Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:29])[C@@H:18]([N:23]3[CH2:28][CH2:27]O[CH2:25][CH2:24]3)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@H:18]([N:23]1[CH2:28][CH2:27][CH2:25][CH2:24]1)[C:17]([NH:16][C@H:13]1[C@H:11]2[C@H:10]([CH2:9][N:8]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:12]2)[CH2:15][CH2:14]1)=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(C)(=O)=O)C[C@H]21)N1CCCC1

Procedure:
The title compound was prepared by substituting (2S)—N-[(3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl]-4-methyl-2-pyrrolidin-1-ylpentanamide from Example 250 for (S)—N-((3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-methyl-2-morpholinopentanamide and methanesulfonyl chloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in the procedures described in Example 319: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.24-8.26 (m, 1H), 4.35 (p, J=6.8 Hz, 1H), 3.79 (dd, J=9.9, 2.6 Hz, 1H), 3.50 (dd, J=9.9, 7.0 Hz, 1H), 3.35 (dd, J=9.6, 7.0 Hz, 1H), 3.17-3.21 (m, 2H), 3.04 (s, 3H), 2.67-2.75 (m, 4H), 2.60-2.63 (m, 2H), 1.99-2.07 (m, 1H), 1.78-1.95 (m, 3H), 1.58-1.68 (m, 6H), 1.32-1.39 (m, 1H), 0.99 (d, J=6.2 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H); MS (ESI+) m/z 372 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].OC1CC(=O)NC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][C:42]=1[O:49][CH3:50]>C1COCC1.C(Cl)Cl>[C:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][NH:39][C:10](=[O:12])[C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[C:42]([O:49][CH3:50])[CH:43]=1)#[N:48]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COc1cc(C#N)ccc1CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CC(O)C(=O)N1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C#N)ccc1CNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
16.0 g of Boc-proline (50 mmol), dissolved in 80 ml of THF, were stirred with 5.7 g of hydroxysuccinimide and 10.2 g of DCC in methylene chloride at 0° C. for 30 min. Then 8.0 g (50 mmol) of 4-aminomethyl-3-methoxybenzenenitrile [sic] dissolved in 50 ml of THF were added dropwise at 0° C., and the mixture was stirred at room temperature for 20 h. The solid was filtered off, the filtrate was mixed with the same volume of ethyl acetate and washed with cooled 5% strength NaHSO4 solution and saturated NaCl solution. 11.5 g (65%) of product were obtained. 1H-NMR (DMSO-d6 ; δ in ppm): 8.38 (m, NH); 7.50-7.35 (m, 3H); 4.40-4.05 (m, 3H, N--CH2 --Ar/N--CH--CO); 3.87 (s, OCH3); 3.50-3.25 (m, 2H, N--CH2); 2.2.5-2.00 [sic] (m, 1H); 1.90-1.65 (m, 3H); 1.40 and 1.30 (2s; 9H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17][S:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29]Br)[CH:23]=1)(=[O:20])=[O:19].CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:29][C:24]2[CH:23]=[C:22]([O:21][S:18]([CH3:17])(=[O:20])=[O:19])[CH:27]=[CH:26][C:25]=2[Cl:28])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Oc1ccc(Cl)c(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(OS(C)(=O)=O)ccc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of piperazin-3-one-1-carboxylic acid tert-butyl ester (7.10 g, 35.3 mmol) in dry DMF (200 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 2.10 g, 53.0 mmol). The reaction mixture was stirred for 15 min, and then a solution of the benzylbromide from Step B (10.0 g, 35.3 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction was poured into EtOAc (300 ml), and washed with H2O (3×50 ml). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (60% ethyl acetate/hexane) to provide the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([C:31]3[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=3)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2nc(Cl)ncc2Cl)CC1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2nc(-c3ccc(S(C)(=O)=O)cc3)ncc2Cl)CC1

Procedure:
The title compound is prepared from 4-(2,5-dichloro-pyrimidin-4-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described for Intermediate 14. LC (method 7): tR=1.58 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]1=O.[CH3:15][C:16]1(C)[CH2:20]C[CH2:18][C:17]1=O.N>CO>[CH3:15][C:16]1([CH3:20])[C:7]2=[N:2][CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[CH2:18][CH2:17]1
Reactant: CC1(C)CCCC1=O
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: CC1(C)CCc2cc([N+](=O)[O-])cnc21
Yield: 23.8 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (0.8 g, 4.0 mmol), 2,2-dimethyl-cyclopentanone (0.45 g, 4.0 mmol) and ammonia solution (2.0 M) in methanol (40 mL) was refluxed overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane) to give a yellow solid (0.183 g, 24% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[S:18][C:16]=2[N:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Product: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)=[O:18])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:40]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1CCN(CCCC(C2C=CC(C(C)(C)C(OCC)=O)=CC=2)=O)CC1>>[ClH:1].[OH:40][C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH3:31])([CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=2)[OH:18])[CH2:13][CH2:14]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Product: CCOC(=O)C(C)(C)c1ccc(C(O)CCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
When in the procedure of Example 2 an appropriate amount of ethyl 4-[3-[4-(diphenylmethylene)-1-piperidinyl]-1-oxopropyl]-α,α-dimethylbenzene acetate hydrochloride is substituted for ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride, ethyl 4-[3-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxypropyl]-α,α- dimethylbenzeneacetate hydrochloride is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[C:6]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[N:5]=1)([CH3:3])=[CH2:2].[N+](=[CH2:27])=[N-]>C(OCC)C.C(O)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:2][C:1]1([C:4]2[CH:9]=[C:8]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[CH:7]=[C:6]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:5]=2)[CH2:27][CH2:3]1
Reactant: C=C(C)c1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC1(c2cc(S(=O)(=O)c3ccc(N)cc3)cc(N3CCCC3)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
0.164 g (0.00048 Mol) 4-(2-Isopropenyl-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine were dissolved in ethyl ether (100 ml) and cooled to 0° C. A solution of diazomethane in ethyl ether (30 ml) was carefully added. Upon addition of a catalytic amount of Pd(OAc)2 gas evolution started. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. After addition of a few drops of acetic acid the solvent was evaporated and the residue chromatographed on SiO2 with ethyl acetate hexane 1:2. It was obtained 0.136 g (71%) of 4-[2-(1-Methyl-cyclopropyl)-6-pyrrolidin-1-yl-pyridine-4-sulfonyl]-phenylamine as pale yellow cristals; mp.: 235-236° C. (dec.).
Reaction SMILES: [C:1]([S:4]C)(C)=O.O(CC)[K].C1(O)C=CC=CC=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]=[C:30]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:31])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C@H:29]([S:4][CH3:1])[C@H:30]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:31])=[O:23])([CH3:18])([CH3:19])[CH3:20]
Reactant: CSC(C)=O
Reactant: CC(=C[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CCO[K]
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CS[C@H]([C@@H](C)C(=O)OCc1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of AcSMe (24.4 g, 0.27 mol) in THF (580 ml) cooled in an ice-bath was added KOEt (22.8 g, 0.27 mol). After stirring for 3.5 h at room temperature, phenol (11.9 ml, 0.14 mol) and a solution of (2S)-2-(2-benzyloxycarbonyl-propenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (15.6 g, 0.045 mol) in THF (50 ml) were successively added to the mixture. After 45 min, the mixture was quenched with saturated NH4Cl aqueous solution and concentrated in vacuo. The residue was diluted with EtOAc (600 ml), and washed with 1N NaOH aqueous solution (300 ml×3) and saturated brine (200 ml). The organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc=9/1) to give (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester which was contaminated with PhOH. The collected fraction which included (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was washed with 5N NaOH aqueous solution (300 ml) and H2O (300 ml) to remove phenol, and dried over anhydrous MgSO4. The organic layer was concentrated in vacuo to obtain (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (12.5 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.Cl.[NH2:21][OH:22]>CCO>[OH:22][NH:21][C:4](=[NH:5])[C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1]
Reactant: N#Cc1ccc(F)cc1F
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)c1ccc(F)cc1F
Temperature: 70 °C

Procedure:
To a mixture of 2,4-difluorobenzonitrile (1.39 g, 10 mmol) and DIEA (5.13 ml, 30 mmol) in EtOH (15 ml) was added 2.12 g of hydroxylamine hydrochloride (30 mmol) and the reaction was heated at 70° C. for 48 h. Half of the solvent was removed under reduced pressure. The mixture was poured in DCM (100 ml) and water (30 ml). 2.5 ml of NaOH 1N was added until pH=9-10. The organic layer was separated and the aqueous phase was extracted with DCM. The organic layers were combined, washed with water, dried over MgSO4, filtered and evaporated under reduced pressure to afford N-hydroxy-2,4-difluoro-benzamidine which was used without further purification for the next step.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nn1cccc1C(=O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nn1cccc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution containing 1-amino-2-(2-fluorobenzoyl)pyrrole (25.8 g, 0.126 mol) and N-(tert-butoxycarbonyl)glycine (22.4 g, 0.128 mol) in 300 ml of dichloromethane was added dicyclohexylcarbodiimide (26.4 g, 0.128 mmol) in two portions over 3 minutes. The reaction mixture was stirred at ambient temperature for 2 hours and then filtered. The filtrate was evaporated to an oil which was purified by HPLC (silica gel, 4:3 hexane-ethyl acetate) to give 37.2 g (82%) of crystals, m.p. 114°-116°.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][N:4]=[C:5]([C:13](=[O:15])[CH3:14])[C:6]([O:8]C(C)(C)C)=[O:7].S(Cl)(Cl)(=O)=O>C(O)(=O)C>[F:1][CH:2]([F:16])[O:3]/[N:4]=[C:5](/[C:13](=[O:15])[CH3:14])\[C:6]([OH:8])=[O:7]
Reactant: CC(=O)C(=NOC(F)F)C(=O)OC(C)(C)C
Solvent: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)/C(=N/OC(F)F)C(=O)O
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a solution of tert-butyl 2-difluoromethoxyimino-3-oxobutyrate (9.4 g) in acetic acid (9.4 ml) was added sulfuryl chloride (2.55 ml) under ice-cooling. After stirred at ambient temperature for an hour, the reaction mixture was concentrated under reduced pressure. The residual oil was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized with diisopropyl ether to give (Z)-2-difluoromethoxyimino-3-oxobutyric acid (4.73 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[Si]([N:27]1[CH2:32][CH2:31][N:30](C)[CH2:29][CH2:28]1)(C(C)(C)C)(C)C>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CN1CCN([Si](C)(C)C(C)(C)C)CC1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O

Procedure:
In a manner similar to that of Example 1, 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (II, R1 : cyclopropyl; X: fluoro) is reacted with 1-butylmethylsilyl piperazine (III, R2 : hydrogen; R3 and R4 : methyl; R5: t-butyl) to give a solid compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([C:25]2[S:26][C:27]([NH2:30])=[CH:28][N:29]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([C:25]2[S:26][C:27]([NH:30][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:28][N:29]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1cnc(N2CCOCC2)s1
Product: O=C(Nc1cnc(N2CCOCC2)s1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-morpholin-4-yl-thiazol-5-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-morpholin-4-yl-thiazol-5-ylamine. LCMS calcd for C18H15F3N4O3S (m/e) 424, obsd 425 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:22])([F:21])[C:15]([F:20])([F:19])C([O-])=O.[Na+]>CN1CCCC1=O.[Cu]I>[F:19][C:15]([F:20])([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[C:14]([F:22])([F:21])[F:13]
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C1CCCc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of 10 g (0.044 mol) of 7-bromo-1,2,3,4-tetrahydronaphthalenone in 300 mL of N-methylpyrrolidone was added 32.23 g (0.17 mol) of CuI and 31.59 g (0.17 mol) of sodium pentafluoropropanoate and the mixture was heated for 3 h at reflux under an argon atmosphere. After cooling to room temperature, the resulting suspension was poured into a mixture of H2O--Et2O (1:1) and filtered over celite. The layers were separated and the organic phase was washed with H2O and dried over MgSO4. The solvent was removed, to afford a residue that was chromatographed on silica gel (hexane-AcOEt), to give the desired product as a colourless oil (8.75 g, yield: 80%).
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]([O: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]([O: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: COc1cccc2sc(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: COc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 66.3 %

Procedure:
A 15 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 (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methoxybenzothiazole (92 mg, 0.46 mmol) and 1.5 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 (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 107 mg (66%) of the title compound as an off white solid. mp 200°-205°. FDMS: m/e=424. α[D]589 =+60.56 (c=0.96, chloroform).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17]Br)=[N:13][NH:12][C:11]=1[NH2:19].NC1NN=C(CCCO)C=1[C:30]1SC2C=CC=C[C:33]=2[N:34]=1.CNC.C1COCC1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][N:34]([CH3:33])[CH3:30])=[N:13][NH:12][C:11]=1[NH2:19]
Reactant: Nc1[nH]nc(CCCBr)c1-c1nc2ccccc2s1
Reactant: Nc1[nH]nc(CCCO)c1-c1nc2ccccc2s1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)CCCc1n[nH]c(N)c1-c1nc2ccccc2s1

Procedure:
The title compound (100 mg) was prepared using 200 mg (0.59 mmol) of 4-benzothiazol-2-yl-5-(3-bromopropyl)-2H-pyrazol-3-ylamine, which was derived from 3-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-propan-1-ol, and 5 mL of a 2 M solution of dimethylamine in THF (10 mmol). MS (m/z, ES+): 302.1 (M+1, 100%).
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].[CH2:21]([O:28][C:29]([NH:31][C@H:32]1[CH2:36][O:35][NH:34][C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.B(F)(F)F.CCOCC>[CH2:21]([O:28][C:29]([NH:31][C@H:32]1[CH2:36][O:35][N:34]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@H](NC(=O)OCc3ccccc3)C2=O)O1
Reaction time: 48 h
Yield: 5 %

Procedure:
In 5 ml of dichloromethane were dissolved 155 mg of Compound (1) and 119 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution were added two drops of boron trifluoride etherate (47% ether solution) and 2 g of Molecular Sieves (3A). The mixture was allowed to stand at room temperature for 2 days. The reaction solution, after removing the Molecular Sieves, was washed with a cooled aqueous solution of sodium hydrogen carbonate, followed by drying (MgSO4). The solvent was evaporated off under reduced pressure, and the residue was purified by subjecting to a silica gel preparative thin-layer chromatography [developed with 1,2-dichloroethane-ethyl acetate (5:1)] to give 12.5 mg of the subject Compound (9).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]O)=[CH:31][CH:30]=1>C(#N)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:2]([NH:1][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[C:3]([CH:10]=1)[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5]
Reactant: COc1ccc(CO)cc1
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(CNc2ccc(Cl)cc2C(=O)N(C)OC)cc1
Temperature: 70 °C
Yield: 74.2 %

Procedure:
A solution of 8 (3.75 g, 17.3 mmol) in 50 mL of acetonitrile was treated with p-toluenesulfonic acid monohydrate. The reaction mixture was heated to 70° C. with stirring. 4-Methoxybenzyl alcohol (2.63 g, 19.0 mmol) in acetonitrile (3 mL) was added dropwise via syringe keeping the reaction temperature at 70° C. The reaction was stirred at 70° C. for 12 h, allowed to cool to ambient temperature, and concentrated in vacuo. Chromatography afforded 9 (4.3 g, 75%) as light yellow solid.
Reaction SMILES: CS(C)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13](Br)[CH:12]=1.[OH-].[K+]>C(OC(=O)C)C>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)[CH:12]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(C)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(C)cc1-n1ccnc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
To a degassed DMSO (20 mL) solution of imidazole (1.0 g, 15 mmol) was added 4-methyl-2-bromoanisole (1.25 mL, 10 mmol), KOH (1.12 g, 20 mmol) and Cu2O (280 mg, 2 mmol) under nitrogen. The resulting mixture was stirred at 140° C. for 24 hrs under N2. After cooling to room temperature, the mixture was poured into ethylacetate (EA) (50 mL) and filtered. The filtrate was washed with water (50 mL×3) and dried over anhydrous magnesium sulfate. After rotary evaporation, the crude oil was purified via column chromatography on silica gel with eluent of EA/MeOH (9/1, v/v), affording a light yellow solid (57%). 1H-NMR (300 MHz, CDCl3) δ(ppm) 7.78 (s, 1H), 7.16 (m, 3H), 7.09 (d, J=1.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.81 (s, 3H), 2.33 (s, 3H).