, partitioned in water (50 mL) and ethyl acetate (50 mL). Ethyl acetate layer was separated, dried (MgSO4), concentrated to give 3-(2-methylcarbamoyl-pyrimidin 5-yl)acrylic acid benzyl ester as a solid, this was washed with hexanes and dried to give the 0.122 g of the product. LCMS (APCI) 298 (M+)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([O:23]C3CCCCO3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1.C1CCCCC=1>[OH-].[Pd+2].[OH-].C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[CH:11][CH:10]=1
Reactant: OCCCCCCOc1ccc(/C=C/c2ccc(OC3CCCCO3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: OCCCCCCOc1ccc(CCc2ccc(O)cc2)cc1
Yield: 84.1 %

Procedure:
A mixture of 3.3 g of (E)-4-(6-hydroxyhexyloxy)-4′-(tetrahydropyran-2-yloxy)stilbene (C), 0.6 g of palladium hydroxide, 34 ml of cyclohexene and 50 ml of ethanol was refluxed for 16 hours. The cooled mixture was filtered over celite and evaporated. 2.2 g of 4-{2-[4-(6-Hydroxy-hexyloxy)-phenyl]-ethyl}-phenol (L, 86%) was obtained after dissolution in 600 ml of dichloromethane, two extractions with 50 ml of water, drying over magnesium sulphate and evaporation. Apparently, deprotection of (K) had occurred under the reaction conditions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]([NH:28]O)=[NH:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH:11]([CH2:23][CH2:24][CH2:25][C:26]([NH2:28])=[NH:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCC(=N)NO)CCC2c2ccc(F)cc2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2C(CCCC(=N)N)CCC2c2ccc(F)cc2)cc1
Yield: 76.6 %

Procedure:
(2RS,5RS)-4-[5-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-butyramidine (1.1 g, 2.62 mmol) was dissolved in EtOH (50 ml) and acetic acid (5 ml) and hydrogenated on Ra—Ni at room temperature for 2 h. The catalyst was filtered off, the filtrate evaporated and the crude product crystallized from saturated NaHCO3 solution to give (2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-butyramidine (0.81 g, 76%) as a light brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17](Cl)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([N:37]3[CH2:38][CH2:39][N:34]([CH:32]=[O:33])[CH2:35][CH2:36]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CN1CCNCC1
Reactant: COc1ccccc1Oc1c(Cl)nc(Cl)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: COc1ccccc1Oc1c(Cl)nc(N2CCN(C=O)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure described in Synthesis Example 2 was repeated by use of 4-t-butyl-N-[2,6-dichloro-5-(2 -methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (5) and 1-formylpiperazine, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[N:14](C)[N:13]=[C:12]([C:16]23[CH2:23][CH2:22][C:19]([CH2:24][CH2:25][CH2:26][CH:27]([OH:29])[CH3:28])([CH2:20][CH2:21]2)[CH2:18][CH2:17]3)[N:11]=1.[CH2:30]([S-])C.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([C:16]23[CH2:23][CH2:22][C:19]([CH2:24][CH2:25][CH2:26][CH:27]([OH:29])[CH3:28])([CH2:18][CH2:17]2)[CH2:20][CH2:21]3)[N:13]([CH3:30])[N:14]=1
Reactant: COc1ccc(-c2nc(C34CCC(CCCC(C)O)(CC3)CC4)nn2C)c(Cl)c1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)CCCC12CCC(c3nc(-c4ccc(O)cc4Cl)nn3C)(CC1)CC2
Temperature: 100 °C

Procedure:
5-{4-[5-(2-Chloro-4-methoxyphenyl)-1-methyl-1-H-1,2,4-triazol-3-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-ol (5-J) (0.036 g, 0.086 mmol) was placed in a small vial with 0.5 mL of DMF. Sodium ethanethiolate (0.0218 g, 0.260 mmol) was added to the solution. The vial was sealed and heated to 100° C. for 1.5 h. The incomplete reaction required another 1.5 equivalents of sodium ethanethiolate (0.011 g). The vial was resealed and heated at 100° C. for 1 h. The product, 3-chloro-4-{5-[4-(4-hydroxypentyl)bicyclo[2.2.2]oct-1-yl]-1-methyl-1-H-1,2,4-triazol-3-yl}phenol (5-K) was purified by preparative reverse phase HPLC on a C-18 silica gel column using a gradient of acetonitrile-water buffered with 0.1% trifluoroacetic acid. The effluent containing the pure triazole was made basic with 10% NaHCO3, evaporated in vacuo to remove most of the acetonitrile, and extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated, and the residue dried under vacuum to provide the desired compound. MS (ESI+)=404.4 (M+1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[F:28][C:29]1[C:30]([CH3:36])=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:32][C:31]1[CH:33]=[CH:34][CH:35]=[C:29]([F:28])[C:30]=1[CH3:36])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: Cc1c(N)cccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1c(F)cccc1NCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
5.8 g of sodium triacetoxyborohydride (27.0 mmol) was added to a solution of 3.5 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (18.7 mmol), 2.25 g of 3-fluoro-2-methylaniline (18.0 mmol) and 1.0 ml of acetic acid (18.0 mmol) in methylene chloride (190 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 3.97 g of the title compound (yield: 74%).
Reaction SMILES: [C:1]([N:9]1[CH2:17][C@@H:16]([OH:18])[CH2:15][C@H:10]1[C:11]([O:13]C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:1]([N:9]1[CH2:17][C@@H:16]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:15][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)O)N(C(=O)c2ccccc2)C1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A solution of (cis)-1-benzoyl-4-hydroxy-L-proline, methyl ester (169.2 g, 0.679 mole) and triethylamine (104.2 ml, 0.747 mole) in dichloromethane (3.3 liters) was cooled to -10° C. under nitrogen and treated dropwise with methanesulfonyl chloride (59.85 ml, 0.74 mole). The reaction was stirred an additional 30 minutes at -5° C. to -10° C. and the volatiles were removed in vacuo. The residue was treated with ethyl acetate and washed with water, 1N HCl, saturated sodium bicarbonate solution, and brine. The organic solution was dried, filtered, and concentrated in vacuo. The residue was dissolved in THF (2.1 liters) and treated with 3.36 N LiOH solution (423 ml) and stirred at room temperature for 1 hour. The THF was removed in vacuo and the aqueous solution was acidified to pH 4. The resulting solid was filtered, washed with ice water, and recrystallized from 95% ethanol-ethyl acetate to afford 130 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].I[CH2:9][CH2:10][CH3:11].[H-].[Na+]>CN(C=O)C>[CH2:9]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH2:10][CH3:11]
Reactant: O=Cc1ncc[nH]1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1ccnc1C=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
In DMF 15 ml, 2-imidazole carboxaldehyde (500 mg) was dissolved. Then, the solution was added with 1-iodopropane (1.52 ml) and sodium hydride (208 mg), followed by stirring at room temperature for 5 days. After completion of the reaction, the solvent was distilled off and the residue was then added with chloroform, followed by washing with water and saturated saline solution. The resultant was dried with anhydrous sodium sulfate, and the solvent was distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (600 mg) as a yellow oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].Cl[CH2:17][CH2:18][S:19][S:20][CH2:21][CH2:22]Cl.[OH-].[K+]>CS(C)=O>[CH2:17]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:14]=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1)[CH2:18][S:19][S:20][CH2:21][CH2:22][N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1ccc(CN2CCNCC2)cc1
Reactant: ClCCSSCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccc(CN2CCN(CCSSCCN3CCN(Cc4ccc(C#N)cc4)CC3)CC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 4-cyanobenzylpiperazine (4.0 g), bis(2-chloroethyl) disulfide (1.9 g), potassium hydroxide (5.0 g), and dimethylsulfoxide (50 ml) is heated at 80° C. until the solution turns pink in color. The heat is then removed and the reaction mixture allowed to stir overnight at room temperature. The solution is diluted with water, and the product extracted with ether, dried, and concentrated to give 4.4 g of an oil, which is purified on a silica gel column (methylene chloride: methanol, 98:2). The resulting light brown oil is dissolved in ether and the salt precipitated with ethereal hydrochloric acid to give, after recrystallization from aqueous ethanol, 1,1'-(dithiodi-2,1-ethanediyl)bis[4-(4-cyanobenzyl)piperazine] tetrahydrochloride as a white crystalline solid, m.p. 272°-275° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:12](Cl)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:8][C:12](=[O:14])[CH3:13])[CH:7]=1
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1cc(Br)ccc1[N+](=O)[O-]
Yield: 67.1 %

Procedure:
A solution of 5-bromo-2-nitrobenzenamine (0.5 g, 2.3 mmol), acetyl chloride (0.18 ml, 2.5 mmol) and potassium carbonate (0.64 g, 4.6 mmol) was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. Crude N-(5-bromo-2-nitrophenyl)acetamide (0.40 g, 70%) was obtained after removing of the solvents. A solution of N-(5-bromo-2-nitrophenyl)acetamide (0.3 g, 1.1 mmol) and benzoyl piperazine (0.44 g, 2.3 mml) was stirred at 105° C. under argon atmosphere for 16 hours. The reaction was quenched with 500 ml water and extracted with ethyl acetate (2×10 ml). N-(5-(4-benzoylpiperazin-1-yl)-2-nitrophenyl)acetamide (0.4 g, 93%) was obtained after flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.31 (s, 3H), 3.40-3.57 (m, 8H), 6.56 (dd, J=2.8, 9.7 Hz, 1H), 7.48 (m, 5H), 8.21 (d, J=9.7 Hz, 1H), 8.38 (d, J=9.7 Hz, 1H), 11.0 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 26.4, 47.1, 47.3, 61.4, 103.8, 108.5, 127.2, 127.6, 129.0, 129.1, 130.7, 135.5, 138.3, 155.7, 170.1, 171.1
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Br:12])[CH:3]=1.[F:13][C:14]([F:35])([F:34])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([C:15]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:14]([F:35])([F:13])[F:34])=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)=[O:8])=[C:4]([Br:12])[CH:3]=1
Reactant: Nc1cc(Br)c(C(=O)O)cc1F
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cc(Br)c(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 1 h
Yield: 57.8 %

Procedure:
4-Amino-2-bromo-5-fluorobenzoic acid (2.045 mmol, 0.479 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.045 mmol, 0.7 g) and triethylamine (6.14 mmol, 0.853 mL, 0.621 g) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (3.07 mmol, 1.826 mL, 1.952 g; 50% solution in ethyl acetate) was added and the reaction stirred for 1 hour. The reaction mixture was diluted with dichloromethane and saturated sodium hydrogen carbonate solution and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (660 mg). MS (ESI) m/z 558.5 [M+H]+
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C(C)=CC=CC=1>[CH2:10]([O:9][C:1](=[S:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11]
Reactant: CCOC(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=S)c1ccccc1
Yield: 115.3 %

Procedure:
Prepare a solution of ethyl benzoate (10 g, 66.5 mmol) in xylene (100 mL). Add Lawesson's reagent (14.5 g, 36 mmol). Reflux the reaction for 5 hours, then concentrate in vacuo to an oil. Chromatograph (silica gel, 100% Hexane) to afford thiobenzoic acid O-ethyl ester (6.9 g). 1H NMR (CDCl3) δ 8.20 (d, J=8 Hz, 2H), 7.52 (t, J=7 Hz, 1H), 7.39 (t, J=7 Hz, 2H), 4.69-4.78 (m, 2H), 1.55 (t, J=7 Hz, 3H).