Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:17][CH:18]=2)[CH2:13]1)=O)C1C=CC=CC=1.[H][H].[C:31]([OH:34])(=[O:33])[CH3:32]>[C].[Pd]>[C:31]([OH:34])(=[O:33])[CH3:32].[NH2:11][C@H:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:17][CH:18]=2)[CH2:13]1
Reactant: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC(=O)OCc1ccccc1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](N)CC2

Procedure:
(S)-2 -[2-(Benzyloxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide (100 mg) and 20 mg of 10% palladium-carbon were suspended in 5 ml of acetic acid and the suspension was stirred at room temperature for 3 hours in an atmosphere of hydrogen. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanoldiethyl ether to give 72 mg of (S)-2-(2-amino-1,2,3,4-tetrahydronaphthalen-7-yloxy)-N,N-dimethylacetamide acetate having a melting point of 135 to 142° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CO[C@@H](C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 73.5 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (13) (0.50 g, 1.2 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 0.7 mL (1.4 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 0.34 mL of benzyl alcohol (0.34 mL, 0.36 g, 3.3 mmol) and 0.28 mL of pyridine (0.26 g, 3.3 mmol) in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 0.44 g (74% yield) of the title compound (31a) as a colorless oil. Rf=0.47 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.02 (s, 6H), 2.22-2.29 (m, 2H), 3.18-3.22 (m, 2H), 3.45 (t, J=6.4 Hz, 2H), 3.81 (s, 3H), 3.84 (s, 1H), 3.93 (d, J=9.2 Hz, 1H), 4.17 (d, J=9.2 Hz, 1H), 4.27 (d, J=11.2 Hz, 1H), 4.53 (d, J=10.8 Hz, 1H), 5.20 (s, 2H), 6.85 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.35-7.40 (m, 5H) ppm. MS (ESI) m/z 521.16 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O.[OH-].[Li+]>O1CCCC1.O>[C:16]([O:15][C:13]([NH:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:20])=[O:2])=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)Cc1ccccc1CNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 5a in tetrahydrofuran (0.3 M) at room temperature was added a solution of lithium hydroxide monohydrate (1.2 M) in H2O (0.4 M). The reaction was stirred at room temperature overnight. The tetrahydrofuran was removed under reduced pressure. The remaining aqueous phase was acidified with concentrated hydrochloric acid. The precipitated product was filtered off and dried to afford a white solid. (98%) 1H NMR (400 MHz, DMSO-d6) δ 12.34 (br s, 1H), 7.29 (m, 1H), 7.19 (m, 4H), 4.12 (m, 2H), 3.65 (s, 2H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[S:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH:47]([NH2:49])[CH3:48]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:49][CH:47]([C:43]2[S:42][CH:46]=[CH:45][N:44]=2)[CH3:48])=[O:40])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)c1nccs1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nccs4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (36 mg, yield 78%).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([C@H:37](O)[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([O:1][C:2]2[CH:26]=[CH:25][C:5]([C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:35][CH:36]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CCCC[C@@H](O)c1ccc(CC(C)C)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCC[C@H](Oc1ccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)cc1)c1ccc(CC(C)C)cc1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a mixture of ethyl 4-[3-(4-hydroxybenzoyl)indol-1-yl]butyrate (275 mg), (R)-1-(4-isobutylphenyl)pentan-1-ol (179 mg) and triphenylphosphine (213 mg) in a mixture of tetrahydrofuran and toluene (1:4, 10 ml) was added diethyl azodicarboxylate (0.13 ml) at -25° C. After stirring for 1 hour, the reaction mixture was concentrated in vacuo. The concentrate was chromatographed on silica gel using hexane and ethyl acetate (3:1) to give ethyl (S)-4-[3-[4-[1-(4-isobutylphenyl)pentyloxy]benzoyl]indol-1-yl]butyrate (279 mg).
Reaction SMILES: [CH2:1]([N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C)[CH3:2].Br[CH2:11][CH3:12].NCC1[O:19][N:18]=[C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:29]4[S:30][CH:31]=CC=4[C:27](=[O:33])[N:26]([CH3:34])[CH2:25][C:24]=23)[N:16]=1>CN(C)C=O>[CH2:7]([N:3]([CH2:1][C:2]1[O:19][N:18]=[C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:29]4[S:30][CH:31]=[CH:11][C:12]=4[C:27](=[O:33])[N:26]([CH3:34])[CH2:25][C:24]=23)[N:16]=1)[CH2:4][CH3:6])[CH3:9]
Reactant: CCBr
Reactant: CN1Cc2c(-c3noc(CN)n3)ncn2-c2sccc2C1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2ccsc2-3)no1
Reaction time: 1 h
Yield: 21.2 %

Procedure:
3.75 ml (21.8 mmol) of N-ethyldiisopropylamine and 0.94 ml (12.6 mmol) of 1-bromoethane were added to a solution of 1.0 g (3.16 mmol) of 7-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepin-4-one in 30 ml of dimethylformamide and the mixture was stirred at 70° for 1 hour. The reaction solution was subsequently evaporated, whereupon the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). There were obtained 250 mg (21%) of 7-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepin-4-one as a colourless foam, Rf=0.56 (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]([NH:10]C(=O)OCC1C=CC=CC=1)([CH3:9])[CH3:8].O=[C:27]([CH3:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[NH2:25][C:24]1[C:3]2[C:2](=[CH:23][CH:22]=[CH:21][C:4]=2[O:5][CH2:6][C:7]([NH2:10])([CH3:8])[CH3:9])[N:1]=[C:27]([CH3:34])[C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CC(C)(COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N

Procedure:
Prepared as in Example Ba from benzyl 1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-ylcarbamate (Example Dc) and ethyl 3-oxobutanoate as a yellow-brown solid (91%). 1H NMR (400 MHz, DMSO-d6) δ 1.15 (s, 6H), 1.31 (t, J=4 Hz, 3H), 2.54 (s, 3H), 3.87 (s, 2H), 4.31 (q, J=4 Hz, 2H), 6.85 (d, J=4 Hz, 1H), 7.21 (d, J=4 Hz, 1H), 7.49 (t, J=8 Hz, 1H), 8.38 (brs, 2H). MS 318 (MH+).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]CS([O-])(=O)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH3:19][O:20][C:21](=[O:37])[CH:22]([O:34][CH2:35][CH3:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCCC>C(#N)C>[CH3:19][O:20][C:21](=[O:37])[CH:22]([O:34][CH2:35][CH3:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:13][CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=2)=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]
Reactant: CS(=O)(=O)Oc1ccc(CCCS(=O)(=O)[O-])cc1
Reactant: CCOC(Cc1ccc(O)cc1[N+](=O)[O-])C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1[N+](=O)[O-])C(=O)OC
Yield: 81.5 %

Procedure:
2-(4-Methanesulfonyloxyphenyl)ethylmethanesulfonate (1.14 g; 3.87 mmole), 2-ethoxy-3-(4-hydroxy-2-nitrophenyl)propanoic acid methyl ester (1.04 g; 3.86 mmole) and potassium carbonate (1.07 g; 7.75 mmole) were mixed in acetonitrile (approx. 100 ml). The reaction mixture was heated to reflux for 6 hours and according to TLC the reaction was not complete. Another portion of 2-(4-methanesulfonyloxyphenyl)ethylmethanesulfonate (0.2 g; 0.68 mmole) was added. The reaction mixture was heated to reflux over night, and then evaporated to dryness. Ethyl acetate and water were added into the residue. The phases were separated and the organic phase was washed with brine, dried with magnesium sulfate and evaporated. Chromatography of the crude product on silica gel with a gradient of ethyl acetate/heptane as eluant gave 1.47 g (81% yield) of 2-ethoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)-2-nitrophenyl]propanoic acid methyl ester.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]1[N:47]=[C:48]([CH:62]([CH3:64])[CH3:63])[N:49](COCC[Si](C)(C)C)[C:50]=1[C:51](O)=[O:52].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:51]([C:50]2[NH:49][C:48]([CH:62]([CH3:63])[CH3:64])=[N:47][C:46]=2[CH3:45])=[O:52])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: Cc1nc(C(C)C)n(COCC[Si](C)(C)C)c1C(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(C)C)[nH]c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
HATU (103 mg, 0.27 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (56.2 mg, 0.18 mmol), 4-methyl-2-(1-methylethyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (54 mg, 0.18 mmol) and diisopropylethylamine (47 uL, 0.27 mmol) in DMF (1 mL). The reaction mixture was stirred at RT overnight and the solvent was removed under vacuum. The residue was dried in vacuo and the residue was treated with TFA (0.5 mL) in DCM (1.0 mL) at RT and stirred overnight. Neutralized with saturated NaHCO3 and extracted with 10% MeOH in DCM. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (0-5% 2M NH3 solution of MeOH in DCM) and HPLC to afford the title compound (50 mg, 60%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.68 (1H, br. s.) 7.56 (1H, br. s.) 7.31-7.40 (2H, m) 7.23 (1H, s) 7.14 (1H, d, J=1.3 Hz) 7.02 (1H, s) 4.62 (2H, d, J=6.4 Hz) 2.96 (1H, dt, J=13.7, 6.8 Hz) 2.56 (3H, s) 1.30 (6H, d, J=7.0 Hz). LCMS: m/z 461 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-:12].[K+].[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:18]1[C:19]2[C:20](=[O:12])[C:14]3[C:19](=[C:18]([O:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH:17]=[CH:16][CH:15]=3)[C:20](=[O:12])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Reactant: [OH-]
Agent: [K+]
Product: O=C1c2cccc(Oc3ccc4ccccc4c3)c2C(=O)c2cccc(Oc3ccc4ccccc4c3)c21
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 50 parts of 2-naphthol and 17 parts of potassium hydroxide were dissolved in 500 parts of toluene, and the mixture was refluxed under heat. After stirred for 4 hours, the solution was allowed to cool, and the precipitated solid was filtered. Then, under a nitrogen stream, the precipitate, 24 parts of 1,5-dichloroanthraquinone and 7.2 parts of copper powder were dissolved in 500 parts of DMF, and the mixture was refluxed under heat for 5 hours. The reaction solution poured into an aqueous potassium hydroxide solution, and the precipitated solid was filtered, washed, and dried. Then, after removal of inorganic materials with toluene, the solid obtained was recrystallized from 2-ethoxyethanol, filtered, washed, and dried, to give 19 parts of 1,5-bis(2-naphthyloxy)anthraquinone as an intermediate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]CCCC.[C:16]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=O)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C[O:33]CC1>>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][C:26]([OH:33])([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: Brc1cccc2cc[nH]c12
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc3cc[nH]c23)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution of 7-bromoindole (1.25 g, 6.4 mmol) in THF (15 mL) under Argon was cooled to −70° C., and n-BuLi (9.6 mL, 19.2 mmol) was added over 20 min. The reaction mixture was warmed to −5° C. in an ice bath and was stirred at this temperature for 30 min. The mixture was cooled to −70° C. and a solution of N-Boc-piperidone (2.5 g, 12.8 mmol) in THF (10 mL) was added over 15 min. The reaction was stirred for 45 min at −70° C. and was then warmed to room temperature. The reaction was quenched with water (10 mL) and partitioned between water (25 mL) and ethyl acetate (50 mL). The organic layer was washed with water (15 mL) and brine (30 mL), then dried (MgSO4), filtered and concentrated. The remaining brown oil was chromatographed, eluting with acetone:hexanes (1:4) to afford 1.17 g (58% yield) of 4-hydroxy-4-(1-H-indol-7-yl)-piperidine-1-carboxylic acid tert-butyl ester XVI.
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6](=S)[NH:7][NH2:8])[CH2:2][CH2:3][CH3:4].[Cl:14][CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[ClH:14].[CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:21]([CH3:23])[NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CCCCN(CCCC)C(=S)NN
Solvent: CCO
Product: CCCCN(CCCC)c1n[nH]c(C)c1C(=O)OCC
Product: Cl
Temperature: 60 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
A stirred solution of 14.3 g (0.07 mole) of 4,4-di-n-butyl-3-thiosemicarbazide in 100 mL of absolute ethanol was cooled to 10° C. under nitrogen atmosphere, treated with 11.6 g (0.07 mole) of ethyl 2-choroacetoacetate, warmed to 60° C., then cooled to ambient temperature and stirred for 18 hr. The reaction mixture was heated to reflux in order to dissolve the precipitate, filtered to remove amorphous sulfur and concentrated in vacuo to give a solid. The solid was recrystallized from acetone to yield 8 g of white crystalline product, mp 159°-162° C., as the hydrochloride salt.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([NH2:18])=[O:17])[CH2:11]1)=O)(C)(C)C.S(=O)(=O)(O)O>CO.O1CCOCC1>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([NH2:18])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCCN(C(N)=O)C1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1COCCO1
Product: NCC1CCCN(C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
3-(tert-Butoxycarbonylaminomethyl)piperidine-1-carboxamide (150 mg, 0.583 mmoles) (prepared as described in Preparative Example 241, Step A above) was dissolved in methanol (3 mL). 10% conc. sulfuric acid in 1,4-dioxane (7.9 mL) was added and the mixture was stirred at 25° C. for 1 h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH− form) was added until the pH was basic. The resin was filtered off, washed with methanol, evaporated to dryness and chromatographed on a silica gel column (15×2 cm) using dichloromethane followed by 15% (10% conc, ammonium hydroxide in methanol)-dichloromethane as the eluant to give the 3-(aminomethyl)piperidine-1-carboxamide (80 mg, 87%): FABMS: m/z 158.1 (MH+); HRFABMS: m/z 158.1294 (MH+). Calcd. for C7H16N3O: m/z 158.1293; δH (CDCl3+drop CD3OD) 1.20 (1H, m, CH2), 1.48 (1H, m, CH2), 1.60 (1H, m, CH), 1.68 (1H, m, CH2), 1.83 (1H, m, CH2), 2.64 (bm, 2H, —CH2NH2), 2.82 (1H, m, CH2), 3.02 (1H, m, CH2), 2.98 (2H, m, CH2), 3.70 (1H, m, —CH2NH2), 3.78 (1H, m, —CH2NH2) and 5.24 ppm (1H, bs, NH); δC (CDCl3+drop CD3OD) CH2: 24.1, 28.6, 44.0, 44.8, 47.9; CH: 38.3; C, 159.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19].ClC(Cl)[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29].[C:31](=[O:34])(O)[O-:32].[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[CH:11]=[O:32].[Cl:28][C:25]1[CH:24]=[C:23]([Cl:29])[CH:22]=[CH:27][C:26]=1[CH2:31][OH:34]
Reactant: Clc1ccc(C(Cl)Cl)c(Cl)c1
Reactant: O=C([O-])O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: Cc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(Cl)cc1Cl
Product: OCc1ccc(Cl)cc1Cl
Temperature: 160 °C
Reaction time: 2 h
Yield: 71.21 %
Yield: 16.94 %

Procedure:
To a 600 cc Hastoloy C autoclave was charged 48.52 g of a crude chlorination mixture containing 10.93% 2,4-dichlorotoluene, 70.39% α,2,4-trichlorotoluene, 18.52% α,α,2,4-tetrachlorotoluene, 0.10% α,α,2,4-pentachlorotoluene (the percentages represent gas chromatograph area percents), 39 g of sodium bicarbonate and 146 ml of water. The autoclave was flushed with nitrogen and pressure tested to 1500 psig. The autoclave was then vented to atmospheric pressure and heated. The temperature was increased to 160° C. and maintained for two hours. The pressure increased from atmosphere pressure to between 200 and 400 psig. After two hours, the autoclave was cooled to 80° C., vented and the product removed. After separation of the aqueous phase, the crude aldehyde mixture was flash distilled affording 11.84% 2,4-dichlorotoluene, 16.94% 2,4-dichlorobenzaldehyde and 71.21% 2,4-dichlorobenzyl alcohol.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=C(C#N)[CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[C:19]([OH:22])(=[O:21])[CH3:20].Cl>O>[O:1]=[C:2]1[C:8]2[CH:9]=[C:20]([C:19]([OH:22])=[O:21])[CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2
Reactant: N#Cc1ccc2c(c1)C(=O)c1ccccc1OC2
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1OC2

Procedure:
Reflux a mixture of 7.43 gm. (0.0316 mole) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-9-carbonitrile, 130 ml. of acetic acid, 13 ml. of water and 13 ml. of concentrated hydrochloric acid for 156 hours. Cool the reaction mixture, separate the solids by filtration and dry (yield 6.20 gm., m.p. 264°-269° C.). Recrystallize from acetic acid to obtain the title product (m.p. 270.5°-271.5° C.).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:8](C(O)=O)[C:7]2[CH:12]=[CH:13][CH:14]=C[C:6]=2[NH:5]1.[H][H].CI.[CH3:20][N:21]([CH:23]=[O:24])[CH3:22]>>[CH3:20][N:21]1[C:22]2[CH:14]=[CH:13][CH:12]=[CH:7][C:6]=2[N:5]([C:4]([NH2:8])=[O:3])[C:23]1=[O:24]
Reactant: [H][H]
Reactant: O=C(O)n1c(=O)[nH]c2ccccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cn1c(=O)n(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80% sodium hydride (0.04 g) was added portionwise to a solution of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (endo-8-methyl-8azabicyclo[3.2.1]oct-3-yl ester (0.4 g) in dry DMF (10 ml). After hydrogen evolution had subsided methyl iodide (0.082 ml) was added and the reaction mixture was stirred at room temperature for 2 hrs. The solvent was removed under vacuum and the residue was taken up in methylene chloride and washed with water. The organic phase was dried over MgSO4 and concentrated to dryness. Pure title compound was obtained by flash chromatography technique (eluent: methylene chloride/methanol/32% NH4OH 90:10:1) on Silicagel. The oily base was transformed into the hydrochloride salt. 0.21 g M.p. >250° C. MS (C.I.): 316 m/e [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[NH2:36])[N:27]=1)=[O:25].C(O)(=O)C.O>C1(C)C=CC=CC=1.[Ti]>[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[N:36]=[CH:11][C:10]([OH:17])([C:13]([F:14])([F:16])[F:15])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:20][CH3:21])([CH3:18])[CH3:19])[N:27]=1)=[O:25]
Reactant: COc1ccc(Cl)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Agent: [Ti]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(Cl)ccc3OC)C(F)(F)F)cccc2n1

Procedure:
224 mg (0.69 mmol) of 4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 195 mg (0.96 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester are dissolved in 20 ml of toluene. After 5.0 ml of concentrated acetic acid is added, it is refluxed for 16 hours in a water separator. After the solvent is removed, the residue is taken up in 10 ml of tetrahydrofuran, 0.3 ml (1.4 mmol) of titanium tetraethylate is added, and the reaction is allowed to reflux again. After the solvent is removed as well as after purification on silica gel with hexane/ethyl acetate (0-100%), 120 mg (33% of theory) of the product is obtained.