Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([NH2:12])=[S:11].Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[S:11][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:12]=1
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)NCCc1ccccn1
Solvent: CO
Product: O=C(O)c1csc(NCCc2ccccn2)n1
Yield: 90.9 %

Procedure:
2-(2-Pyridin-2-yl-ethylamino)-thiazole-4-carboxylic acid (375 mg) was prepared according to General Procedure B using (2-pyridin-2-yl-ethyl)-thiourea (300 mg) and 3-bromo-2-oxo-propionic acid (295 mg) in methanol (3 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:25])=[CH:9][C:6]=1[C:7]#[N:8].CO>C(Cl)(Cl)Cl>[NH2:8][C:7]1[C:6]2[C:5](=[CH:12][CH:11]=[C:10]([N:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[CH3:24])[C:14]3=[O:25])[CH:9]=2)[NH:3][N:2]=1
Reactant: Cc1ccncc1N1CCN(c2ccc(F)c(C#N)c2)C1=O
Reactant: NN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3[nH]nc(N)c3c2)C1=O
Temperature: 170 °C
Yield: 45.3 %

Procedure:
Hydrazine hydrate (5 mL) was added to solution of 2-fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitrile (103A: 265 mg) in 2-methoxymethanol (5 mL). The resulting mixture was heated to 170° C. and maintained for 20 hours. The reaction was monitored by TLC (20% MeOH in CHCl3). The reaction mixture was partitioned between ice water and DCM. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (10% MeOH in CHCl3) afforded 125 mg of the product (45.3% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C@H:10]2[CH2:12][C@H:11]2[CH2:13][CH2:14][OH:15])[CH2:6][CH2:5]1.[H-].[Na+].F[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>CN(C=O)C>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([O:15][CH2:14][CH2:13][C@@H:11]2[CH2:12][C@@H:10]2[CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][C:2]([F:1])([F:16])[F:17])[CH2:5][CH2:6]2)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(CC(F)(F)F)CC1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(CC(F)(F)F)CC2)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-((1S,2R)-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]cyclopropyl)ethanol (30 mg, 0.119 mmol) in DMF (1 mL) was added NaH (60%, 7.2 mg, 0.179 mmol) at RT. The mixture was stirred for 15 min. 1-fluoro-4-(methylsulfonyl)benzene (20.8 mg, 0.119 mmol) was added to the reaction mixture. It was heated at 50° C. for 3 hours. The reaction was quenched with water, extracted with EtOAc. The organic layer was dried by sodium sulfate and concentrated. The residue was purified by Mass directed RPHPLC. The product fraction was basified with 1 M sodium bicarbonate aq. solution, extracted with EtOAc. Solvent was removed under vacuum to yield the Example 4. LCMS calc: 405.47; obs: 406.04 (M+1); Human GPR119 EC50: 175.6 nM. 1H NMR (CDCl3, 500 MHz) 7.90 (d, 2H), 7.02 (d, 2H), 4.15 (m, 2H), 3.05 (s, 3H), 2.97 (m, 4), 2.34 (m, 2H), 2.18 (m, 1H), 1.78 (m, 2H), 1.45-1.58 (m, 3H), 0.96 (m, 1H), 0.82 (m, 1H), 0.65 (m, 2H), −0.88 (m, 1H)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[N:6][CH:7]=1.[CH3:24][S:25][CH3:26].ClN1C(=O)CCC1=O.C[O-].[Na+]>CO.O>[CH3:24][S:25](=[N:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[N:6][CH:7]=1)[CH3:26]
Reactant: CSC
Reactant: CC(C)n1nc(-c2ncc(N)nc2-c2ccccc2)ccc1=O
Agent: C[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)n1nc(-c2ncc(N=S(C)C)nc2-c2ccccc2)ccc1=O
Temperature: 22.5 °C
Reaction time: 20 h

Procedure:
To a suspension of 6-(5-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (1.01 g) was added dimethyl sulfide (0.263 ml) and N-chlorosuccinimide (435 mg) under −5° C. The mixture was stirred at −5° C. for 30 minutes and at 20-25° C. for 20 hours. A solution of 28% sodium methoxide in MeOH (1.13 ml) was added to the mixture and the solution was stirred at the same temperature for an hour. After addition of water (10 ml), the organic layer was collected, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (1:99 v/v) to give 6-{5-[(dimethyl-lambda˜4˜-sulfanylidene)amino]-3-phenyl-2-pyrazinyl}-2-isopropyl-3(2H)-pyridazinone as a solid (0.80 g).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:15][CH2:14][C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][C:7]=2[CH2:6]1)=[O:4].O.[NH2:17][NH2:18]>>[CH3:1][O:2][C:3]([N:5]1[CH2:15][CH2:14][C:8]2[N:9]=[N:10][C:11]([NH:17][NH2:18])=[CH:12][C:7]=2[CH2:6]1)=[O:4]
Reactant: NN
Reactant: COC(=O)N1CCc2nnc(Cl)cc2C1
Solvent: O
Product: COC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
16.5 g of 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid methyl ester and 70 cc of hydrazine hydrate are heated in a water bath for 1 hour. The title compound has a M.P. of 178°-180° (decomp., from acetonitrile).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]([CH3:31])[C:15]1=[O:32])=[O:12])=[CH:5]2.I[CH2:34][C:35]([OH:37])=[O:36].[H-].[Na+]>CN(C=O)C>[C:35]([CH2:34][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]([CH3:31])[C:15]1=[O:32])=[O:12])=[CH:5]2)([OH:37])=[O:36]
Reactant: CN1C(=O)C(NC(=O)c2cc3cc(O)ccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)c2cc3cc(OCC(=O)O)ccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3-Dihydro-3-(5-hydroxyindole-2-carbonylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (0.1 g, 0.236 mmol) and iodoacetic acid (0.044 g, 0.236 mmol) were combined in dry DMF (2 ml) and treated with sodium hydride (18.8 mg of a 60% suspension in mineral oil; 0.472 mmol). The mixture was stirred at ambient temperature for 1 hour, then evaporated to dryness in vacuo. To the residue were added water, dilute sodium bisulfite solution, then saturated sodium bicarbonate. The aqueous phase was washed with EtOAc, made acidic with 6N HCl, and extracted with EtOAc. The acid layer extract was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 180:10:1:1 of CH2Cl2 :MeOH:HOAc:H2O. The product fractions were evaporated to dryness in vacuo and the residue triturated with ether to give the title compound which was dried in vacuo at 90° C. overnight: (mp 150°-180° C. (↑)).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[NH:7]2.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+]>CN(C=O)C.O.[Cu]=O>[C:21]1([N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=3)[CH:5]=[C:6]2[C:16]([O:18][CH3:19])=[O:17])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc2c(OC)c(OC)c(OC)cc2[nH]1
Reactant: Brc1ccccc1
Agent: O=[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(OC)c(OC)c(OC)cc2n1-c1ccccc1
Reaction time: 6 h

Procedure:
Methyl 4,5,6-trimethoxyindole-2-carboxylate (533 mg), bromobenzene (0.22 mL), copper oxide (64 mg) and potassium hydroxide (336 mg) were suspended in dry DMF (10 mL), and the suspension was refluxed and stirred for 6 hours under an argon atmosphere. After cooling, the reaction mixture was dissolved in water (100 mL) and filtered through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and chloroform (20 mL), and water-soluble carbodiimide hydrochloride (192 mg) and N,N-dimethylaminopyridine (small amount) were added to the solution. The mixture was stirred overnight at room temperature. After concentrating the reaction mixture under reduced pressure, water was added to the residue to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (ethyl acetate:hexane=1:3) to obtain the title compound.
Reaction SMILES: S(O)(O)(=O)=O.CS[C:8](=[NH:10])[NH2:9].[OH-].[K+].[NH2:13][CH2:14][C:15]1[NH:20][C:19](=[O:21])[NH:18][C:17](=[O:22])[C:16]=1[Cl:23]>>[ClH:23].[Cl:23][C:16]1[C:17](=[O:22])[NH:18][C:19](=[O:21])[NH:20][C:15]=1[CH2:14][NH:13][C:8]([NH2:10])=[NH:9]
Reactant: NCc1[nH]c(=O)[nH]c(=O)c1Cl
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: Cl
Product: N=C(N)NCc1[nH]c(=O)[nH]c(=O)c1Cl
Temperature: 80 °C
Yield: 66.1 %

Procedure:
Subsequent to addition of 455 mg of 2-methyl-isothiourea sulfate to 33 ml of a 0.1 N aqueous solution of potassium hydroxide under ice cooling, 600 mg of the 6-aminomethyl-5-chlorouracil obtained in Example 22 were added, followed by heating for 2 hours at 80° C. under stirring. After the reaction mixture was allowed to cool down, a crystallized matter was collected by filtration and washed with 2 N hydrochloric acid, whereby 287 mg of the title compound were obtained (yield: 33%).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([CH3:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[ClH:10].[CH3:11][NH:12][CH3:13].[CH2:14]=O.Cl>C(O)C>[ClH:10].[CH3:11][N:12]([CH3:14])[CH2:13][CH2:2][C:1]([C:4]1[S:5][C:6]([CH3:9])=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1ccc(C)s1
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C(=O)CCN(C)C)s1
Yield: 65.7 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 10.0 grams (0.071 mole) of 2-acetyl-5-methylthiophene, 7.0 grams (0.086 mole) of dimethylamine hydrochloride, 2.5 grams of paraformaldehyde and 0.4 ml of concentrated hydrochloric acid in 10 ml of ethanol was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure to a residual solid. The solid was recrystallized from methanol-di-ethyl ether to give 10.9 grams of 3-dimethylamino-1-(5-methyl-2-thienyl)propan-1-one hydrochloride; m.p. 145°-147° C.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[CH2:6]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[C:26](=[O:29])([OH:28])[O-].[Na+].[I-].[K+]>CN(C)C=O.O>[C:10]([OH:9])(=[O:23])[C:26]([OH:28])=[O:29].[O:23]1[CH2:24][CH2:25][N:20]([CH2:2][CH2:3][S:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]3[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=3[CH2:6]2)[CH2:21][CH2:22]1
Reactant: C1COCCN1
Reactant: BrCCSC1Cc2ccccc2Oc2ccccc21
Reactant: O=C([O-])O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C(=O)O
Product: c1ccc2c(c1)CC(SCCN1CCOCC1)c1ccccc1O2
Reaction time: 64 h

Procedure:
A mixture of 1.5 g of 10-(β-bromoethylthio)-10,11-dihydrodibenz [b,f]oxepin, Example 3, 0.5 g of morpholine, 1.0 g of sodium bicarbonate and 1.0 g of potassium iodide in 15 ml of dimethylformamide is stirred at 60°-70° C. for 64 hours. The reaction mixture is permitted to cool before being diluted with water. The biphasic mixture is extracted with ether and the combined ether extracts are shaken with a large excess of 2N hydrochloric acid. The acid solution is basified with potassium carbonate liberating the amine as an oil which is extracted into ether. The ethereal solution is dried and the ether is removed under vacuum regenerating an oil which is converted to its oxalate. The salt is recrystallized from a methanol-acetone-ether mixture to give colorless plates, mp 196°-198° C. of 10,11-dihydro-10-(β-morpholinoethylthio)dibenz[b,f]oxepin oxalate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]2[NH:15][CH2:16][CH2:17][N:18]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([CH3:3])=[CH2:2]>CO.[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]2[NH:15][CH2:16][CH2:17][N:18]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(NC2=NCCN2)cc2cc[nH]c12
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc(NC2=NCCN2)cc2cc[nH]c12

Procedure:
A solution of 7-isopropenyl-5-(2-imidazolin-2-ylamino)indole (0.25 g, 1.0 mmol) and 10% Pd/C (100 mg) in 10 mL of MeOH was stirred for 12 h under H2 (18 psi) The reaction mixture was filtered and concentrated in vacuo, yielding an oil which, in NMR analysis, was highly pure and corresponds to the desired product. The product obtained was converted to the succinate salt and recrystallized from isopropanol-CHCl3 to afford 0.13 g of the product as a light brown solid: mp 254-255° C.; H NMR (CD3OD) δ 7.28 (d, J=1.8 Hz, 1H), 7.27 (d, J=3.2 Hz, 1H), 6.82 (d, J=1.8 Hz, 1H), 6.43 (d, J=3.2 Hz, 1H) 3.67 (s, 4H), 3.30 (hep, 1H), 2.18 (s, 3H); Anal. Calc. for C14H18N4.1.0C4H6O4 requires C, 60.32; H, 6.19; N, 15.63. Found: C, 60.17; H, 6.25; N, 15.59.
Reaction SMILES: [Br-].Cl[C:3]1[C:8]2=[C:9]([CH2:12][N+:13]([CH2:18][CH3:19])([CH2:16][CH3:17])CC)[CH:10]=[CH:11][N:7]2[N:6]=[CH:5][N:4]=1.[C:20]1([C@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[CH2:30][N:31](C(C)C)C(C)C.N1CCC(NC(=O)OC(C)(C)C)CC1.C(O)(C(F)(F)F)=O>CC(N(C)C)=O>[NH2:31][CH:30]1[CH2:17][CH2:16][N:13]([CH2:12][C:9]2[CH:10]=[CH:11][N:7]3[C:8]=2[C:3]([NH:28][C@@H:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:27])=[N:4][CH:5]=[N:6]3)[CH2:18][CH2:19]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC[N+](CC)(CC)Cc1ccn2ncnc(Cl)c12
Reactant: C[C@@H](N)c1ccccc1
Agent: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Br-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: C[C@@H](Nc1ncnn2ccc(CN3CCC(N)CC3)c12)c1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a mixture of Compound 1A (100 mg, 0.29 mmol) and (R)-1-phenylethanamine (34.9 mg, 0.29 mmol) in 0.6 mL of DMA was added DIEA (37.2 mg, 0.29 mmol). The mixture was stirred at room temperature for 17 h upon which time DIEA (74.4 mg, 0.58 mmol) and tert-butyl piperidine-4-ylcarbamate (86.4 mg, 0.43 mmol) were added. The mixture was heated at 70° C. for 3 h and cooled to room temperature. TFA (2.00 mL, 260 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was purified by prep HPLC to give Compound 1C in 62% yield. Compound 1C had an analytical HPLC retention time=1.58 min. (YMC S5 ODS column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=351.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([O:14]C)=O.[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[OH:14][C:12]1[C@H:8]2[C@H:7]([CH2:11][CH2:10][CH2:9]2)[N:6]([CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([CH3:1])[CH:3]=2)[C:35](=[O:36])[C:34]=1[C:29]1[NH:28][C:27]2[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=2[S:31](=[O:33])(=[O:32])[N:30]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1cccc(C)c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cccc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)[C@@H]3CCC[C@@H]32)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl (1R,2S)-2-[(3-methylbenzyl)amino]cyclopentane-carboxylate (74 mg, 0.30 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 100 mg, 0.30 mmol) in anhydrous N,N-dimethylformamide (3 mL) under a nitrogen atmosphere, N-methylmorpholine (0.10 mL, 0.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (63 mg, 0.33 mmol) were added sequentially. The mixture was stirred at 25° C. for 16 h, diluted with ethyl acetate, washed with 1.0 M aqueous hydrochloric acid and saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the amide intermediate, which was used directly in the next step without further purification.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:29]=[C:30]([Cl:35])[CH:31]=[C:32]([Cl:34])[CH:33]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3cc(Cl)cc(Cl)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2cc(Cl)cc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
Lithium hydroxide monohydrate (0.020 g, 0.48 mmol) was added to a stirred solution of {6-chloro-4-[4-(3,5-dichloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.065 g, 0.122 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(3,5-dichloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.058 g, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s, 1 H) 8.26 (d, J=8.80 Hz, 2H) 8.15 (s, 2 H) 8.05-8.08 (m, 1 H) 7.97 (d, J=8.80 Hz, 1 H) 7.91 (s, 1 H) 7.56 (d, J=8.80 Hz, 2 H) 7.48 (d, J=8.60 Hz, 1 H) 6.97 (s, 1 H) 3.84 (s, 2 H) 2.03 (s, 3H). MS calcd. for C25H16Cl3O4S [(M−H)−] 517, obsd. 517.1.
Reaction SMILES: [Cl:1]C1C=CC(OC)=C([C@@]2(F)C3C(=CC(C(F)(F)F)=CC=3)N(C([NH:23][C@@H:24]([CH:32]([CH3:34])[CH3:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=O)C2=O)C=1.C(N(CC)CC)C>>[ClH:1].[C:28]([O:27][C:25](=[O:26])[C@H:24]([CH:32]([CH3:33])[CH3:34])[NH2:23])([CH3:31])([CH3:30])[CH3:29]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)c2cc(C(F)(F)F)ccc21
Solvent: CCN(CC)CC
Product: CC(C)[C@H](N)C(=O)OC(C)(C)C
Product: Cl
Yield: 52 %

Procedure:
(S)-tert-butyl 2-((S)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indoline-1-carboxamido)-3-methylbutanoate (XVIII5): Following general procedure (F), after forming the intermediate, L-valine t-butyl ester hydrochloride (0.321 g, 1.53 mmol) and triethylamine (0.41 mL, 2.92 mmol) were added. After work-up and purification, 0.40 g of the title compound as a white foam solid was obtained (52% yield). mp: 56–60° C. MS: 489 (no mother ion). Anal. Calcd. for C26H27ClF4N2O5: C, 55.87; H, 4.87; N, 5.01. Found: C, 55.95; H, 4.89; N, 4.89. 1H NMR (CDCl3): δ 0.99 (d, J=6.9 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.51 (s, 9H),2.33 (m, 1H), 3.55 (s, 3H), 4.50 (dd, J=8.5 Hz, 4.5 Hz, 1H), 6.78 (dd, J=8.8 Hz, 1.2 Hz, 1H), 7.27 (m, 1H), 7.37 (dd, J=8.7 Hz, 2.6 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.81 (dd, J=2.6 Hz, 0.9 Hz, 1H), 8.6 (s, 1H), 8.70 (d, J=8.4 Hz, 1H). IR (KBr, cm−1): 3338, 2972, 1761, 1735, 1717, 1531, 1491, 1439, 1319, 1261, 1173, 1132, 1061.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.C(#N)C.Br[C@H:22]([CH3:37])[C:23]([N:25]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[CH2:27][C@H:26]1[C:34]([OH:36])=[O:35])=[O:24]>ClCCl>[CH2:6]([O:5][C:3]([C@@H:2]([NH:1][C@@H:22]([CH3:37])[C:23]([N:25]1[C:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=2[CH2:27][C@H:26]1[C:34]([OH:36])=[O:35])=[O:24])[CH2:8][CH2:9][CH3:10])=[O:4])[CH3:7]
Reactant: CCC[C@H](N)C(=O)OCC
Reactant: C[C@@H](Br)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CCC[C@H](N[C@@H](C)C(=O)N1C2=C(CCCC2)C[C@H]1C(=O)O)C(=O)OCC

Procedure:
Introduce into a reactor 105 g of ethyl (2S)-2-aminopentanoate, 135 ml of triethylamine and 135 ml of acetonitrile, and then bring the mixture to 60° C. and slowly add a solution of 200 g of the compound obtained in Step A in 1.3 litres of dichloromethane, and subsequently reflux for 4 hours. After returning to ambient temperature, wash the mixture with water and with a dilute acetic acid solution, and then evaporate off the solvents to yield (2S)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}-2,3,4,5,6,7-hexa-hydro-1H-indole-2-carboxylic acid.
Reaction SMILES: C(/N=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[CH2:15][CH3:16])CCC.C(OCC)(=[O:19])C.CCCCCCC>>[CH2:15]([C:8]1[C:9]([F:14])=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[CH:6]=[O:19])[CH3:16]
Reactant: CCOC(C)=O
Reactant: CCCC/N=C/c1c(F)ccc(F)c1CC
Solvent: CCCCCCC
Product: CCc1c(F)ccc(F)c1C=O

Procedure:
2-Ethyl-3,6-difluoro-benzaldehyde was prepared from butyl-[1-(2-ethyl-3,6-difluoro-phenyl)-meth-(E)-ylidene]-amine by flash chromatography (silica gel, ethyl acetate/heptane gradient): yellow oil; 1H-NMR (CDCl3): 1.22 (3H, t, CH3), 3.02 (2H, m, CH2), 6.99 (1H, ddd, ArH), 7.23 (1H, ddd, ArH), 10.45 (1H, d, CH═O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[CH:14][NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10](=O)[N:9]2[CH3:23])=[CH:4][CH:3]=1.ClC(Cl)C(Cl)Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH:14]=[N:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:10]=3[N:9]2[CH3:23])=[CH:4][CH:3]=1
Reactant: CN1C(=O)C(=CNc2ccccc2)C(=O)N1c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)C(Cl)Cl
Product: Cn1c2c(cnc3ccccc32)c(=O)n1-c1ccc(Cl)cc1

Procedure:
The mixture of 650 mg of 1-(p-chlorophenyl)-2-methyl-4-anilinomethylidene-pyrazolidin-3,5-dione, 2.0 g of ethyl polyphosphate and 10 ml of 1,1,2,2-tetrachloroethane is refluxed for 24 hours. The solution is poured onto 10 ml of 2 N aqueous sodium hydroxide and the organic layer chromatographed on silica gel plates, using toluene:ethanol:conc. ammonium hydroxide (80:20:1) as eluent, to yield the 2-(p-chlorophenyl)-1-methyl-pyrazolo[4,3-c] quinolin-3-one with an Rf=0.48. When using dichloromethane:methanol (19:1) as eluent, said compound has the Rf=0.33; it is identical with that of Example 4.