Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][C:12]3[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:11]=3[CH2:10]2)=[N:6][CH:5]=1)(O)=[O:2].[CH2:24]([NH2:29])[CH2:25][CH:26]([CH3:28])[CH3:27].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:27][CH:26]([CH3:28])[CH2:25][CH2:24][NH:29][C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:10][C:11]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:14][C:12]=3[CH2:13]2)=[N:6][CH:5]=1)=[O:2]
Reactant: CC(C)CCN
Reactant: CC(C)(C)OC(=O)N1CC2=C(C1)CN(c1ncc(C(=O)O)s1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)c1cnc(N2CC3=C(CN(C(=O)OC(C)(C)C)C3)C2)s1

Procedure:
tert-Butyl 5-(5-carboxythiazol-2-yl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carboxylate (186 mg, 0.55 mmol), isoamylamine (0.42 ml, 2.6 mmol), triethylamine (153 μl, 1.1 mmol) and HATU (209 mg, 0.55 mmol) were stirred at room temperature in 20 ml of DMF for 2 h. The solvent was evaporated off, and the residue was admixed with water and ethyl acetate. The organic phase was removed and concentrated, and the crude product was converted further directly. Yield: 225 mg, M+H+: 407.20.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]O)[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][S:38]([CH3:37])(=[O:40])=[O:39])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 85.4 %

Procedure:
The non-polydispersed alcohol 19 (0.835 g, 1.97 mmol) was dissolved in 3.5 ml dry dichloromethane and placed under a nitrogen atmosphere. Triethylamine (0.301 ml, 0.219 g, 2.16 mmol) was added and the mixture was chilled in an ice bath. After two minutes, the methanesulfonyl chloride (0.16 ml, 0.248 g, 2.16 mmol) was added. The mixture was stirred for 15 minutes at 0° C., then at room temperature for two hours. The reaction mixture was filtered through silica gel to remove the triethylammonium chloride, and the filtrate was washed successively with water, saturated NaHCO3, water and brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 9/1 ethyl acetate/methanol) to give non-polydispersed compound 20 as a clear oil (0.819 g, 83%). FAB MS: m/e 503 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:31][CH3:32])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CCI
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OCC1CC1
Temperature: 70 °C
Yield: 23.1 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.740 mmol) and ethyl iodide (153 mg, 0.984 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 23%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](I)[CH3:24]>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:23][CH3:24])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCc1cc(O)c(OCc2ccccc2)c(OCCCCl)c1
Product: CCOc1cc(CC)cc(OCCCCl)c1OCc1ccccc1
Yield: 77 %

Procedure:
1-Benzyloxy-2-[3-chloropropoxy]-4-ethyl-6-ethoxy benzene was prepared in 77% yield as a white solid from 1-Benzyloxy-2-[3-chloropropoxy]-4 -ethyl-6-hydroxybenzene and ethyliodide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Cl[CH2:11][O:12][CH3:13]>CN(C=O)C>[CH3:11][O:12][CH2:13][O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1cccnc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
Pyridin-3-ol (25 g, 260 mmol) was added to a stirring mixture of NaH (11 g of a 60 wt % dispersion with mineral oil, 260 mmol) and DMF (350 mL) at 0° C. After 30 min, the reaction mixture was allowed to warm to RT, stirred for 90 min, and then chloromethoxymethane (20 mL, 260 mmol) was added. After 18 h, the reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3, the layers were separated, the organic layer was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate was concentrated. The residue was dissolved with CH2Cl2, the solution was filtered through a plug of silica gel (sequential elution; 9:1→1:1 hexane-ethyl acetate), and the second filtrate was concentrated to give 10 g (27%) of 3-(methoxymethoxy)pyridine as a clear yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:15][NH2:16].O1CCCC1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([NH:16][CH3:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)Cl
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 5-fluoro-2-nitrobenzene-1-sulfonyl chloride (2.0 g, 8.35 mmol) in dichloromethane (50 mL) was cooled using an ice water bath. 2M methylamine in tetrahydrofuran (5.0 mL, 10.0 mmol) was added. The resulting solution was stirred for 2 hours. The reaction mixture was washed with 2N HCl solution (2×100 mL), brine (100 mL) and then dried over magnesium sulphate. The solution was filtered before concentrating under reduced pressure to afford 5-fluoro-N-methyl-2-nitrobenzenesulfonamide (1.79 g, 7.64 mmol).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([CH3:34])=[C:11]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:7]=1)(=O)C.[CH3:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:30]([O:29][C@@H:23]([C:11]1[C:12]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[C:13]2[C:8](=[CH:9][C:10]=1[CH3:34])[N:7]=[C:6]([C:5](=[O:4])[N:36]([CH3:35])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:15]=[CH:14]2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:31])([CH3:33])[CH3:32]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(COC(C)=O)ccc2c1-c1ccc(Cl)cc1
Reactant: CNc1ccccc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C(=O)N(C)c3ccccc3)ccc2c1-c1ccc(Cl)cc1

Procedure:
(S)-Ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamoyl) quinolin-6-yl)acetate was prepared following the procedure used to prepare compound (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)-7-methylquinolin-6-yl)acetate of Example 16, except that N-methylaniline was used instead of dimethylamine HCl salt. LCMS-ESI+ (m/z): 545.2, 547.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][Cl:17])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:18]([O-])=O)[CH:4]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:18])[C:6](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][Cl:17])[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1N
Temperature: 40 °C
Yield: 99.9 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 2.02 g (6.58 mmol) of methyl 4-methoxy-5-(3-chloropropoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-12, and 40 mL of methanol. The resulting mixture was heated to 40° C. under stirring. To the mixture was added 0.2 g of 5 wt. % palladium/carbon (containing 49% water) at the same temperature. The resulting mixture was heated to the same temperature for 2 hours, while hydrogen was introduced into the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to precipitate a crystalline product. The crystalline product was dried under reduced pressure, to give 1.80 g (isolated yield: 98.1%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of methyl 4-methoxy-5-(3-chloropropoxy)anthranilate as a white crystalline product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][NH2:29]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:29][CH2:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccc2ccccc2c1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc3ccccc3c2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and C-Naphthalen-2-yl-methylamine in DME. ES-MS m/e (%): 342 (M+H+, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][C:9]([OH:11])=O.[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1>>[NH2:12][C:13]1[C:22]2[N:23]=[C:24]([CH2:31][CH2:32][CH2:33][CH3:34])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:9](=[O:11])[CH2:8][S:7][C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[C:21]=2[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: O=C(O)CSc1ncccn1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)CSc1ncccn1

Procedure:
Using the general method of Example 105 (2-pyrimidinylthio)acetic acid (0.11 g, 64 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.2 g, 0.64 mmol) to provide N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(2-pyrimidinylsulfanyl)acetamide as a white solid, m.p. 156-160° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16][CH2:17]O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(F)c(Br)c1
Yield: 90.3 %

Procedure:
To a solution of compound 3-bromo-4-fluoro-benzoic acid (430 g, 1.97 mol, 1 eq) in EtOH (2.3 L) was added dropwise thionyl chloride (287 mL, 3.94 mol, 2 eq) at 10° C. Then the mixture was heated to reflux overnight. The mixture was concentrated in vacuum to give a residue. The residue was dissolved in ethyl acetate (800 mL), washed with aqueous sodium hydrogen carbonate, brine (300 mL) and water (200 mL), then concentrated in vacuo to give title compound as a white solid (440 g, 1.78 mol, 90.3%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][S:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[N+:27]([C:30]1[C:31]([S:36]Cl)=[N:32][CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>ClCCl>[CH2:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][S:36][C:31]1[C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=[CH:33][N:32]=1)[CH2:13][S:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1SCl
Reactant: CC(C)(C)SSC[C@H](N)C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)SSC[C@H](NSc1ncccc1[N+](=O)[O-])C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
(R)-2-amino-N-benzyl-3-(tert-butyldisulfanyl)propanamide (Compound tk93) (60 mg, 0.201 mmol) and triethylamine (0.034 ml, 0.241 mmol) were dissolved in dichloromethane (1 ml), and the solution was cooled to 0° C. 3-Nitro-2-pyridinesulfenyl chloride (46.0 mg, 0.241 mmol) was added and the mixture was stirred at 0° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (R)—N-benzyl-3-(tert-butyldisulfanyl)-2-(((3-nitropyridin-2-yl)thio)amino)propanamide (Compound tk94) (87 mg, 96%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:10][C:9]([C:11]2[S:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)CCC.Br[C:38]1[S:39][CH:40]=[CH:41][CH:42]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:39]1[CH:40]=[CH:41][CH:42]=[C:38]1[C:9]1[S:10][C:6]([C:13]2[S:12][C:11]([C:9]3[S:10][CH:6]=[CH:7][CH:8]=3)=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccc([Sn](CCCC)(CCCC)CCCC)s2)s1
Reactant: Brc1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: c1csc(-c2ccc(-c3ccc(-c4cccs4)s3)s2)c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 141.4 %

Procedure:
5,5′-bis(tributylstannyl)-2,2′-bithiophene (2.16 g, 2.90 mmol) was dissolved in dry DMF (45 mL) and transferred via cannula to Pd(PPh3)4 (0.101 g, 0.087 mmol) in a Schlenk flask. 2-bromothiophene (1.14 g, 6.96 mmol) was added via syringe and the solution was degassed with nitrogen. Reaction was then heated to 90° C. for 18 hours. Reaction was quenched with water, extracted with chloroform (3×), and the combined organics washed with brine. Organics were dried with magnesium sulfate and concentrated by rotary evaporator yielding crude material as a waxy orange solid. The solid was recrystallized from boiling toluene and collected by filtration. Filtered solid was then redissolved in boiling chloroform and stirred with activated charcoal for 15 minutes. The charcoal was removed by filtering through celite and the chloroform removed by rotary evaporator to yield product as a yellow solid (0.676 g, 2.05 mmol, 70%). Characterization data matches literature. Z. H. Li, et al., Org. Lett. 9:3659-3662 (2007).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([CH2:17][S:18]([CH2:21][S:22]([CH2:25][C:26](O)=O)(=[O:24])=[O:23])(=[O:20])=[O:19])(O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:17]/[S:18]([CH2:21][S:22](/[CH:25]=[CH:26]/[C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=2)(=[O:23])=[O:24])(=[O:19])=[O:20])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: COc1ccc(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2ccc(OC)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Yield: 85 %

Procedure:
A solution of 4-methoxy-3-nitrobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 85% yield. m.p. 263-265° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH4+:12].[OH-]>COCCO>[F:10][CH:9]([F:11])[O:8][C:7]1[C:2]([NH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: FC(F)Oc1cccnc1Br
Agent: [OH-]
Solvent: COCCO
Product: Nc1ncccc1OC(F)F
Temperature: 100 °C
Yield: 80.4 %

Procedure:
To a steel bomb were charged with 2-methoxyethanol (20 ml), 2-bromo-3-(difluoromethoxy)pyridine (1.95 g, 8.7 mmol), conc. aqueous NH4OH (28-30%, 5 ml, 79 mmol) and Cu2O (0.25 g, 1.7 mmol). The reaction mixture was heated at 100° C. for 23 h, then cooled to 0° C., and partitioned between mixture of EtOAc/aq. 3 N NaOH/H2O (40 ml/10 ml/30 ml). The organic phase layer was collected, washed with saturated aqueous NaHCO3 solution (30 ml), brine (40 ml), dried (Na2SO4), and concentrated to produce 1.12 g of 3-(difluoromethoxy)pyridin-2-amine which was carried forward without further purification:
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15](C(=O)C(C)C)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-:23].[Na+].Cl>CO>[C:3]([C:5]1[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])=[CH:14][CH:15]=[CH:16][C:4]=1[C:3]([OH:2])=[O:22])(=[O:23])[CH:4]([CH3:16])[CH3:5]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)C(C)C)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCN(C)C(=O)c1cccc(C(=O)O)c1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dissolve 5-isobutyryl-N-methyl-N-propyl-isophthalamic acid methyl ester (50 mg, 0.16 mmol) in methanol (3 mL) and add dropwise 2 N NaOH (0.16 mL). Stir the mixture at room temperature for 6 h, store overnight at 4° C. and acidify to about pH=6 by 5 N HCl. Concentrate to near dryness and dilute the residue with ethyl acetate. Wash with saturated aqueous sodium chloride solution and extract the organic layer, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>C(#N)C>[CH3:20][N:21]([CH3:25])[C:22](=[O:23])[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OC(=O)N(C)C)nc(C(Cl)(Cl)Cl)n1
Yield: 48 %

Procedure:
A mixture of 5.7 g (0.025 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 5.1 g (0.05 mole) triethylamine, and 100 ml acetonitrile was stirred and 5.4 g (0.05 mole) dimethylcarbamoyl chloride was added to the mixture. The reaction mixture was stirred 2 hours under reflux, and allowed to cool. A solid was filtered out after cooling and washed with water to give 3.6 g (48% yield; mp 83.5°-84.5° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[N:12]=[C:11]([C:21]([O:23]CC)=O)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][NH2:27].CO>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[N:12]=[C:11]([C:21]([NH:27][CH3:26])=[O:23])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(Sc2cccc(Br)c2)n(-c2ccccc2Cl)n1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc(Sc2cccc(Br)c2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of ethyl 5-[(3-bromophenyl)thio]-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylate (687 mg) in methanol (8 mL) was added 40% methylamine-methanol solution (1.6 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 600 mg, yield 90%).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:27])[CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=CC=1)([O-])=O.[CH2:28]([NH2:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1>[CH2:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[C:11]([NH:34][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C1CCCN1C(=O)OCc1ccccc1
Reactant: CCCCCCN
Solvent: C1CCOC1
Product: CCCCCCNC(=O)C1CCCN1C(=O)OCc1ccccc1

Procedure:
To a solution of 25.9 g. (0.07 mol.) of N-carbobenzoxy-DL-proline p-nitrophenyl ester in 250 ml. of dry tetrahydrofuran is added 14.1 g. (0.140 mol.) of n-hexylamine in 50 ml. of tetrahydrofuran, and the resulting solution is left overnight at room temperature. The solvent is removed in vacuo, the residue is diluted with ether, and this solution is then washed thoroughly with 1 N aqueous sodium hydroxide, water and then dilute hydrochloric acid. On drying the ether solution and concentrating in vacuo, a pale yellow oil comprising 1-[(benzyloxy)carbonyl]-2-[(hexylamino)carbonyl]pyrrolidine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16]C)=[O:15])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:18].[OH-].[Na+].Cl>C(O)C>[C:14]([C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH2:4][C:3]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=3[Cl:1])=[C:6]([CH3:18])[NH:7]2)=[CH:12][CH:11]=1)([OH:16])=[O:15]
Reactant: COC(=O)c1ccc2c(Cc3ccc(Cl)cc3Cl)c(C)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]c2cc(C(=O)O)ccc2c1Cc1ccc(Cl)cc1Cl
Yield: 96.3 %

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-6-(methoxycarbonyl)-2-methylindole (0.330 g), ethanol (15 ml) and 10% aqueous sodium hydroxide (10 ml) is heated under reflux for 1.5 hours. This is processed with hydrochloric acid to have a pH of 3, and the crystal formed is taken out through filtration. This is dried to obtain 6-carboxy-3-(2,4-dichlorobenzyl)-2-methylindole (73) (0.305 g)
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([NH2:23])[CH2:18][CH2:17][CH2:16]3)[O:4][N:3]=1.[O:24]=[C:25]1[NH:30][CH2:29][CH2:28][N:27]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:26]1[CH2:41][C:42](O)=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([NH:23][C:42](=[O:43])[CH2:41][CH:26]2[C:25](=[O:24])[NH:30][CH2:29][CH2:28][N:27]2[S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:18][CH2:17][CH2:16]3)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccccc2-c2ccc3c(c2)CCC[C@H]3N)n1
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)C2CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCNC(=O)C2CC(=O)N[C@@H]2CCCc3cc(-c4ccccc4-c4nc(C)no4)ccc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a 100 mL round bottom flask was added (1R)-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-amine (25.0 mg, 0.06 mmol), followed by 2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid (50 mg, 0.016 mmol), dry CH2Cl2 (10 mL), HATU (12 mg, 0.03 mmol), EDCI (13 mg, 0.068 mmol) and hunig base (0.022 mL, 0.123 mmol). The resulting mixture was stirred at rt for 20 h. Removed solvent to dryness. Solvent was removed. The residue was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (97:3) gave final compound. MS m/z: 600.3 (M+H). Calc'd. for C32H33N5O5S -599.71.s