Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:57]=[CH:56][CH:55]=[C:54]2[C:50]=1[CH2:51][O:52][C:53]2=[O:58]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:49]2[CH:57]=[CH:56][CH:55]=[C:54]3[C:50]=2[CH2:51][O:52][C:53]3=[O:58])=[CH:15][CH:16]=1
Reactant: O=C1OCc2c(O)cccc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cccc3c2COC3=O)cc1

Procedure:
Analogously to Method G, 0.210 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.094 g of 4-hydroxy-3H-isobenzofuran-1-one are reacted. The title compound is obtained as a white solid. Rf=0.32 (1:1 EtOAc-heptane); Rt=5.84.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12]CCl)=[CH:8][S:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1NC(=O)CCCl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of 4-(3-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester ([51486-30-7], 0.1 g, 0.43 mmol) in dimethylformamide (1.5 mL) was added potassium carbonate (0.88 g, 0.64 mmol) and 4-hydroxybiphenyl (0.087 g, 0.514 mmol) and the reaction mixture was then stirred overnight at 90° C. After such time the reaction mixture was allowed to cool to room temperature, water was added (in excess of 5 mL) leading to precipitation. The precipitate was then filtered, washed with water and dried in vacuo to yield the title compound as a white solid (0.16 g, 87%).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][C:34]1([CH3:37])[CH2:36][O:35]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:33][C:34]([OH:35])([CH3:37])[CH3:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC1(C)CO1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CC(C)(C)O)CC4)cn3)nc2n1C1CCCC1
Yield: 29.2 %

Procedure:
Following General Procedure E, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 0.115 mmol) and 2,2-dimethyloxirane (72 mg, 0.805 mmol) gave 7-cyclopentyl-2-{5-[4-(2-hydroxy-2-methyl-propyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (17 mg, 29%). MS (ESI) m/z 507.3 (M+H)|
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)[O:13][C:12]3=[O:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].[Na+].[I-]>C1COCC1>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][N:18]([CH2:17][CH2:16][CH:14]1[O:13][C:12](=[O:33])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:15]1)[CH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][CH:22]=1)[CH3:51]
Reactant: COc1ccc2nccc(CCNCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Reactant: CCOC(=O)CCCBr
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(CCc1ccnc2ccc(OC)nc12)CCC1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
A solution of the compound of Example 72 (0.2 g, 0.44 mmol) in THF (3 mL) was treated with DIPEA (0.147 mL, 2 eq.), ethyl 4-bromobutyrate (0.087 g, 1 eq.) and NaI (0.067 g, 1 eq.). The mixture was heated at 80° C. for 2 h, then partitioned between EA and water. The org. phase was dried over MgSO4 and concentrated. The residue was purified by FC (EA) to give the title compound as a yellowish oil (0.17 g, 68% yield).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10].[NH2:17][C:18]1[C:27]2[N:28]=[C:29]([CH2:34][O:35][CH2:36][CH3:37])[N:30]([CH2:31][CH2:32][CH3:33])[C:26]=2[C:25]2[CH:24]=[C:23]([OH:38])[CH:22]=[CH:21][C:20]=2[N:19]=1.CN(C=O)C>O>[CH2:36]([O:35][CH2:34][C:29]1[N:30]([CH2:31][CH2:32][CH3:33])[C:26]2[C:25]3[CH:24]=[C:23]([O:38][CH2:8][C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:10])[CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:17])[C:27]=2[N:28]=1)[CH3:37]
Reactant: O=C(CBr)N1CCOCC1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(O)cc3c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCC(=O)N4CCOCC4)cc3c21
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Cesium carbonate (1.62 g, 5.00 mmol) was added to a solution of 2-bromo-1-morpholin-4-yl-ethanone (414 mg, 1.99 mmol), 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (500 mg, 1.66 mmol), and anhydrous DMF (20 mL). The reaction mixture was heated at 75° C. overnight, allowed to cool, and poured into deionized water (300 mL). The resulting mixture was stirred for 30 minutes and then extracted with chloroform (3×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by chromatography on a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-35% methanol/dichloromethane (10:90) in dichloromethane). The resulting solid was recrystallized from acetonitrile to yield 333 mg of 2-(ethoxymethyl)-8-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 196-197° C. Anal. calcd for C22H29N5O4: C, 61.81; H, 6.84; N, 16.38. Found: C, 61.72; H, 6.86; N, 16.62.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:21])([F:20])[C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:11][O:10]1.C([O-])([O-])=O.[K+].[K+].FC(F)(F)S(O[CH2:34][C:35]([F:38])([F:37])[F:36])(=O)=O>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:20])([F:21])[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:17][N:18]=2)[CH2:11][O:10]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(C(F)(F)C2(c3ccc(F)cc3F)CO2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(C2(C(F)(F)c3ccc(OCC(F)(F)F)cn3)CO2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a magnetically stirred mixture of 6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-ol (600 mg, 2.005 mmol) and K2CO3 (305 mg, 2.206 mmol) in acetone (6.76 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (558 mg, 2.406 mmol) in a 20 mL vial under an atmosphere of air. The reaction mixture was stirred at 25° C. for 16 h. As the reaction progressed the reaction mixture became a cloudy beige suspension. The reaction was quenched with MeOH (2 mL) and then volatiles were removed under a gentle stream of N2. The resulting residue was partitioned with water and CH2Cl2 and the organic layer was removed. The aqueous layer was washed CH2Cl2 (2×) and combined organic layers were dried by passing through a phase separator. Volatiles were removed under a gentle stream of N2 and the crude orange oil was carried on without further purification (779 mg, 97%): 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=2.9 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.38 (dd, J=14.7, 8.2 Hz, 1H), 7.28 (d, J=2.9 Hz, 1H), 6.88-6.80 (m, 1H), 6.78-6.71 (m, 1H), 4.44 (q, J=7.9 Hz, 2H), 3.43 (d, J=5.1 Hz, 1H), 3.00-2.95 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −73.75 (s, 3F), −107.01 (dd, J=257.0, 8.5 Hz, 1F), −107.55-−108.43 (m, 2F), −109.41 (q, J=8.5 Hz, 1F). ESIMS m/z 382 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.[C:19](OC(=O)C)(=[O:21])[CH3:20].Cl>O1CCCC1.C(OCC)C>[C:19]([C:8]1[S:7][C:6]2[C:10]([Cl:11])=[C:2]([Cl:1])[C:3]([O:12][CH3:13])=[CH:4][C:5]=2[CH:9]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ccsc2c(Cl)c1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2cc(C(C)=O)sc2c(Cl)c1Cl
Reaction time: 2 h

Procedure:
To a solution of 5.0 g of 6,7-dichloro-5-methoxybenzo[b]thiophene in 30 ml of dry tetrahydrofuran and 10 ml dry ethyl ether under nitrogen at -20° is added 11.7 ml of 2.2M n-butyllithium, while the temperature is maintained at -20°. After stirring for 2 hours at this temperature, the reaction mixture is added dropwise through a transfer needle to a stirred solution of 22 ml of freshly distilled acetic anhydride in 40 ml of dry tetrahydrofuran at -20°. Five minutes after the addition, the reaction mixture is poured onto 100 ml 10% hydrochloric acid. The mixture is extracted twice with dichloromethane, the organic layers are collected and dried and the solvent is removed to give a solid. The solid is washed with ethyl ether to give 1.5 g of 2-acetyl-6,7-dichloro-5-methoxybenzo[b]thiophene as a fluffy solid. Recrystallization of the residue obtained by evaporation of the filtrate from ethyl ether-hexane gives an additional 0.6 g of 2-acetyl-6,7-dichloro-5-methoxybenzo[b]thiophene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Cl.Cl[C:28]1[S:32][C:31]([S:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)(=[O:35])=[O:34])=[CH:30][CH:29]=1>>[CH3:42][N:39]1[CH2:38][CH2:37][N:36]([S:33]([C:31]2[S:32][C:28]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:29][CH:30]=2)(=[O:35])=[O:34])[CH2:41][CH2:40]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)s2)CC1
Agent: Cl
Product: CN1CCN(S(=O)(=O)c2ccc(C#Cc3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)s2)CC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 1-(5-chloro-thiophene-2-sulfonyl)-4-methyl-piperazine hydrochloride (example B.41) (159 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (48 mg, 16%). MS (ISP) 600.2 [(M+H)+]; mp 250° C.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:49]=[C:50]2[C:56]3([CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]3)[CH2:55][N:54]([C:69]3[C:70]4[C@H:77]([CH3:78])[CH2:76][CH2:75][C:71]=4[N:72]=[CH:73][N:74]=3)[C:51]2=[CH:52][CH:53]=1.[Cl:79][C:80]1[CH:81]=[C:82]([NH2:86])[CH:83]=[CH:84][CH:85]=1.C1(C)C=CC=CC=1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:79][C:80]1[CH:81]=[C:82]([NH:86][C:48]2[CH:49]=[C:50]3[C:56]4([CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]4)[CH2:55][N:54]([C:69]4[C:70]5[C@H:77]([CH3:78])[CH2:76][CH2:75][C:71]=5[N:72]=[CH:73][N:74]=4)[C:51]3=[CH:52][CH:53]=2)[CH:83]=[CH:84][CH:85]=1
Reactant: Nc1cccc(Cl)c1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Br)ccc43)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Nc5cccc(Cl)c5)ccc43)c21
Temperature: 95 °C
Yield: 59.5 %

Procedure:
A pear-shaped flask was charged with Pd(OAc)2 (0.9 mg, 0.004 mmol) and rac-BINAP (81 mg, 0.13 mmol) and purged with N2. To the flask was added (R)-tert-butyl 5-bromo-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 0.040 mmol), 3-chlorobenzenamine (10 mg, 0.080 mmol), NaOBut (7.7 mg, 0.080 mmol) and toluene (0.5 mL). The mixture was heated at about 95° C. for 2 days. After cooling to about room temperature, the reaction was diluted with EtOAc, filtered through Celite, and concentrated. The crude product was purified by column chromatography (DCM:MeOH, 80:1) to give (R)-tert-butyl 5-(3-chlorophenylamino)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (13 mg, 59%) as a yellow oil. LCMS (APCI+) m/z 546 [M+H]+; Rt=4.24 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:36][O:37][CH2:38][C:39]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)=[O:40]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COCC(=O)N1CCC(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1

Procedure:
A mixture of N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (20.0 mg, 0.0413 mmol), methoxyacetyl chloride (5.66 μL, 0.0619 mmol) and N,N-diisopropylethylamine (40.0 μL, 0.230 mmol, Aldrich, Cat. No. M9653) in dimethylsulfoxide (DMSO) (0.5 mL) was stirred at r.t. for 4 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=557.2.
Reaction SMILES: FC1C=CC(CNC)=CC=1.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][CH3:19])=[CH:15][CH:14]=1.[F:22][C:23]1[CH:45]=[CH:44][C:26]([CH2:27][NH:28][C:29]([C:31]2[S:35][C:34]([C:36]3[CH:41]=[N:40][CH:39]=[C:38](I)[N:37]=3)=[N:33][C:32]=2[CH3:43])=[O:30])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:45]=[CH:44][C:26]([CH2:27][NH:28][C:29]([C:31]2[S:35][C:34]([C:36]3[CH:41]=[N:40][CH:39]=[C:38]([N:18]([CH2:17][C:16]4[CH:20]=[CH:21][C:13]([O:12][CH3:11])=[CH:14][CH:15]=4)[CH3:19])[N:37]=3)=[N:33][C:32]=2[CH3:43])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Reactant: CNCc1ccc(OC)cc1
Agent: CNCc1ccc(F)cc1
Product: COc1ccc(CN(C)c2cncc(-c3nc(C)c(C(=O)NCc4ccc(F)cc4)s3)n2)cc1
Yield: 72 %

Procedure:
Following the procedure described in Example 14, making variations as required to replace 4-fluoro-N-methyl-benzylamine with (4-methoxy-benzyl)-methyl-amine to react with 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro benzylamide, the title compound was obtained in 72% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.55 (s, 1H), 8.06 (s, 1H), 7.29-7.37 (m, 2H), 7.17-7.24 (m, 2H), 6.99-7.07 (m, 2H), 6.80-6.87 (m, 2H), 6.20 (bs, 1H), 4.75 (s, 2H), 4.53 (d, J=4.0 Hz, 2H), 3.74 (s, 3H), 3.11 (s, 3H), 2.70 (s, 3H); MS (ES+) m/z 478.2 (M+1), Rt=1.58 min.
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:25][CH2:24][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:16]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([N:15]2[CH2:25][CH2:24][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:16]2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)c2ncoc2-c2ccccc2)CC1
Temperature: 25 °C

Procedure:
5-Phenyl-1,3-oxazole-4-carboxylic acid (40 mg, 0.211 mmol), ethyl isonipecotate (36.2 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C18H20N2O4: 328.1423, found 328.1430.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([C:35]3[O:34][CH:38]=[CH:37][CH:36]=3)=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)c1ccco1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccco4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 72.3 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.650 g, 2.22 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 2-furoyl chloride (0.290 g, 2.22 mmol) was added and the mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-furylcarboxamide (0.51 g, 73%) as a white solid: mp 121-123° C.; 1H NMR (DMSO-d6) δ d 11.13 (s, 1H), 9.01 (t, J=5.7 Hz, 1H), 7.88-7.68 (m, 4H), 7.18 (d, J=3.3 Hz, 1H), 6.66 (m, 1H), 5.20-5.13 (dd, J=5.4 and 12.5 Hz, 1H), 4.90 (d, J=5.6 Hz, 2H), 2.97-2.84 (m, 1H), 2.65-2.49 (m, 2H), 2.10-1.98 (m, 1H); 13C NMR (DMSO-d6) δ d 172.73, 169.80, 167.52, 166.94, 158.09, 147.49, 145.27, 139.06, 134.80, 132.98, 131.52, 127.09, 121.88, 113.86, 111.91, 48.86, 37.64, 30.92, 21.97; Anal. Calcd. For C19H15N3O6+0.18H2O: C, 59.34; H, 4.03; N, 10.93. Found: C, 59.47; H, 4.16; N, 10.49.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][B:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[O:29][C@@H:28]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][B:30]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[O:29][C@@H:28]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(B2O[C@H](CCN)C[C@H](CC(=O)OC(C)(C)C)O2)cc1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: COc1ccc(B2O[C@H](CCn3c(C(C)C)cc(-c4ccccc4)c3-c3ccc(F)cc3)C[C@H](CC(=O)OC(C)(C)C)O2)cc1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-(4-methoxyphenyl)-1,3,2-dioxaborinan-4-yl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].[CH:24](N)=[O:25]>C(O)=O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][CH:24]=[O:25])=[O:5]
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: NC=O
Solvent: O=CO
Product: O=CNNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (200 mg) in formic acid (4 ml) was added formamide (26 mg), and the mixture was stirred at ambient temperature for 3 hours. The solvent was azeotropically removed with toluene. The residue was diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residual solid was treated with hot ethanol (2 ml), allowed to cool to ambient temperature, filtered and washed with ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(2-formylhydrazino)quinoline (180 mg) as pale yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:27])[C:5]2[C:10]([C:11]#[C:12][CH2:13][CH2:14][OH:15])=[CH:9][N:8]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:6]=2[N:7]=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>N1C=CC=CC=1.C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[NH:1][C:2]1[N:3]=[C:4]([Cl:27])[C:5]2[C:10]([C:11]#[C:12][CH2:13][CH2:14][O:15][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:9][N:8]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:6]=2[N:7]=1)[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: COc1c(C)cnc(Cn2cc(C#CCCO)c3c(Cl)nc(N)nc32)c1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc(Cl)c2c(C#CCCOC(=O)OCC)cn(Cc3ncc(C)c(OC)c3C)c2n1
Temperature: 0 °C

Procedure:
A suspension of 4-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl]-but-3-yn-1-ol (see example 2) (0.73 g) in anhydrous pyridine (5 mL) and DCM (25 mL) was treated with ethyl chloroformate (1 mL) at rt for 30 min. The mixture was cooled to 0° C., treated with addition EtOCOCl (1 mL), and the temperature was allowed to slowly reach rt overnight. The reaction mixture was diluted with DCM (30 mL) and washed sequentially with H2O, NH4OH 1M, and brine. The DCM was evaporated, but not the residual pyridine, Addition of MeOH (20 mL) induced crystallization of the product, as white needles. HPLC Rt=6.28 min.