Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:26][C:25]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:24]=1[F:23]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2Cl)n1Cc1ccc(F)cc1F
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A mixture of (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 43; 150 mg, 0.47 mmol), tetrabutylammonium iodide (174 mg, 0.47 mmol) and 2,4-difluorobenzyl bromide (240 μL, 1.9 mmol) in dimethylformamide (3 mL) was heated at 80° C. overnight. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated, purified by chromatography, eluting with 50-60% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-1-(2,4-difluoro-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (123 mg, 59%) as a light brown solid. APCI(+)-MS (M+H) 447.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[CH2:28])[CH:22]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]1([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[CH3:28])[CH:22]=3)[C:9]=2[OH:8])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=C(c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccccc2)c1)c1ccccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1C(C)c1cccc(-c2cccc(-c3ccccc3)c2O)c1
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A solution of 34 (1.1 g, 2.35 mmol) in methanol (15 mL) and ethyl acetate (30 mL) was treated with 20% palladium on activated carbon (50% wet, 0.05 g) and was hydrogenated at 40 psi in a Parr shaker for 3 hr. The catalyst was filtered out and washed with ethyl acetate. The filtrate was stripped and the crude product was purified by chromatography on silica (50 g) 2% ethyl acetate in hexane (3 L) to afford pure E1 (0.85 g, 95%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13](OC)=[O:14])=[CH:4][C:3]1=[O:17].[BH4-].[Na+].CO.Cl>O1CCCC1>[OH:14][CH2:13][CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]([CH3:1])[C:3](=[O:17])[CH:4]=1
Reactant: COC(=O)Cc1cc(=O)n(C)c2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)cc(CCO)c2ccccc21
Yield: 87.2 %

Procedure:
Methyl 1,2-dihydro-l-methyl-2-oxo-4-quinoline acetate (2.35 g, 10.16 mmol) was dissolved in dry tetrahydrofuran (50 ml) and sodium borohydride (1.92 g, 50.8 mmol) was added thereto. The mixture was refluxed. Under the same conditions, methanol (19 ml) was slowly added dropwise thereto (over 1 hour) and the mixture was refluxed for 1 hour. To the reaction mixture was acidified (pH about 2) with 2N-hydrochloric acid. The solvent was distilled off and water (300 ml) was poured to the residue. The mixture was extracted with chloroform (300 ml×3). The organic layer was separated, dried (over magnesium sulfate) and the solvent was distilled off. The residue was crystallized with ether to give the entitled compound (1.80 g) as white crystals (yield 87.2%, mp 149°-150 ° C. (chloroform--hexane)).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=3)[CH2:12][O:11]2)=[CH:6][CH:5]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl.[BrH:28]>CS(C)=O.O.C(OCC)(=O)C.CC(C)=O>[CH3:21][N:22]([CH2:23][CH2:24][CH2:25][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[O:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[CH:17][C:18]1=2)[CH3:27].[BrH:28]
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Reactant: CN(C)CCCCl
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
To a mixture 5.42 g sodium hydride in 120 ml of dimethylsulfoxide, previously heated at 60° C. for 30 minutes, under nitrogen flow, a solution of 30 g of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile obtained in Example 2 in 75 ml of dimethylsulfoxide is added, without exceeding 25° C. The solution is maintained under stirring for 30 minutes and, in 10 minutes, 33 g of 3-(dimethylamino)propylchloride are added without exceeding 25° C. After about 2-hour stirring at 25° C., the mixture is cooled at 10° C. and 300 ml of water are added dropwise and then 120 ml of ethyl acetate. The mixture is stirred and diluted with 1650 ml of water and 120 ml of ethyl acetate. The mixture is let 1 hour under stirring, then the phases are separated; the organic one is collected and the aqueous one is washed with 3×150 ml of ethyl acetate. After separation of the phases, the aqueous one is discarded and the collected organic ones are washed with 900 ml of water. The organic phase is dehydrated with anhydrous Na2SO4 and is concentrated under vacuum at 50° C. until an oil is obtained, which is treated with 60 ml of acetone. The mixture is stirred in order to obtain a solution, that is cooled at 10° C. and treated with about 10 ml of 48% HBr in order to adjust the pH value from 9.8-9.5 to 7.0. After 1 hour-stirring at pH=7 constant, the solvent is evaporated under vacuum at 50° C. and the residue is treated with 100 ml of acetone. The suspension is stirred at 25° C. for 30 minutes, then it is cooled at 0-5° C. and it is let at cold for 15 hours. The product is filtered, washed with cold acetone (0-5° C.) and is dried under vacuum at 50° C. Thus 34.88 g of citalopram hydrobromide with a purity (HPLC)=99.15% are obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]([CH2:11][NH:12][C:13]([C:15]([O:17][Li])=O)=[O:14])[CH2:8][C:7]=2[CH:19]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:51][CH2:52][CH2:53][O:54][CH:55]1[CH2:60][CH2:59][CH:58]([NH:61][C:62]2[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[C:64]([C:71]([F:74])([F:73])[F:72])[CH:63]=2)[CH2:57][CH2:56]1>CN(C)C=O.O>[N+:68]([C:65]1[CH:66]=[CH:67][C:62]([NH:61][CH:58]2[CH2:57][CH2:56][CH:55]([O:54][CH2:53][CH2:52][NH:51][C:15](=[O:17])[C:13]([NH:12][CH2:11][CH:9]3[CH2:8][C:7]4[CH:19]=[C:3]([C:2]([F:1])([F:21])[F:20])[CH:4]=[CH:5][C:6]=4[O:10]3)=[O:14])[CH2:60][CH2:59]2)=[CH:63][C:64]=1[C:71]([F:72])([F:73])[F:74])([O-:70])=[O:69]
Reactant: [Li]OC(=O)C(=O)NCC1Cc2cc(C(F)(F)F)ccc2O1
Reactant: NCCOC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCOC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)C(=O)NCC1Cc2cc(C(F)(F)F)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
The mixture of lithio ([[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]carbamoyl)formate (170 mg, 0.58 mmol), EDAC.HCl (166 mg, 0.87 mmol), HOBt (58.3 mg, 0.43 mmol) and triethylamine (87.3 mg, 0.86 mmol) in N,N-dimethylformamide (10 ml) was stirred for 1 hour before the addition of N-[4-(2-aminoethoxy)cyclohexyl]-4-nitro-3-(trifluoromethyl)aniline (100 mg, 0.29 mmol). The resulting solution was stirred overnight at room temperature, diluted with water (100 ml), and extracted with dichloromethane (3×50 ml). The organic fractions were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by HPLC to afford N1-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]-N2-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]ethanediamide as a yellow solid (52 mg, 29%). (ES, m/z): [M+H]+ 619.10; 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=9.3 Hz, 1H), 7.80 (br s, 1H), 7.72 (br s, 1H), 7.41 (m, 2H), 6.84 (m, 2H), 6.63 (dd, J=9.0, 2.4 Hz, 1H), 5.00 (m, 1H), 3.78 (m, 1H), 3.60-3.55 (m, 3H), 3.53-3.50 (m, 2H), 3.35 (br m, 3H), 2.98 (dd, J=16.2, 7.2 Hz, 1H), 2.12 (m, 4H), 1.46-1.34 (m, 2H), 1.29-1.22 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(O[CH:22]1[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:33]([O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:23]1[O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)C.Cl[Sn](Cl)(Cl)Cl.ClCCl>C[Si](C)(C)N[Si](C)(C)C.N1C=CC=CC=1.ClCCCl>[NH2:1][C:2]1[C:3]2[N:10]([C@@H:22]3[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:54])[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C@@H:33]([O:34][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C@H:23]3[O:24][C:25](=[O:32])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Nc1ncnc2pc[nH]c12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1ncnc2pcn([C@@H]3O[C@H](COC(=O)c4ccccc4)[C@@H](OC(=O)c4ccccc4)[C@H]3OC(=O)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.3 %

Procedure:
A mixture of 7-amino-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 10, 0.3 g, 1.97 mmol) in 1,1,1,3,3,3-hexamethyldisilazane (HMDS, 5 mL), pyridine (5 mL) and ammonium sulfate (50 mg) was heated under reflux for 18 h. The reaction mixture was allowed to cool to room temperature and the excess of HMDS and pyridine were evaporated in vacuo. The silyl derivative of compound 10 was dried under high vacuum for 3 h. The dried material was dissolved in 1,2-dichloroethane (30 mL) to which 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (1.28 g, 2.4 mmol) was added. The mixture was cooled in an ice bath. A solution of SnCl4 in dichloromethane (1 M, 2.8 mL, 2.8 mmol) was added keeping the flask under an argon atmosphere. After stirring the mixture in the ice bath for 4 h, the ice bath was removed and the reaction was continued at ambient temperature for 18 h. Methanol (10 mL) was added and after 10 min it was diluted with dichloromethane (100 mLL). The organic layer was washed with saturated sodium hydrogen carbonate solution (50 mL) and the resultant emulsion was filtered through a Celite pad. Organic layer was separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layer was dried (Na2SO4) and evaporated. The solid thus obtained was crystallized from a mixture of ethyl acetate and methanol to give 0.65 g (56%) of the title compound, mp 248-250° C. (dec). 1H nmr (DMSO-d6): δ 4.85(m,2 t C5H2), 4.96 (m, 1 H, C4'H), 6.01 (m, 1 H, C3'H), 6.19 (m, 1 H, C2'H), 6.51 (d, 1 H, C1'H), 7.44-8.05 (m, 15 H, 3Bz), 8.44 and 8.47 (2s, 2 H, NH2), 8.75 (d, 1 H, C5H), and 8.95 (d, 1 H, J =57 Hz, C2H). Anal. Calcd. for C31H25N4O7P.0.5 H2O: C, 61.49; H, 4.33; N, 9.25. Found: C, 61.61; H, 3.88; N, 9.21.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[OH:23][CH:24]([C:26]1[N:27]=[C:28]([CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[S:29][CH:30]=1)[CH3:25]>ClCCl>[C:24]([C:26]1[N:27]=[C:28]([CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[S:29][CH:30]=1)(=[O:23])[CH3:25]
Reactant: CC(O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (15% solution in dichloromethane, 28 g) are added dropwise to a solution of tert-butyl 4-[4-(1-hydroxyethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (VIII-1, 2.06 g) in dichloromethane (40 ml). The reaction mixture is stirred at room temperature overnight, 5 g of silica gel are then added and the solvent is removed under reduced pressure. The residue is purified chromatographically. This gives tert-butyl 4-(4-acetyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.65 g).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16](=[N:18][OH:19])[NH2:17])=[C:5]2[C@@H:4]2[CH2:20][CH2:21][N:3]12.[Cl:22][CH2:23][C:24](OC(=O)CCl)=O>CN(C)C=O>[Cl:22][CH2:23][C:24]1[O:19][N:18]=[C:16]([C:15]2[N:14]=[CH:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2](=[O:1])[N:3]4[CH2:21][CH2:20][C@H:4]4[C:5]=23)[N:17]=1
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Yield: 57.6 %

Procedure:
34.5 g (122 mmol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were stirred with 23 g (140 mmol) of chloroacetic anhydride in 200 ml of N,N-dimethylformamide at room temperature overnight and at 110° for 2 hours. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel while eluting with methylene chloride/methanol 19/1. There were obtained 24 g (58%) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one of m.p. 205°-207°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:26][CH2:27][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:29][CH2:30]3)=[O:24])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(Nc3ccc4[nH]ccc4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc4[nH]ccc4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 35 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(5-indolylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.092 g, 0.84 mmol), the title compound (0.020 g, 35%) was obtained. ESI-MS m/z: 572 (M+H)+; 1H-NMR (CDCl3, δ): 1.15-1.82 (m, 4H), 1.46 (t, J=7.3 Hz, 3H), 2.40-2.59 (m, 2H), 2.60-4.15 (m, 3H), 3.62 (q, J=7.3 Hz, 2H), 6.61 (s, 1H), 7.00-7.37 (m, 7H), 7.47 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 8.33 (s, 1H), 8.37 (s, 1H), 8.63 (s, 1H), 8.64 (s, 1H), 10.58 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.Cl.C([BH3-])#N.[Na+]>CO>[OH:1][CH:2]1[CH2:6][CH2:5][S:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C(=O)O)c1ccc(CC2SCCC2=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1ccc(CC2SCCC2O)cc1
Reaction time: 8 h

Procedure:
2-[4-(3-Oxothiolan-2-ylmethyl)phenyl]propionic acid (100 mg) obtained in Example 26 was dissolved in methanol (3.0 ml), and to the solution was added concentrated hydrochloric acid (0.3 ml), and then sodium cyanoborohydride (50 mg) was added. The mixture was stirred overnight, then concentrated under reduced pressure, and extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was dissolved in methanol (3.0 ml), and to the solution was added aqueous lithium hydroxide monohydrate (16 mg, 2.0 ml). The mixture was stirred for 30 minutes, then concentrated under reduced pressure, then the residue was acidified with diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over magnesium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give isomers of the title compound, compounds of Example 27-A (colorless crystals, 21 mg, 21%) and Example 27-B (colorless oil, 44 mg, 44%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])[C:15]([OH:17])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:39][CH3:40]>>[CH2:39]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH2:33][NH:32][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH:13]=1)[CH3:40]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1OC/C=C(\C)CCC=C(C)C
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)c(OC/C=C(\C)CCC=C(C)C)c1
Yield: 72 %

Procedure:
In a manner identical to Example 15, 3,4-digeranyloxybenzoic acid (2.13 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7mn), thereby yielding 1.93 g (72%) of the aimed compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[S:11]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=O)(=[O:14])(=[O:13])[NH2:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:18]([C:17]3[CH:16]=[C:15]([S:11]([NH2:12])(=[O:14])=[O:13])[CH:23]=[CH:22][CH:21]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Agent: N
Product: NS(=O)(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-sulfamoylbenzoic acid (Oakwood). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.83 (t, J=7.9 Hz, 1H), 8.21 (ddd, J=7.9, 1.8, 1.0 Hz, 1H), 8.45 (dt, J=7.9, 1.4 Hz, 1H), 8.58 (dt, J=8.0, 1.9 Hz, 1H), 8.73-8.77 (m, 2H), 9.31 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:31]1C[CH:32]1[CH2:34][N:35]1[C:43]2[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=2[C:37]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)=[N:36]1>ClCCl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[NH:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][CH:32]([OH:31])[CH2:34][N:35]2[C:43]3[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=3[C:37]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)=[N:36]2)[CH2:13][CH2:12]1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(Nc3nc4ccccc4s3)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A solution of 220 mg (0.66 mmol) of 4-(benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in MeOH and stirred over 100 mg of sodium bicarbonate for 1 h. The solid was filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 220 mg (0.60 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 240 mg (66%) of a white solid. MS (electrospray): exact mass calculated for C30H33F3N6O2S: 598.23; m/z found, 599.3 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.78 (d, J=8.22 Hz, 1H), 7.72 and 7.68 (A and B of AB quartet, J=8.41 Hz, 2H), 7.64 (d, J=8.22 Hz, 1H), 7.56 (bd, J=8.02 Hz, 1H), 7.51 (bd, J=8.02 Hz, 1H), 7.29 (bd, J=7.63 Hz, 1H), 7.08 (bt, J=7.63 Hz, 1H), 5.29 (br s, 1H), 4.88 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.23-4.16 (m, 1H), 4.16-4.08 (m, 1H), 4.06-3.98 (m, 2H), 3.92-3.65 (m, 3H), 3.03-2.70 (m, 4H), 2.52-2.41 (m, 3H), 2.26-2.18 (m, 1H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 2.16-2.08 (m, 2H), 1.66-1.44 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:19][C:18]([NH:20][C:21](=[O:35])[C:22]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH3:24])[CH3:23])=[N:17][C:16]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([NH:25][C:22]([CH3:24])([C:21](=[O:35])[NH:20][C:18]2[S:19][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:16]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:17]=2)[CH3:23])=[O:34])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2sc(NC(=O)C(C)(C)NC(=O)c3ccc(F)cc3)nc2-c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(CN2CCNCC2)s1

Procedure:
A solution of 4-{2-[2-(4-Fluoro-benzoylamino)-2-methyl-propionylamino]-4-phenyl-thiazol-5-ylmethyl}-piperazine-1-carboxylic acid tert-butyl ester (70 mg) and TFA (1.5 mL) in dichloromethane (3 mL) was stirred at RT for 2 h and concentrated. The residue was partitioned between dichloromethane and aq. K2CO3. The organic extract was dried over MgSO4, concentrated and purified by HPLC to give the title compound. m/z 482.2 (MH+). 1H NMR (CD3OD) 7.98-7.96 (m, 2H), 7.57 (d, J=8 Hz, 2H), 7.41 (t, J=8 Hz, 2H), 7.35 (d, J=8 Hz, 2H), 7.21 (t, J=8 Hz, 2H), 3.75 (s, 2H), 2.88-2.85 (m, 4H), 2.55-2.45 (m, 4H).
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:17].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH2:30])(=[O:29])=[O:28]>C1(C)C=CC=CC=1>[O:28]=[S:27]1(=[O:29])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:3]([C:4]2[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[C:11]3[C:6]([C:5]=2[OH:17])=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:30]1
Reactant: CSC(SC)=C1C(=O)c2ccccc2C(C)(C)C1=O
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 14.7 %

Procedure:
A solution of the product of Example 9G (450 mg) and 2-aminobenzenesulfonamide (180 mg, 1.05 mmol) in toluene (10 mL) was stirred at 100° C. for 2.5 hours, cooled to 25° C. and filtered. The filtrate was concentrated in vacuo, and the residue was chromatographed eluting with dichloromethane to give the title compound (57 mg, 15%). 1H NMR (300 MHz, CDCl3): δ 16.77, 16.61 (two s, 1 H), 14.36, 13.98 (two s, 1 H), 8.27 (m, 2 H), 7.99 (d, J=8.09 Hz, 2 H), 7.57 (m, 2 H), 7.31 (m, 2 H), 1.71 (s, 3 H), 1.56 (s, 3 H).