Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:10]=[CH:9][C:8]=1[C:19]#[N:20].[OH-:21].[Na+]>>[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:10]=[CH:9][C:8]=1[C:19]([NH2:20])=[O:21]
Reactant: [OH-]
Reactant: Cc1ccccc1-n1ncc(C#N)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccccc1-n1ncc(C(N)=O)c1N
Temperature: 40 °C
Reaction time: 2 h

Procedure:
300 ml of 96% strength sulphuric acid are cautiously added to 40.0 g (201.8 mmol) of 5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carbonitrile (Example 8A) while cooling in ice. The mixture is then heated to 40° C. and stirred for 2 hours at this temperature. After cooling, it is poured into 2 l of ice-water and cautiously neutralized with 50% strength sodium hydroxide solution. After extraction with ethyl acetate three times (2 l each time) the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate, and the solvent is distilled off under reduced pressure. 36.0 g (82% of theory) of product (purity>90%) are obtained and are employed without further purification in subsequent reactions.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[S:7]1C=CC=C1CC(O)=O.Br[CH:17]([CH:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19]>CN(C)C=O.CCOCC>[C:2]([S:7][CH:17]([CH:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])(=[O:4])[CH3:1]
Reactant: COC(=O)C(Br)C(C)C
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)Cc1cccs1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C(SC(C)=O)C(C)C
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
Potassium tert-butoxide (20.4 g) was added portionwise with stirring and cooling to thiolacetic acid (13.85 g) in dry dimethylformamide (150 ml). Stirring was continued for five minutes, then methyl 2-bromo-3-methylbutanoate (32.3 g) was added with ice-cooling (about 10° C. internal temperature). After stirring at room temperature overnight, the reaction mixture was diluted with ether (about 1 liter), washed with water (3 times), dried over magnesium sulfate and run down under vacuum. The title product was obtained as an orange oil, 29.2 g (93%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)=[CH:12][CH:11]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1ccc(F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 3 ml of N,N-dimethylformamide were dissolved 334 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 4-fluorobenzyl alcohol, 84 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 4 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 357 mg of 5-(4-fluorobenzyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (12)).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=1[NH2:16].C(N(CC)C(C)C)(C)C.[C:31]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>ClCCl>[C:31]([N:38]1[CH2:39][CH2:40][N:41]([C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=2[Br:13])=[O:4])[CH2:42][CH2:43]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)cc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(Cl)cc2Br)CC1
Reaction time: 8 h
Yield: 191.1 %

Procedure:
To a stirring solution of triphosgene (2.7 g, 9.0 mmol) in dichloromethane (100 mL) was added, dropwise via an addition funnel, a solution of 2-bromo-4-chloroaniline (5 g, 24.2 mmol) and N,N-diisopropylethylamine (6.9 g, 53.2 mmol) in dichloromethane (50 mL). After complete addition and an additional hour, a solution of N-Boc-piperazine (5 g, 26.6 mmol) in dichloromethane (50 mL) was added. After stirring overnight, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was separated and washed consecutively with 1 M citric acid, brine, sat. aq sodium bicarbonate and finally with brine, then dried with MgSO4, filtered and concentrated in vacuo. The residue was then dissolved in a minimal amount of chloroform and chromatographed over silica gel, eluting with 20% ethyl acetate in hexanes followed by 30% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo and the resulting solid was suspended in diethyl ether, sonicated and then filtered and dried in vacuo to give 7.2 g (71%) of a white powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([OH:16])[CH:15]=1.[H-].[Na+].Br[CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCOC(C)=O>CN(C=O)C>[Si:24]([O:23][CH2:22][CH2:21][O:16][C:14]1[CH:15]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:11]=[CH:12][C:13]=1[CH3:17])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1OCCO[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 5-(1,3-benzoxazol-2-yl)-2-methylphenol (355 mg, 1.6 mmol) in DMF (10 mL) was cooled to 0° C. and NaH (70 mg, 1.7 mmol) was added slowly. After 15 min, (2-bromoethoxy)(tert-butyl)dimethylsilane (370 μL, 1.7 mmol) was added. The reaction was then elevated to 90° C. for 1 h and EtOAc (100 mL) was added. The EtOAc solution was washed with brine (3×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column (silica gel, hexanes:EtOAc 1:5) to afford 2-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethoxy)-4-methylphenyl]-1,3-benzoxazole.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([NH:16][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2nc3cc(N)ccc3s2)cc1
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1ccc2sc(-c3ccc(C)cc3)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
To a solution of 2-p-tolylbenzo[d]thiazol-5-amine (110 mg, 0.46 mmol) in pyridine (3 mL) at room temperature was added butyryl chloride (53 μL, 0.50 mmol). The resulting mixture was stirred at room temperature for 2 days. Ethyl acetate was added and the organic layer was washed with saturated aqueous copper sulfate, followed by aqueous sodium bicarbonate and finally with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 25 mg (18%) of the title compound (LCMS RT=7.10 min, MH+ 311.0)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:43]([O:50][C@H:51]([CH3:55])[C:52](O)=O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)CC)C>ClCCl>[CH2:43]([O:50][C@@H:51]([C:55]1[O:18][C:5]2[C:6]([C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)O
Reactant: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](OCc1ccccc1)c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
To 1-(5-fluoro-2-hydroxyphenyl)-2-(3-fluorophenyl) ethanone (11 g, 44.31 mmol), in Dichloromethane (110 ml), HATU (33.7 g, 88.63 mmol) and (R)-Benzyloxypropionic acid (9.58 g, 53.17 mmol) were added and stirred for ˜10 min. Triethylamine (67 ml, 478 mmol) was added dropwise and stirred at room temperature (RT) for 24 h. The reaction mixture was quenched with water and extracted with Dichloromethane (2×250 ml). The organic layer was dried with sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography with ethyl acetate:Petroleum ether to afford the title compound as a off-white solid (10.9 g, 63%). 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.85 (dd, J=8.1, 3.0 Hz, 1H), 7.58 (dd, J=9.1, 4.1 Hz, 1H), 7.47-7.39 (m, 1H), 7.39-7.34 (m, 1H), 7.28-7.20 (m, 3H), 7.20-7.14 (m, 2H), 7.16-7.14 (m, 1H), 6.99-7.89 (m, 2H), 4.50-4.31 (m, 3H), 1.56 (d, J=6.4 Hz, 3H). Mass: 392.9 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:23](OC)(OC)OC>CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]=[CH:23]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1
Reactant: COC(OC)OC
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCC(n3cnc4ccccc43)CC2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 200 mg of N-(1-benzyl-piperidin-4-yl)-benzene-1,2-diamine (from Step A) in 6 mL of trimethyl orthoformate was added 0.2 mL concentrated HCl. After stirring at 80° C. for 16 hours, the reaction mixture was diluted with 30 ml of EtOAc. The organic phase was washed with 15 mL saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×20 mL EtOAc. The combined organic phases were washed with 10 mL of brine, dried over MgSO4 and concentrated under reduced pressure to give 198 mg yellow solid. 1H NMR (400 MHz, CDCl3): δ2.11-2.22 (m, 6H), 3.06 (m, 2H), 3.58(s, 2H), 4.20 (s, 1H), 7.24-7.34(m, 7H),7.42(m, 1H), 7.81 (m, 1H), 8.04(s, 1H). ESI-MS 292 (M+H); HPLC A: 1.80 min.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:17]1=[O:27].Cl[C:37]([O:39][CH3:40])=[O:38].C(N(CC)CC)C>C(Cl)Cl>[CH3:40][O:39][C:37]([N:24]1[CH2:25][CH2:26][CH:21]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH2:15][C:14]3[C:13]([Cl:28])=[CH:12][C:11]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)=[CH:10][C:9]=3[Cl:8])[C:17]2=[O:27])[CH2:22][CH2:23]1)=[O:38]
Reactant: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCNCC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(F)cc4)cc3Cl)C2=O)CC1
Yield: 93.3 %

Procedure:
Treat a solution of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-piperidin-4-yl-pyrrolidin-2-one trifluoroacetic acid (Preparation 29) (0.10 g, 0.19 mmol) in CH2Cl2 (3 mL) with methyl chloroformate (0.03 mL, 0.36 mmol) and triethylamine (0.07 mL, 0.48 mmol). Stir the reaction for 1 hr at room temperature. Quench the reaction with 1N HCl and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 0.085 g (74%) of product. MS (m/e): 479 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH3:14].[OH-:21].[Na+].O>C(O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:13]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)[CH:14]=[C:5]2[C:6]([OH:11])=[O:21]
Reactant: [OH-]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: CC(=O)c1ccco1
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2ccco2)nc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.4 %

Procedure:
To a 500 ml three necked round bottom flask was added 5-bromoisatin (20 g) and 2-acetyl-furan (9.7 g) in ethanol (150 ml) followed by NaOH (9.2 g) in one lot and the resulting brown solution was allowed to stir at RT for 5 minutes. To the above reaction mixture was added water (5 ml) at RT and the reaction mixture was heated to reflux for 2 hours. The completion of the reaction was monitored on TLC using MDC:MeOH (9:1) as a mobile phase. After completion of the reaction, the reaction mixture was filtered hot and water (150 ml) was added to filtrate. The filtrate was then acidified with 5N HCl to pH 6.0-6.5 and the precipitate formed was filtered and washed with water (3*50 ml) followed by ethanol (2*10 ml) to yield 6-bromo-2-(furan-2-yl)quinoline-4-carboxylic acid (20 g).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1)([CH3:3])[CH3:2].[NH2:16][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]1.C(P(=O)(OCC)OCC)#N.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:16][C@@H:17]2[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]2)=[O:15])=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1nc(C(=O)O)c2ccccc21
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Reaction time: 14 h
Yield: 97.7 %

Procedure:
To a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid (300 mg, 1.47 mmol) and 1-tert-butyl 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (396 mg, 1.62 mmol, Bioorg. Med. Chem., 2002, 10, 1399-1415) in N,N-dimethylformamide (15 mL) were added diethyl cyanophosphonate (0.27 mL, 1.76 mmol) and N,N-diisopropylethylamine (0.31 mL, 1.76 mmol) at room temperature. The resulting mixture was stirred for 14 h at the same temperature and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (200 mL), and the solution was washed with water (50 mL×2), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (3:1) to give 618 mg (98%) of the title compound as a white amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[C:4]([F:12])[CH:3]=1.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:20]\[NH:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[CH2:9][CH3:10])=[C:4]([F:12])[CH:3]=1.[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:20]/[NH:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[CH2:9][CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: NNc1ccccc1
Reactant: CCC(=O)c1ccc(Br)cc1F
Solvent: CCO
Product: CC/C(=N/Nc1ccccc1)c1ccc(Br)cc1F
Product: CC/C(=N\Nc1ccccc1)c1ccc(Br)cc1F

Procedure:
Into a 1000-mL round-bottom flask, was placed a solution of 1-(4-bromo-2-fluorophenyl)propan-1-one (32 g, 138.53 mmol, 1.00 equiv) in ethanol (300 mL), 1-phenylhydrazine (15.0 g, 138.89 mmol, 1.00 equiv), TSA-H2O (1.32 g, 6.95 mmol, 0.05 equiv). The resulting solution was heated to reflux for 1 h in an oil bath. The resulting mixture was concentrated under vacuum to yield (Z)-1-(1-(4-bromo-2-fluorophenyl)propylidene)-2-phenylhydrazine and (E)-1-(1-(4-bromo-2-fluorophenyl)propylidene)-2-phenylhydrazine as a yellow solid. MS: 322 (MH+)
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(C(C)C)C(C)C)C.[C:22]([C:25]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][C:38]=3[Cl:47])=[CH:33][CH:32]=2)[C:28]([CH3:48])=[N:27][C:26]=1[CH3:49])(=[O:24])[NH2:23].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[C:22]([C:25]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][C:44]([NH:2][C@@H:3]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:45])=[CH:39][C:38]=3[Cl:47])=[CH:33][CH:32]=2)[C:28]([CH3:48])=[N:27][C:26]=1[CH3:49])(=[O:24])[NH2:23]
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.2 %

Procedure:
A mixture of (S)-ethyl 2-amino-4-methylpentanoate hydrochloride (111 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction was incomplete so the temperature was increased to 50° C. and the reaction mixture was stirred for a further 3 hours. The reaction mixture was diluted with EtOAc (20 mL), and washed sequentially with water (50 mL), saturated brine (50 mL), and water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford (S)-ethyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-4-methylpentanoate (224 mg, 81%) which was used without further purification.
Reaction SMILES: Br[CH2:2][CH3:3].[CH3:4][C:5]1([CH3:18])[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][NH:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:2]([N:7]1[CH2:6][C:5]([CH3:18])([CH3:4])[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8]1)[CH3:3]
Reactant: CCBr
Reactant: CC1(C)CNCc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1Cc2cc([N+](=O)[O-])ccc2C(C)(C)C1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Bromoethane (0.75 g, 6.88 mmol) was added to a solution of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.4 g, 6.79 mmol) and K2CO3 (2 g, 14.47 mmol) in N,N-dimethylformamide (80 mL). The mixture was stirred at 50° C. for 4 hours. The solvent was removed under vacuum to give a residue which was purified by silica gel column chromatography eluting with 10% ethyl acetate/heptane to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[C:26](Cl)(=[O:30])[C:27](Cl)=[O:28].[N:32]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[C:7]2[C:14]([C:26](=[O:30])[C:27]([NH2:32])=[O:28])=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1cccc(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)ncnc2n1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a suspension of 110 mg (0.30 mmol) of [[6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]acetic acid methyl ester in 3 mL of chloroform was added 0.106 mL of oxalyl chloride followed by 0.10 mL of pyridine. The reaction was stirred for 48 hours at ambient temperature then an additional 0.100 mL of oxalyl chloride and 0.100 mL of pyridine was added. This mixture was stirred and additional 4 days then quenched into solution prepared from 4 mL of water and 2 mL of concentrated ammonium hydroxide. The mixture was partitioned by the addition of 20 mL of ethyl acetate and 10 mL of water. The organic phase was dried with sodium sulfate and concentrated to 91 mg of crude solid. The residue was purified by flash chromatography (7 g of silica, ethyl acetate) to provide 69 mg (53%) of [[5-(aminooxoacetyl)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.15 (t, J=7.4 Hz, 3H), 2.95 (q, J=7.4 Hz, 2H), 3.78 (s, 3H), 5.05 (s, 2H), 5.50 (s, 2H), 5.68 (br s, 1H), 6.60 (br s, 1H), 6.98 (d, J=7.4 Hz, 1H), 7.2 (s, 1H), 7.26 (m, 2H), 8.46 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][CH:4]=1.C(NC(C)C)(C)C.[Li]C.[CH:22](N1CCCCC1)=[O:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[CH:22]=[O:23]
Reactant: O=CN1CCCCC1
Reactant: COCOc1ccc(OC)cc1
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(OC)c(C=O)c1
Temperature: -40 °C
Reaction time: 3 h

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)benzene (20 g, 0.1 2 mol) in THF is added diisopropylamine (0.24 g, 2.4 mmol). The solution is cooled to −40° C. followed by addition of MeLi (3M/THF, 72 mL, 0.216 mol) slowly. The resulting mixture is warmed to 0° C., stirred at 0° C. for 3 h, cooled back down to −40° C. and added N-formylpiperidine (24 mL, 0.216 mol). After stirring at −40° C. for 2 h, the mixture is quenched with a mixed solution of HCl (37%, 120 mL) and THF (250 mL). The temperature is then raised to rt and diluted with water (200 mL) and EtOAc (200 mL). The pH of the mixture is adjusted to 8-9 with solid K2CO3 and extracted with EtOAc (300 mL) twice. The organic layer is combined, dried over Na2SO4, and concentrated. The residue is purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)benzaldehyde.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:9](=[O:10])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:10]=[C:9]1[C:5]2=[C:4]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:3]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:2](=[O:1])[C:6]2=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1nc(-c2ccccc2)c2c(=O)nc(-c3ccccc3)c1=2
Product: O=C1C2=C(c3ccccc3)N(C(=O)c3ccccc3)C(=O)C2=C(c2ccccc2)N1C(=O)c1ccccc1

Procedure:
5.8 parts of 1,4-diketo-3,6-diphenylpyrrolo-[3,4-c]-pyrrole are stirred with 50 parts of benzoyl chloride at 190° C. for 22 hours. The starting material dissolves in the course of the reaction. On cooling of the reaction mixture, most of the reaction product precipitates. The reaction mixture is introduced into 320 parts of methanol, with stirring, and the mixture is stirred for 2 hours, without heating. The precipitated product is filtered off, washed with methanol and dried. 4.9 parts of ochre-coloured crude product which is purified by crystallisation from 50 parts of dimethylformamide, with addition of a filtration assistant, are obtained. 3.8 parts of 1,4-diketo-2,5-dibenzoyl-3,6-diphenylpyrrolo-[3,4-c]-pyrrole are obtained in the form of brownish-yellow crystals (formula XVIII). ##STR22##