Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([C:32]([CH3:34])=[CH2:33])=[CH:20][C:10]=1[C:11]([N:13]([CH2:17][C:18]#[CH:19])[CH2:14][C:15]#[CH:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([OH:40])[CH2:36][CH2:37][C:38]#[CH:39].CCCCCCC>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:21]([C:32]([CH3:34])=[CH2:33])=[CH:20][C:10]=1[C:11]([N:13]1[CH2:17][C:18]2[C:15](=[CH:16][CH:39]=[C:38]([CH2:37][CH2:36][CH2:35][OH:40])[CH:19]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCN(CC#C)C(=O)c1cc(C(=C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C#CCCCO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(CCCO)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of 2,4-bis-benzyloxy-5-isopropenyl-N,N-di-prop-2-ynyl-benzamide (0.545 g, 1.21 mmol) in ethyl acetate (10 mL) was added 4-pentyn-1-ol (0.30 mL, 3.2 mmol) and RhCl(PPh3)3(0.161 g, 0.17 mmol). Solvent was removed under vacuum, and the mixture stirred at room temperature overnight. Additional 4-pentyn-1-ol (2.5 mL, 26 mmol) and RhCl(PPh3)3 (0.155 g, 0.17 mmol) were added and the mixture stirred for 48 hours. The mixture was loaded onto a silica gel column and eluted with 7:3 ethyl acetate:heptane to yield the desired product (0.254 g, 39% yield). LC/MS: m/z 534.25 [M+H]+
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.CCOC(C)=O.C1C=CC2N(O)N=NC=2C=1.[N:46]1([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:54][C@H:52]([OH:53])[CH2:51][C@H:47]1C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:46]1([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:54][C@H:52]([OH:53])[CH2:51][C@H:47]1[C:22]([NH:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:24]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)NOCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)NCC(=O)NOCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To Boc-Leu-Gly-NHOBzl (3.89 g; 9.89 mmol) obtained in Example 1 (C) was added under ice cooling 4.5N-HCl/AcOEt (30 ml), and the solution was brought back to room temperature. The reaction was carried out for 1 hour. The solvent was distilled off under reduced pressure and the residue was dissolved in THF (100 ml). The solution was cooled with a coolant at -20° C. After TEA (1.40 ml; 10.0 mmol) was added dropwise, HOBt (1.22 g; 9.03 mmol) and Boc-Hyp-OH (1.99 g; 8.60 mmol) were added and DCC (2.31 g; 11.2 mmol) dissolved in THF (10 ml) was added dropwise. The reaction was carried out for 1 hour at -10° C. and overnight in a refrigerator. Insolubles were filtered off and the solvent was then distilled off under reduced pressure. The residue was dissolved in AcOEt and the solution was washed successively with water, 1N-HCl, water, 10% Na2CO3 and water and then dried over anhydrous MgSO4. The solvent was distilled off under reduced pressure and the residue was recrystallized from AcOEt to give Boc-Hyp-Leu-Gly-NHOBzl (2.45 g; 56%) as colorless crystals. m.p. 168°-173° C., specific rotation [α]D28 -50.8 (c= 1.0, EtOH).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C1COCC1.Cl>[OH-].[Pd+2].[OH-].CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C=CC=Cc1cccs1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CCCCc1cccs1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76.2 %

Procedure:
A mixture of ethyl 5-(2-thienyl)-2,4-pentdienoate (20.20 g), 10% palladium hydroxide (Pd(OH)2) (2.04 g), THF (200 ml), MeOH (100 ml) and 1 N HCl (10 ml) was stirred at r.t. under nitrogen atmosphere for 3.5 hours. After removal of insoluble solids, the filtrate was evaporated in vacuo, and the residue was dissolved with a mixture of AcOEt and water. The organic layer was washed with saturated aqueous solution of NaHCO3, water and brine, and dried over MgSO4, and evaporated in vacuo to give ethyl 5-(2-thienyl)pentanoate (15.70 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[C:20]1([C:26]2[C:27]3[C:32]([C:33]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[C:34]4[C:39]=2[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35]4)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]1([C:26]2[C:39]3[C:34]([C:33]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[C:32]4[C:27]=2[CH:28]=[C:29]([C:2]2[N:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH:5]=[C:4]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:3]=2)[CH:30]=[CH:31]4)=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Brc1nc(-c2ccccc2)cc(-c2ccccc2)n1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2cc(-c3ccccc3)nc(-c3ccc4c(-c5ccccc5)c5ccccc5c(-c5ccccc5)c4c3)n2)cc1
Yield: 85.9 %

Procedure:
2-Bromo-4,6-diphenylpyrimidine 3.4 g (11 mmol), 9,10-diphenylanthracene-2-boronic acid 4.9 g (13 mmol) and tetrakis(triphenylphosphine)palladium 0.25 g (0.22 mmol) were dissolved in 60 mL of 1,2-dimethoxyethane. A 2.0M sodium carbonate aqueous solution 30 mL was added thereto, and the solution was refluxed for 8 hours under argon atmosphere by heating. After finishing the reaction, the solution was filtered, and a solid matter obtained was washed with water, methanol and toluene to obtain 5.3 g (yield: 86%) of a greenish white solid matter. Mass spectral analysis of the above solid matter resulted in confirming that m/e was 560 versus a molecular weight of 560.23 and that it was the aimed compound 2.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]([CH3:10])([CH3:9])[CH2:6][O:7][CH3:8].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[CH2:4][C:5]([CH3:10])([CH3:9])[CH2:6][O:7][CH3:8])(=[O:29])=[O:28]
Reactant: COCC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(C)(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A solution of (S)-tert-butyl 1-hydroxy-5-methoxy-4,4-dimethylpentan-2-ylcarbamate (7.8 g, 30 mmol) in methylene chloride (150 mL) and Et3N (10.4 mL, 75 mmol) was cooled to −20° C., MsCl (6.9 g, 60 mmol) was added with fast dropwise addition maintaining the internal temperature at −20° C. The reaction mixture was stirred for 1 h in rt. The reaction was quenched with water (100 mL), extracted with CH2Cl2 (3×100 mL), washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give (S)-2-(tert-butoxycarbonylamino)-5-methoxy-4,4-dimethylpentyl methanesulfonate (10.1 g, 100%) as an oil that was used in the next step without further purification.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[CH3:13][N:14]1[CH:18]=[C:17]([CH2:19][C:20]([NH2:22])=[S:21])[N:16]=[CH:15]1>>[CH3:13][N:14]1[CH:18]=[C:17]([CH2:19][C:20]2[S:21][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:22]=2)[N:16]=[CH:15]1
Reactant: Cn1cnc(CC(N)=S)c1
Reactant: O=C1c2ccccc2CC1Br
Agent: Cl
Product: Cn1cnc(Cc2nc3c(s2)Cc2ccccc2-3)c1

Procedure:
Starting compounds: 2-bromo-1-indanone, (1-methyl-4-imidazolyl)thioacetamide hydrochloride
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].[C:16]([O:20][C:21](=[O:27])[N:22]([CH2:24][CH2:25]N)[CH3:23])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>O1CCOCC1>[C:16]([O:20][C:21](=[O:27])[N:22]([CH2:24][CH2:25][N:6]1[C:5](=[O:15])[C:4]2[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:1])[CH:3]=2)[C:7]1=[O:14])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Product: CN(CCN1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O)C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 93 %

Procedure:
A mixture of 5-amino-6-nitro-isoindole-1,3-dione (2.07 g, 10 mmol), (2-Amino-ethyl)-methyl-carbamic acid tert-butyl ester (3.485 g, 20 mmol), imidazole (1.36 g, 20 mmol) in dioxane (30 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 140° C. for 38 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (500:10:1) afforded the title compound (3.39 g, 93%). 1H NMR (CDCl3) δ 1.08 (s, 9H), 2.78 (s, 3H), 3.42 (m, 2H), 3.68 (m, 2H), 7.48 (s, 1H), 8.34 (s, 1H), 8.42 (br s, 2H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To 200 g (1.00 mol) (S)-1-(4-bromophenyl)ethylamine in 800 ml DCM are slowly added 94.5 mL (1.00 mol) acetic anhydride while cooling the mixture to 20-30° C. After that the cooling is removed and the reaction mixture is stirred at r.t. over night. Afterwards the mixture is consecutivly washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and water once again. The org. layer is dried over MgSO4 and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][CH:14]1[C:19]2([CH3:23])[CH:20]([CH3:22])[CH2:21][CH:16]([CH:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18]2)[N:15]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>C1COCC1>[CH3:13][CH:14]1[C:19]2([CH3:23])[CH:20]([CH3:22])[CH2:21][CH:16]([C:17]([C:37]([O:39][CH2:40][CH3:41])=[O:38])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18]2)[N:15]1[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1CC2(C)C(C)CC1N(Cc1ccccc1)C2C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C(=O)OCC)CC2(C)C(C)CC1N(Cc1ccccc1)C2C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of diisopropylamine (13.2 mL, 94 mmol) in THF (175 mL) at -60° C. under nitrogen was added n-BuLi (36.2 mL, 94 mmol, 2.6M hexane). The mixture was stirred for 30 minutes, cooled to -78° C. and ethyl 3,4,8-trimethyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane-6-carboxylate (26.8 g, 85 mmol) in THF (225 mL) was added. The mixture was stirred for 3 hours, then ethyl chloroformate (8.96 mL, 94 mmol) in THF (20 mL) was added dropwise. The mixture was stirred for 24 hours, quenched with saturated NH4Cl, and poured into water (1000 mL). The solution was extracted with ether (3X), and the organic layers were combined and dried over MgSO4. The ether layer was treated with charcoal and the solvent was removed in vacuo to afford 32.1 g (97%) of diethyl 3,4,8-trimethyl-2-(phenylmethyl)-2-azabicyclo-[2.2.2] octane-6,6-dicarboxylate as a golden oil.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl>[OH-].[Na+]>[CH3:1][S:2]([CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(CS(C)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Cc1ccc(C(=O)O)cc1
Temperature: 0 °C
Yield: 100.8 %

Procedure:
A solution of commercially available methyl 4-(methanesulphonylmethyl)benzoate (1.00 g, 4.4 mmol) in 2M NaOH (25 mL) was heated at reflux for 30 minutes under N2. The reaction mixture was cooled to 0° C. and acidified with 2M HCl (15 mL) to a pH below 2. The white precipitate was filtered and dried to provide the title compound as a white solid (0.95 g, 97% yield): 1HNMR (DMSO-d6) δ2.97 (s, 3H), 4.61 (s, 2H), 7.49 (d, J=0.5 Hz, 2H), 7.94-7.98 (d, J=0.5 Hz, 2H), 13.00 (s, 1H): MS (ESI) [M−H]− at m/z 213.
Reaction SMILES: FC[CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1.[F:39][CH2:40][CH2:41]CN=[N+]=[N-]>>[F:39][CH2:40][CH2:41][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1
Reactant: O=C1C(=O)N(Cc2cn(CCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Reactant: [N-]=[N+]=NCCCF
Product: O=C1C(=O)N(Cc2cn(CCCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
was prepared according to the procedure for compound 11, with the exception that 3-fluoropropylazide was used in place of the 2-fluoroethylazide.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:35]CCl>C(O)C.O>[ClH:35].[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCN2c3ccccc3CCc3ccccc32)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester was dissolved in ethanol (10 ml) and a 12 N sodium hydroxide solution (1.25 ml) was added. The mixture was stirred at room temperature for 4 h. A concentrated hydrochloric acid solution was added until pH 1. Dichloromethane (300 ml) was added followed by water until the solid material was dissolved. The phases were separated and the organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo to give a residue, which was re-evaporated twice with acetone and then recrystallized from a mixture of acetone and ethyl acetate. This afforded 1.4 g (65%) of the title compound.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[S:13][C:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1.O>CN(C=O)C>[CH2:1]([S:8][C:12]1[S:13][C:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)s2)cc1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)c2ccc(SCc3ccccc3)s2)cc1
Temperature: 25 °C

Procedure:
Benzyl mercaptan (1.24 g, 0.01 mol) was added to a stirred mixture of sodium hydride (50% oil dispersion, 0.44 g, 0.11 mol) and degassed DMF (10 mL). The resulting mixture was warmed cautiously until gas evolution ceased. After cooling to 25° C., a solution of 2-bromo-5-(4-methoxybenzoyl)thiophene (2.97 g, 0.01 mol) in DMF (10 mL) was added dropwise. After complete addition, the mixture was heated on the steam bath for 2.5 hours and poured into waTER (200 mL). The aqueous mixture was extracted with ether (2×200 mL) and the extracts were washed with water, saturated NaCl solution and dried (Na2SO4). After evaporation of the solvent, the residue was collected with the aid of hexane and dried, 1.98 g, m.p. 103°-105° C.
Reaction SMILES: O.[CH2:2]([NH2:6])[CH2:3][CH2:4][CH3:5].[C:7](OCC)(=[O:10])[C:8]#[CH:9].[Na+].[Cl-]>C(O)(=O)C>[CH2:2]([NH:6][C:7](=[O:10])[C:8]#[CH:9])[CH2:3][CH2:4][CH3:5]
Reactant: C#CC(=O)OCC
Reactant: CCCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C#CC(=O)NCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 30 mL of water and 7.68 g (105 mmol) n-Butylamine is added dropwise 9.8 g (100 mmol) ethyl propiolate at 0° C. for 30 minutes. The mixture was stirred for 2 h at 0° C., then acetic acid (2 mL) was added. The mixture was stirred for another 10 minutes and saturated with NaCl, followed by extraction with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated aqueous solution of NaHCO3 (20 mL), dried over Na2SO4, and removed by rotary evaporation to give product (12.0 g, yield 95%, purity 69% by GC).
Reaction SMILES: C(S([N:7]=[C:8]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2)[C:9]1[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.Cl.CCOCC>CO>[NH2:7][CH:8]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2)[C:9]1[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1
Reactant: CCN(CC)C(=O)c1ccc(C(=NS(=O)C(C)(C)C)c2cccc3cccnc23)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccc(C(N)c2cccc3cccnc23)cc1

Procedure:
Treatment of 15 (135 mg, ˜0.30 mmol) with HCl in ether (0.3 mL, 0.6 mmol) in MeOH (2 mL) at 25° C., for 5 min. Concentration in vacuo, dilution with water, washing with EtOAc. The solution was then made basic with K2CO3(aq), extracted with and evaporated to give (+)-6 (53 mg, 53% from 14). 1H NMR (CDCl3): δ 1.2 (m, 6H), 2.2 (s, 2H), 3.4 (m, 4H), 6.40 (s, 1H), 7.30–7.58 (m, 7H), 7.71 (m, 1H), 8.15 (m, 1H), 8.92 (m, 1H).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>CN(C=O)C>[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3([C:19]#[N:20])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:16][CH:17]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(OCCCN2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
NaH (14.6 g, 0.61 mol) was suspended in DMF (100 mL). [4-(3-Pyrrolidin-1-ylpropoxy)phenyl]acetonitrile (25.5 g, 0.10 mol) was dissolved in DMF (100 mL) and added dropwise to the ice-cooled suspension of NaH. The reaction mixture was stirred at room temperature for 30 min followed by dropwise addition of 2-bromoethylether (36.2 g, 0.16 mol) in DMF (200 mL) in ice-cold condition. The reaction mixture was poured into ice-cold water. The solid was filtered, washed with water, dried and the resulting solid was washed with 5% EtOAc in hexane to give the title compound (22 g, 67%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][O:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.[H-].[Na+].[CH2:23]([C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:40]I)[CH3:24].O>CC(OC)(C)C>[CH2:23]([C:25]1[O:29][C:28]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)=[N:27][C:26]=1[CH2:40][O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][O:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1)[CH3:24]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1CI
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@@H]1CCC[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COC[C@@H]1CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C1

Procedure:
300 mg of tert-butyl 2-((1R,3S)-3-hydroxymethylcyclohexylmethoxy)-2-methylpropionate are dissolved in 10 ml of MTBE, and 50 mg of sodium hydride (60% in mineral oil) are added. After gas evolution ceases, 600 mg of 5-ethyl-4-iodomethyl-2-(4-trifluoromethylphenyl)oxazole are added, and the suspension is heated under reflux overnight. After addition of water and MTBE, the phases are separated, and the organic phase is washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. The residue is purified by preparative HPLC, resulting in 190 mg of tert-butyl 2-{(1S,3R)-3-[5-ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxymethyl]-cyclohexylmethoxy}-2-methylpropionate as yellow oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([CH2:22][CH2:23]C)[N:18]=1)(C)(C)C>C(Cl)Cl>[CH2:22]([C:19]1[N:18]=[C:17]([CH2:16][CH2:15][NH2:14])[O:21][N:20]=1)[CH3:23]
Reactant: CCCc1noc(CCNC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1noc(CCN)n1

Procedure:
TFA (0.5 ml) is added to a stirred solution of [2-(3-propyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (0.093 g, 0.39 mmol) in DCM (1 ml). After 1 hour the solvents are removed to afford the titled compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Clc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 49.4 %

Procedure:
The title compound (74 mg) was prepared as in Example 177, Steps C and D, using 215 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 296 mg of 4-chlorophenylboronic acid. MS (ESI): exact mass calculated for C18H22ClN3, 315.15. found, m/z 316.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.59-7.53 (m, 2H), 7.36-7.30 (m, 2H), 4.48 (m, 1H), 3.44-3.37 (m, 2H), 3.34-3.27 (m, 2H), 3.22-3.15 (m, 2H), 2.81-2.74 (m, 2H), 2.06-1.84 (m, 6H), 1.65-155 (m, 2H).