Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:12]([Br:23])=[C:13]2[C:18](=[CH:19][C:20]=1[CH3:21])[N:17]=[C:16]([CH3:22])[CH:15]=[CH:14]2)[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl(O)(=O)(=O)=O>C(OC(=O)C)(C)(C)C>[C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:12]([Br:23])=[C:13]2[C:18](=[CH:19][C:20]=1[CH3:21])[N:17]=[C:16]([CH3:22])[CH:15]=[CH:14]2)[O:10][C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1ccc2c(Br)c([C@H](O)COC(=O)C(C)(C)C)c(C)cc2n1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: Cc1ccc2c(Br)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-hydroxyethyl pivalate (330 mg, 0.87 mmol) in t-butylacetate (10 mL) was added perchloric acid (0.3 mL, 3.5 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours, quenched with slowly addition of NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product. LCMS-ESI+: calc'd for C22H30BrNO3: 436.1 (M+H+); Found: 436.2 (M+H+).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:23]=[CH:22][C:11]([CH:12]([OH:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>N1C=CC=CC=1>[C:24]([O:21][CH:12]([C:11]1[CH:22]=[CH:23][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OC(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 1 L round-bottom flask equipped with magnetic stirrer and nitrogen inlet was added 700 ml anhydrous THF containing BHT as inhibitor, 98 g anhydrous pyridine, and 51.6 g (211 mmol) of 4,4′-dimethoxybenzhydrol. The reaction mixture was cooled to −10° C. and 26.5 g (254 mmol) methacryloyl chloride was added dropwise over 10 minutes. The reaction mixture was stirred at −10-0° C. for 1 hour and then stirred at ambient temperature for 20 hours. The solid was filtered and the filtrate was extracted using Et2O/water. The organic layer was washed with 1 N NaHCO3, 1 N HCl, brine, and water and then dried with MgSO4, filtered, and concentrated under reduced pressure to give the desired crude product which was recrystallized from cold ether/hexanes at −20° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:20][CH2:19]2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N2CCCC2)CC1)C1CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](N5CCCC5)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure D, {6-bromo-4-[trans-4-(pyrrolidin-1-yl)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (25 mg, 0.150 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.150 mmol) to afford the desired product (20 mg, 67%), as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.03 (dd, J=8.7, 1.9 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 4.15 (t, J=10.6 Hz, 1H), 3.99 (s, 3H), 3.16 (s, 4H), 2.94 (s, 1H), 2.89-2.79 (m, 1H), 2.38 (d, J=12.5 Hz, 2H), 2.28 (d, J=11.9 Hz, 2H), 1.99 (s, 4H), 1.70-1.50 (m, 4H), 1.23-1.17 (m, 2H), 1.13-1.06 (m, 2H); ESI MS m/z 520 [C30H34ClN3O3+H]+; HPLC 98.7% (AUC), tR=10.99 min.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:10][C:9]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:8]=2[O:7]1)C.[OH-].[Na+]>C(O)C>[C:16]1([C:6]2([CH2:5][C:4]([OH:22])=[O:3])[O:10][C:9]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:8]=3[O:7]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC1(c2ccccc2)Oc2ccc(Cl)cc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1(c2ccccc2)Oc2ccc(Cl)cc2O1

Procedure:
A mixture of 32 g. of ethyl(2-phenyl-5-chloro-1,3-benzodioxol-2-yl)acetate, 200 cc. of 95% ethanol and 150 cc. of 4% NaOH is refluxed for 2 hours. The alcohol is then removed under vacuum and, after cooling, the mixture is acidified with dilute HCl. The precipitated solid is filtered off and recrystallised from benzene-hexane, m.p. 117°-119°C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=O.[C:9]([NH:12][CH2:13][CH2:14][N:15]1[C:19]([CH3:20])=[CH:18][C:17](C=O)=[C:16]1[CH3:23])(=[O:11])[CH3:10].N1CCCCC1>N1C=CC=CC=1>[C:9]([NH:12][CH2:13][CH2:14][N:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH:3]=[CH:2][C:1]([O:7][CH3:8])=[O:6])=[C:19]1[CH3:20])(=[O:11])[CH3:10]
Reactant: CC(=O)NCCn1c(C)cc(C=O)c1C
Reactant: COC(=O)CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COC(=O)C=Cc1cc(C)n(CCNC(C)=O)c1C
Reaction time: 24 h
Yield: 56.7 %

Procedure:
6.1 g (0.05 mol) of monomethyl malonate are dissolved in 20 ml of pyridine. After addition of 10.4 g (0.05 mol) of 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole-3-aldehyde (see Example 13) and 1 ml of piperidine, the mixture is heated under reflux for 15 hours. After addition of a further 27 g of monomethyl malonate, heating is continued for a further 24 hours, the mixture is concentrated, the residue is taken up in water, the mixture is extracted with methylene chloride and the methylene chloride phase is washed with dilute acid and alkali and concentrated. Column chromatography with methylene chloride:methanol=98:2 as the mobile phase gives 7.5 g of product, which can be recrystallized from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.[C:21](O)(=[O:25])/[CH:22]=[CH:23]/[CH3:24].[OH-].[NH4+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:11]3[C:21](=[O:25])[CH2:22][CH:23]([CH3:24])[O:20][C:12]=3[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Reactant: C/C=C/C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OC(C)CC2=O
Yield: 29 %

Procedure:
A mixture of 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine (2.76 g, 0.01 mole) and crotonic acid (0.87 g 0.01 mole) in polyphosphoric acid (27 g) was stirred and heated on a steam bath for 4 hr. The reaction mixture was cooled to 50° and poured onto ice (100 g) with stirring. The resulting solution was basified to pH 8.0 with concentrated ammonium hydroxide, giving a suspension which was then extracted with methylene chloride (3×100 mL). The combined extracts were washed with 0.1N sodium hydroxide (2×100 mL), water (100 mL) and then dried over anhydrous magnesium sulfate. Evaporation of solvent in vacuo gave the title compound (1.0 g, 29%). This was recrystallized from 95% ethanol to give 2,4-diaino-5-(3,4-dihydro-7,8-dimethoxy-2-methyl-4-oxo-2H-1-benzopyran-5-ylmethyl)pyrimidine as the hemihydrate, mp 128°-132°. Anal. Calcd for C17H20N4O4.1/2H2O: C, 57.78; H, 5.99; N, 15.85. Found: C, 57.79; H, 6.02; N, 15.86.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.Cl>C1COCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: Cl
Solvent: C1CCOC1
Product: OCCc1ccc(CBr)cc1
Temperature: 0 °C
Yield: 90 %

Procedure:
3.85 g (18.81 mmol) of 4-bromomethylphenylacetic acid are dissolved in 150 ml of THF, and 20 ml of a 1M solution of BH3 in THF is added slowly with stirring, at 0° C. The reaction mixture is then slowly warmed to room temperature and stirred overnight at room temperature. 2M hydrochloric acid is added, and the reaction mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated. 3.64 g (16.92 mmol) of the 2-[4-(bromomethyl)phenyl]ethanol thus obtained are, without further purification, dissolved in 36 ml of DMSO, and 1.65 g (25.38 mmol) of potassium cyanide are added. The reaction mixture is stirred at room temperature for 1 h and then poured into diethyl ether/sat. aqueous sodium bicarbonate solution. The organic phase is washed three times with water, dried over magnesium sulfate, filtered and concentrated. This gives 2.5 g of product.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])=[O:28])([O:3]C)=[O:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CC(C)=O.O>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[S:27]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:28])=[O:29])([OH:3])=[O:2]
Reactant: COC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1S(=O)(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)O)N2S(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
To a solution of 756 mg of benzyl α-(3ξ-carbomethoxy-2-phenylmethanesulfonyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-heptan-6-yl)-α-isopropylideneacetate dissolved in a mixture of 9 ml of acetone and 2.7 ml of water is added 1.85 ml of 1.012 N aqueous solution of sodium hydroxide under ice-cooling. After 15 minutes, the reaction mixture is poured into ice water, mixed with ethyl acetate, adjusted to pH 2 with 2 N-hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract is washed with water, dried on sodium sulfate, and evaporated under reduced pressure to yield 705 mg of benzyl α-(3ξ-carboxy-2-phenylmethanesulfonyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:10]1[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CCO>[OH:1][CH2:2][CH:3]([N:10]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cnn(C(CO)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn(C(CO)c2ccccc2)c1
Temperature: 90 °C

Procedure:
A mixture of ethyl 1-(2-hydroxy-1-phenylethyl)-1H-pyrazole-4-carboxylate (110 mg, 0.423 mmol) in EtOH (2 ml) was treated with NaOH (2N, 0.634 ml, 1.268 mmol) and heated to 90° C. for 30 min. The reaction mixture was acidified with 1N HCl, and all volatiles were removed in vacuo. The remaining residue was suspended in MeOH (10 ml) and filtered. Concentration of the filtrate afforded the title compound. LCMS RtM=1.58 min, [M+H]+=233.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([O:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[C:33](Cl)=[O:34])[CH3:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:31]=[CH:32][C:23]=3[O:22][CH2:20][CH3:21])=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCOc1ccc2ccccc2c1C(=O)Cl
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: CCOc1ccc2ccccc2c1C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-ethoxy-1-naphthoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-ethoxy-1-naphthamide as a white powder, m.p. 219° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.33 (t, J=5.8 Hz, 1H), 8.22 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.7 Hz, 11H), 7.87-7.84 (m, 1H), 7.64-7.56 (m, 2H), 7.47-7.22 (m, 5H), 6.60 (s, 2H), 4.69 (t, J=7.2 Hz, 2H), 4.09 (q, J=7.2 Hz, 2H), 3.37 (m, 2H), 2.01 (m, 2H), 1.64 (m, 2H), 1.18 (t, J=7.2 Hz, 3H); MS (EI) m/e 453.2157 (453.2165 calcd for C27H27N5O2).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]2([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:4]=1)=[O:2].CC(=CC)C.P([O-])(O)(O)=[O:33].[Na+].Cl([O-])=O.[Na+]>CC(O)(C)C.O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C:13]([C:5]2[CH:4]=[C:3]([C:1]([OH:33])=[O:2])[C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)([OH:26])[CH2:14][CH2:15]1)=[O:20])([CH3:23])([CH3:25])[CH3:24]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C=O)c3ccccc3c2)CC1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(=O)O)c3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.5 g (4.2 mmol) of tert-butyl 4-(4-formyl-2-naphthyl)-4-hydroxypiperidine-1-carboxylate in 25 mL of 2-methyl-2-propanol was added 2.3 mL (21 mmol) of 2-methyl-2-butene followed by dropwise addition of a solution of 1.00 g (8.45 mmol) of sodium dihydrogen phosphate and 877 mg (59.7 mmol) of sodium chlorite in 15 mL of water. The resulting mixture was stirred at ambient temperature for 2 h then evaporated in vacuo to remove all volatiles. The residue was diluted with water (5 mL) and an aqueous 2 N HCl solution was then added dropwise to the stirred mixture until a pH of 4 was achieved. The aqueous phase was then extracted with ethyl acetate (3×5 mL) and the combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the crude title compound as a colorless oil. LC/MS 394.2 (M+23).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].CS[C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=2[N:17]=1>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[N:13]=[CH:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=4)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=3[N:17]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Agent: [H-]
Agent: [Na+]
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Yield: 66.3 %

Procedure:
By following the general procedure of Examples 2 and 3, 524.2 mg (5.569 mM) of 4-aminopyridine was reacted with 687.4 mg (17.2 mM) of sodium hydride and 1983.8 mg (5.550 mM) of 2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one to provide 66.3% yield (85.8% purity) of 2-(pyridin-4-ylamino)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]1[N:19]2[C:20]3[CH:26]=[CH:25][N:24](S(C4C=CC(C)=CC=4)(=O)=O)[C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1.[OH-].[Na+]>O1CCOCC1>[C:15]1([C@@H:3]2[C@H:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4]2)[N:19]2[C:20]3[CH:26]=[CH:25][NH:24][C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@H]4CN(C(=O)OC(C)(C)C)CC[C@H]4C)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1c1ncc2cnc3[nH]ccc3n12
Temperature: 60 °C
Yield: 108.2 %

Procedure:
To a solution of (3R,4R)-tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (40 g, 78 mmol) in 1,4-dioxane (160 mL) was added NaOH (1 N aqueous, 157 mL). The mixture was heated at about 60° C. for about 1 h. The mixture was allowed to cool to ambient temperature. The mixture was partitioned with HCl (4 N aqueous, 50 mL) and extracted with DCM (2×300 mL). The combined organic extracts were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered then coned in vacuo. The product was purified on silica gel (330 g) using 1-5% MeOH in DCM to give (3R,4R)-tert-butyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate (30 g, 99%): LC/MS (Table 1, Method b) Rt=2.00 min; MS m/z: 356 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([O:25]CC)=[O:24])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([OH:25])=[O:24])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)CC(C)(C)Cc1cc(F)c(OCCCNc2ccccn2)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(CC(=O)O)Cc1cc(F)c(OCCCNc2ccccn2)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of STEP 9 (0.254 g, 0.54 mmol) was dissolved in 10 ml methanol and 10 ml 1 N sodium hydroxide solution. The reaction was stirred at room temperature for 18 h, and acidified with trifluoroacetic acid (5 ml). Solvents were evaporated and residue was purified on HPLC using acetonitrile gradient 10-50% in 30 min to yield 0.213 g. NMR spectra of the product were consistent for the proposed structure. FAB-MS:(M+2)=441.3. H MNR (CDCl3) δ1.05 (s, 6H), 2.20 (p, 2H), 2.22 (s, 2H), 2.63 (s, 2H), 2.68 (q, 2H), 4.20 (t, 2H), 6.74 (t, 1H), 6.93 (dd, 1H), 6.97 (s, 1H), 7.15 (s, 1H), 7.83 (m, 2H), 9.66 (br, 1H); Anal Calcd. for C20H24N2O3FBr plus 1.75 CF3COOH: C, 44.18; H, 4.06; N, 4.38. Found: 44.05; H, 4.16; N, 4.25.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:35][C:36]1[CH:46]=[CH:45][C:39]([CH2:40][NH:41][CH:42]2[CH2:44][CH2:43]2)=[C:38]([O:47][C@H:48]([CH2:50][CH:51]=[CH2:52])[CH3:49])[CH:37]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:41]([CH:42]4[CH2:44][CH2:43]4)[CH2:40][C:39]4[CH:45]=[CH:46][C:36]([CH3:35])=[CH:37][C:38]=4[O:47][C@H:48]([CH2:50][CH:51]=[CH2:52])[CH3:49])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1CNC1CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN(Cc4ccc(C)cc4O[C@@H](C)CC=C)C4CC4)nn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (95 mg, 0.163 mmol) in acetonitrile (3 mL) at 0° C. was added (S)—N-(4-Methyl-2-(pent-4-en-2-yloxy)benzyl)cyclopropanamine (40 mg, 0.163 mmol) and Hunig's Base (0.028 mL, 0.163 mmol). It was stirred at 0° C. for 2 h and then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was then purify by 20% EtOAc/hexane to obtain (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((cyclopropyl(4-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)amino)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.128 mmol, 79% yield) as an oil. LCMS (M+1)=702.5.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].N12CCCN=C1CCCCC2>C(#N)C>[C:22]([O:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 72 %

Procedure:
To a suspension of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (2 g) in anhydrous acetonitrile were added 3-t-butoxycarbonylaminopyrrolidine (1.86 g) and 1,8-diazabicyclo[5,4,0]undec-7-en (DBU, 1.02 g) and then the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform (50 ml). The resulting solution was washed with 10% aqueous citric acid solution (20 ml), and with saturated saline solution successively. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was dissolved in hot methanol (20 ml) and then cooled. The resulting crystals were collected by filtration to give 7-(3-t-butoxycarbonylamino-1-pyrrolidinyl)-1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (2.25 g) as yellowish white prisms, mp 224°-226° C. (decompd.).
Reaction SMILES: [CH2:1]([N:8]([C:47](=[O:51])[C:48]([OH:50])=[O:49])[CH2:9][CH:10]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:25]([OH:34])=[C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:23]=2)=[O:20])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([N:8]([C:47](=[O:51])[C:48]([OH:50])=[O:49])[CH2:9][CH:10]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([NH:21][C:22]2[CH:23]=[C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:25]([OH:34])=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:27]=2)=[O:20])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(C(CN(Cc2ccccc2)C(=O)C(=O)O)C2CCCCC2)cc1)Nc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCc1ccc(C(CN(Cc2ccccc2)C(=O)C(=O)O)C2CCCCC2)cc1)Nc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1

Procedure:
A mixture of Example 39 (34.0 mg, 0.050 mmol) and 10% Pd/C (5.0 mg) in ethanol (2.0 mL) at room temperature was stirred under hydrogen for 16 hours, filtered through diatomaceous earth (Celite®) with ethanol rinsing, and concentrated to provide the desired product.