Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:38][C:39]1[CH:44]=[N:43][CH:42]=[C:41]2[S:45][C:46]([C:48]3[S:52][C:51]([NH2:53])=[N:50][N:49]=3)=[CH:47][C:40]=12.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:38][C:39]1[CH:44]=[N:43][CH:42]=[C:41]2[S:45][C:46]([C:48]3[S:52][C:51]([NH:53][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=4)=[N:50][N:49]=3)=[CH:47][C:40]=12
Reactant: Nc1nnc(-c2cc3c(Cl)cncc3s2)s1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C(F)(F)F)c1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C(F)(F)F)c1)C(=O)Nc1nnc(-c2cc3c(Cl)cncc3s2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-2-((tert-Butoxycarbonyl)amino)-3-(3-(trifluoromethyl)phenyl)propanoic acid (1 g, 3 mmol) purchased from Peptech was mixed with EDC (0.766 g, 4 mmol) and HOBt (0.810 g, 6 mmol) in 5 mL DMF in a round bottom flask. The mixture was stirred at room temperature for 30 minutes. 5-(4-Chlorothieno[2,3-c]pyridin-2-yl)-1,3,4-thiadiazol-2-amine (0.268 g, 1 mmol) was added to the flask followed by addition of DIEA (1.4 mL, 8 mmol). The mixture was heated at 50° C. for one hour. After the DMF was removed under reduced pressure, the remaining residue was mixed with 200 mL EtOAc. The EtOAc solution was washed three times with saturated ammonium chloride aqueous solution, three times with saturated aqueous NaHCO3, and then dried over Na2SO4. After removing the solvent, the product was obtained and used directly in the next step.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: CCCCCCCCN1CCC(CN)CC1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: CCCCCCCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 38.7 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-octylpiperidine (0.452 g, 2.0 mmol) according to procedure used for Example 2 to give 0.180 g of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=O.[NH2:17][C:18]([NH2:20])=[S:19].[H-].[Na+].O>O1CCOCC1>[CH:14]([C:6]1[C:5]([C:3]2[CH2:2][S:19][C:18](=[NH:17])[N:20]=2)=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1nn2ccccc2c1C(=O)CCl
Reactant: NC(N)=S
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn2ccccc2c1C1=NC(=N)SC1
Yield: 61.4 %

Procedure:
A mixture of 200 mg (0.63 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone, 100 mg of thiourea and 160 mg of sodium hydride were stirred in 2 ml of dioxane containing 120 μl of H2O at 60-70° C. for 30 minutes. 100 mg of 4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)thiazol-2(5H)-imine was obtained after workup. Compound 1087.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([NH:11]C(=O)OCC2C=CC=CC=2)[CH3:10])=[C:4]([O:22][CH3:23])[C:3]=1[CH:24]1[CH2:27][N:26]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:25]1.[ClH:33].O>CO>[ClH:1].[ClH:33].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([NH2:11])[CH3:10])=[C:4]([O:22][CH3:23])[C:3]=1[CH:24]1[CH2:25][N:26]([CH2:28][C:29]([F:30])([F:32])[F:31])[CH2:27]1
Reactant: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CN(CC(F)(F)F)C1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1c(C(C)N)cc(Cl)c(Cl)c1C1CN(CC(F)(F)F)C1
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of benzyl (1-{4,5-dichloro-2-methoxy-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)carbamate (190 mg, 0.39 mmol) in methanol (11 mL) was treated with 0.25 M HCl in water (3.9 mL, 0.98 mmol), degassed with nitrogen for 5 minutes, treated with 5% Pt/C (Degussa type) (96 mg, 50 wt %), and stirred under a balloon of hydrogen for 1 hour. The reaction mixture was filtered over a PTFE disposable filter. The filtrate was concentrated to give the desired product (180 mg, 99%) that was used without further purification. LCMS for C14H18Cl2F3N2O (M+H)+: m/z=357.1, 359.1. Found: 357.0, 359.0.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:13]([OH:15])=[O:14])=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH2:3][CH2:2]1>C(OC(=O)C)(=O)C>[CH2:3]1[C:4]2[C:9](=[CH:8][C:7]3[C:10](=[O:12])[O:15][C:13](=[O:14])[C:6]=3[CH:5]=2)[CH2:1][CH2:2]1
Reactant: O=C(O)c1cc2c(cc1C(=O)O)CCC2
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc3c(cc21)CCC3
Yield: 94.9 %

Procedure:
The product of above-mentioned (b) (0.28 g, 1.4 mmol) was heated under reflux in acetic anhydride (6.7 ml) overnight. The reaction solution was poured into ice-cold water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.25 g of the title compound.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[Si]([O:35][CH2:36][C:37]([C:39]1[N:40]=[CH:41][N:42]2[CH:46]=[C:45]([C:47]3[CH2:48][C@@H:49]4[C@@H:66]([C@H:67]([OH:69])[CH3:68])[C:65](=[O:70])[N:50]4[C:51]=3[C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)=[O:53])[S:44][C:43]=12)=[O:38])(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>C1COCC1.[Cl-].[Na+].O>[OH:35][CH2:36][C:37]([C:39]1[N:40]=[CH:41][N:42]2[CH:46]=[C:45]([C:47]3[CH2:48][C@@H:49]4[C@@H:66]([C@H:67]([OH:69])[CH3:68])[C:65](=[O:70])[N:50]4[C:51]=3[C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)=[O:53])[S:44][C:43]=12)=[O:38]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)CO[Si](C)(C)C(C)(C)C)c4s3)C[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)CO)c4s3)C[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Acetic acid (0.345 ml) and 2.04 ml of a 1 M tetra-n-butylammonium fluoride/THF solution were added to a solution of 255 mg of 4-nitrobenzyl(5R,6S)-2-(7-t-butyldimethylsilyloxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate in 8 ml of THF. The mixture was stirred at room temperature for 3 hr. Brine was added to the reaction solution. The mixture was adjusted to pH 8.1 by the addition of a saturated sodium hydrogencarbonate solution, and extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. Diethylether(5 ml) was added to the residue. The insoluble was collected by filtration to give 196 mg of 4-nitrobenzyl(5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]4=[O:37])=[CH:23][C:22]=3[F:38])=[CH:17][CH:16]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:38][C:22]1[CH:23]=[C:24]([N:27]2[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]2=[O:37])[CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH2:11][CH:10]([CH2:9][OH:8])[O:14][N:13]=2)=[CH:16][CH:17]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO[Si](C)(C)C(C)(C)C)C4)cc3)c(F)c2)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO)C4)cc3)c(F)c2)C(=O)O1
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
N-[((5S)-3-{4′-[5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydroisoxazol-3-yl]-2-fluoro-1,1′-biphenyl-4-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (164 mg, 0.3 mmol) was dissolved in tetrahydrofuran (5 ml) at room temperature. A solution of tetrabutylammonium fluoride in tetrahydrofuran (1M; 0.3 ml, 0.3 mmol) was added and the reaction mixture stirred for 30 minutes. The solvent was removed in vacuo then dichloromethane (2 ml) added. Purification by chromatography (SiO2 10 g bond elut; 0 to 6% methanol/dichloromethane) yielded a white solid. This was washed with water (50 ml) to yield 37.9 mg (29%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[C:10]1=[O:18].FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:44][C:45]([F:56])([F:55])[C:46]1[CH:47]=[C:48]2[C:52](=[CH:53][CH:54]=1)[CH2:51][NH:50][CH2:49]2.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15](=[O:17])[N:50]2[CH2:49][C:48]3[C:52](=[CH:53][CH:54]=[C:46]([C:45]([F:44])([F:56])[F:55])[CH:47]=3)[CH2:51]2)[C:10]1=[O:18]
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2Cl)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2Cl)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(2-chloro-4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 268A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 5-(trifluoromethyl)isoindoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.59 (t, J=9.9, 2H), 7.48-7.30 (m, 2H), 7.13 (dd, J=2.7, 8.5, 1H), 7.06-6.94 (m, 1H), 4.92 (d, J=19.6, 4H), 4.36 (d, J=16.2, 1H), 4.24-4.10 (m, 2H), 3.77-3.60 (m, 2H), 2.77-2.56 (m, 1H), 2.04 (dq, J=8.1, 13.4, 1H); MS (DCI) m/z 441.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([N+:19]([O-])=O)[CH:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]2[CH:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[C:9]=2[CH:10]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c([N+](=O)[O-])cc(Cl)cc21
Agent: [Fe]
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCn1ccc2c(N)cc(Cl)cc21
Temperature: 25 °C
Yield: 110.8 %

Procedure:
6-Chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (1.82 g, 5.35 mmol) was treated with iron powder (1.49 g, 27 mmol) in acetic acid (80 ml) and stirred at room temperature. After 1 h the crude was filtered over Celite and the solvent was removed in vacuum. A mixture of a solution of sodium bicarbonate 4% and ethyl acetate was added and the resulting mixture was filtered over Celite. The organic phase was washed with water and brine, dried over magnesium sulphate and the solvent was removed to give 1.76 g (93% yield) of the title compound as a dark solid, that was used in the next step without further purification. Purity 85%.
Reaction SMILES: I.[NH:2]1[CH2:7][CH2:6][CH2:5][N:4]=[C:3]1[NH:8][NH2:9].Cl.[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>[N:15]1[CH:16]=[CH:17][C:12]([C:11]2[N:4]3[CH2:5][CH2:6][CH2:7][NH:2][C:3]3=[N:8][N:9]=2)=[CH:13][CH:14]=1
Reactant: NNC1=NCCCN1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: I
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Product: c1cc(-c2nnc3n2CCCN3)ccn1
Yield: 13.3 %

Procedure:
A solution of 750 mg (3.1 mmol) (1,4,5,6-tetrahydro-pyrimidin-2-yl)-hydrazine hydroiodide (Krezel, Izabella; Pharmazie; 1994; p. 27-31) and 552 mg (3.1 mmol) isonicotinoyl chloride hydrochloride in 3 ml pyridine was heated at 120° C. o.n. The reaction mixture was cooled and diluted with aq. sat. K2CO3 and extracted with chloroform. The combined organic extracts were dried and concentrated. Flash chromatography (DCM/MeOH 10:1) afforded 83 mg (18%) of the title compound. 1H NMR: 1.91 (m, 2 H) 3.24 (m, 2 H) 4.13 (m, 2 H) 7.67 (m, 2 H) 8.65 (m, 2 H)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=O)[C:12]=2[N:13]=1)=[O:7].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.O>[C:21]1([N:27]2[CH2:32][CH2:31][N:30]([C:18]([CH:14]3[C:12]4[N:13]=[C:9]([NH:8][C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)=[O:7])[S:10][C:11]=4[CH2:17][CH2:16][CH2:15]3)=[O:20])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1nc2c(s1)CCCC2C(=O)O)c1ccco1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nc2c(s1)CCCC2C(=O)N1CCN(c2ccccc2)CC1)c1ccco1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,1-Carbonyldiimidazole (CDI, 0.31 g, 1.9 mmol) was added to a solution of 2-[(furan-2-carbonyl)amino]-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid (0.5 g, 1.7 mmol) in CH2Cl2 (10 mL), and the resultant mixture was stirred for a period of 2 hours at room temperature. Following cooling of the suspension to 0° C., N-phenylpiperazine (0.28 g, 1.73 mmol), dissolved in CH2Cl2 (10 mL), was added dropwise over a period of 5 minutes. After stirring for 30 min at 0° C. and overnight at room temperature, there were added a few drops of water. Following drying over Na2SO4 and filtration, the solvent was removed and the residue was purified via column chromatography. The product furan-2-carboxylic acid(4-(4-phenylpiperazin-1-carbonyl)-4,5,6,7-tetrahydrobenzthiazol-2-yl]amide was obtained in a yield of 514 mg (corresponding to 69% of the theoretical yield).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCN2CCCCC2)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and piperidine are converted to the named compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)([O-])=O>C(OCC)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1cccc([N+](=O)[O-])c1
Solvent: CCOCC
Product: Nc1cccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)c1
Yield: 84 %

Procedure:
Using (3aR*,10aS*)-9-(3-nitrobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the title compound was synthesized in otherwise the same manner as Reference Example 7. Yield 84%, m.p. 176°-178° C. (diethyl ether).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[C:14]([C:18]2[S:19][C:20]([C:24](=[O:26])[CH3:25])=[C:21]([CH3:23])[N:22]=2)[CH:15]=[N:16][CH:17]=1.[C:27](OCC)(=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].S([O-])(O)(=O)=O.[K+]>O1CCCC1.C(OCC)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[S:19][C:20]([C:24](=[O:26])[CH2:25][C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:21]([CH3:23])[N:22]=2)[CH:15]=[N:16][CH:17]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1sc(-c2cncc(F)c2)nc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1sc(-c2cncc(F)c2)nc1C
Reaction time: 2 h

Procedure:
Under argon, lithium bis(trimethylsilyl)amide (21 ml, 1 M/L in tetrahydrofuran) was initially charged in tetrahydrofuran (150 ml). At −78° C., 1-[2-(5-fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]ethanone (5.0 g, 21 mmol, prepared analogously to Biorg. & Med. Chem. Lett 1056 (2007) and 2828 (2010)) dissolved in diethyl ether was slowly added dropwise and the reaction mixture was stirred for 2 h. Diethyl oxalate (3.1 g, 21 mmol) dissolved in ether was added dropwise and the reaction mixture was stirred at room temperature for 16 h. Subsequently, potassium hydrogensulphate solution (5%) was added and the mixture was extracted repeatedly with ethyl acetate. The combined organic phases were dried and the solvent was removed under reduced pressure. This gave 7.1 g (99% of theory) of ethyl 4-[2-(5-fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]-2,4-dioxobutanoate.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:31])[N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])=[O:31])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: O=C(NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Yield: 67.4 %

Procedure:
To a degassed solution of [4-(4-{[N,N-bis-(2-hydroxyethyl)carbamoyl]methoxy}phenyl)-butyl]carbamic acid benzyl ester 25 (0.19 g, 0.43 mmol) in ethanol (4 mL) was added 10% palladium on activated carbon (0.1 g, 50% wet). The mixture was hydrogenated overnight at atmospheric hydrogen. The catalyst was filtered through a pad of diatomaceous earth and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 20-5:1:0.1-1 dichloromethane/methanol/concentrated ammonium hydroxide, v/v) to provide 26 (0.09 g, 72%) as a colorless oil. 1H NMR (300 MHz, CD3OD) δ 1.56 (m, 4H), 2.56 (t, 2H), 2.65 (t, 1H), 3.29 (m, 1H), 3.55 (m, 4H), 3.72 (m, 4H), 4.90 (s, 2H), 6.86 (d, 2H), 7.09 (d, 2H). m/z (ESI): 311 [C16H26N2O4+H]+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[S:19]1[C:23]([C:24]([N:26]2[CH2:31][C:30]3([CH2:36][CH2:35][N:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH2:45][O:46][Si](C(C)(C)C)(C)C)[C:39]=4[F:54])[CH2:33][CH2:32]3)[O:29][CH2:28][CH2:27]2)=[O:25])=[CH:22][C:21]2[CH:55]=[CH:56][CH:57]=[CH:58][C:20]1=2>C1COCC1>[S:19]1[C:23]([C:24]([N:26]2[CH2:31][C:30]3([CH2:36][CH2:35][N:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH2:45][OH:46])[C:39]=4[F:54])[CH2:33][CH2:32]3)[O:29][CH2:28][CH2:27]2)=[O:25])=[CH:22][C:21]2[CH:55]=[CH:56][CH:57]=[CH:58][C:20]1=2
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2cc4ccccc4s2)CCO3)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1cc2ccccc2s1)N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1
Reaction time: 0.5 h

Procedure:
TBAF (1M solution in THF, 2 mL) was added to a solution of benzo[b]thiophen-2-yl(9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 79, step a) (0.370 g) in THF (4 mL). After 0.5 h, the solution was concentrated. Purification by silica gel chromatography eluting with 10:1 ethyl acetate:triethylamine gave the subtitled compound as a gum. Yield 0.26 g.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][O:28][C:29]1[C:37]2[N:36]=[C:35]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[N:34]([CH3:44])[C:33]=2[CH:32]=[CH:31][CH:30]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:35]3[N:34]([CH3:44])[C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[C:37]=4[N:36]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1cccc2c1nc(N1CCNCC1)n2C
Product: COc1cccc2c1nc(N1CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC1)n2C

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 4-methoxy-1-methyl-2-piperazin-1-yl-1H-benzimidazole
Reaction SMILES: ClS(C1C=CC(C(O)=O)=CC=1)(=O)=O.CC1OC(C)CNC1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.[CH3:36][CH:37]1[CH2:42][N:41]([S:43]([C:46]2[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=2)(=[O:45])=[O:44])[CH2:40][CH:39]([CH3:55])[O:38]1>>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:50](=[O:51])[C:49]2[CH:53]=[CH:54][C:46]([S:43]([N:41]3[CH2:40][CH:39]([CH3:55])[O:38][CH:37]([CH3:36])[CH2:42]3)(=[O:45])=[O:44])=[CH:47][CH:48]=2)=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: CC1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC(C)O1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: CC1CNCC(C)O1
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC1CN(S(=O)(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC(C)O1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 616 μL of 2,6-dimethylmorpholine via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 120 mg of 4-(2,6-dimethylmorpholinosulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2,6-dimethylmorpholinosulfonyl)benzamide. MS (Q1) 486.3 (M)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]=2[OH:16])[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]1[O:16][C:14]2[C:15]3[CH:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:13]=2[N:17]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)NCCC1CCc2ccc(NC(=O)CCCCOCc3ccccc3)c(O)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CC(=O)NCCC1CCc2ccc3nc(CCCCOCc4ccccc4)oc3c21
Yield: 90.7 %

Procedure:
N-{3-[2-(Acetylamino)ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}-5-(benzyloxy)pentanamide (100 mg, 0.236 mmol) and pyridinium p-toluenesulfonate (11.8 mg, 0.0471 mmol) were heated under reflux in xylene (5 mL) for 2.5 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=30/70→60/40) to give the title compound (87.0 mg, yield 91%).