Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>C(#N)C>[CH:34]1([C:37]([O:16][NH:15][C:14]([CH2:13][C@@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)=[O:17])=[O:38])[CH2:36][CH2:35]1
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: O=C(Cl)C1CC1
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)C2CC2)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 66.2 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (500 mg, 1.1 mmol) in acetonitrile (5 mL) was added cyclopropanecarbonyl chloride (0.15 mL, 1.7 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (50 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[2-cyclopropanecarbonyloxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (380 mg, 66% yield): mp, 130–132° C.; 1H NMR (DMSO-d6) δ 0.81–1.01 (2 ms, 8H, 4CH2), 1.31 (t, J=7 Hz, 3H, CH3), 1.70–1.80 (m, 1H, CH), 2.97–3.05 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.97–4.04 (m, 2H, CH2), 4.17 (d, J=18 Hz, 1H, NCHH), 4.59 (d, J=18 Hz, 1H, NCHH), 5.66 (t, J=8 Hz, 1H, NCh), 6.87–6.94 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.49 (d, J=8 Hz, 1H, Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.54 (s, 1H NH), 12.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.77, 8.92, 10.28, 14.69, 15.46, 34.61, 46.60, 51.11, 55.48, 63.80, 111.94, 112.11, 116.81, 117.31, 117.49, 119.27, 131.22, 132.77, 136.96, 142.25, 147.94, 148.57, 166.59, 168.85, 171.72, 172.41; Anal Calcd for C28H31N3O7+0.7 H2O: C, 62.96; H, 6.11; N, 7.87. Found: C, 62.64; H, 5.89; N, 7.78.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)=[CH:6][CH:7]=1.C(O)=[O:18]>>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[Cl:15])[O:8][C:5]1[N:4]=[N:3][C:2]([OH:18])=[CH:7][CH:6]=1
Reactant: Clc1ccc(Oc2ccc(Cl)c(Cl)c2)nn1
Reactant: O=CO
Product: Oc1ccc(Oc2ccc(Cl)c(Cl)c2)nn1

Procedure:
A solution of 3-chloro-6-(3,4-dichloro-phenoxy)-pyridazine (1.74 g, 6.32 mmol) in formic acid (25 mL) was heated at 100° C. for 3 hours. The solvent was removed by evaporation in vacuo yielding the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH:23]2[CH3:26])=[CH:18][C:17]=1[OH:27]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][C:16]([O:15][CH3:14])=[C:17]([OH:27])[CH:18]=4)[CH:23]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1cc2c(cc1O)CCNC2C
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1cc2c(cc1O)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-ol to provide the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]2[S:25][C:20]3=[N:21][CH:22]=[CH:23][N:24]=[C:19]3[CH:18]=2)=[O:16])[CH:13]=1)=[O:6].Cl.[CH3:31][NH:32][CH3:33]>C(O)C>[CH3:31][N:32]([CH3:33])[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]2[S:25][C:20]3=[N:21][CH:22]=[CH:23][N:24]=[C:19]3[CH:18]=2)=[O:16])[CH:13]=1)=[O:6]
Reactant: CNC
Reactant: Cc1ccc(NC(=O)c2ccnc(Br)c2)cc1NC(=O)c1cc2nccnc2s1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccnc(N(C)C)c2)cc1NC(=O)c1cc2nccnc2s1
Temperature: 150 °C
Yield: 49.3 %

Procedure:
To a solution of N-(5-(2-bromoisonicotinamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 30 (25 mg, 0.053 mmol) in ethanol (1 mL) was added dimethylamine HCl (24.07 mg, 0.534 mmol) and TEA (10 eq). The resulting mixture was heated at 80° C. overnight and 2 h at 150° C. in microwave. Quenched in 3% citric acid solution and extracted with CH2Cl2 (2×). The combined organic layers were dried with Na2SO4 and evaporated. Triturating with ethyl acetate/heptane gave the title compound N-(5-(2-(dimethylamino)isonicotinamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 31a (11.3 mg, 49%). NMR (400 MHz, DMSO-d6) 2.26 (s, 3H), 3.11 (s, 6H), 7.03 (d, J=5.1 Hz, 1H), 7.10 (br s, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.63 (dd, J=8.2 and 1.9 Hz, 1H), 7.87 (d, J=1.9 Hz, 1H), 8.23 (d, J=5.1 Hz, 1H), 8.56 (br s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 10.39 (br s, 1H), 10.54 (br s, 1H). (m/z)=433 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[O:30][CH2:31][CH2:32][CH2:33]Br)(=[O:25])[CH3:24].[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>C(#N)C.C(O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:29]4[CH:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:37]=[CH:36][CH:35]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:29]4[CH:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:37]=[CH:36][CH:35]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1cccc(OCCCBr)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CC(=O)Nc1cccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.25 g, 42 mmol), K2CO3 (8 g, 58 mmol) and 3-(3-acetamidophenoxy)propyl bromide (11.4 g, 42 mmol) in acetonitrile (350 ml) was heated at reflux for 3 hours. At the end of the reaction, the reaction was cooled, filtered and the solids washed with dichloromethane (100 ml). The organic solvent was removed on a rotary evaporator to leave a crude oil (18 g). Purification was by flash chromatography on a silica gel column. The product thus purified was an oil, 12.2 g, 70%. Analytically pure sample was prepared by dissolving 3 g of free base in ethanol and treating with fumaric acid solution in ethanol (850 mg:5 ml). The N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide hemifumarate crystals obtained weighed 2.73 g, m.p.=184°-186° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 73.8 %

Procedure:
To a solution of 4-(4-Fluoro-phenoxy)-phenol (200 mg, 0.979 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (70 mg, 1.76 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (348 mg, 0.979 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain title the product (280 mg, 74%).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:59]=[CH:58][C:49]([C:50]([NH:52][N:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)=[O:51])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:27])[NH:45][C:46]4[CH:59]=[CH:58][C:49]([C:50]([NH:52][N:53]5[CH2:54][CH2:55][CH2:56][CH2:57]5)=[O:51])=[CH:48][CH:47]=4)=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(C(=O)NN2CCCC2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)NN5CCCC5)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-amino-N-(pyrrolidin-1-yl)benzamide as the aniline component. (8%, MS=582.3 (M+H))
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=O.S(N)([NH2:17])(=O)=O.O>S1(CCCC1)(=O)=O>[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)#[N:17]
Reactant: NS(N)(=O)=O
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: N#Cc1ccc2c(c1)COC2=O
Temperature: 135 °C
Reaction time: 0.08 h

Procedure:
5-Chlorocarbonylphthalid (24.3 g, 0.124 mole) was dissolved in sulfolane (51 g). Sulfamide (13.8 g 0.144 mole) was added and the temperature was raised to 135° C. for 3 hours. At about 90° C., gas evolution took place. The mixture was allowed to cool and water (100 g) was added. The temperature was held at 85-90° C. for 5 min and then the solution was cooled to 60° C. The crystals were filtered off and washed with water (60 g) and acetic acid (30 g). Then the title compound was dried in vacuo. Yield: 19 g, 96%. Purity: 98.2% (hplc, peak area).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[F:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[F:34])[CH2:27][NH:26][C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:11]=1[CH:22]([CH3:24])[CH3:23])=[O:36]
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3cccnc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure F, ethyl3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-6-carboxylate (Compound 46, 439 mg, 0.896 mmol) ) in EtOH (12 ml) was added NaOH (179 mg, 4.48 mmol) and H2O (1 ml). The reaction was stirred at 25° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a light yellow solid.
Reaction SMILES: [CH:1]1([N:5]([CH3:28])[C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21]OC)=[CH:16][C:15]=3[Cl:24])[CH:10]=[CH:9][C:8]=2[O:25]C)[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)[Br:30]>ClCCl>[Br:30][CH2:21][C:17]1[CH:18]=[C:19]([Cl:20])[C:14]([O:13][C:11]2[CH:10]=[CH:9][C:8]([OH:25])=[C:7]([CH:12]=2)[C:6]([N:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH3:28])=[O:27])=[C:15]([Cl:24])[CH:16]=1
Reactant: BrB(Br)Br
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)N(C)C3CCC3)c2)c(Cl)c1
Solvent: ClCCl
Product: CN(C(=O)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O)C1CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound of Step F in dichloromethane (2.2 ml) at room temperature was added boron tribromide (1M in dichloromethane, 1.5 ml, 1.5 mmol). The reaction mixture was stirred at room temperature for about two hours, and quenched with water (20 ml). After stirring for about 15 minutes, the solution was extracted with dichloromethane (3×15 ml). The combined organic extracts were washed with brine (50 ml), treated with activated carbon, filtered through diatomaceous earth, dried and concentrated to give the title compound (163 mg) as an off-white solid which was used in the next step without further purification. MS (APCI−) Calc: 457.0, found: 456.0 (M−1).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:36]1[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=1)(=[O:44])=[O:43]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)cc1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3,4-dimethoxybenzenesulfonyl chloride (12 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 28 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-3,4-dimethoxybenzenesulfonamide (percentage yield: 96%), was obtained.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][C@H:8]([N:10]([C:15]([C:17]2[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)(=[O:3])[NH2:2].C(OCC)(=O)C.[ClH:45]>C(OCC)(=O)C>[ClH:45].[ClH:45].[C:1]([C@H:4]1[CH2:5][NH:6][CH2:7][C@@H:8]([N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:15]([C:17]2[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)=[O:16])[CH2:9]1)(=[O:3])[NH2:2]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(N)=O)C2)nc2ccccc21
Reaction time: 1 h

Procedure:
tert-Butyl (3R,5S)-3-carbamoyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (260 mg) was dissolved in ethyl acetate (3 ml), 4N hydrogen chloride-ethyl acetate (5 ml) was added, and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure to give the object product (220 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:32]([O:34]CC)=[CH2:33])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:44])[CH3:43])=O)(C)(C)C.[ClH:45]>C(OCC)(=O)C>[ClH:45].[C:32]([C:29]1[C:28](=[O:37])[N:27]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][C:9]([CH3:44])([CH3:43])[CH2:10]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31])(=[O:34])[CH3:33]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNC(C)(C)C4)cn3)nc2n(C2CCCC2)c1=O
Yield: 38.1 %

Procedure:
4-{6-[8-Cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.400 g, 0.663 mmol) was dissolved in ethyl acetate (10 mL) and 6 N HCl (10 mL) and stirred at room temperature for 2 hours. The solvent was evaporated to give a yellow solid, which was dried in a vacuum oven for 5 hours at 50° C. The solid was triturated with EtOH (20 mL) and filtered to give 6-acetyl-8-cyclopentyl-2-[5-(3,3-dimethyl -piperazin-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.120 g, 38.1%). 1H NMR δ(400 MHz, DMSO-d6) 9.15 (s, 2H), 8.93 (s, 1H), 8.04 (d, J=3.2 Hz, 1H), 7.82 (d, J=9.1 Hz, 1H), 7.64 (m, 1H), 5.78 (m, 1H), 3.31 (m, 2H), 3.24 (m, 2H), 3.18 (s, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 2.18 (m, 2H), 1.85 (m, 2H), 1.73 (m, 2H), 1.54 (m, 2H), 1.35 (s, 6H). MS (APCI) Calc'd for M+H: 476.3. Found: 476.1. Anal. Calc'd for C26H33N7O24.38HCl: C, 49.16; H, 5.93; N, 15.43. Found; C, 49.55; H, 6.80; N, 14.76.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:21]=3[N:22](S(C3C=CC(C)=CC=3)(=O)=O)[C:23]=2[CH:24]=1.[OH-].[Na+]>CO.C(Cl)Cl>[O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:21]=3[NH:22][C:23]=2[CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(N5CCN(CCc6ccccc6)CC5=O)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(N4CCN(CCc5ccccc5)CC4=O)ccc3c2C1
Yield: 47.1 %

Procedure:
tert-Butyl 7-(2-oxo-4-phenethylpiperazin-1-yl)-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (450 mg, 0.716 mmol) and NaOH (800 mg, 20 mmol) were stirred in MeOH/CH2Cl2 (5 mL/5 mL) for 16 h. The mixture was partitioned between CH2Cl2 and water and the organic layer removed, dried and concentrated. The residue was purified by column chromatography (40 g ISCO column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 90% methylene chloride) to provide the title compound (160 mg, 47%) as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.32-7.25 (m, 4H), 7.22-7.17 (m, 2H), 6.88-6.86 (dd, J=8.3, 1.8 Hz, 1H), 4.51 (s, 2H), 3.69 (t, J=5.6 Hz, 2H), 3.64 (t, J=5.3 Hz, 2H), 3.33 (m, 2H), 2.88-2.83 (m, 2H), 2.83-2.74 (m, 4H), 2.69-2.63 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:32][CH2:31][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24]5[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26][N:25]=5)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>CO.O1CCOCC1>[ClH:33].[ClH:33].[CH3:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[CH:15]([N:13]2[CH2:14][C:11]4([CH2:31][CH2:32][NH:8][CH2:9][CH2:10]4)[CH2:12]2)[CH2:16][CH2:17]3)[CH:29]=1
Reactant: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)ncn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3c(c2)CCC3N2CC3(CCNCC3)C2)ncn1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
2-[(R)-5-(6-Methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3-1f, 72.6 g, 167 mmol) was suspended in methanol (363 mL) and 4M HCl in 1,4-dioxane (251 mL) was added. After stirring for 2 hours, the slurry was concentrated to dryness. The crude material was re-suspended in MeOH (500 mL) and concentrated (3×). The resulting solids were further dried under vacuum at 45° C. to afford 2-[5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-dihydrochloride (3-1g, 74.1 g, 99.9%). MS (ES+) 335.2 (M+H)+. 1H NMR (CD3OD) δ 2.16-2.23 (m, 5H), 2.59 (br s, 1H), 2.78-2.80 (m, 3H), 3.12 (br s, 1H), 3.19-3.24 (m, 4H), 3.37-3.49 (m, 1H), 4.14-4.23 (m, 3H), 4.49 (br s, 1H), 5.11 (br s, 1H), 7.84 (d, 1H), 8.30-8.34 (m, 2H), 8.46 (s, 1H), 9.36 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:14][C:15]1[N:16]=[C:17]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:18]2[S:23][C:22]([CH:24]=O)=[CH:21][C:19]=2[N:20]=1>>[Cl:14][C:15]1[N:16]=[C:17]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:18]2[S:23][C:22]([CH2:24][N:10]3[CH2:9][CH2:8][C:7]([OH:13])([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:12][CH2:11]3)=[CH:21][C:19]=2[N:20]=1
Reactant: OC1(c2ccccn2)CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: OC1(c2ccccn2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction of 2′,3′,5′,6′-tetrahydro-1′H-[2,4]bipyridinyl-4′-ol with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 using standard reductive amination conditions yielded 1′-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-2′,3′,5′,6′-tetrahydro-1′H-[2,4]bipyridinyl-4′-ol, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 402. 400 MHz 1H NMR CDCl3 9.16 (s, 2H); 8.47 (d, 1H, J=4.8 Hz); 7.70 (t, 1H, J=7.7 Hz); 7.45 (d, 1H, J=7.9 Hz); 7.26 (s, 1H); 7.19 (t, 1H, J=6.2 Hz); 4.00 (t, 4H, J=4.6 Hz); 3.87 (s, 2H); 3.85 (t, 4H, J=4.7 Hz); 2.875 (d, 2H, J=11.0 Hz); 2.63 (t, 2H, J=11.2 Hz); 2.16 (m, 2H); 1.63 (d, 2H, J=12.6 Hz). LC-MS (m+1)=505.18
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(F)c(F)c(F)cc2c1O
Product: CCOC(=O)c1cnc2c(F)c(F)c(F)cc2c1Cl
Yield: 65.6 %

Procedure:
A solution of ethyl 4-hydroxy-6,7,8-trifluoroquinoline-3-carboxylate (59.0 g) and POCl3 (500 ml) was refluxed for 8 h. Excess POCl3 was distilled off, the residue was removed into the mixture of ice and water. Solid NaHCO3 was added into the mixture to pH 7˜8 and the precipitated solid was isolated by filtration. The crude was recrystallized by toluene to afford the title compound (41.3 g, 65.6% yield), mp: 110-112° C.