Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[N:33][C:32]([CH:35]=[C:36]([CH3:38])[CH3:37])=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:34]=[N:33][C:32]([CH:35]=[C:36]([CH3:38])[CH3:37])=[CH:31][N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: CC(C)=Cc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)=Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 930 mg, 2.82 mmol) in methylene chloride (10 mL) was treated with oxalyl chloride (490 μL, 5.64 mmol) and N,N-dimethylformamide (1 drop). The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo, and the residue was dried in vacuo. The residue was then dissolved in benzene, and the solvents were concentrated in vacuo. The residue was dried in vacuo. This material was dissolved in methylene chloride (10 mL), cooled to 0° C., and then treated with a mixture of 2-amino-5-(2,2-dimethylvinyl)-pyrazine (420 mg, 2.82 mmol) and pyridine (340 μL) in methylene chloride (10 mL). The ice bath was removed, and the solution was stirred at 25° C. overnight. The mixture was extracted with methylene chloride and a 0.1N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) afforded the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methylpropenyl)-pyrazin-2-yl]-propionamide (1.10 g, 85%) as a light yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:57][C:58](=[O:71])[C@H:59]([CH2:64][CH2:65][CH2:66][NH:67][C:68](=[NH:70])[NH2:69])[NH:60][N+]([O-])=O)C1C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([NH:60][C@H:59]([C:58]([OH:71])=[O:57])[CH2:64][CH2:65][CH2:66][NH:67][C:68](=[NH:69])[NH2:70])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: N=C(N)NCCC[C@H](N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC1=C(OC)C(=O)C(CCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 18 %

Procedure:
To a solution of p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinone-6-yl)propionate (187 mg, 0.5 mmol) and N-nitro-L-arginine benzyl ester di-p-toluenesulfonate (327 mg, 0.5 mmol) in N,N-dimethylformamide (5 ml) was added triethylamine (0.25 ml, 1.7 mmol). The mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solvent was distilled off and the residue was chromatographed on a column of silica gel (5 g) using methanol-chloroform (1:19, v/v) as eluent. The eluate was evaporated and the residue was dissolved in acetic acid (2 ml). With palladium black catalyst (30 mg), the solution was hydrogenated at room temperature for 10 hours. After completion of the reaction, the catalyst was removed and the solvent was distilled off. Methanol (5 ml) was added to the residue and the resulting solution was ice-cooled. A solution of ferric chloride (324 mg, 2 mmol) in water (1 ml) was added and the mixture was stirred for 15 minutes. The resulting mixture was passed through a column of Amberlite XAD-2 (3 g) with water to remove the inorganic matter. Elution with methanol gave a crude compound, which was then concentrated. The residue was chromatographed on a Sephadex LR20 column (1.5×45 cm) [eluent: ethanol-0.1M acetic acid (3:2, v/v)]. The eluate was distilled off to give 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionyl-L-arginine (37 mg).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:7]([O:9][CH2:10]C)=[O:8].C[O-].[Na+].[Br:25]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:25])[C:3](=[O:2])[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]=1[CH3:13])=[O:8]
Reactant: CCOC(=O)C(C=CC(=O)OC)=C(C)Nc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1C
Temperature: 25 °C
Yield: 38.4 %

Procedure:
MeOH (200 mL) was added to a flask containing 4-(1-phenylamino-ethylidene)-pent-2-enedioic acid 5-ethyl ester 1-methyl ester (5.88 g, 20.3 mmol). NaOMe solution (4.7 mL, 20.3 mmol, 4.375 M in MeOH) and N-bromosuccinimide (4.35 g, 24.4 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between saturated NH4Cl and CH2Cl2. The aqueous layer was extracted with additional CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was chromatographed (0-45% EtOAc/hexanes) to give 2.51 g of the title compound (containing about 14% of the corresponding ethyl ester) as a yellow solid. MS: (+) m/z 343.93, 346.07 (M+Na, 79/81Br).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=O)[CH3:3].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:34][CH2:35][C@@H:36]([OH:53])[C@@H:37]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCN(C(C)C)C(C)C>ClCCl>[OH:53][C@H:36]([CH2:35][NH:34][C:9](=[O:11])[C:8]1[CH:12]=[C:4]([C:2]([CH3:3])=[CH2:1])[CH:5]=[N:6][CH:7]=1)[C@@H:37]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:49])[CH3:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C=C(C)c1cncc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)c1cncc(C(=O)NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.5 %

Procedure:
To 5-(prop-1-en-2-yl)nicotinic acid (200 mg, 1.23 mmol) in dichlormethane (10 ml) at rt, EDCI (330 mg, 1.72 mmol) and HOBT (200 mg, 1.48 mmol) were added. After stirring at rt for 10 minutes, tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (344 mg, 1.23 mmol) was added followed by DIPEA (0.2 ml). After stirring overnight at rt, reaction mixture was worked up as usual and residue was column purified (90% ethylacetate/10% hexanes) to yield 280 mg of tert-butyl (2S,3R)-3-hydroxy-1-phenyl-4-(5-(prop-1-en-2-yl)nicotinamido)butan-2-ylcarbamate, which on stirring with 4N HCl in dioxane for 4 h yields the HCl salt of N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-5-(prop-1-en-2-yl)nicotinamide.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[N:9]#[C:10]Cl>O1CCCC1>[NH2:9][C:10]1[NH:1][C:2]([C:7]#[N:8])=[C:3]([C:4]#[N:5])[N:6]=1
Reactant: N#CCl
Reactant: N#C/C(N)=C(/N)C#N
Solvent: C1CCOC1
Product: N#Cc1nc(N)[nH]c1C#N
Temperature: 25 °C

Procedure:
Diaminomaleonitrile (26.2 g) was added in portions to a solution containing cyanogen chloride (14.9 g) in tetrahydrofuran (200 ml). The mixture was then warmed to room temperature and finally heated under reflux for 1 hour. The resulting brown solid was collected by filtration and washed with a solution of sodium acetate. The remaining solid was dissolved in a sodium bicarbonate solution and treated with charcoal, filtered and acidified to give 2-amino-4,5-dicyanoimidazole, m.p. 276°-278°.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl.O=S(Cl)[Cl:13]>O1CCOCC1>[ClH:13].[Cl:1][CH2:3][C:4]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NC1(CO)CCCC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Product: NC1(CCl)CCCC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
To a solution of 1-hydroxymethylcyclopentanamine HCl salt (Method B1c; 20 g, 0.17 mol) in anh. p-dioxane (65 mL) was added HCl (4M in p-dioxane; 65 mL, 0.26 mol). The resulting solution was stirred for 20 min. at room temp., then SOCl2 (22.7 g, 0.19 mol) was added dropwise. The reaction mixture was heated at 80° C. for 2 d, cooled to room temp., and concentrated under reduced pressure to give 1-chloromethylcyclopentanamine HCl salt (29 g, 100%): CI-MS m/z 171 ((M+H)+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:24]([C:23]3[CH:26]=[CH:27][C:20]([O:19][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:21][CH:22]=3)[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CCCCCCOc1ccc(C=O)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCOc1ccc(-c2nc3ccc(C(=O)OC)cc3[nH]2)cc1
Temperature: 145 °C
Reaction time: 48 h
Yield: 30.5 %

Procedure:
A mixture of Methyl 3,4-diaminobenzoate (1.84 g) and 4-hexyloxy benzaldehyde (2.30 g) in nitrobenzene (40 ml) was stirred for 48 hours at 145° C. After cooling, the mixture was evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel eluted with (n-hexane:ethyl acetate=2:1) gave 5-Methoxycarbonyl-2-(4-hexyloxyphenyl)benzimidazole (1.19 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[NH:6][C:7]2=[O:12].C(=O)(O)[O-].[Na+].Br[CH2:25][CH2:26][OH:27]>C(#N)C>[OH:27][CH2:26][CH2:25][N:16]1[CH2:17][CH2:18][CH:13]([C:5]2[NH:6][C:7](=[O:12])[C:8]3[C:3]([CH:4]=2)=[C:2]([CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH2:14][CH2:15]1
Reactant: OCCBr
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNCC3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCO)CC3)cc12
Yield: 33.8 %

Procedure:
5-Methyl-3-(piperidin-4-yl)-2H-isoquinolin-1-one (1.0 g), sodium bicarbonate (0.52 g) and 2-bromoethanol (0.67 g) were dissolved in acetonitrile (20 mL) and the solution was heated under reflux. After the completion of the reaction, the reaction mixture was concentrated and water was added to the obtained residue. The mixture was extracted with chloroform, and the extract was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography to give 3-[1-(2-hydroxyethyl)piperidin-4-yl]-5-methyl-2H-isoquinolin-1-one (0.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]4[C:18](=O)[C:17](=[O:20])[C:16]=4[O:21]CC)[CH2:11]3)[CH2:9][N:8]([C:24]([NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)=[O:25])[C:5]2=[CH:6][CH:7]=1.[CH3:33][NH2:34].O1CCCC1.N.CO>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]4[C:16](=[O:21])[C:17](=[O:20])[C:18]=4[NH:34][CH3:33])[CH2:11]3)[CH2:9][N:8]([C:24]([NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)=[O:25])[C:5]2=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOc1c(N2CCC3(C2)CN(C(=O)Nc2ncc(Cl)s2)c2ccc(Cl)cc23)c(=O)c1=O
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CNc1c(N2CCC3(C2)CN(C(=O)Nc2ncc(Cl)s2)c2ccc(Cl)cc23)c(=O)c1=O

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 45, with the exceptions that the 5-chloro-N-(5-chlorothiazol-2-yl)-1′-(2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide obtained in Example 450 was used instead of ethyl 2-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)-2-oxoacetate, and that a solution of methylamine-tetrahydrofuran was used instead of a saturated solution of ammonia-methanol.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:38])[CH2:9][N:10]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])[C:12]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[O:34][CH:35]([F:37])[F:36])=[N:11]2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].O>CN(C=O)C.C(OCC)(=O)C>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([O:34][CH:35]([F:36])[F:37])=[C:27]([C:12]2[C:13]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])=[CH:14][N:10]([CH2:9][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:3][CH2:4]3)=[O:38])[N:11]=2)[CH:32]=1
Reactant: NC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (126 mg, 0.24 mmol) in DMF (3 mL) was added potassium carbonate (76 mg, 0.55 mmol), ethyl 2-bromoacetate (0.03 mL, 0.27 mmol). The resulting mixture was stirred at 25° C. for 1 h and diluted with 100 mL of ethyl acetate. Water (50 mL) was added. Phases were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column: Xbridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 20% B to 85% B in 10 min; 254 nm. This resulted in 29.3 mg (98%) of ethyl 2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]acetate as a white solid. LCMS (Method 25) [M+H]+=631.2, RT=1.89 min. 1H NMR (400 MHz, CD3OD-d4) δ: (ppm) 8.98 (d, 1H, J=6.8 Hz), 8.53-8.52 (m, 2H), 8.25 (s, 1H), 7.58 (d, 1H, J=2.4 Hz), 7.44 (dd, 1H, J=2.4, 8.8 Hz), 7.29 (d, 1H, J=8.8 Hz), 7.09 (dd, 1H, J=4.4, 6.8 Hz), 6.51 (t, 1H, J=73.6 Hz), 5.20-5.13 (m, 2H), 4.32 (d, 1H, J=13.2 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.91 (d, 1H, J=13.2 Hz), 3.36 (s, 2H), 3.21-3.09 (m, 1H), 2.78-2.68 (m, 2H), 1.94-1.83 (m, 2H), 1.34-1.22 (m, 2H), 1.16 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415 mmol), 1-naphthalenesulfonyl chloride (15 mg, 0.072 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT. The two enantiomers were separated by Chiral chromatography (Chiracel OD).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[N:5]=[CH:6][CH:7]=1.[F:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:13][C:12]=1[C:24]([F:27])([F:26])[F:25].Cl.FC(F)(F)C1C=CC=C[C:32]=1[O:33]C1CCNCC1>>[CH3:8][N:4]1[C:3](=[O:9])[C:2]([NH:1][C:32]([N:19]2[CH2:20][CH2:21][CH:16]([O:15][C:14]3[CH:13]=[C:12]([C:24]([F:27])([F:25])[F:26])[C:11]([F:10])=[CH:23][CH:22]=3)[CH2:17][CH2:18]2)=[O:33])=[CH:7][CH:6]=[N:5]1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Fc1ccc(OC2CCNCC2)cc1C(F)(F)F
Reactant: Cn1nccc(N)c1=O
Agent: Cl
Product: Cn1nccc(NC(=O)N2CCC(Oc3ccc(F)c(C(F)(F)F)c3)CC2)c1=O
Yield: 51 %

Procedure:
Compound 60 is prepared from intermediate 4c and from 4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 51%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH3:36])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH3:36])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 68.7 %

Procedure:
A 200 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (1.36 g, 5.20 mmol), potassium carbonate (2.16 g, 15.6 mmol), 2-chloro-4-ethylbenzothiazole (1.23 g, 6.20 mmol) and 14 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (750 mL) and washed with brine (6×250 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 1.51 g (69%) of the title compound as an amorphous foam. FDMS: m/e=422. α[D]589 =62.74 (c=0.67, chloroform).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([NH2:12])=[O:11].S(Cl)(Cl)=O.[CH3:17][C@H:18]1[CH2:23][N:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[CH2:21][C@@H:20]([CH3:35])[N:19]1[S:36](C1C=CC=C2C=1CC(C(O)=O)C2)(=[O:38])=[O:37]>C1COCC1>[CH3:35][C@H:20]1[CH2:21][N:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=2)[CH2:23][C@@H:18]([CH3:17])[N:19]1[S:36]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH2:3][CH:2]([C:10]([NH2:12])=[O:11])[CH2:1]2)(=[O:37])=[O:38]
Reactant: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2
Reactant: NC(=O)C1Cc2ccccc2C1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C(N)=O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
4-|cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl|-indan-2-carboxylic acid amide. Thionyl chloride (42 μL, 0.577 mmol) was added to 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxyphenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid (250 mg, 0.502 mmol) in THF (4 mL) at 50 C for 1 h and then concentrated. The crude mixture was then dissolved in THF (4 mL) and ammonium hydroxide (300 μL) was added. The cloudy brown solution was stirred for an additional 3 h at room temperature. The solution was then concentrated and purified by silica gel column chromatography (0-20% MeOH in dichloromethane) to afford 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid amide (190 mg, 76%). 1H NMR (400 MHz, CD3OD) δ ppm. 7.71 (d, 1H), 7.47 (d, 1H), 7.34 (t, 1H), 7.10 (d, 2H), 6.94-6.91 (m, 2H), 4.20-4.14 (m, 1H), 4.05-3.90 (m, 1H), 3.54 (d, 2H), 3.41-3.21 (m, 5H), 2.77 (dd, 1H), 2.68 (dd, 1H), 1.51 (d, 3H), 1.49 (d, 3H). LCMS: 498.7 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(CCCCCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: BrCCCCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
To a stirred solution of 9.1 (0.9 g, 3.32 mmol) in anhydrous acetone (40 mL), was added anhydrous K2CO3 (1.38 g, 10 mmol) and benzyl bromide (0.624 g, 3.65 mmol) and the mixture was refluxed for 6 h. The reaction mixture was cooled to room temperature, diluted with acetone and solid materials were filtered off. The filtrate was evaporated under reduced pressure and the residue obtained was dissolved in diethyl ether (50 mL). The ethereal solution was washed with water and brine, dried (MgSO4) and evaporated. Purification by flash column chromatography on silica gel (5% Et2O-hexane) afforded 10.1 (0.938 g, 78% yield) as a white solid (m p 32-34° C.).
Reaction SMILES: C([O:3][P:4]([C:9]([P:30](=[O:37])([O:34]CC)[O:31]CC)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:12]=1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl.[2H]C([2H])(Cl)Cl.O1CCCC1.O>[C:17]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([P:30](=[O:31])([OH:34])[OH:37])[P:4](=[O:3])([OH:5])[OH:8])[CH:16]=[CH:15][CH:14]=1)#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCC#Cc1cccc(C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC)c1
Agent: C[Si](C)(C)Br
Agent: [2H]C([2H])(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCCC#Cc1cccc(C=C(P(=O)(O)O)P(=O)(O)O)c1
Reaction time: 6.5 h
Yield: 16 %

Procedure:
Tetraethyl[2-[3-(1-tridecynyl)phenyl]ethenylidene]bisphosphonate (3.247 g, 5.85 mmol) prepared according to Example 1 was dissolved in a mixture of CH2Cl2 -CD2Cl2 (25 ml, 4:1), and stirred under argon while trimethylsilyl bromide (3.5 ml, 26.5 mmol) was added. After the reaction was stirred for 6.5 hours, the solvent was removed under reduced pressure and the residue was briefly placed on the vacuum line. Hydrolysis was effected in tetrahydrofuran-water (9:1, 10 ml), stirring for 39 hours at room temperature. After stripping off the solvent, the residue was recrystallized from heptane-ether to give the product as a white solid, 0.416 g, 0.94 mmol, 16% yield; 1H NMR (CD3OD) ∂ 0.89 (t, J=6.9 Hz, 3H), 1.21 to 1.65 (several m, 18H), 2.40 (t, J=7.0 Hz, 2H), 7.55 (m, 2H), 7.71 (m, 2H), 8.03 (dd, J=46.1, 29.2 Hz, 1H); HRMS calcd for (M+H)+C21H33O6P2 m/z 443.1752, found 443.1700.