Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][C:8](=[O:9])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].CCCCCC>O1CCCC1.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([CH2:22][O:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][C:8](=[O:9])[C:4]=2[CH:3]=1)=[O:24])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: O=C1COc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)C(=O)CO2
Yield: 98 %

Procedure:
3.00 g (20 mmol) XVIII, 3.96 g (40 mmol) K2CO3 and 5.54 ml (50 mmol) bromoacetic acid ethyl ester were heated under reflux for 72 h in 150 ml tetrahydrofuran. After filtration, the solvent was removed. Flash chromatography (200 g SiO2, n-hexane:ethyl acetate=2:1) produced 4.63 g (19.6 mmol, 98%) XIX.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:21])([O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18](O)=[O:19])[CH:14]=[CH:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1C=CC=CC=1.C(=O)([O-])O.[NH4+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(#N)C>[NH2:22][C:18]([CH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:8]([CH3:21])([CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:19]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(N)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(1-tert-Butoxycarbonyl-1-methylethoxy)phenylacetic acid (2.0 g, 6.79 mmol) is dissolved in acetonitrile (15 mL). Subsequently, pyridine (0.34 mL, 4.22 mmol) and ammonium hydrogencarbonate (699 mg, 8.84 mmol) were added thereto, and the mixture was stirred for 10 minutes at room temperature. Thereafter, di-tert-butyl dicarbonate [Boc2O (2.03 mL, 8.84 mmol)] was added thereto, and the resultant mixture was stirred for 14 hours. The reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and saturated brine. The resultant mixture was subjected to drying over magnesium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained (1.07 g, 3.65 mmol, 53.6%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:17]([O:21][C:22](=[O:23])[NH:24][CH2:25][C:26](=[O:27])[NH:16][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A suspension of 7.9 mmol C-(4-chloro-phenyl)-C-phenyl-methylamine hydrochloride (CA [5267-39-0]) in 100 ml acetonitrile was treated successively with 7.9 mmol N-tert.butyloxycarbonyl glycine, 39 mmol DIPEA and 8.7 mmol TBTU. After stirring for 1 hour at room temperature, the mixture was concentrated. Chromatography (SiO2; ethyl acetate/cyclohexane) yielded the title compound as a colorless solid. Yield=84%.
Reaction SMILES: [C:1](O)(=O)[C:2](O)=O.[CH2:7]([O:11][C:12](=[O:27])[CH2:13][C:14]1[C:15]([NH2:26])=[N:16][NH:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[CH2:8]CC.Cl.O.[CH2:30](O)C>>[CH2:7]([O:11][C:12](=[O:27])[CH2:13][C:14]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:17][N:16]2[CH:2]=[CH:1][CH:30]=[N:26][C:15]=12)[CH3:8]
Reactant: CCO
Reactant: O=C(O)C(=O)O
Reactant: CCCCOC(=O)Cc1c(N)n[nH]c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Product: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn2cccnc12

Procedure:
A suspension of 23.0 g (0.057 mole) of 3-amino-5-(4-chlorophenyl)-1H-pyrazole-4-acetic acid butyl ester ethanedioate and 9.6 g (0.057 mole) of malonaldehyde bis(dimethylacetal) (99%) in 250 ml of absolute ethanol was treated with 5 ml of concentrated hydrochloric acid and 10 ml of water.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[C:23]([OH:25])[C:22]([C:26](=[O:28])[CH3:27])=[CH:21][C:20]=2[CH2:29][CH3:30])=[CH:10][CH:9]=[CH:8][C:7]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]C)=[O:38].O.[OH-].[Li+]>O1CCCC1.O>[C:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[C:23]([OH:25])[C:22]([C:26](=[O:28])[CH3:27])=[CH:21][C:20]=2[CH2:29][CH3:30])[C:6]=1[CH2:5][CH2:4][C:3]([OH:41])=[O:2])([OH:39])=[O:38]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCCc1cccc(OCCCCCC(=O)OC)c1CCC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(C)=O)c(O)cc1OCCCCCCc1cccc(OCCCCCC(=O)O)c1CCC(=O)O
Reaction time: 18 h
Yield: 99.9 %

Procedure:
2-(6-Methoxy-6-oxohexyloxy)-6-[6-[[4-acetyl-2-ethyl-5-hydroxyphenyl]oxy]hexyl]benzenepropanoic acid methyl ester (25.8 mg, 0.0452 mmol) was dissolved in tetrahydrofuran (5 mL). Lithium hydroxide monohydrate (18.9 mg, 0.452 mmol) was dissolved in water (1 mL) and added to the reaction. The reaction was stirred for 18 h. The reaction was then concentrated, brought up in water, acidified to pH 5 with 1N HCl, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and evaporated. The resulting oil recrystallized with hexane:ethyl acetate to give 24.5 mg (100%) of product. MS: Calcd. For C31H42O8+H, 543.2958; Found, 543.2946
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>CN(C)C=O.C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Yield: 144 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (0.3 g, 1.67 mmol) in N,N-dimethylformamide (4.0 mL) was added 60% sodium hydride (0.073 g, 1.83 mmol) at 0° C. with stirring, and the mixture was stirred at the same temperature for 15 min. Then, 3-bromobenzylbromide (0.44 g, 1.75 mmol) was added to the mixture at 0° C. with stirring, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was diluted with ethyl acetate and washed with 5% aqueous potassium hydrogensulfate solution and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (0.84 g, yield 72%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].C([O-])(O)=O.[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O.O1CCOCC1>[CH2:20]([O:19][C:17](=[O:18])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a stirred solution of 10 g of 4-aminoacetophenone (74 mmol, 1 eq) in a mixture of 60 ml of water and 100 ml of dioxane at 0° C., 12.43 g of NaHCO3 (148 mmol, 2 eq) and 15.3 g of benzyl chloroformate (85 mmol, 1.15 eq, purity 95%) are added. The mixture is stirred at room temperature for 4 h and then concentrated under reduced pressure to remove the dioxane. The suspension is diluted with 70 ml of water and 150 ml of ethyl acetate. The phases are separated and the organic layer is washed with 2×50 ml of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 19.5 g of the product as solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(O[N:35]1[N:43]=[N:42][C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClCCO>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26][N:35]4[C:36]5=[N:41][CH:40]=[CH:39][CH:38]=[C:37]5[N:42]=[N:43]4)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: OCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)On3nnc4cccnc43)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a DMF (1 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B, 0.1 g, 0.28 mmol) and HATU (0.128 g, 0.336 mmol) was added DIEA (0.146 ml, 0.840 mmol), followed by 2-chloroethanol (0.0270 g, 0.336 mmol). After stirring at ambient temperature for 30 minutes, the reaction was directly purified by reverse phase column chromatography (Biotage SP4 system C18 25+M, 5 to 65% acetonitrile/water) to obtain the intermediate (R)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate as white solid (94.7 mg, 71% yield). This isolated intermediate was dissolved in excess chloroethanol (1 mL), followed by addition of drops of DIEA at ambient temperature and stirred overnight to reach completion. The reaction was directly purified by reverse phase column chromatography (Biotage SP4 system C18 25+M, acetonitrile/water 5 to 73) to obtain the titled product as white foamy solid (56 mg, 48% yield). MS (apci) m/z=419.9 (M+H).
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)C(N(C(C)C)C(C)C)=O.[F:21][C:22]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]2[C:23]=1[CH2:24][O:25][C:26]2=[O:35].[BH4-].[Na+]>>[F:21][C:22]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([CH2:26][OH:35])[C:23]=1[CH2:24][OH:25]
Reactant: O=C1OCc2c(F)cc(C(F)(F)F)cc21
Agent: CC(C)N(C(=O)c1cc(F)cc(C(F)(F)F)c1)C(C)C
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cc(C(F)(F)F)cc(F)c1CO

Procedure:
Prepared in analogy to Example A16 (a) from 4-Fluoro-6-trifluoromethyl-3H-isobenzofuran-1-one e and sodium borohydride. Colorless oil. MS (m/e): 225.1 ([M+H+, 100%).
Reaction SMILES: [CH3:1][I:2].[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]([CH3:15])[NH:7][C:8](=[S:14])[NH:9]2>CC(C)=O>[IH:2].[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]([CH3:15])[NH:7][C:8]([S:14][CH3:1])=[N:9]2
Reactant: CI
Reactant: CC1NC(=S)Nc2cccc(Cl)c21
Solvent: CC(C)=O
Product: CSC1=Nc2cccc(Cl)c2C(C)N1
Product: I
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl iodide (1.16 ml, 19 mmol) was added to a suspension of 5-chloro-4-methyl-3,4-dihydro-1H-quinazoline-2-thione (1.32 g, 6.2 mmol) in acetone (15 ml), and the mixture was stirred at r.t. over the weekend (the reaction is usually complete after 12 h). The precipitated product (2.08 g, 87%) was sufficiently pure for the next step.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=1.O1CCCC1.CCCCCC.C([Li])CCC.[C:34](=[O:36])=[O:35]>O>[CH3:7][C:5]1[O:6][C:2]([C:34]([OH:36])=[O:35])=[C:3]([C:8]2[CH:17]=[CH:16][C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[CH:9]=2)[N:4]=1
Reactant: Cc1nc(-c2ccc3c(c2)CCCC3)c(Br)o1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1nc(-c2ccc3c(c2)CCCC3)c(C(=O)O)o1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a mixed solution of 5-bromo-2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)oxazole (11.0 g) and tetrahydrofuran (100 mL) was added dropwise a 1.6N n-butyllithium hexane solution (24 mL) at −78° C. under a nitrogen atmosphere. After stirring the reaction mixture at −78° C. for 10 min, CO2 gas was blown into the reaction mixture for 30 min. The reaction mixture was poured into water and washed with ether. The aqueous layer was acidified with conc. hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give [2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]carboxylic acid (7.4 g, yield 76%) as crystals. Recrystallization from ethyl acetate gave colorless crystals. melting point: 183–185° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]([O:12]C)=[O:11])=[C:5]([CH2:7][O:8][CH3:9])[N:6]=1.C1C[O:17][CH2:16][CH2:15]1.O.[OH-].[Li+].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:16]([NH:1][C:2]1[S:3][C:4]([C:10]([OH:12])=[O:11])=[C:5]([CH2:7][O:8][CH3:9])[N:6]=1)(=[O:17])[CH3:15]
Reactant: C1CCOC1
Reactant: COCc1nc(N)sc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COCc1nc(NC(C)=O)sc1C(=O)O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-amino-4-(methoxymethyl)thiazole-5-carboxylate (2.0 g, 9.9 mmol) and THF (75 mL, 925 mmol) were added to a 250 mL round-bottomed flask. The resulting suspension was then sonicated until clear. Water (75 mL, 9.9 mmol) and then lithium hydroxide (0.71 g, 30 mmol) were added, and the mixture was stirred at 80° C. for approximately 30 minutes. LCMS indicated that the reaction was complete, and the solvent was removed under reduced pressure. The resulting residue was dissolved in pyridine (75.00 mL, 0.9273 mol). Acetic anhydride (1.026 mL, 0.01088 mol) was added to the pyridine solution, and the mixture was stirred at reflux for approximately 2 hours until LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure to provide crude 2-acetamido-4-(methoxymethyl)thiazole-5-carboxylic acid which was then taken up in DCM (200 mL). Thionyl chloride (2.164 mL, 29.67 mmol) was then added, and the mixture was stirred at reflux for approximately 2 hours. The reaction was followed by LCMS, (aliquots were removed and quenched with MeOH). Once the reaction was complete, the solvents were removed under reduced pressure and the crude product 2-acetamido-4-(methoxymethyl)thiazole-5-carbonyl chloride was taken up in DCM (50.00 mL). A DCM suspension of 4-aminopyridin-3-yl diethylcarbamodithioate (1.9 g, 7.9 mmol) and DIPEA (6.9 mL, 40 mmol) were added, and the suspension was stirred for 1 hour until LCMS indicated that the reaction was complete. The solvent was reduced, and the resulting oil was passed through a plug of silica gel, and washed with approximately 700 mL of 10% MeOH in DCM to give crude 4-(2-acetamido-4-(methoxymethyl)thiazole-5-carboxamido)pyridin-3-yl diethylcarbamodithioate (4.4 g, 9.7 mmol, 98% yield), which was used in the next step without further purification. LCMS (M+H) 454 calc. for C18H24N5O3S3 454.6.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:23])[CH:21]=[CH2:22].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CO>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:23])[CH:21]=[CH2:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C=CC(=O)O
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
To an ice-cold solution of 0.158 g (0.5 mM) of 7-amino-4-(3-bromoanilino)-quinazoline [J Med Chem, 1995:3482] and 0.108 g of acrylic acid in 5.0 mL of dry dimethylformamide (DMF) was added 0.288 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDAC). After stirring for 5 minutes, the mixture became a solution, and the ice bath was removed. The reaction continued to stir at room temperature for 3 hours. The reaction was then poured into a mixture of ice and water and made basic with the addition of a saturated solution of sodium bicarbonate. This aqueous mixture was extracted three times with ethyl acetate, and the pooled extracts were dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to afford a light yellow solid. The solid was dissolved in 100 mL of methanol, filtered, and concentrated in vacuo to approximately 10 mL. The solid which precipitated from solution was collected and dried in vacuo at 80° C. to give 50 mg of N-[4-(3-bromo-phenylamino)-quinazolin-7-yl]acrylamide, mp >265° C. Chemical ionization mass spectra: m/e 369.
Reaction SMILES: [N:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:12][CH:11]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33](C(OCC)=O)=[CH:32][CH:31]=3)=[O:28])[C:10]2=[O:41])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:42].[Li+].[CH3:44][OH:45].Cl>O1CCCC1.C(Cl)(Cl)Cl>[N:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:12][CH:11]([NH:26][C:27](=[O:28])[NH:29][C:30]3[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=3)[C:44]([OH:45])=[O:42])[C:10]2=[O:41])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [OH-]
Reactant: CO
Reactant: CCOC(=O)c1ccc(NC(=O)NC2CN(C3CCCCC3)c3ccccc3N(CC(=O)N3CCCC3)C2=O)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccc(C(=O)O)c1)NC1CN(C2CCCCC2)c2ccccc2N(CC(=O)N2CCCC2)C1=O
Temperature: 45 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
1-[1-(Pyrrolidin-1-ylcarbonylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)urea was suspended in tetrahydrofuran (20 ml), aqueous lithium hydroxide (0.37 g) solution (10 ml) and methanol (20 ml) were added, the mixture was stirred at 40-50° C. for one hour. 1N hydrochloric acid and chloroform were added and extracted. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, isopropyl ether was added to crystals so precipitated for trituration, collected by filtration, to thereby obtain 0.81 g of the title compound (Yield: 85.1%).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=O.O.[NH2:17][CH2:18][CH:19]([OH:21])[CH3:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][O:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]1[N:17]([CH2:18][CH:19]([OH:21])[CH3:20])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: CC(O)CN
Reactant: COc1ccc2c(c1)CC(CC=O)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)Cc1ccn(CC(C)O)c1-2
Reaction time: 0.58 h
Yield: 67.2 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-5-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 2.94 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). There were obtained 1.6 g (67%) of (RS)-1-(6-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol as a brown oil which was used directly in the next reaction.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([CH3:12])[CH3:11])=[O:4].Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>C(N(CC)CC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]2[N:21]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]3([CH3:12])[CH3:11])=[O:4])[C:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][C:26]=3[C:17]=2[CH:16]=1
Reactant: CC1(C)CCCCN1C(=O)CBr
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)N2CCCCC2(C)C)C1

Procedure:
The title compound is prepared by following Method 8 by using 2-bromo-1-(2,2-dimethylpiperidin-1-yl)ethanone, 4-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[Si:5](Cl)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.2 %

Procedure:
To a solution of 2-bromoethanol (5.0 g, 40.3 mmol) in DCM (20 mL) was added tert-butyldimethylsilyl chloride (9.1 g, 60.5 mmol) followed by the additions of triethylamine (8.14 g, 80.6 mmol) and 4-dimethylaminopyridine (49.2 mg, 0.4 mmol). The mixture was stirred at room temperature for 15 h and concentrated in vacuo. The residue was partitioned between 1N HCl and ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford yellow oil, which was purified by column chromatography eluting with PE:EA (50:1) to afford 123a as colorless oil (6.0 g, 62.4%). LCMS: (M+H)+ 241.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:31][CH2:30][C:24]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1.[C:32]([CH2:34][C:35](O)=[O:36])#[N:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:22][CH2:23][C:24]3([CH2:25][CH2:26][N:27]([C:35](=[O:36])[CH2:34][C:32]#[N:33])[CH2:28][CH2:29]3)[CH2:30][CH2:31]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cc1c2ccc(Nc3ncc(Cl)c(NC4CCC5(CCNCC5)CC4)n3)cc2nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c2ccc(Nc3ncc(Cl)c(NC4CCC5(CC4)CCN(C(=O)CC#N)CC5)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.7 %

Procedure:
To a solution of 5-chloro-N2-(2,3-dimethyl-2H-indazol-6-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (485.3 mg, 1.10 mmol) and 2-cyanoacetic acid (137.0 mg, 1.61 mmol) in a mixture of DCM (40 mL) and DMF (10 mL) were added HATU (520.8 mg, 1.37 mmol) and Et3N (0.36 g, 3.55 mmol). After addition, the reaction mixture was stirred at rt for 6 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50) to give the title compound as a beige solid (171.0 mg, 30.6%).