Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:31])[N:21]([CH3:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:30][N:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](=[O:31])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CN(CCc1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
N-Methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester (1.84 g, 4.12 mmol) was dissolved in dichloromethane (6 ml). The solution was cooled to 0° C. Trifluoroacetic acid (6 ml) was added. The solution was stirred for 10 min at 0° C. The solvent was removed in vacuo at 20° C. The residue was dissolved in dichioromethane (100 ml) and the solvent was removed in vacuo. This latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (70 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 350 mg of (2R)-2-(methylamino)-3-(2-naphthyl)propionic acid N-methyl-N-phenethylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]1([N:33]=[C:34]=[O:35])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:34]([NH:33][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:35])=[CH:20][CH:21]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc5ccccc45)cc3)c2cc1OC
Yield: 52 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, 1-naphthyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 20 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 41 mg of the title compound (yield: 52%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([CH:19]=[O:20])[CH:11]=[C:12]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH:13]=2)[N:8]=[C:7]([CH3:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([CH2:19][OH:20])[CH:11]=[C:12]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH:13]=2)[N:8]=[C:7]([CH3:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2]
Reactant: CCC(C)c1cc(C=O)c2nc(C)c(C)c(OC(C)=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C)c1cc(CO)c2nc(C)c(C)c(OC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 84 %

Procedure:
210 Milligrams of 4-acetoxy-6-s-butyl-8-formyl-2,3-dimethylquinoline obtained in Example 33 was dissolved in 4 ml of methanol, to which 7 mg of sodium borohydride dissolved in 4 ml of methanol was added dropwise and the mixture was stirred at room temperature for 1 minute. After the addition of 20 ml of water, the reaction mixture was extracted with ethyl acetate. The resultant organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (10:1) to obtain 186 mg of 4-acetoxy-6-s-butyl-8-hydroxymethyl-2,3-dimethylquinoline (yield 84%). Its NMR spectral data are shown in the following Table 2.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].Cl[Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18]>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[C:10]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:14]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Product: CCN(CC)C(=O)c1c(Cl)cccc1[Si](CC)(CC)CC

Procedure:
The title compound was prepared according to General Method A from the compound of Example e and 1.4 eq chlorotriethylsilane. Purification by HPLC with 1:19 ethyl acetate/hexanes gave 6.0 g of the desired product as a clear oil, a 92% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](SC)=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.O.[NH2:18][NH2:19]>CO>[NH2:12][C:11]1[NH:19][N:18]=[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:10]=1[C:13]#[N:14]
Reactant: CSC(Nc1cccc(Cl)c1)=C(C#N)C#N
Reactant: NN
Solvent: CO
Solvent: O
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N

Procedure:
A mixture of 15 g (60.1 mmol) of 3-(3-chloro-phenylamino)-2-cyano-3-methylmercapto-acrylonitrile [for preparation see: EP 0 010 396 A1], 3.13 ml (63.2 mmol) of hydrazine hydrate and 100 ml of methanol is heated under reflux for 3 hours and then concentrated by evaporation in vacuo. Recrystallization of the residue from ethyl acetate/hexane yields the title compound; m.p. 195-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22]O.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]1[CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20]1
Reactant: CC(C)(CO)CNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)CN(c2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)C1
Yield: 73.5 %

Procedure:
Dissolve 7-chloro-6-(3-hydroxy-2,2-dimethyl-propylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (prepared as described in Preparation 30) (250 mg, 0.66 mmol) in DCM (30 mL). Add diethyl azodicarboxylate (150 mg, 0.86 mmol), and triphenylphosphine (226 mg, 0.86 mmol) and stir at 40° C. for 16 h. Quench with saturated aqueous sodium bicarbonate solution, extract with DCM three times. Combine the organic layers, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:8 EtOAc:hexanes) to provide 7-chloro-6-(3,3-dimethylazetidin-1-yl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (175 mg, 74%). MS (ES) m/z:=361.2 [M+H]. Deprotection and the succinate salt formation of the free amine is achieved essentially as described in Example 34 to give the title compound (91 mg, 71%).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]3[C:13]=2[C:14](=[O:26])[N:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)[N:16]=3)[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:30])=O.CN(C)C=O>ClCCl>[CH:1]1([C:4]2[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]3[C:13]=2[C:14](=[O:26])[N:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([Cl:30])=[O:22])=[CH:19][CH:18]=2)[N:16]=3)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a suspension of finely ground 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (0.19 g. 0.55 mmol) in dichloromethane (4 ml) was added oxalyl chloride (1.6 ml, 0.01 mol) followed by a drop of dimethyl formamide. The mixture was stirred under nitrogen at 45° C. for 8 h. The solvent was removed in vacuo to yield 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoyl chloride as a pale yellow solid, LCMS m/z [M+MeOH—Cl]+ @ RT 1.46 min: 95% purity. Used without further purification. Step 5 N-(3-Dimethylamino propyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzamide
Reaction SMILES: C([Mg]Cl)(C)C.[CH3:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[CH:9][C:8]=1[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][CH:21]=[CH:20]2.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>C1COCC1>[CH:28]1([NH:31][C:11](=[O:13])[C:10]2[CH:15]=[CH:16][C:7]([CH3:6])=[C:8]([C:17]3[CH:26]=[C:25]4[C:24](=[CH:19][CH:18]=3)[C:23](=[O:27])[NH:22][CH:21]=[CH:20]4)[CH:9]=2)[CH2:30][CH2:29]1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]ccc3c2)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Reaction time: 0.17 h

Procedure:
A solution of isopropylmagnesium chloride (2M, 0.4 mL) in THF was added dropwise to a stirred solution of 4-methyl-3-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-benzoic acid, methyl ester (Intermediate 3) (76 mg) and cyclopropylamine (0.15 mL) in THF (2 mL). The mixture was stirred for 10 min., quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo and the residue was purified by HPLC to give the title compound as a solid (40 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:20][C:21]1[N:22]=[CH:23][N:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]2)[CH:25]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:20][C:21]1[N:22]=[CH:23][N:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:25]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCC(Cc1cn(C2C=CCCC2)cn1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC(Cc1cn(C2CCCCC2)cn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
10% palladium-carbon catalyst (hydrated, 200 mg) was suspended in a solution of the compound (250 mg) obtained in Step 1 of this Example in ethanol (6 mL). The suspension was stirred at room temperature for 3 hours under a hydrogen atmosphere at normal pressure. The reaction solution was filtered through celite, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluting solvent: methylene chloride/methanol=20/1−10/1) to obtain the title compound (240 mg).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1([CH3:27])[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)[O:11]1.Cl>C1COCC1.CCOCC>[CH3:9][C:10]1([CH3:27])[CH:19]=[C:18]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]2[C:12](=[CH:13][C:14]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)[O:11]1
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2=O
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccccc1

Procedure:
To a stirred solution of phenylmagnesium bromide [from bromobenzene and magnesium in dry tetrahydrofuran] was added 2,2-dimethyl-7-(2-dimethylaminoethoxy)-chroman-4-one in dry THF and the resulting solution was boiled under reflux for 2 weeks. The cooled reaction mixture was decomposed with 2.5 N hydrochloric acid and the organic layer separated and dried (magnesium sulphate). Removal of the solvent gave a yellow oil which was chromatograhed on silica in 3% ether-97% light petroleum (b.p. 60°-80°) gave the title compound as a colourless oil. Dissolution in dry ether and passage of dry hydrogen chloride through the solution gave the hydrochloride salt, m.p. 186.5°-187.5°. An analogous procedure yielded 7-(2-N-benzyl-N-methyl-aminoethoxy)-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromene as a colourless oil.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:36](C)=O.[Na+]>C(Cl)Cl>[CH3:36][N:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@@H]3CCNC3)ccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC[C@@H](NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)C1
Yield: 93.4 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid ((R)-1-methyl-pyrrolidin-3-yl)-amide (42 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (R)-pyrrolidin-3-ylamide dihydrochloride (51 mg), 37% formaldehyde (500 uL), and Na(OAc)3BH (40 mg) in DCM (500 uL). LC/MS: m/z 440.5.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:16])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1)([CH3:3])[CH3:2].Cl.[NH2:18][OH:19].N1C=CC=CC=1>CO>[CH:1]([O:4][C:5](=[O:16])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:18][OH:19])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)COc1cccc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)OC(=O)COc1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.4 %

Procedure:
A solution of (3-formyl phenoxy)acetic acid isopropyl ester (3.7 g, 17 mmol) in methanol (55 mL) was stirred under nitrogen as hydroxylamine hydrochloride (1.2 g, 17 mmol) and pyridine (6 mL, 74 mmol) were added. The reaction was stirred for 15 h at room temperature. The volatiles were removed in vacuo and the residue was diluted with ethyl acetate. The resulting solution was washed with 1N HCl, and the resulting aqueous solution was washed with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (4.13 g, 100%) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (d, 6H) 4.67-4.72 (m, 2H) 5.15-5.34 (m, 1H) 7.01-7.07 (m, 1H) 7.33-7.36-7.43 (m, 2H) 8.17 (s, 1H). LRMS m/z calcd. for C12H15NO4([M+H]+): 237.1. Found: 238.1.
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[Cl:15][C:16]1[C:17]2[CH:24]=[CH:23][S:22][C:18]=2[N:19]=[CH:20][N:21]=1.Cl[C:26]([O:28][CH3:29])=[O:27].[Cl-].[NH4+]>C1COCC1>[Cl:15][C:16]1[C:17]2[CH:24]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: Clc1ncnc2sccc12
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2c(Cl)ncnc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 9.6 %

Procedure:
A solution of THF (50 mL) and Hünig's base (2.14 mL, 15.2 mmol) were cooled to −78° C. and n-BuLi (2.5 M in hexanes, 5.7 mL, 14.1 mmol) added drop wise. The solution was warmed to 0° C. for 10 minutes, re-cooled to −78° C. and 4-chlorothieno[2,3-d]pyrimidine (2.0 g, 11.7 mmol) added. The anion was stirred for 10 minutes at −78° C., methyl chloroformate (1.0 mL, 12.9 mmol) added drop wise and the reaction maintained at −78° C. for 0.5 hours. The reaction was allowed to warm to ambient temperature. After 1 hour, the mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (4×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash-column chromatography (100% DCM) to yield yellow solid (0.256 g, 10%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])[NH:3]1.[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[C:24]([CH3:35])[NH:23][C:22]=1[CH:36]=O.N1CCCCC1.Cl>C(O)C>[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[O:27])=[C:24]([CH3:35])[NH:23][C:22]=1[CH:36]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])[NH:3][C:2]1=[O:1]
Reactant: O=C1Cc2c(cccc2-c2cncc(C(=O)O)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cncc(C(=O)O)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 60 °C

Procedure:
A mixture of 5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-nicotinic acid (381 mg, 1.5 mmol), 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (374 mg, 1.5 mmol) and piperidine (1 mL) in ethanol (5 mL) was heated in a sealed cube at 60° C. for 5 hours. The reaction was acidified with 1N HCl and the resulted precipitate was collected by vacuum filtration, washed with water and dried to give the title compound.
Reaction SMILES: Br[C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH:15]1([C:18]2[CH:22]=[C:21]([NH2:23])[NH:20][N:19]=2)[CH2:17][CH2:16]1>CCCCO>[CH:15]1([C:18]2[NH:19][N:20]=[C:21]([NH:23][C:2]3[C:7]([I:8])=[CH:6][N:5]=[C:4]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:3]=3)[CH:22]=2)[CH2:17][CH2:16]1
Reactant: Brc1nc(-c2ccccc2)ncc1I
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCCCO
Product: Ic1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Yield: 64.1 %

Procedure:
To a solution of 4-bromo-5-iodo-2-phenylpyrimidine (1.18 g, 3.29 mmol, 1.0 equiv.) in n-BuOH (20 mL) was added 3-cyclopropyl-1H-pyrazol-5-amine (0.811 g, 6.58 mmol, 2 equ). After heating at 90° C. for 24 hours, the reaction was filtered to afford N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-iodo-2-phenylpyrimidin-4-amine (0.85 g, 88.7%). LC-MS (m/z): 404.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6): δ 0.74-0.77 (m, 2H), 0.98-1.02 (m, 2H), 1.96-2.01 (m, 1H), 6.40 (s, 2H), 7.50-7.54 (m, 3H), 8.27-8.30 (m, 2H), 8.63 (s, 1H), 8.88 (s, 2H), 12.32 (s, 1H).
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:22])[N:12]([CH3:21])[C:13]3[C:18]([C:19]=2O)=[CH:17][CH:16]=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:21])[C:11](=[O:22])[C:10]=1[C:8]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)c(C(=O)NC2CCCCC2)c(O)c2ccccc21
Product: Cn1c(=O)c(C#N)c(Cl)c2ccccc21
Yield: 82 %

Procedure:
A solution of Compound 2 (1.5 g, 5 mmol) in 20 mL phosphorus oxychloride was heated at 90° C. for 2 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 903 mg (82%) of white solids. M.P. 235° C. 1H NMR (DMSO-d6): 3.66 (s, 3H), 7.50 (t, J=7.7 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.91 (t, J=8.7 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H). EIMS m/z 219 (M+1), 241 (M+23). Anal. (C17H7ClN2O) C, H, N.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]2[N:20]([C:23](=[O:45])[CH:24]([NH:28][C:29](=[O:44])[CH:30]([N:32]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH3:33])[CH3:31])[CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:22][CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[N:32]([CH3:33])[CH:30]([C:29](=[O:44])[NH:28][CH:24]([C:23]([N:20]1[CH2:21][CH2:22][CH:9]2[NH:8][CH2:12][CH:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]12)=[O:45])[CH:25]([CH3:27])[CH3:26])[CH3:31])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccccc1)CN2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2NCC(Oc3ccccc3)C21
Reaction time: 1 h

Procedure:
To a solution containing 16 (370 mg, 0.59 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. After 1 h, the reaction mixture was diluted with DCM and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford crude 18 which was used without further purification.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH3:16])[C:12](OC)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>>[NH:1]([C:12](=[O:13])[C@@H:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:6])([CH3:5])[CH3:4])[CH3:16])[NH2:2]
Reactant: COC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: NN
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NN
Temperature: 72 °C
Yield: 88.7 %

Procedure:
A solution of hydrazine (234 mg, 7.31 mmol, 1.5 equv. in 8 ml of THF) was added to (S)-methyl 2-(tert-butoxycarbonylamino)propanoate (1000 mg, 4.88 mmol, 1.0 equv.), it was stirred in a sealed tube and refluxed (72° C.) overnight (18 hours), the solvent was removed to yield the desired product (880 mg, white solid) in 84% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[O:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:36][CH:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:6]=2[N:7]=1
Reactant: OC1CCOCC1
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(Cl)c23)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A solution of 4-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), tetrahydro-2H-pyran-4-ol (1.1 equiv), and sodium tert-butoxide (1.2 equiv) in 1,4-dioxane (0.22 M) were combined in a sealable flask. The reaction mixture was put under a nitrogen atmosphere, the sealable flask was sealed, and the mixture was stirred at 70° C. for 16 h. The mixture was cooled to room temperature and concentrated to afford an oil, which was suspended in DCM and purified using flash chromatography (0-50% ethyl acetate in hexane) to afford the desired product (89% yield) as a clear oil. MS (ESI) m/z 517.5 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 100.1 %

Procedure:
To a solution of 2-hydroxy-3-methylbenzaldehyde (3.0 g, 22.07 mmol) in N,N-dimethylformamide (50 mL), potassium carbonate (3.65 g, 26.4 mmol) was added and furthermore benzyl bromide (2.9 mL, 24.2 mmol) was added thereto. The mixture was stirred at room temperature for 26 hours, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (5.0 g, 100%).