Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].CN1CCOCC1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>O1CCCC1>[C:25](=[O:26])([O:27][C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1)[O:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:2](=[O:3])[CH3:1]
Reactant: CC(=O)NCCc1c[nH]c2ccc(O)cc12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)NCCc1c[nH]c2ccc(OC(=O)Oc3ccc([N+](=O)[O-])cc3)cc12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To N-acetylserotonin (0.9 g; 4 mmol) was added N-methylmorpholine (0.92 ml, 8 mmol), and 4-nitrophenyl chloroformate (1.61 g; 8 mmol) dissolved in tetrahydrofuran. Reaction was carried out for 0.5 h under an argon atmosphere. The solvent was evaporated. The residue was purified by column chromatography (SiO2, methanol/methylene chloride) to give 0.92 g (yield 60%) of crystalline yellow product with a melting point 153-156° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)([Cl:30])=O>O1CCOCC1.C(#N)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][C:23]([CH2:26][Cl:30])=[CH:22][CH:21]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2cc3c(Nc4ccc5c(c4)OCO5)ncnc3[nH]2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: ClCc1ccc(-c2cc3c(Nc4ccc5c(c4)OCO5)ncnc3[nH]2)cc1
Reaction time: 16 h

Procedure:
To a suspension of 1.83 g of {4-[4-(benzo[1,3]dioxol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol in 56 ml of dioxane/acetonitrile 1:1 under N2-atmosphere, 3.1 ml of thionylchloride are added. After 16 h stirring, the suspension is diluted with ethyl acetate and NaHCO3-solution. The aqueous layer is separated off and extracted twice with ethyl acetate. The organic phases are washed with water and brine, dried (MgSO4) and concentrated to yield the title compound; MS-ES+: (M+H)+=379; HPLC (conditions see Examples 67-78) tR =11.4 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[C:5]([N+:21]([O-])=O)=[C:4]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1>C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:6]([NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[C:5]([NH2:21])[C:4]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCCc2nccs2)c1C
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCCc2nccs2)c1C
Yield: 94 %

Procedure:
Under a nitrogen purge, 5% platinum on carbon (0.5 g) and toluene (5 mL) were added to a pressure vessel. A solution of (2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl} amine (4.7 g, 11 mmol) in toluene (35 mL) was then added. The vessel was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for 24 hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to yield 4.12 g of 5,6-dimethyl-2-phenoxy-N4-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}pyridine-3,4-diamine as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[C:6](=[O:14])[C:5]2[CH:15]=[C:16]([CH3:18])[S:17][C:4]1=2)[CH3:2].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6](=[O:14])[C:5]2[CH:15]=[C:16]([CH3:18])[S:17][C:4]1=2)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2sc(C)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(C)sc21
Temperature: 90 °C

Procedure:
A mixture of 0.24 part of ethyl 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylate and 3 parts by volume of 2N sodium hydroxide is heated at 90°C for 5 minutes. After cooling the solution is neutralized with acetic acid to give a precipitate whic is collected by filtration, whereby 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylic acid is obtained as crystals. Recrystallization from chloroform-ethanol gives colorless prisms melting at 232°-233°C. This product is identical with the product in Example 13.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH2:23][C:24]2[CH:25]=[C:26]([O:40][CH2:41][CH3:42])[C:27](I)=[C:28]([O:30][S:31]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])=[O:32])[CH:29]=2)=[CH:18][N:17]=1>>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:27]2[C:26]([O:40][CH2:41][CH3:42])=[CH:25][C:24]([CH2:23][C:19]3[C:20]([NH2:22])=[N:21][C:16]([NH2:15])=[N:17][CH:18]=3)=[CH:29][C:28]=2[O:30][S:31]([CH2:34][C:35]([CH3:36])([CH3:38])[CH3:37])(=[O:32])=[O:33])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Br)cc1)C(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)(C)C)c1I
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)(C)C)c1-c1ccc(N)cc1
Yield: 22.6 %

Procedure:
Starting from 272 mg (1.01 mmol) N-(4-bromo-phenyl)-2,2,2-trifluoro-acetamide and 265 mg (0.51 mmol) 2,2-dimethyl-propane-1-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 56 mg of the title compound are isolated as a yellowish foam after two chromatography operations.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][C:16]([O:18]CC)=[O:17])[N:10]=[C:9]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[N:8]=[C:7]2[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[C:42](=[O:43])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:44])[CH:40]=3)[N:35]([CH3:45])[C:34]2=[O:46])[CH2:29][CH2:28]1)[CH3:2].[OH-].[Na+].Cl.CCOCC>CO>[C:16]([CH2:15][O:14][C:13]1[CH:12]=[C:11]2[C:6]([C:7]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[C:42](=[O:43])[C:41]5[C:36](=[CH:37][CH:38]=[C:39]([CH3:44])[CH:40]=5)[N:35]([CH3:45])[C:34]4=[O:46])[CH2:29][CH2:28]3)=[N:8][C:9]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:10]2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])([OH:18])=[O:17]
Reactant: CCOC(=O)COc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OCC(=O)O
Yield: 101.3 %

Procedure:
In 30 ml of methanol was dissolved 900 mg (1.42 mmol) of Compound 54 obtained in Example 54, 15 ml of 2N-sodium hydroxide was added, and the mixture was stirred under heating at reflux for 4 hour. After cooling, 4N-hydrochloric acid was added to the reaction mixture and the mixtute was neutralized and subjected to extraction with chloroform. The organic layer was washed, dried and concentrated to give the residue. Ether was added to the above residue to give the precipitate which was collected by filtration and dried to give 870 mg (yield: 100%) of Compound 56 as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.C([C:14](CC)([C:18]([O-:20])=[O:19])C([O-])=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].N1C=CC=[CH:31][C:30]=1C(O)=O>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[N:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([CH2:14][C:18]([O:20][CH2:30][CH3:31])=[O:19])[CH:3]=1
Reactant: O=C(O)c1ccccn1
Reactant: Brc1cnc2cccnc2c1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cnc2cccnc2c1
Temperature: 110 °C
Yield: 402.5 %

Procedure:
A mixture of 3-bromo-1,5-naphthyridine (540 mg, 2.58 mmol), diethylmalonate (0.8 mL, 5.17 mmol) and cesium carbonate (2.53 g, 7.75 mmol) in 1,4-dioxane (6 mL) was degassed with argon for 15 min then picolinic acid (64 mg, 0.517 mmol) and CuI (50 mg, 0.258 mmol) was added. The mixture was heated in a sealed tube at 110° C. for 24 hours then cooled to room temperature, diluted with ethyl acetate (10 mL), washed with water (10 mL) and brine (10 mL). The organic phase was dried over sodium sulphate then evaporated in vacuo and purified by column chromatography on silica gel (hexane:EtOAc 70:30) to afford 450 mg of ethyl 1,5-naphthyridin-3-ylacetate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:15]=[CH:14][C:8]2[N:9]([CH3:13])[C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1.ICC[CH2:19][C:20]([CH3:25])([N+:22]([O-:24])=[O:23])[CH3:21].[CH3:26]N(C=O)C>O>[CH3:3][O:4][C:5]1[CH:15]=[CH:14][C:8]2[N:9]([CH2:13][CH2:19][C:20]([CH3:25])([N+:22]([O-:24])=[O:23])[CH3:21])[C:10](=[O:12])[N:11]([CH3:26])[C:7]=2[CH:6]=1
Reactant: COc1ccc2c(c1)[nH]c(=O)n2C
Reactant: CN(C)C=O
Reactant: CC(C)(CCCI)[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)n(C)c(=O)n2CCC(C)(C)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1.1 g (28 mmol) 60% sodium hydride are added to 2.5 g (14 mmol) 5-methoxy-1-methyl-1,3-dihydro-benzimidazol-2-one in 30 mL DMF while being cooled with the ice bath. After 30 minutes a solution of 1-iodo-4-methyl-4-nitro-pentane in 20 mL DMF is piped in and the mixture is stirred overnight. It is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with water, dried and evaporated down. The solid remaining is stirred with diethyl ether.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([CH3:12])([CH3:11])[S:4]1)[OH:2].[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:13][NH:14][C:15]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[C:5]([CH3:11])([CH3:12])[S:4]1)=[O:16]
Reactant: CN=C=O
Reactant: CC(C)C1=NC(=NO)SC1(C)C
Product: CNC(=O)ON=C1N=C(C(C)C)C(C)(C)S1

Procedure:
2-oxo-4-isopropyl-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-isopropyl-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 89°-91° C. The 2-oxo-4-isopropyl-5,5-dimethyl-3-thiazoline-oxime starting material (m.p. 220°-222° C.) was prepared from 2,4-dimethyl-2-thiocyanato-3-pentanone (b.p. [0.02 mm] 64°-66° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[S:12][C:11](SC)=[N:10][C@H:9]2[CH3:15])=[CH:4][CH:3]=1.[N+:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[S:12][C:11](=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N+:16]([O-:18])=[O:17])[NH:10][C@H:9]2[CH3:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CSC1=N[C@@H](C)[C@H](c2ccc(Cl)cc2)S1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=C1N[C@@H](C)[C@H](c2ccc(Cl)cc2)S1)[N+](=O)[O-]
Reaction time: 5 h
Yield: 63.5 %

Procedure:
9 g of trans-5-(4-chlorophenyl)-4-methyl-2-methylthio-2-thiazoline, 4.7 g of ethyl nitroacetate, and 0.06 g of zinc chloride were added into a 100 ml capacity of four neck flask, and the mixture was heated under nitrogen flow at the temperature ranging from 110˜130° C. for about five hours. After the completion of the reaction, the product mixture was dissolved with chloroform, washed with water, dried with magnesium sulfate, and then condensed under reduced pressure. The oily product obtained was purified by column chromatography to give 7.6 g of the title compound.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:18]([OH:20])=[O:19])[CH2:6][S:7][S:8][CH2:9][C@H:10]([NH:14][C:15](=[O:17])[CH3:16])[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].O.[CH2:22]([NH:29][CH2:30][CH2:31][NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH2+:29][CH2:30][CH2:31][NH2+:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.[C:15]([NH:14][C@H:10]([C:11]([O-:13])=[O:12])[CH2:9][S:8][S:7][CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C:18]([O-:20])=[O:19])(=[O:17])[CH3:16]
Reactant: CC(=O)N[C@@H](CSSC[C@H](NC(C)=O)C(=O)O)C(=O)O
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: O
Product: CC(=O)N[C@@H](CSSC[C@H](NC(C)=O)C(=O)[O-])C(=O)[O-]
Product: c1ccc(C[NH2+]CC[NH2+]Cc2ccccc2)cc1

Procedure:
To a 63% solution of N,N'-diacetyl-L-cystine in water (67 mmole, 21.8 g) was added N,N'-dibenzylethylenediamine (67 mmole, 16.0 g). The exothermic reaction gave a slightly oily product which could be recrystallised from water to give 12.0 g (32%) of the title substance as white crystalline needles.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].CN(C)[CH2:9][CH2:10][S:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)(=[O:13])=[O:12].CI.O>CS(C)=O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:14]([CH3:1])[S:11]([CH:10]=[CH2:9])(=[O:13])=[O:12])=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: CN(C)CCS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Solvent: O
Product: C=CS(=O)(=O)N(C)c1ccc([N+](=O)[O-])cc1
Reaction time: 18 h
Yield: 92.9 %

Procedure:
0.49 g (4.4 mmol) of potassium tert.butoxide are added at ambient temperature to a solution of 1.1 g (4 mmol) of 4-(2-dimethylamino-ethylsulphonylamino)-nitrobenzene (Example 379a) in 20 ml of DMSO. After 1.5 hours stirring 0.85 g (6 mmol) of methyl iodide are added. The mixture is stirred for 18 hours, then the reaction solution is poured into water and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and the solvent is eliminated in vacuo. 0.9 g of ethenesulphonic acid-N-(4-nitrophenyl)-N-methyl-amide are obtained as a crude product. 0.75 g of this crude product are dissolved in ethanol and combined with an excess of dimethylamine. After 18 hours stirring the mixture is evaporated to dryness.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[N:39]O)[NH2:38])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:39]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:10])[CH2:12]3)[O:28][N:38]=2)=[CH:33][CH:32]=1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4ccc(F)cc4)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 41.4 mg (0.269 mmol) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 78.2 mg (59% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32](S(C)=O)=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32]([O:10][CH2:9][CH2:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1
Reactant: OCCCc1cccnc1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCCc2cccnc2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of 3-pyridinepropanol (0.960 g, 7.0 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (10 ml). The reaction mixture is transferred to an erlenmeyer flask and diluted to 75 ml with water. The mixture is cooled to 0° C. and stirred. During this time, a yellow precipitate is formed. This solid is collected by filtration and slurried in a 2:1 EtOAc:hexane mixture. This slurry is stirred for 10 minutes, filtered, and the collected solid is placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.242 g, 58%). Mass (m/z): 417.2 (M++1), 415.2 (M+−1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[C:16]([CH2:23][CH2:24][CH3:25])=[N:17][NH:18][C:19]=1[C:20]([NH2:22])=[O:21]>ClCCl.N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[C:16]([CH2:23][CH2:24][CH3:25])=[N:17][NH:18][C:19]=1[C:20]([NH2:22])=[O:21])=[O:8])[CH2:2][CH3:3]
Reactant: CCCc1n[nH]c(C(N)=O)c1N
Reactant: CCCOc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCOc1ccccc1C(=O)Nc1c(CCC)n[nH]c1C(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-n-propoxybenzoyl chloride (57.6 g, 0.291 mol) in dichloromethane (50 ml) was added dropwise to a stirred, ice-cooled suspension of 4-amino-3-propyl-1H-pyrazole-5-Carboxamide (the compound of Preparation 8 of WO 98/49166) (35.0 g, 0.208 mol) in dry pyridine (350 ml) and the resulting mixture stirred for 18 hours at room temperature, then evaporated under reduced pressure. The residue was azeotroped with toluene (2×100 ml) and the resulting brown solid triturated with ether (100 ml) to give the title compound (83.0 g) as a beige solid.
Reaction SMILES: Cl[C:2]1(OC)[CH:10]=[CH:9][C:8]2[N:7]([C:11](=O)[C:12]([CH3:14])=C)C(C(O)=O)C[C:4]=2[CH2:3]1.[C:21](SCC(C)C(N1C2C(=CC(Cl)=CC=2)CC1C(O)=O)=O)(=O)[C:22]1C=CC=C[CH:23]=1>>[CH:11]1([NH:7][CH:8]2[CH2:4][CH2:3][CH2:2][CH2:10][CH2:9]2)[CH2:12][CH2:14][CH2:23][CH2:22][CH2:21]1
Reactant: C=C(C)C(=O)N1C2=C(CC1C(=O)O)CC(Cl)(OC)C=C2
Reactant: CC(CSC(=O)c1ccccc1)C(=O)N1c2ccc(Cl)cc2CC1C(=O)O
Product: C1CCC(NC2CCCCC2)CC1

Procedure:
By substituting 5-chloro-2,3-dihydro-5-methoxy-1-(2-methyl-1-oxo-2-propenyl)-1H-indole-2-carboxylic acid in the procedure of Example 25, 1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-5-chloro-2,3dihydro-1H-indole-2-carboxylic acid, dicyclohexylamine was obtained. The latter salt was then treated with 5% aqueous potassium hydrogen sulfate as in Example 15 to give the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[H-].[Na+].Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34].C(=O)(O)[O-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COCCOCCBr
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COCCOCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6.59 g (20 mmol) of N-benzyloxycarbonyl-tyrosine-methyl ester is dissolved in 25 ml of anhydrous N,N-dimethylformamide and mixed at 0° C. under argon with 0.81 g (20.5 mmol) of sodium hydride dispersion (60% in mineral oil). The batch is allowed to stir for 10 minutes, then 3.75 g (20.5 mmol) of 1-bromo-2-(2-methoxyethoxy)-ethane is added, the reaction temperature is allowed to increase to room temperature and stirred for another three hours. For working-up, the batch is taken up in toluene and shaken out several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate, filtered and concentrated by evaporation. The oily residue is chromatographed for purification on silica gel with hexane/diethyl ether/triethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[OH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:17][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccc(Br)cc2C=O)cc1
Temperature: 170 °C
Yield: 95.5 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (4.04 g, 20 mmol) (Alfa) in N,N-dimethylacetamide (30 mL) was added anhydrous K2CO3 (2.76 g, 20 mmol), and methyl 4-hydroxybenzoate (3.1 g, 20 mmol, Aldrich). The reaction mixture was heated at 170° C. for 1 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:8 then 1:4) to give 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester as a white solid (Yield 6.4 g, 95%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10]>C(O)(=O)C>[N+:9]([C:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[OH:8])([O-:11])=[O:10]
Reactant: Oc1ccc(I)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of p-iodophenol (2.2 g, 10 mmol) in 18 mL acetic acid was added a solution of HNO3 (0.7 mL, 70%) in 5 mL acetic acid dropwise over 10 minutes. The resulting mixture was stirred at ambient temperature. After 30 minutes, the reaction mixture was diluted by 100 mL ice-water. The precipitate was collected, washed with 100 mL water. Purification by flash column chromatography afforded 1.2 g of 2-nitro-4-iodophenol.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8](CC(O)=O)=[CH:9][CH:10]=[CH:11][CH:12]=1>CN(C)C=O.C(Cl)Cl>[C:7]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccccc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
Oxalyl chloride (246 μl, 2.86 mmol) and one drop of dimethylformamide were added dropwise to a suspension of biphenylacetic acid (30 mg, 1.41 mmol) in methylene chloride (10 ml). The mixture was stirred at room temperature for 20 minutes. The solvent was evaporated and the residue was coevaporated with toluene twice to give 310 mg of the title product as a yellow solid.