Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:11][C:9](=O)[CH2:8][CH2:7]1.[C:12](O)(=O)C>>[CH3:12][C:9](=[O:11])[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCC1CCC(=O)O1
Reactant: CC(=O)O
Product: CCCCC=CCCC(C)=O
Yield: 52 %

Procedure:
Using the same procedure as described under A) but starting with a solution consisting of γ-nonalactone (obtained according to the literature) (5.0 g, 32.0 mmoles) into 45 g of acetic acid and a supported catalyst obtained according to procedure a), there were obtained (after bulb to bulb distillation at 40 mbar, oven=190°) 3.6 g of the corresponding 5-decen-2-one (purity: 70%; yield: 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9](=[O:16])[CH:10]=[C:11]([CH2:14][OH:15])O[CH:13]=2)=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:21]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9](=[O:16])[CH:10]=[C:11]([CH2:14][OH:15])[NH:21][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=c1cc(CO)occ1OCc1ccc(Cl)cc1
Agent: Cl
Agent: [OH-]
Product: O=c1cc(CO)[nH]cc1OCc1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
5-(4-Chloro-benzyloxy)-2-hydroxymethyl-pyran-4-one (638, 8.00 g, 3.00 mmol) was suspended in ammonium hydroxide (200 mL) in an 80 mL sealed tube. The reaction was heated at 90° C. overnight. Upon cooling, the reaction was lowered to pH 10 with 6N HCl to provide a beige solid that was collected by filtration (639, 7.8 g, 98%).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:10])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[I-:11].[Na+].COC(C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[I:11][CH2:2][O:3][C:4](=[O:10])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCC(CC)C(=O)OCCl
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CCC(CC)C(=O)OCI

Procedure:
2-Ethyl butyric acid chloromethyl ester (700 g) was dissolved in acetone (3 L). To this solution was added sodium iodide (1.0 kg). The resulting reaction mixture was heated at reflux until reaction completion (2 h (hours), monitored by GC). The solution was then cooled to ambient temperature where tert-butyl methyl ether (7 L) and 5% aqueous sodium thiosulfate (4 L) were added. The phases were separated and the organic phase was washed with aqueous sodium thiosulfate (4 L), low pyrogen water (4 L) and 10% sodium chloride solution (4 L). The organic layer was dried over magnesium sulfate (350 g), filtered, and the filter cake was washed with tert-butyl methyl ether (2×0.7 L). The filtrate was evaporated to a small volume (ca. 2 L) to give 2-ethyl butyric acid iodomethyl ester, as a solution in tert-butyl methyl ether.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.[CH3:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH2:45]Br)=[N:37]1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:21]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[CH:3]([CH2:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]([CH3:35])[N:37]=2)[C:4](=[O:34])[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]1=2)([CH3:23])[CH3:22]
Reactant: Cn1nc(CBr)c2ccccc21
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 22.8 %

Procedure:
To a stirring solution of 330 mg (0.73 mmol) of 2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL DMF at 0° C. is added dropwise over 5 min 1.75 mL (0.87 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, then a solution of 180 mg (1.18 mmol, 1.1 equiv) of 1-methyl-3-bromomethyl-1H-indazole in 3 mL DMF is added. The resulting solution is stirred 3 h at RT and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 2/1 as eluent followed by further purification via silica gel MPLC using a Si60 column and hexane/EtOAc 1/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 100 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.74 (d, 1H, J=8.3), 7.25-6.76 (m, 16H), 4.85 (m, 1H), 4.11 (s, br, 2H), 3.97 (dd, 1H, J=5.6, 7.8), 3.77 (s, 3H), 3.70 (s, 3H), 3.63 (dd, 1H, J=7.8, 15.9), 3.48 (dd, 1H, J=5.6, 15.9), 0.92 (d, 6H, J=6.8); low resolution MS (FAB)m/e 602 (MH+), 437. Anal. (C36H35N5O4) Calcd. C, 71.86; H, 5.86; N, 11.64; Found C, 71.69; H, 5.91; N, 11.56.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C(Cl)(Cl)Cl>[C:36]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17]1)(=[O:39])[CH2:37][CH3:38]
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Reactant: CCC(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)N1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (6.5 g, 0.021 mole) and triethylamine (2.5 g, 0.025 mole) in chloroform (75 ml) was slowly dropped propionyl chloride (2.3 g. 0.025 mole) in chloroform (10 ml). After stirring at ambient temperature two hours the reaction mixture was concentrated to an oil which was dissolved in ether then washed with water, dilute HCl, again twice with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered then concentrated to a solid (7.2 g, 95%, m.p. 98°-105° C.). A sample was twice recrystallized from hexanes to yield 3-propionyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, m.p. 109°-110° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[C:11](Cl)(Cl)=[O:12].Cl.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[C:27]([C:29]3[CH:38]=[C:37]4[C:32]([CH2:33][CH2:34][NH:35][CH2:36]4)=[CH:31][CH:30]=3)[N:26]=[C:25]([NH2:39])[N:24]=2)[CH2:19][CH2:18]1>>[NH2:39][C:25]1[N:26]=[C:27]([C:29]2[CH:38]=[C:37]3[C:32]([CH2:33][CH2:34][N:35]([C:11]([NH:10][C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[O:12])[CH2:36]3)=[CH:31][CH:30]=2)[CH:28]=[C:23]([N:20]2[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]2)[N:24]=1
Reactant: Nc1nc2ccccc2s1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3nc5ccccc5s3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 1,3-benzothiazol-2-amine (Aldrich, Cat. #108812), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=501.2.
Reaction SMILES: CS(Cl)(=O)=O.O[CH:7]([C@H:14]1[CH2:18][N:17]([C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[N-:41]=[N+:42]=[N-:43].[Na+]>O.ClCCl.C(N(CC)CC)C>[N:41]([CH:7]([C@H:14]1[CH2:18][N:17]([C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](c1ccccc1)N1C[C@H](C(O)c2ccccc2)CC1=O
Agent: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C[C@H](C(N=[N+]=[N-])c2ccccc2)CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Under ice-cooling, triethylamine (0.46 ml) and methanesulfonyl chloride (217 μl, 2.80 mmol) were added to dichloromethane (10 ml) solution of 4-(R)-[1-hydroxy-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (738 mg, 2.50 mmol), and the mixture was stirred at the same temperature for 1 hour. The reaction solution was mixed with 10% citric acid (20 ml) under ice-cooling and extracted with chloroform (30 ml×2). The organic layer was washed with saturated brine (100 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the resulting residue was dissolved in N,N-dimethylformamide (10 ml), mixed with sodium azide (488 mg, 7.50 mmol) and then heated at 60° C. for 1.5 hours. After spontaneous cooling, the reaction solution was mixed with water (50 ml) and extracted with ethyl acetate (70 ml×3), and the organic layer was washed with saturated brine (150 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was applied to a silica gel column chromatography. By eluting with n-hexane:ethyl acetate (3:2), 701 mg (87%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][C@@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])=[O:9])[CH2:4]1.O[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1.C(OCC)(=O)C>[CH3:19][S:16]([C:14]1[CH:13]=[CH:12][C:11]([O:20][C@@H:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])=[C:10]([C:8]([N:5]2[CH2:6][CH2:7][CH:3]([CH2:2][O:1][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH2:4]2)=[O:9])[CH:15]=1)(=[O:17])=[O:18]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(CO)C1)C(F)(F)F
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(COc2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Temperature: 70 °C
Reaction time: 23 h

Procedure:
To a solution of 70 mg rac-(3-Hydroxymethyl-pyrrolidin-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C1) in 1.4 ml tetrahydrofuran were added 30 mg 4-hydroxybenzotrifluoride and 50 mg diphenyl-2-pyridylphosphine. 43 mg Di-tert-butyl azodicarboxylate was added. The mixture was stirred at 70° C. for 23 hours. The solvent was removed in vacuo. The oil was purified on silica gel (eluent: ethyl acetate) to yield a yellow gum. The gum was dissolved in ethyl acetate. The solution was washed 3 times with HCl 5N, once with water, dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound as a light yellow foam. MS (m/e): 540.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2C(=O)C3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[C:41]([O-:44])(=O)[CH3:42].[Na+].C(O[C:50](=O)[CH3:51])(=O)C>>[NH2:10][C:9]1[N:8]=[CH:51][C:50]([C:29]2[CH:30]=[CH:31][C:26]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:41](=[O:44])[C:42]4[CH:15]=[N:16][N:17]([C:18]5[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=5)[C:21]#[N:22])[C:11]=4[N:10]=3)=[CH:27][CH:28]=2)=[CH:27][CH:26]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(C#N)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Product: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1

Procedure:
A solution of 2-(4-bromo-phenyl)-1-(4-chloro-phenyl)-9-(3-methanesulfinyl-phenyl)-1,9-dihydro-purin-6-one (2, 2.60 g, 4.81 mmol) in acetic anhydride (22 mL), sodium acetate (1.48 g, 18.0 mmol) is added and the resulting mixture is then heated at reflux for 4 h. The reaction mixture is concentrated to a dry residue. It is taken in ethyl acetate and washed successively with 10% sodium bicarbonate solution and brine, dried over Na2SO4, concentrated, and purified by column chromatography to provide (3-(2-(4-bromophenyl)-1-(4-chlorophenyl)-6-oxo-1H-purin-9(6H)-yl)phenylthio)methyl acetate (3).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[N:5][C:4]=1SC)#[N:2].[CH3:27][NH2:28]>C(O)C>[C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[C:6]([C:17]2[CH:18]=[CH:19][C:20]([S:23][CH3:24])=[CH:21][CH:22]=2)=[N:5][C:4]=1[NH:28][CH3:27])#[N:2]
Reactant: CN
Reactant: CSc1ccc(-c2nc(SC)c(C#N)c(=O)n2-c2ccc(C)cc2)cc1
Solvent: CCO
Product: CNc1nc(-c2ccc(SC)cc2)n(-c2ccc(C)cc2)c(=O)c1C#N
Yield: 28.6 %

Procedure:
A suspension of 5-cyano-1-(4-methylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-dihydropyrimidine (2 g, 5.3 mmol) (prepared according to the procedure disclosed in example 6) in ethanol (20 ml) with methylamine (0.33 g, 10.6 mmol) was refluxed for 2 hr. Then the reaction mass poured on to ice and the resulted solid filtered, washed thoroughly with water. The resulted solid purified by column chromatography using ethyl acetate and hexane mixture as eluent to yield title compound (0.55 g, yield 25.5%, mp 268-271° C., purity 97.34% by HPLC). 1H-NMR (CDCl3):δ 2.32 (s, 3H), 2.43 (s, 3H), 2.95 (d, 3H), 5.8 (s, 1H, D2O exchangeable), 6.95-6.97 (d, 3H), 7.02-7.04 (d, 1H), 7.11-7.13 (d, 1H), 7.22-7.26 (m, 3H). IR (KBr) cm−1: 3294, 2919, 2205 (—CN), 1666 (—C═O). MS m/z: 363.1 (M+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[CH2:19]([N:21]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=3[CH2:34][C:22]1=2)[CH3:20]>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:31]2[CH:30]=[CH:29][C:28]3[C:23]4[CH2:24][CH2:25][C:26](=[O:27])[N:21]([CH2:19][CH3:20])[C:22]=4[CH2:34][C:33]=3[CH:32]=2)=[O:11])=[CH:8][C:7]=1[S:15]([NH2:16])(=[O:18])=[O:17]
Reactant: CCN1C(=O)CCC2=C1Cc1ccccc12
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCN1C(=O)CCC2=C1Cc1cc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
Under nitrogen, aluminum chloride (0.7 g, 4.9 mmol) is slurried in dichloromethane (15 mL) then 4-chloro-3-sulfamoyl-benzoyl chloride (287 mg, 1.13 mmol) is added and allowed to stir at ambient temperature for 30 minutes. Then 1-ethyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one (240 mg, 1.13 mmol) is added in 4 mL dichloromethane. The reaction is allowed to stir at ambient temperature for 1.5 hours. The reaction mixture is poured over ice-water and extracted with dichloromethane, the organic layer is separated and concentrated to give crude title compound as a brown oil. Recrystallization from warm dichloromethane afforded the title compound as a yellow powder (125 mg, 26% yield). 1H NMR (MeOD) 1.26 (t, 2H, J=7.01 Hz), 2.76-2.83 (m, 4H), 3.6 (s, 2H), 3.77 (q, 2H, J=7.01), 5.19 (s, 2H), 7.19 (d, 1H, J=8.11 Hz), 7.68-7.73 (m, 2H), 7.86 (d, 1H, J=1.09), 7.94 (dd, 1H, J=2.19, 8.11 Hz), 8.46 (d, 1H, J=1.97 Hz), MS (m/z): 431 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH:11]3[CH2:14][CH:15]([OH:20])[CH:16]([N:17]=[N+:18]=[N-:19])[CH:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[C:21](=[O:24])([O-])O.[Na+]>C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1C=CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH:11]3[CH2:14][CH:15]([O:20][CH:7]4[CH2:6][CH2:5][CH2:3][CH2:21][O:24]4)[CH:16]([N:17]=[N+:18]=[N-:19])[CH:10]3[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1OC1CC(O)C(N=[N+]=[N-])C21
Reactant: O=C([O-])O
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1OC1CC(OC3CCCCO3)C(N=[N+]=[N-])C21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1RS, 2RS, 3aSR, 8bRS)-1-azido-2-hydroxy-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-carboxylic acid methyl ester (2) (2.5 g) was dissolved in anhydrous THF (40 ml) followed-by addition of a catalytic amount of p-toluenesulfonic acid and 2,3-dihydropyrane (1.64 ml) and stirring for 16 hours at room temperature. A saturated aqueous solution of sodium hydrogencarbonate (50 ml) was added to the reaction mixture followed by extraction with ethyl acetate (150 ml, 100 ml), combining of the organic layers, washing with water (50 ml) and saturated brine (50 ml) and concentration after drying with magnesium sulfate. The resulting residue was purified with column chromatography (silica gel: ethyl acetate/cyclohexane 1/10) to obtain the target confound (3.2 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:25][C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[C:30]([C:35]#[N:36])[CH:29]=4)[C:21](OC)=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH2:25][C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[C:30]([C:35]#[N:36])[CH:29]=4)[CH2:21][OH:22])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Cc1cc2ccc(C#N)cc2[nH]1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(CO)Cc3cc4ccc(C#N)cc4[nH]3)cc2)C1
Yield: 86.4 %

Procedure:
2.7 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(6-cyano-2-indolyl)propionate was dissolved in 30 ml of tetrahydrofuran, followed by the addition of 6606 mg of sodium borohydride. 12 ml of methanol was added dropwise to the thus prepared solution while stirring under ice cooling, and the resulting mixture was stirred at room temperature for 3 hours. The resulting reaction solution was mixed with 10% citric acid aqueous solution, extracted with dichloromethane, and then dried. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a dichloromethane/methanol mixture as an elution solvent. In this way, 2.2 g of the title compound was obtained in an oily form.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3CC(C)(C)C([O-])=O)[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CC[O:34]C(C)=O.CCCCCC>C1COCC1>[C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([OH:34])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(Cc1cccc2nc(C#Cc3ccccc3)ccc12)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1cccc2nc(C#Cc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(Phenylethynyl)quinoline-5-ylpivalate (15.4 mg, 0.0468 mmol) was dissolved in THF (0.78 mL), followed by cooling down to 0° C. After LiAlH4 (0.06 mL, 0.117 mmol) was added thereto, the resulting mixture was warmed to room temperature and stirred for 1 hr. The completion of the reaction was confirmed by TLC (EtOAc/Hexane=1:1). When the reaction was completed, a saturated aqueous solution was added thereto, and the resulting mixture was extracted with diethylether, to thereby obtain an organic layer. The organic layer was dried over anhydrous MgSO4 and filtrated. The filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc/Hexane=1:1, R.f: 0.7), to thereby obtain 2-(phenylethynyl)quinoline-5-ol (5.6 mg, 49%) as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[C:10]([NH:13][C:14]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][CH:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:24][NH:25][CH3:26])[CH2:16][CH2:15]1)(=[O:12])[CH3:11].Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].CCCl>C(Cl)Cl>[ClH:33].[C:10]([NH:13][C:14]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][O:22][CH:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:24][N:25]([CH3:26])[C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:18][CH2:19]1)(=[O:12])[CH3:11]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCC(OCCN1CCC(NC(C)=O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1(c2ccccc2)CCN(CCOC(CN(C)C(=O)OCc2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C

Procedure:
0.41 ml of triethylamine is added to a solution of 0.5 g of the compound obtained in EXAMPLE 11, step B), in 10 ml of DCM, the mixture is then cooled to 0° C. and 0.14 ml of benzyl chloroformate is added dropwise. The reaction mixture is washed twice with water, dried over MgSO4 and concentrated under vacuum. The residue is chromatographed on silica gel H using DCM and then a DCM/MeOH mixture (94/6; v/v) as the eluent. The product obtained is taken up with DCM, acidified to pH 1 by the addition of hydrochloric ether and concentrated under vacuum to give 0.39 g of the expected hydrochloride after crystallization from iso ether. M.p.=135° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:15]2[CH:16]=[C:17]([C:28]([OH:30])=O)[C:18]([O:20][CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:37]C=2C=1.C(Cl)CCl.[NH4+].[OH-]>C(Cl)Cl.CN(C=O)C.Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:15]2[CH:16]=[C:17]([C:28](=[O:30])[NH2:37])[C:18]([O:20][CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NC1CCCCc2cc(OCC3CCCCC3)c(C(=O)O)cc21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCCc2cc(OCC3CCCCC3)c(C(N)=O)cc21
Reaction time: 0.5 h
Yield: 333.4 %

Procedure:
To 9-tert-butoxycarbonylamino-3-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid (1.5 g, 3.60 mmol) in CH2Cl2/DMF (4:1, 25 mL) was added HOBT (0.53 g, 4.0 mmol) and EDC (0.76 g, 4.0 mmol) and the mixture allowed to stir for 30 min. To this was added NH4OH (27% aqueous, 0.30 mL, 4.0 mmol) and stirring was continued for 3 h. The mixture was diluted with 1 M HCl and extracted with EtOAc. The combined extracts were washed with water, sat'd NaHCO3, dried over magnesium sulfate,and concentrated to a solid. The solid was recrystallized from Et2O to yield a white solid (5.0 g, 68%). MS [M−H]− 415, m.p. 193-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH:5][CH2:6][CH:7]([OH:14])[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[Br:19][C:20]1[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl>>[Br:19][C:20]1[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:21]=1[CH2:22][O:14][CH:7]([CH2:6][NH:5][C:4]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:2]([Cl:1])[CH:3]=1)[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: OC(CNc1ccc(Cl)c(Cl)c1)Cn1ccnc1
Reactant: ClCc1ccc(Br)cc1Br
Product: Clc1ccc(NCC(Cn2ccnc2)OCc2ccc(Br)cc2Br)cc1Cl

Procedure:
Reaction of 1-[3-(3,4-dichloroanilino)-2-hydroxypropyl]-imidazole with 2,4-dibromobenzyl chloride yields 1-[2-(2,4-dibromobenzyloxy)-3-(3,4-dichloroanilino)-propyl]-imidazole.