Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1.C([Mg]Br)(C)C.O1CCCC1.[O:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1.[Cl-].[NH4+].C([SiH](CC)CC)C>O1CCCC1.FC(F)(F)C(O)=O>[CH2:7]([C:5]1[S:6][C:2]([CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)=[CH:3][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: CCOC(=O)c1cc(Br)sc1CC
Reactant: O=C1CCOCC1
Agent: CC(C)[Mg]Br
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(C2CCOCC2)sc1CC
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of ethyl 5-bromo-2-ethylthiophene-3-carboxylate (5.00 g) synthesized in Example 69 (4) in tetrahydrofuran (50 mL) was added dropwise 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (22.8 mL) at −45° C., and the mixture was stirred for 1 hr under an argon atmosphere. Tetrahydro-4H-pyran-4-one (5.26 mL) was added dropwise, and the mixture was stirred at −45° C. for 1 hr, and then at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3, volume ratio) to give a colorless oil. To a solution of the obtained oil in trifluoroacetic acid (25 mL) was added triethylsilane (2.86 mL), and the mixture was stirred at room temperature for 1.5 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title compound (1.35 g, 26%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:29]=[C:28]([C:30]2[CH:31]=[N:32][C:33]3[N:34]([C:36]([CH2:39][C:40]4[CH:41]=[C:42]5[C:47](=[CH:48][CH:49]=4)[N:46]=[CH:45][CH:44]=[CH:43]5)=[CH:37][N:38]=3)[N:35]=2)[CH:27]=[CH:26][C:10]=1[C:11]([NH:13][C@@H:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([O:17]C(C)(C)C)=[O:16])=[O:12]>C(Cl)Cl>[F:8][C:9]1[CH:29]=[C:28]([C:30]2[CH:31]=[N:32][C:33]3[N:34]([C:36]([CH2:39][C:40]4[CH:41]=[C:42]5[C:47](=[CH:48][CH:49]=4)[N:46]=[CH:45][CH:44]=[CH:43]5)=[CH:37][N:38]=3)[N:35]=2)[CH:27]=[CH:26][C:10]=1[C:11]([NH:13][C@@H:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([OH:17])=[O:16])=[O:12].[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1F)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.0 mL, 0.013 mol) was added to a solution of tert-butyl (2S)-2-(2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoylamino)-3,3-dimethylbutanoate (0.092 g, 0.16 mmol) in methylene chloride (1.0 mL) and stirred at RT for 2 h. The volatiles were removed under reduced pressure to give the desired product as a TFA salt. LCMS: (M+H)=513.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].[C:10](Cl)(Cl)=[S:11]>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2]([N:1]=[C:10]=[S:11])[C:3]([CH3:9])=[N:4]1
Reactant: S=C(Cl)Cl
Reactant: Cc1nn(C)c(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nn(C)c(C)c1N=C=S
Reaction time: 0.33 h
Yield: 101.5 %

Procedure:
A mixture of 4-amino-1,3,5-trimethylpyrazole (1.32 g, 10.6 mmol) in 50 mL each of CHCl3 and saturated aqueous NaHCO3 was treated dropwise with thiophosgene (0.812 mL, 10.6 mmol) and stirred vigorously for 20 minutes. The layers were separated and the organic phase was washed with brine. After drying (Na2SO4), the solvent was evaporated in vacuo to provide the title compound (1.8 g, brown oil) suitable for use directly in the next step.
Reaction SMILES: ClC1C=CC=C(Cl)N=1.[N+]([O-])(O)=O.S(=O)(=O)(O)O.Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([Cl:28])[N:20]=1.[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>C(Cl)(Cl)Cl>[C:29]([N:32]1[CH2:37][CH2:36][N:35]([C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([Cl:28])[N:20]=2)[CH2:34][CH2:33]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: Clc1cccc(Cl)n1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])O
Product: CC(=O)N1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1

Procedure:
2,6-Dichloropyridine is nitrated with fuming nitric acid and concentrated sulfuric acid. The product, 2,6-dichloro-3-nitropyridine, is allowed to react with N-acetyl-piperazine in chloroform to give 2-(4-acetyl-1-piperazinyl)-6-chloro-3-nitropyridine (m.p. 137°-138° C.). The compound obtained is treated with aqueous ammoniaethanol in an autoclave to give 2-(4-acetyl-1-piperazinyl)-6-amino-3-nitropyridine (m.p. 202°-203° C.), which is then acetylated with acetic anhydride in acetic acid to give 6-acetylamino-2-(4-acetyl-1-piperazinyl)-3-nitropyridine (m.p. 189°-193° C., 221°-223° C.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH:37]1[CH:36]=[C:33]([CH2:34][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:19]([C:18]2[CH:27]=[CH:28][C:15]([CH2:14][N:7]([CH2:8][C:9]3[NH:13][CH:12]=[CH:11][N:10]=3)[CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)=[CH:16][CH:17]=2)=[O:20])[C:32]([O:31][C:30]([F:29])([F:40])[F:41])=[CH:39][CH:38]=1
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: O=C(NCCCCNCc1ccccc1OC(F)(F)F)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 2-trifluoromethoxybenzaldehyde (manufactured by Avocado Co., Ltd.) (0.0290 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (39.7 mg) of the subject compound as a white solid.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][S-:22].[Na+].Cl>CN(C)C=O>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([S:22][CH3:21])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: C[S-]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) in 6 ml N,N-dimethylformamide were added 13.8 mol cesium carbonate and 10.0 mmol sodium methanethiolate and the mixture was stirred at 90° C. for 30 min. The reaction mixture was then cooled to room temperature and acidified to pH1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colourless oil which was used in the next step without further purification (yield 99%). MS (m/e): 244.9 ([M−H]−, 100%).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH2:5][CH2:6][CH3:7].C[O-].[Na+]>CO>[CH2:5]([CH:4]1[NH:8][S:9](=[O:11])(=[O:10])[NH:12][C:3]1=[O:2])[CH2:6][CH3:7]
Reactant: CCCC(NS(N)(=O)=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC1NS(=O)(=O)NC1=O
Yield: 121205.7 %

Procedure:
A solution of 2-(aminosulfonyl)aminopentanoic acid methyl ester (13 g; 0.05 mmol) in methanol (150 ml) was added to a solution of sodium methoxide (5.54 g, from 2 g of Na) in 150 ml of methanol and the resulting reaction mixture was refluxed for 18 hours. The mixture was cooled, neutralized with BIO-RAD® 50W-X8 H+ ion exchange resin, and filtered. The filtrate was concentrated in vacuo to yield an oil which was crystallized from methanol/hexane to afford 10.8 g (quantitative) of 4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =H; R2 =propyl; R3 =H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].C([NH3+])CCC>>[CH2:19]([NH:23][C:17]([CH:12]([CH2:13][C:14]([OH:16])=[O:15])[CH2:11][S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:18])[CH2:20][CH2:21][CH3:22]
Reactant: O=C1CC(CSc2nc3ccccc3s2)C(=O)O1
Reactant: CCCCN
Agent: CCCC[NH3+]
Product: CCCCNC(=O)C(CSc1nc2ccccc2s1)CC(=O)O

Procedure:
A mixture of 7 parts of 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylic anhydride and 3.6 parts of n-butylamine is heated at 55° for 3 hours to give the butylammonium salt of the above amide as a viscous oil (mixture of isomers).
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH2:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(OCC)C>[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:12](=[O:13])[C:11]3[CH:15]=[CH:16][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)[CH2:29][CH2:28]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(CC2CCNCC2)cc1OC1CCCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CCC(Cc3ccc(OC)c(OC4CCCC4)c3)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of 20 ml of tetrahydrofuran (THF) containing 1 g of 4-methoxybenzoyl chloride is added dropwise to a solution of 30 ml of THF containing 0.73 g of 4-(3-cyclopentyloxy-4-methoxybenzyl)piperidine, 0.78 ml of triethylamine and 0.2 g of 4-N,N-dimethylaminopyridine, and the mixture is stirred under argon at room temperature. The reaction mixture is stirred at room temperature for 4 hours, diluted with 150 ml of diethyl ether, washed with a saturated aqueous sodium carbonate solution and then with water, and washed with a 1N HCl solution and then washed again with water. The organic phase is dried over magnesium sulphate and concentrated. The residual oil is filtered over silica by the flash chromatography technique using a toluene/ethanol mixture (97:3) as eluant. 4-(3-Cyclopentyloxy-4-methoxybenzyl)-1-(4-methoxybenzoyl)piperidine is obtained in the form of an oil.
Reaction SMILES: [C-:1]1([CH2:6][NH2:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[SH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50](O)=[O:51]>CC(C)=O>[C-:1]1([CH2:6][NH:7][C:50](=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][SH:39])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13]
Reactant: NC[c-]1cccc1
Reactant: O=C(O)CCCCCCCCCCS
Agent: [Fe+2]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC(C)=O
Product: O=C(CCCCCCCCCCS)NC[c-]1cccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
Compound 4 (0.175 g, 0.81 mmol), N,N′-dicyclohexylcarbodiimide (0.169 g, 0.82 mmol), 1-hydroxybenzotriazole (0.126 g, 0.82 mmol), and 11-mercaptoundecanoic acid (0.179 g, 0.82 mmol) were combined in degassed acetone (12 mL). The solution was stirred at r.t. for 18 h under an atmosphere of Ar. The reaction mixture was concentrated in vacuo and dissolved in dichloromethane (100 mL). After washing with water (3×50 mL), the organic phase was dried over Na2SO4, filtered, and concentrated to a crude residue that was purified by column chromatography on silica gel (2:3, EtOAc:hexanes) to yield the pure product as a pale orange solid (0.288 g, 0.69 mmol, 85%). 1H NMR (CDCl3): δ 1.25-1.38 (m, 13H, (CH2)6+SH), 1.57-1.66 (m, 4H, COCH2CH2+CH2CH2SH) 2.17 (t, JH-H=7.8 Hz, 2H, COCH2), 2.51 (psuedo dt, JN-H=7.3 Hz, 7.4 Hz, 2H, CH2SH), 4.13-4.15 (m, 4H, NHCH2+ferrocene-H), 4.16 (bs, 5H, ferrocene-H), 4.18 (pt, 2H, ferrocene-H), 5.56 (bs, 1H, NH). 13C{1H} NMR (CDCl3): δ 24.9, 26.0, 28.6, 29.2, 29.5, 29.5, 29.6, 29.6, 34.2, 37.0, 39.0, 68.4, 68.5, 68.8, 85.0, 172.6.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([O:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CN(C)C=O.O>[CH2:40]([O:3][CH2:4][CH:5]([O:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: C=CCCCCC(CO)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCCC(COCCCCCCCCCCCCCCCC)OC
Reaction time: 18 h

Procedure:
To a suspension of 7.4 g of 60% sodium hydride in 100 ml of dimethylformamide was added a solution of 8-hydroxy-7-methoxy-1-octene in 150 ml of dimethylformamide over 1.5 hours. A 63.4 g portion of the tosylate of 1-hexadecanol was added and the mixture was stirred for 18 hours, poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was purified by chromatography giving 41.5 g of the title compound as a oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][NH2:16])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[N:24]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][NH:16][C:29]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:30])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: COc1cccn2nc(C3(CN)CC3)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccn2nc(C3(CNC(=O)N4CCCC4)CC3)nc12
Reaction time: 24 h

Procedure:
Under an argon atmosphere C-[1-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropyl]-methylamine (0.050 g, 0.23 mmol) was dissolved in THF (1 mL) and Et3N (0.048 mL, 0.35 mmol). 1-Pyrrolidinecarbonyl chloride (0.032 mL, 0.29 mmol) was added. Stirring was performed at RT for 24 h. Aq. NaHCO3 and H2O were added. The aqueous phase was extracted with DCM (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford Pyrrolidine-1-carboxylic acid [1-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-amide as a crude product.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1C=CC=CC=1>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCCNc1ccc2c(c1)CCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: O=C(O)CCCCN(C(=O)c1ccc(Cl)cc1)c1ccc2c(c1)CCC2
Yield: 88.5 %

Procedure:
6.3 g of ethyl 5-(indan-5-ylamino)valerate and 3.1 g of ethyl diisopropylamine are reacted in 50 ml of benzene with 4.2 g of p-chlorobenzoyl chloride. The resulting residue (left after filtering off the precipitate and concentrating the filtrate by evaporation) is saponified as described in Example 77b. Recrystallization of the crude product from ethyl acetate/petrol ether (1:2) yields 7.9 g (88.1% of theory) of 5-{p-chloro-[N-(indan-5-yl)]benzamido}valeric acid, MP 132° to 134°.
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][N:11]2[C:12](=[O:28])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)=[CH:15][C:14]=3[C:24]([F:27])([F:26])[F:25])=O)(C)(C)C.[ClH:31]>C(OCC)C>[ClH:31].[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:28])[N:11]3[CH2:29][CH2:30][NH:8][CH2:9][C@H:10]32)=[C:14]([C:24]([F:26])([F:27])[F:25])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(-c4ccco4)cc3C(F)(F)F)[C@@H]2C1
Agent: Cl
Solvent: CCOCC
Product: O=C1c2c(cc(-c3ccco3)cc2C(F)(F)F)[C@@H]2CNCCN12
Reaction time: 0.25 h
Yield: 68 %

Procedure:
A stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-furyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (44 mg, 0.10 mmol) in diethyl ether (2 mL) was treated with concentrated aqueous hydrogen chloride (1 mL). The resulting mixture was stirred vigorously for 15 min and was then concentrated. Saturated aqueous ammonium hydroxide (2 mL) was added, and the white mixture was concentrated. The resulting residue was purified by radial chromatography (2% ammonium hydroxide in 8% methanol in dichloromethane); the product was then treated with aqueous hydrogen chloride (1N) and lyophilized to give the desired hydrochloric acid salt as a white solid (28 mg, 68%). MS (ESI) 323.3 (M−Cl).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f9) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:20](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-]>CN(C=O)C>[C:14]([C:11]1([CH3:17])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)(=[O:15])[NH2:20]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (1.00 g, 4.00 mmol) in DMF (41 mL) and DIPEA (2.9 mL, 17 mmol) was treated with HATU (2.4 g, 6.3 mmol). The solution was stirred for 20 minutes and NH4Cl (0.450 g, 8.40 mmol) was added. The mixture was stirred overnight and then evaporated to dryness. The residue was partitioned between EtOAc (100 mL) and water (150 mL). The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with HCl (1.0 N solution in water), saturated aqueous NaHCO3 solution, water and brine; dried over Na2SO4; filtered and concentrated. The residue was purified by column chromatography (SiO2, 10% MeOH in DCM) to give tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (781 mg, 78%). LC-MS: (FA) ES+ 265 (M+Na).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[CH2:3][CH:4]=O.C[O:11][C:12]([CH:14](P(OC)(OC)=O)[NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:13]>>[CH2:19]([O:18][C:16]([NH:15][CH:14]([CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[CH:6]([CH3:8])[CH3:7])[C:12]([OH:13])=[O:11])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: CC(C)C(C)(C)CC=O
Product: CC(C)C(C)(C)CCC(NC(=O)OCc1ccccc1)C(=O)O

Procedure:
This aldehyde may be converted to the title compound by reaction with N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester, followed by catalytic reduction and hydrolysis by the procedures described in Example 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:20]#[C:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][CH2:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(C#Cc3nccs3)c2CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCc3nccs3)c2CC1
Yield: 9.9 %

Procedure:
Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-(thiazol-2-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (160 mg, 0.41 mmol) in ethanol (10 mL) to a suspension of 10% Pd/C (Degussa type E101, 160 mg), then acetic acid (0.5 mL). Hydrogenate for 7 h (68-70 psi) then filter the catalyst through Celite® and concentrate in vacuo. Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient over 40 min) to obtain the desired intermediate (16 mg, 10%). MS (ES+) m/z: 393 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.CS(OS(C)(=O)=O)(=O)=O.[Li+].[I-:28]>C(Cl)Cl.CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][I:28])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CCC(O)c1ccc(F)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(C)=O
Product: Fc1ccc(CCCI)cc1
Reaction time: 4 h

Procedure:
To a solution of 2.26 g (14.65 mmol) of 3-(4-fluorophenyl propanol and 3.6 mL (44 mmol) of pyridine in 40 mL of CH2Cl2 at 0° C. was added 5.1 g (29.3 mmol) of methanesulfonic anhydride and the reaction mixture was sitirred for 4 h at rt. The reaction mixture was partitioned between 100 mL of CH2Cl2 and 20 of sat'd NaHCO3 solution. The organic fraction was washed 3 times with sat'd NaHCO3 solution and sat'd NaCl solution, dried over MgSO4 and the filtrate was concentrated several times from heptane to remove pyridine. To the residue in 50 mL of acetone was added 6 g (44 mmol) of LiI and the reaction mixture was Stirred for 20 hr. The reaction mixture was poured into 200 mL of H2O and extracted with ether. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 9:1) to give 3.25 g of the title compound.