Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:12][C:11]2([CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[NH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH4+].[Cl-]>C1COCC1>[CH2:30]([N:10]1[C:11]2([CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)[NH:12][C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: ClCc1ccccc1
Reactant: O=C1NC2(CCN(C(=O)c3ccc(Cl)cc3)CC2)N[C@H]1Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(S)-benzyl-8-(4-chlorobenzoyl)-1,4,8-triazaspiro[4,5-]-decan-2-one (2.1 g, 5.5 mmol) in 20 mL of dry THF there was added sodium hydride (130 mg, 5.5 mmol) at 0° C. and under a blanket of nitrogen. Following stirring over a period of 1 h at 0° C., benzyl chloride (760 mg, 6.0 mmol) was slowly added dropwise, and the mixture was allowed to warm up to RT and then heated under reflux over a period of 4 d. Following the addition of an aqueous saturated NH4Cl solution (30 mL), the reaction mixture was isolated by filtration, the filtrate was extracted with EE (3×20 mL), the combined organic phases were dried over Na2SO4, and the solvent was removed. Further purification was carried out by column chromatography. The product 1,3-(S)-dibenzyl-8-(4-chlorobenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained as a yellow oil in a yield of 2.62 g (99%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21]OS(C)(=O)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH3:21])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a solution of (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-methanesulfonyloxymethylpyrrolidine (6.0 g) in tetrahydrofuran (60 ml) was added slowly lithium aluminum hydride (1.11 g) at 0° C. And then, the reaction mixture was allowed to warm to 40° C. and stirred for one hour. To the reaction mixture were added dropwise water (1.11 ml), 4N-aqueous sodium hydroxide (1.11 ml) and water (3.33 ml). The precipitate was filtered off, and the solvent was removed in vacuo to give (2R,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine (4.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:31]C(=O)C)=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[N:29])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:31])=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]#[N:29])=[CH:25][CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(CC#N)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(CC#N)cc3)c2)=C(C)C1=O
Yield: 72.9 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-cyanomethylaniline (0.060 g, 0.123 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.040 g, 0.0897 mmol, 73%).
Reaction SMILES: [C:1]([Si:5]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:36]([OH:41])(=[O:40])[C:37]([CH3:39])=[CH2:38]>C1(C)C=CC=CC=1>[C:36]([O:41][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])(=[O:40])[C:37]([CH3:39])=[CH2:38]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)(C)C
Reactant: C=C(C)C(=O)O
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)O[Si](C(C)C)(C(C)C)C(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 41.4 g (0.20 mol) of tert-butyldiisopropylchlorosilane, 60 ml of toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 18.9 g (0.22 mol) of methacrylic acid was added dropwise over one hour. After the completion of dropwise addition, the reaction solution was stirred for 2 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 45.4 g of a fraction having a boiling point of 93-95° C./0.27 kPa.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22](OC)=[CH:21]C=3)[N:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[C:28]([CH3:37])=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][CH2:32][CH2:31][CH2:30]2)[C:3]([O:5][CH3:6])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:57]1C=CC=CC=1CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(O)(C(F)(F)F)=O.C1COCC1.ClCCl>[OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:57]=3)[N:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[C:28]([CH3:37])=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][CH2:32][CH2:31][CH2:30]2)[C:3]([O:5][CH3:6])=[O:4]
Reactant: OCc1ccccn1
Reactant: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2cnn(Cc3ccc(OC)cc3)c2c(=O)n1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2cnn(Cc3ccccn3)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.5 %

Procedure:
A solution of methyl 2-hydroxy-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-5-yl)acetate (100 mg, 0.2 mmol) in TFA (1 mL)/dichloromethane (1 mL) was stirred at 55° C. for 6 h and then concentrated. The residue was partitioned between EtOAc and saturated sodium bicarbonate/water. The organic phase was dried over sodium sulfate and concentrated. The residue was dissolved in THF (2.5 mL) and to this solution triphenylphosphine (103 mg, 0.4 mmol) and pyridine-2-ylmethanol (43 mg, 0.4 mmol) was added followed by DIAD (0.076 mL, 0.4 mmol) and the mixture was stirred at ambient temperature for 2.5 h. The mixture was concentrated and purified on silica using EtOAc/hexanes 0-50% to provide the title compound (47 mg, 68%). 1H NMR (400 MHz, CDCl3) δ ppm 8.6 s (1H), 6.8-7.8 (m, 5H), 6.7 (d, 1H), 6.2-6.4 (m, 2H), 5.3 (s, 1H), 4.3 (broad s, 2H), 3.9 (s, 3H), 3.7 (s, 3H), 2.7 (broad s, 2H), 2.0 (s, 3H), 1.7 (broad s, 2H); ES-LCMS: 475.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([S:23]([CH3:26])(=[O:25])=[O:24])[C:3]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:9][C:4]=1[C:5]([O:7]C)=O.[H-].[Na+].CO>CN(C=O)C>[CH3:1][N:2]1[C:3]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:9][C:4]=2[C:5](=[O:7])[CH2:26][S:23]1(=[O:25])=[O:24]
Reactant: COC(=O)c1cc(C#CCOC2CCCCO2)ccc1N(C)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1c2ccc(C#CCOC3CCCCO3)cc2C(=O)CS1(=O)=O
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a solution of methyl 2-(methyl(methylsulfonyl)amino)-5-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl)benzoate (Preparation 51, 0.93 g) in DMF (15 mL) at 0° C. is added NaH (0.20 g; 60% dispersion in mineral oil) portionwise. The reaction mixture is warmed to ambient temperature stirring for 1 h upon which methanol (4 mL) is added and the organic portion is washed with a saturated solution of citric acid (50 mL). The aqueous layer is extracted with Et2O (2×50 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude orange liquid is purified by silica gel column chromatography (2/1, hexanes/EtOAc) to afford 0.59 g (69%) of the title compound as a white solid. Physical characteristics: m.p. 107-108° C.; 1H NMR (300 MHz, CDCl3) δ8.21, 7.71, 7.10, 4.87, 4.48, 4.33, 3.88, 3.55, 3.44, 1.79, 1.62; IR (diffuse reflectance) 2962, 2908, 1684, 1493, 1339, 1211, 1204, 1156, 1135, 1130, 1123, 1030, 899, 886, 838 cm−1; MS (ESI−) 348 (M−H−). Anal. Found: C, 58.37; H, 5.58; N, 3.96.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)[N:3]=1.[F:18][C:19]1[C:20]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23]>>[F:18][C:19]1[C:20]([C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[C:21]([C:22]([N:14]2[CH2:13][CH:12]3[CH:16]([CH2:17][N:10]([C:4]4[N:5]=[C:6]([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[N:3]=4)[CH2:11]3)[CH2:15]2)=[O:23])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cccc(F)c1-c1ncccn1
Reactant: Cc1nc(N2CC3CNCC3C2)nc(C)c1C
Product: Cc1nc(N2CC3CN(C(=O)c4cccc(F)c4-c4ncccn4)CC3C2)nc(C)c1C

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 42 and 3-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI): mass calculated for C24H25FN6O, 432.21; m/z found 433.3 [M+H]+. 1H NMR (600 MHz, CDCl3): 8.41 (dd, J=4.7, 1.8, 2H), 7.66-7.54 (m, 2H), 7.34 (dd, J=7.4, 4.8, 2H), 3.94 (dd, J=12.1, 7.6, 2H), 3.80 (dd, J=11.5, 7.3, 1H), 3.74-3.46 (m, 4H), 3.31-3.01 (m, 3H), 2.40-2.13 (m, 9H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[N:35][C:34]2=[CH:38][C:31]3=[N:32][N:33]2[C:13]=1[N:14]1[CH2:40][CH2:39][C:17]([CH3:41])([O:18][CH2:19][CH:20]=[CH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:28][CH:29]=[CH:30]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+]>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[N:35][C:34]2=[CH:38][C:31]3=[N:32][N:33]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:41])([O:18][CH2:19][CH:20]=[CH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:28][CH:29]=[CH:30]3)[CH2:39][CH2:40]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=Cc1ccccc1CC=C3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=Cc1ccccc1CC=C3
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of the ethyl (2S)-2-(tert-butoxy)-2-[4,23-dimethyl-22-oxa-1,5,7,8-tetraazapentacyclo[21.2.2.16,9.02,7.013,18]octacosa-2,4,6(28),8,10,13(18),14,16,19-nonaen-3-yl]acetate (0.0366 g, 0.066 mmol)) in dioxane (1 mL)/MeOH (1 mL) was added 10N sodium hydroxide (0.066 mL, 0.655 mmol) and the mixture was stirred at 70° C. for 1 h. The reaction was cooled and concentrated. The crude material was purified via preparative HPLC to give the title compound as diastereomers. LCMS (M+H) calcd for C31H38N4O4: 531.29. found: 531.4.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:22])=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=O)C.O.[NH2:25][NH2:26].Cl>O>[CH3:22][C:5]1[C:4](=[O:3])[NH:25][N:26]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:6]=1
Reactant: CCOC(=O)C(C)=CC(=O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: NN
Agent: Cl
Solvent: O
Product: Cc1cc(-c2ccc(-c3ccc(F)cc3)cc2)n[nH]c1=O
Reaction time: 1 h

Procedure:
A mixture of 31.2 g of 2-methyl-4-(4'-fluoro-4-biphenylyl)-4-oxo-2-butenoic acid ethyl ester, 60 ml of 24% aqueous hydrazine hydrate solution and 50 ml of water is boiled for one hour. When it has cooled, 25 ml of concentrated hydrochloric acid is added and the liquid is boiled for an additional 30 minutes. After again cooling the mixture, the 4-methyl-6-(4'-fluoro-4-biphenylyl)-2,3-dihydropyridazin-3-one obtained is filtered off and washed with water. m.p. 247°-248°.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:22])=[CH:7][CH:6]=1.[CH2:25]([Mg]Cl)[CH2:26][CH3:27]>>[OH:21][C:18]1([CH2:25][CH2:26][CH3:27])[CH2:17][CH2:16][C:13]2([C:12](=[O:22])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:23])[F:24])=[CH:6][CH:7]=3)[CH2:15][CH2:14]2)[CH2:20][CH2:19]1
Reactant: O=C1CCC2(CC1)CCN(c1ccc(OCC(F)(F)F)cc1)C2=O
Reactant: CCC[Mg]Cl
Product: CCCC1(O)CCC2(CCN(c3ccc(OCC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 55 from 2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-2-aza-spiro[4.5]decane-1,8-dione (obtained in example 86, step 1) by reaction with propylmagnesium chloride (2M in diethyl ether). MS (m/e): 368.2 [(M-H2O)H+].
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@H:9]1[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@H:9]1[C:11](=[O:13])[CH2:8][C:6]([O:5][CH2:1][CH3:2])=[O:7])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@@H]1C[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 183 %

Procedure:
To 170 ml of an anhydrous tetrahydrofuran solution of 14.71 g (79.0 mmol) of (1R,2S)-2-t-butoxycarbonylcyclopropanecarboxylic acid was added 16.49 g (90.6 mmol) of 1,1-carbonyldiimidazole under cooling with ice, and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed by evaporation under reduced pressure. To 60 ml of an anhydrous tetrahydrofuran solution of the resulting residue was added 150 ml of an anhydrous tetrahydrofuran solution of 197.5 mmol of previously prepared magnesium monoethyl malonate, followed by stirring for 3 days. After completion of the reaction, the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with 0.5N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution, and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 18.53 g (91.8%) of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH3:18])[CH:11]=[C:10]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])([OH:3])=[O:2]>[Pd].C(OCC)(=O)C.O1CCCC1>[C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH3:18])[CH:11]=[C:10]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])([OH:3])=[O:2]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C/CC(=O)O)ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CCCC(=O)O)ccc21
Reaction time: 6 h
Yield: 80.4 %

Procedure:
Palladium on carbon (1.1 g, 10% w/w) was added to a solution of methyl E-4-[5-(3-carboxyprop-1-enyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (10.8 g) in ethyl acetate (300 ml) and tetrahydrofuran (100 ml), and the mixture hydrogenated at atmospheric pressure for 6 hr. The catalyst was removed by filtration through diatomaceous earth, the filter cake washed with ethyl acetate, and the combined filtrate evaporated. The residue was stirred in 1:4 ethyl acetate:hexane (150 ml) and the product isolated by filtration to give methyl 4-[5-(3-carboxypropyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (8.72 g, 80%) as an off-white powder; mp 106°-109°; NMR (300 MHz, DMSO-d6): 0.81(t, 3H, CH3), 1.68-1.83(m, 4H), 2.20(t, 2H), 2.61(t, 2H), 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.02(m, 4H, NCH2, ArCH2Ar'), 6.92(d, 1H), 7.08(s, 1H), 7.23(m, 2H), 7.32(d, 1H), 7.44(m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=[O:7])[CH2:5][CH3:6].[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:2][CH2:3][C:4](=[O:7])[CH2:5][CH3:6])[CH2:11][CH2:10]1
Reactant: CN1CCNCC1
Reactant: CCC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)CCN1CCN(C)CC1
Yield: 73.5 %

Procedure:
A mixture of 30.5 g of 1-chloro-3-pentanone, 25 g of 1-methylpiperazine, 41.9 g of potassium carbonate and 400 ml of acetone was refluxed for 3 h. The mixture was filtered and the acetone was evaporated. The residue was dissolved in aqueous hydrochloric acid and the resulting solution was washed twice with diethyl ether. The aqueous phase was basified with potassium carbonate and extracted twice with dichloromethane. The organic phase was washed, dried and evaporated to yield 33.8 g (73.3%) of crude 1-(4-methylpiperazinyl)pentane-3-one.
Reaction SMILES: C([O:8][C:9]1[C:10]([NH2:21])=[N:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:21][C:10]1[C:9]([OH:8])=[CH:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][N:11]=1
Reactant: Nc1ncc(-c2ccccc2)cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc(-c2ccccc2)cc1O
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution of 3-benzyloxy-5-phenyl-pyridin-2-ylamine (Example I-87, 3.27 g, 11.8 mmol) in methanol (30 mL) was added Pd(OH)2 (2.5 g, 2.37 mmol). The mixture was degassed and charged with hydrogen three times, and then stirred under hydrogen balloon for 5 h. The reaction was filtered through a celite pad, washed with methanol, and condensed. After high vacuum dry, 2-amino-5-phenyl-pyridin-3-ol was obtained (2.04 g, 93% yield). MS m/z 187 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:32])=[CH:14][CH:15]=2)[N:10]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH3:32])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[OH:8])[N:18]=2)[CH2:20]1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3c(O)cccc3F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (500 mg, 1.14 mmol) in CH2Cl2 (15 mL) was added TFA (5 mL). The mixture was stirred for 1 h and then neutralized with a 1 M NaOH solution, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 3-20% EtOAc/CH2Cl2 gave 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol. LC/MS: m/z 339.5 (M+H)+ at 0.56 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1](O)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].ClCC(OC(=O)CCl)=O.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCC(Cl)(Cl)Cl>[C:1]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[Br:17])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Brc1ccccc1
Reactant: CCCCC(=O)O
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C(CCl)OC(=O)CCl
Product: CCCCC(=O)c1ccccc1Br
Temperature: 115 °C
Reaction time: 10 h
Yield: 56 %

Procedure:
In 50 ml of tetrachloroethane were dissolved 5.11 g (0.05 mole) of valeric acid and 9.83 g (0.0575 mole) of monochloroacetic anhydride. To the resulting solution were added 9.42 g (0.06 mole) of bromobenzene and 0.8 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 115° C. for 10 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 6.75 g of valerylbromobenzene.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[NH:8][N:7]=1)(=[O:4])=[O:3].C(O)C.N>O>[NH2:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: N
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1n[nH]c2ccc(N)cc12
Yield: 44.2 %

Procedure:
5-Amino-3-methylsulfonylamino-1H-indazole can be obtained as described in Example 4 from 256 mg of 3-methylsulfonylamino-5-nitro-1H-indazole, 10 ml of ethanol, 2 g of ferrous sulfate, 3.2 ml of water and 2.4 ml of 32% aqueous ammonia. 0.1 g of 5-amino-3-methylsulfonylamino-1H-indazole is thus obtained in the form of an oil used as it is in the following step.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([Cl:30])=[N:28][CH:29]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CO>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:23][C:24]3[CH:25]=[C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([Cl:30])=[N:28][CH:29]=3)=[N:3][CH:4]=[C:5]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:6]=2)[N:9]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 77.3 %

Procedure:
To a stirred solution of 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.0602 g, 0.198 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330, step 2, 0.0494 g, 0.223 mmol) in DMF (1 mL) in a 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 0.80 mL, 0.80 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 45 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (20 mL). The aq phase was acidified to a pH of about 3 to 4 then extracted with 25% isopropanol in chloroform (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue. Upon addition of MeOH to the residue, a tan precipitate came out. The solid was collected via filtration and washed with MeOH to afford N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(morpholinomethyl)pyridin-2-ylamino)-2-chloropyridin-3-yl)methanesulfonamide (0.0774 g, 77% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.26 (s, 1H) 9.66 (br. s., 1H) 8.76 (s, 1H) 8.67 (t, J=2.45 Hz, 2H) 8.31 (d, J=1.56 Hz, 1H) 7.74-8.01 (m, 2H) 3.43-3.66 (m, 6H) 3.14 (s, 3H) 2.38-2.48 (m, 7H). m/z (ESI, pos. ion): 505.9 (M+H)+.