Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][N:13]1[C:21]2[N:20]=[CH:19][NH:18][C:17]=2[C:16](=[O:22])[NH:15][C:14]1=[O:23].CN(C)C=O>O>[CH2:2]([N:18]1[C:17]2[C:16](=[O:22])[NH:15][C:14](=[O:23])[N:13]([CH3:12])[C:21]=2[N:20]=[CH:19]1)[C:3]#[C:4][CH3:5]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
55.3 ml of 1-bromo-2-butyne and 84.9 g of anhydrous potassium carbonate were added to a mixture of 100 g of 3-methyl xanthine [CAS No. 1076-22-8] and 1000 ml of N,N-dimethylformamide. The resulting mixture was stirred at room temperature for 18 hours. 1000 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The resulting white precipitate was collected by filtration. The white solid was washed with water and then t-butyl methyl ether. Thus, 112 g of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC1C2C(=CC(O)=CC=2)C=CN=1.C(OC(N1CCC[C@@H](OS(C)(=O)=O)C1)=O)(C)(C)C.CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(N)nccc3c2)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Agent: Nc1nccc2cc(O)ccc12
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC(Oc2ccc3c(N)nccc3c2)C1
Temperature: 160 °C

Procedure:
For an alternate procedure for the preparation of (S)-3-(1-amino-isoquinolin-6-yloxy)piperidin-1-carboxylic acid tert-butyl ester, a suspension of 1-amino-6-hydroxyisoquinoline (0.8 g, 5.0 mmol), (R)-3-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (1.76 g) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (3.4 g, −2.2 mmol/g loading) in acetonitrile (10 ml) were heated at 160° C. over a period of 15 minutes using the microwave. The excess supported regent was removed by filtration, washing with acetonitrile followed by methanol, and the filtrate evaporated to dryness under reduced pressure. Purification was achieved by chromatography on silica (eluent: 2-10% methanol in ethyl acetate) to afford (S) 3-(1-amino-isoquinolin-6-yloxy)piperidin-1-carboxylic acid tert-butyl ester (72 mg), El-MS: m/z=344.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(Cl)Cl>[CH:24]([NH:27][C:4](=[O:6])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])([CH3:26])[CH3:25]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)NC(=O)c1c(F)cccc1F

Procedure:
A solution of 2,6-difluorobenzoic acid (10 g, 63 mmol) and carbonyldiimidazole (10.26 g, 63.5 mmol) in 300 mL methylene chloride was stirred for 1 hour at ambient temperature. Isopropyl amine (5.39 mL, 63.25 mmol) was added and stirring was continued over night. An equivalent volume of methylene chloride was added, and the reaction mixture was washed with water, 1M NaOH, 1M HCl, and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo to give a near quantitative yield of the amide as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:20])=[N:5][C:6]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:8]=1)#[CH:2]>C(O)C.[Pt](=O)=O>[CH2:1]([C:3]1[C:4]([NH2:20])=[N:5][C:6]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[C:7]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[N:8]=1)[CH3:2]
Reactant: C#Cc1nc(-c2ccncc2)c(-c2ccco2)nc1N
Agent: O=[Pt]=O
Solvent: CCO
Product: CCc1nc(-c2ccncc2)c(-c2ccco2)nc1N
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of 3-ethynyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 65, 50 mg, 0.19 mmol) in ethanol (4 mL) was added platinum dioxide (5 mg). The mixture was hydrogenated at 1 atmosphere and at room temperature for 18 h, filtered, washed with methanol and dichloromethane and evaporated to give the title compound as a white solid (44 mg, 88%).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH:6]([CH3:24])[C:7]([N:9]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][S:11][CH:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])=[O:4].Cl>[OH-].[Na+]>[C:3]([CH2:5][CH:6]([CH3:24])[C:7]([N:9]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][S:11][CH:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])([OH:4])=[O:2]
Reactant: COC(=O)CC(C)C(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CC(=O)O)C(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
(4R)-3-[3-(Methoxycarbonyl)-2-methylpropanoyl]-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (compound 4) (7.1 g) was dissolved in 2N sodium hydroxide (40 ml) and stirred for 1 hour at room temperature. The resulting solution was acidified with dilute hydrochloric acid and the separated crystals were filtered to give 5.1 g (75%) of the titled compound: mp 163°-164° C. (dec.) (ethyl acetate); [α]D25 +174.1° (c=1.0, methanol). IR (nujol, cm-1): 3330 (OH), 1730 and 1710 (COOH), 1629 (CON), 1280, 1234, 856, 771.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:18][CH:17]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][CH:21]=1
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Methyl 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (13.0 g, 35.6 mmol) obtained in Example 16 was dissolved in methanol (400 ml), and 1N aqueous sodium hydroxide solution (50 ml) was added with stirring at room temperature. After stirring for 15 hr, the solvent was evaporated under reduced pressure. Ethyl acetate (50 ml) and water (200 ml) were added for partition. 1N Hydrochloric acid was added to the aqueous layer to acidify same. The precipitated solid was collected by filtration, washed with water (50 ml) and dried under reduced pressure to give the title compound (12.0 g, yield 96%) as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.C([O:14][CH2:15][CH3:16])C>>[CH3:1][C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH:15]=[O:14]
Reactant: CCCCCC
Reactant: CCOCC
Agent: O=S(=O)(O)O
Product: CCCC[C@@H](C)CC=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
In a 300 ml flask were charged 86 ml of hexane and 56 g of (R)-3-methyl-1-heptenyldiethylamine obtained in Step 1, followed by cooling to 0° C. To the solution was added 73 g of 20% sulfuric acid over 1.5 hours, followed by stirring for 20 minutes. After completion of the reaction, 50 ml of diethyl ether was added thereto, and the reaction mixture was washed with water. The solvent was removed by distillation to obtain 34.2 g (86.2%) of a crude product.
Reaction SMILES: C[Si](I)(C)C.[Cl:6][C:7]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[CH:10]=[CH:9][C:8]=1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])=[N:26][NH:27]2)=[CH:23][CH:22]=1>CO>[Cl:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])=[N:26][NH:27]2)=[CH:23][CH:22]=1
Reactant: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3Cl)ccc12
Agent: C[Si](C)(C)I
Solvent: CO
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(O)cc3Cl)ccc12
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
15 cm3 of trimethylsilyl iodide are added to 0.6 g of N-[6-[2-chloro-4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide, described previously, and the mixture is refluxed for 4 hours, followed by addition of 50 cm3 of methanol, and refluxing is continued for 15 minutes. The reaction medium is concentrated to dryness under reduced pressure (2 kPa; 50° C.), 100 cm3 of ethyl acetate are added and the organic phase is washed with 2×50 cm3 of 10% sodium thiosulphate solution and then with 50 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness. The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 0.24 g of N-[6-(2-chloro-4-hydroxyphenyl)-1H-indazol-3-yl]butanamide is obtained in the form of a white foam.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:16][OH:17])[CH:7]=[CH:8][C:9]=1[N:10]1[C:14]([CH3:15])=[CH:13][N:12]=[CH:11]1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[CH2:27][CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]([CH3:15])=[CH:13][N:12]=[CH:11]1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[CH2:27][CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: Cc1cncn1-c1ccc(CO)cc1F
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cncn1-c1ccc(COc2cc3n(c(=O)n2)CCN3C)cc1F

Procedure:
Prepared in a manner similar to that described for E1 using NaH (17.46 mg, 0.727 mmol), (3-fluoro-4-(5-methyl-1H-imidazol-1-yl)phenyl)methanol (100 mg, 0.485 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]-pyrimidin-5(1H)-one (90 mg, 0.485 mmol).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:12])[S:4](=[O:11])(=[O:10])[N:5]=[C:6]([O:8][CH3:9])[N:7]=1.[CH:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([OH:22])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:7]=[C:2]([O:22][C:15]2[CH:14]=[CH:13][C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=2)[N:3]([CH3:12])[S:4](=[O:11])(=[O:10])[N:5]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC1=NS(=O)(=O)N(C)C(Cl)=N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=NS(=O)(=O)N(C)C(Oc2ccc([N+](=O)[O-])cc2)=N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-chloro-5-methoxy-2-methyl-2H-1,2,4,6-thiatriazine-1,1-dioxide (48 g) in methylene chloride (25.5 ml) is added dropwise to a stirred mixture of p-nitrophenol (38 g) and triethylamine (55 g) in methylene chloride (1 l). The mixture is stirred at RT for about 12 hours, refluxed for about 31/2 hours, concentrated in vacuo, the residue is treated with sat'd aq. Na2CO3 solution, and the resulting insoluble solid filtered and washed with water and CH2Cl2. The solid is recrystallized from ethyl acetate/acetonitrile yielding the p-nitrophenoxy compound as a crystalline solid, M.P.=220°-221° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([O:6][CH2:7][C:8]1[C:15]([F:16])=[C:14](F)[C:11]([CH2:12][OH:13])=[C:10]([F:18])[C:9]=1[F:19])[CH3:5].O.Cl>CO.COCCOCCOC>[F:18][C:10]1[C:9]([F:19])=[C:8]([CH2:7][O:6][CH2:4][CH3:5])[C:15]([F:16])=[C:14]([O:2][CH3:1])[C:11]=1[CH2:12][OH:13]
Reactant: CCOCc1c(F)c(F)c(CO)c(F)c1F
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Solvent: CO
Product: CCOCc1c(F)c(F)c(CO)c(OC)c1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of sodium methoxide (generated from 0.13 g sodium) in dry methanol (20 cm3) was added to a solution of 4-(ethoxymethyl)-2,3,5,6-tetrafluorobenzyl alcohol (1.2 g) in dry diglyme. The stirred reaction mixture was heated at 90° C. for a period of 4 hours, under an atmosphere of dry nitrogen, after which time a further portion of sodium methoxide (0.1 g) was added, and heating continued for a further 8 hours. After cooling to the ambient temperature the reaction mixture was poured into water, acidified with dilute aqueous hydrochloric acid, and extracted into ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure. The brown residue was subjected to column chromatography on silica gel using hexane containing increasing amounts of diethyl ether (from 0% to 100%) by volume as eluent. The crude product thus obtained was again subjected to chromatography on silica gel in a similar manner to give 2,3,5-trifluoro-4-(ethoxymethyl)-6-methoxybenzyl alcohol as a pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[CH:9](OCC)(OCC)[O:10]CC.CC(O)C.[ClH:23]>O>[OH2:4].[OH2:10].[ClH:23].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)C(N)C(N)=O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: NC(=O)c1nc[nH]c1O
Temperature: 80 °C
Reaction time: 13 h

Procedure:
Under the nitrogen atmosphere, 10 g of 2-aminomalonamide and 35.4 mL of triethyl orthoformate were added to 200 mL of 2-propanol. After heating to 80° C., the reaction mixture was stirred for 13 hours at the same temperature. Color of the reaction liquid was pale blue when the reaction was completed. Subsequently, the reaction mixture was cooled to 58° C., then added with 10 mL of water followed by 8 mL of conc. hydrochloric acid. After cooling the reaction mixture to 5° C., the crystal was collected by filtration and then washed with 40 mL of acetone to give 16 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a green crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][OH:18])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH3:2].[CH2:32](OC(C1C(C)=C2C(=CC=1C)N=C(COCC1C=CC=CC=1)N(C1C=CC=CC=1S(=O)(=O)NC)C2=O)=O)[CH3:33].C(OCC)C>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][OH:18])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH2:2][CH2:32][CH3:33]
Reactant: CCOC(=O)c1c(C)cc2nc(COCc3ccccc3)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Reactant: CCOC(=O)c1c(C)cc2nc(CO)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCOC(=O)c1c(C)cc2nc(CO)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Reaction time: 8 h

Procedure:
Preparation of 2-Hydroxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: A solution of 2-Benzyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester (15 g, 0.028 mol) in anhydrous THF (270 mL) is degassed under house vacuum. Palladium on activated charcoal (Acros, 10% Pd, 930 mg) is added and the suspension is flushed with hydrogen (balloon). The suspension is stirred under hydrogen overnight. TLC and LCMS analysis indicates that starting material remained. The reaction mixture is filtered through Celite, and the catalyst is washed sequentially with methanol, DCM and methanol. The filtrate is evaporated to give a cream solid. Trituration with diethyl ether provides a white solid which is removed by filtration and dried under high vacuum to provide the title compound. The ethereal filtrate, which contains un-reacted starting material, is evaporated in vacuo and the residue is subjected to a second cycle of hydrogenation (Pd—C, 920 mg): after stirring overnight under hydrogen TLC/LCMS indicated absence of starting material. The reaction mixture is worked-up as above to provide the title compound as a white solid.
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])[CH2:5]2.[CH3:12][C:13]1[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:16]([CH3:27])[NH:15][C:14]=1[CH:28]=O>N1CCCC1.C(O)C>[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=[CH:28][C:14]1[NH:15][C:16]([CH3:27])=[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:13]=1[CH3:12]
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN1CCOCC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1CCCN1CCOCC1
Temperature: 90 °C
Yield: 90 %

Procedure:
A mixture of 5-bromo-1,3-dihydroindol-2-one (212 mg, 1.0 mmol), 3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrole-2-carbaldehyde (250 mg, 1.0 mmol) and 3 drops pyrrolidine in 2.0 ml of ethanol was refluxed at 90° C. for 4 hours and then cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane and dried in a vacuum oven overnight to give 399.8 mg (90%) of 5-bromo-3-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one as a red solid:
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:23]([CH3:35])[CH:22]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.B(F)(F)F.[CH3:40][CH2:41][O:42]CC>C(O)CO>[C:30]([C:29]1([CH2:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([C:16]([C:12]3[CH:13]=[C:14]([CH3:15])[C:8]4[O:7][C:6]([C:4]([OH:3])=[O:5])=[CH:10][C:9]=4[CH:11]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:22][C:23]=2[CH3:35])[O:34][CH2:40][CH2:41][O:42]1)([CH3:31])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc(C)c2o1
Reactant: CCOCC
Agent: FB(F)F
Solvent: OCCO
Product: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carboxylic acid ethyl ester (506 mg, 1.06 mmol) in ethylene glycol (5.0 mL) is treated with BF3-Et2O (3.0 ml). The reaction mixture is heated to 80° C. and stirred for 3 h. The reaction is quenched with water (20 mL) and extracted with CH2Cl2 (30×2 mL). The organic layer is dried over Na2SO4, concentrated, purified on column chromatography (8% EtOAc/Hex) to afford the title compound (550 mg, 99%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=O)=[C:7]([N+:27]([O-:29])=[O:28])[CH:6]=1)(=[O:4])=[O:3].B.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.CO>[CH3:18][N:16]([CH3:17])[CH2:14][CH2:13][C@@H:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:6][C:7]=1[N+:27]([O-:29])=[O:28])[CH2:19][S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN(C)C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: B
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of Example 122F (4.06 g, 9.25 mmol) and 1M borane in THF (20 mL) at room temperature was stirred for 16 hours, treated with methanol (5.0 mL) and concentrated HCl (2 mL), stirred at 80° C. for 3 hours, cooled to room temperature, adjusted to pH>7 with 4M sodium carbonate, diluted with ethyl acetate (150 mL), washed with water (50 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% methanol/dichloromethane to provide the desired product. MS (ESI(+)) m/e 425 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[C:10]([OH:12])=O.Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:18][C:10]([C@H:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1)=[O:12]
Reactant: COC(=O)CN
Reactant: O=C(O)[C@H]1Cc2ccccc2N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)[C@H]1Cc2ccccc2N1
Reaction time: 8 h

Procedure:
To a solution of (2R)-indoline-2-carboxylic acid (1 g, 5.64 mmol) and HCl salt of amino-acetic acid methyl ester (710 mg, 5.64 mmol) and BOP (2.75 g, 1.1 eq) in 15 mL DMF was added 2.95 mL hunig base. The mixture was stirred overnight. The mixture was diluted in sat. NaHCO3, extracted with EtOAc three time, and washed with sat. NaHCO3 and brine. The organic solution was dried over Na2SO4 and concentrated to give the desired methyl{[(2R)-2,3-dihydro-1H-indol-2-ylcarbonyl]amino}acetate. The material was used directly in the next step without further purification.
Reaction SMILES: [CH3:1]N(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2.CI.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:1][O:19][C:18]([CH:15]1[CH2:14][CH2:13][C:12]2[C:17](=[C:8]([O:7][CH3:6])[CH:9]=[CH:10][CH:11]=2)[CH2:16]1)=[O:20]
Reactant: CN(C)C=O
Reactant: COc1cccc2c1CC(C(=O)O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)C1CCc2cccc(OC)c2C1
Reaction time: 8 h

Procedure:
To a DMF solution (30 mL) of 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (5.0 g, 24 mmol) was added MeI (7.1 g, 50 mmol) and K2CO3 (6.9 g, 50 mmol). The mixture was allowed to stir overnight and ethyl acetate (200 mL) was added. The resulting solution was washed with water (3×50 mL) and brine (50 mL) to provide 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester (6.6 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=2[CH3:15])[NH2:11])[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.[O:22]1[CH2:27][CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH2:24][CH2:23]1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:22]1[CH2:23][CH:24]=[C:25]([C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=3[CH3:15])[NH2:11])[CH:5]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:3]=2)[CH2:26][CH2:27]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cc1ccc(N)cc1-c1cc(Cl)nc(N2CCOCC2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1ccc(N)cc1-c1cc(C2=CCOCC2)nc(N2CCOCC2)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
To a solution of 3-(2-chloro-6-morpholinopyridin-4-yl)-4-methylaniline (1.0 equiv.) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 equiv.) in DME and 2M sodium carbonate (3:1, 0.1 M) was added PdCl2(dppf)-DCM adduct (0.1 equiv.). The solution was heated to 100 C for 5 hours. Upon cooling to room temperature, the solution was partitioned between water and ethyl acetate, the organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with 0-50% ethyl acetate and heptanes). The pure fractions were concentrated to yield 3-(2-(3,6-dihydro-2H-pyran-4-yl)-6-morpholinopyridin-4-yl)-4-methylaniline in 69% yield. LCMS (m/z) (M+H)=352.3, Rt=0.50 min.
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH2:8]O>C(O)(=O)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH2:8][Br:1]
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Reactant: Br
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(CBr)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (ice-water bath) mixture of 30% HBr in acetic acid (3 ml) was added 2.5 g 5-methyl-2-nitrobenzyl alcohol and the chilled solution stirred for 2 hours. The mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with H2O, brine and the solvent removed under vacuum to give a mixture of product (50%) and starting material (50%).