Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH4+:15].[OH-].C(O)(C)C>>[Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:15])=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: Clc1ncc(Br)c(NC2CCCC2)n1
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1ncc(Br)c(NC2CCCC2)n1
Yield: 66 %

Procedure:
A solution of 1 (45 g, 200 mmol) in 28% NH4OH/iso-propanol (1/1, 400 mL) was heated at 120° C. in a sealed tube for 22 h. The product was extracted with dichloromethane and the organic layers were washed with brine and dried. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate in hexanes to give the titled compound (2) as a white solid (34 g, 66%). 1H NMR (500 MHz, DMSO-d6) δ 7.77 (1H, s), 6.19 (2H, br. s), 6.12 (1H, d, 1H, J=7.3 Hz), 4.33 (1H, m) 1.90 (2H, m), 1.69 (2H, m), 1.49-1.55 (4H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 257.0, Calculated 257.0.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:17])=[C:7]([O:14][CH2:15][CH3:16])[CH:8]=2)[N:3]=1.[CH2:18]([NH2:20])[CH3:19]>>[CH2:15]([O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:17])[N:3]=[C:2]([NH:20][CH2:18][CH3:19])[C:11]([CH:12]=[O:13])=[CH:10]2)[CH3:16]
Reactant: CCOc1cc2cc(C=O)c(Cl)nc2cc1F
Reactant: CCN
Product: CCNc1nc2cc(F)c(OCC)cc2cc1C=O
Temperature: 150 °C
Reaction time: 3.5 h
Yield: 56 %

Procedure:
A solution of 2-chloro-6-ethoxy-7-fluoroquinoline-3-carbaldehyde SMA 44100 (110 mg, 0.43 mmol) in ethylamine (2.0 M in THF, 2.20 mL, 4.40 mmol) in a 10 mL microwave vial equipped with a magnetic stirrer was stirred for 3.5 h at 150° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=50:50 (10 mL) and the mixture was stirred for 30 min at RT. THF was then removed at 40° C. under vacuum and the residue was basified with a 10 N aq. NaOH solution (pH=8) before extraction with CH2Cl2 (40 mL). The separated organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 90:10) gave 6-ethoxy-2-(ethylamino)-7-fluoroquinoline-3-carbaldehyde SMA 44102 as a yellow solid (63 mg, 56% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.O[C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:12]1[CH2:13][CH2:14][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:16][CH2:17]1)[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](n2ncc3cc(Br)ccc32)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-bromoindazole (15 g), tert-butyl trans-4-hydroxycyclohexylcarbamate (50 g) and triphenylphosphine (50 g) in THF was stirred at 0° C. for 15 minutes. To the reaction solution was added dropwise diisopropylazodicarboxylate (38.5 g) under nitrogen atmosphere at 0° C., and the mixture was stirred at 50° C. for 1 day. Then, the solvent was removed out, ethyl acetate (300 mL) and petroleum ether (90 mL) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:80-1:15 as the eluting solvent) to give Compound Q11 (8.00 g).
Reaction SMILES: [Na].C(OC([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([C:20]([O:22]CC)=O)[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=O)C>C(O)C>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][N:14]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:20]1=[O:22]
Reactant: CCOC(=O)Nc1ccccc1N(CCN(C)C)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CN(C)CCn1c(=O)[nH]c2ccccc21
Yield: 86.8 %

Procedure:
In ethanol (100 ml) was dissolved sodium metal (0.70 g) followed by addition of a solution of N-(2-ethoxycarbonylaminophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine (4.88 g) in ethanol (20 ml). The reaction mixture was refluxed for 16 hours and was concentrated under reduced pressure. The residue was diluted with chloroform and the insoluble matter was filtered off. The solvent was then distilled off and the residue was purified by silica gel chromatography (eluent:chloroform:methanol=10:1) to give 2.69 g of 1,3-dihydro-1-(2-dimethylaminoethyl)-2H-benzimidazol-2-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][N:23]([CH3:27])[C:24](Cl)=[S:25]>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:24](=[S:25])[N:23]([CH3:27])[CH3:22])=[C:6]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=1
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(OC(=S)N(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 3.0 g (14.4 mmol) of 3-tert-butyl-4-hydroxy-benzoic acid methyl ester (Aust. J. Chem., 1978;31:907-916), cesium carbonate (7.04 g, 21.6 mmol), and acetonitrile (50 mL) was heated to reflux and then treated with N,N-dimethylthiocarbamoyl chloride (2.67 g, 21.6 mmol) all at once. The mixture was refluxed for 2 hours, cooled to room temperature, and quenched with 1N HCl. The solution was extracted with EtOAc; the organic layer was washed with 1N NaOH and brine, dried (MgSO4), and concentrated. The residue was chromatographed over silica gel, eluting with 3:2 hexane:EtOAc, to give 3-tert-butyl-4-dimethylthiocarbamoyloxy-benzoic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2([CH2:12][CH3:13])[O:11][CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1.C([Li])CCC.CN(C)[CH:21]=[O:22]>>[CH2:12]([C:7]1([C:4]2[S:5][CH:6]=[C:2]([CH:21]=[O:22])[CH:3]=2)[O:11][CH2:10][CH2:9][O:8]1)[CH3:13]
Reactant: CCC1(c2cc(Br)cs2)OCCO1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CCC1(c2cc(C=O)cs2)OCCO1

Procedure:
In a manner similar to that of Example 9(g), by reaction of 12 g (45.6 mmol) of 2-(4-bromo-2-thienyl)-2-ethyl-[1,3]dioxolane with 20 mL (50 mmol) of 2.5 M butyllithium and 3.9 mL (50 mmol) of dimethylformamide, the desired product is obtained in the form of a yellow oil (m=4.6 g, Y=48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[ClH:28]>>[ClH:28].[NH2:20][CH2:19][CH2:18][O:17][C:15]1[N:16]=[C:11]([NH:10][C:4]2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cn1cc(Br)cc(Nc2cccc(OCCNC(=O)OC(C)(C)C)n2)c1=O
Agent: Cl
Product: Cn1cc(Br)cc(Nc2cccc(OCCN)n2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A mixture of compound 101a (7.0 g, 23.75 mmol), 2-(tert-butoxycarbonylamino)ethyl 4-methylbenzenesulfonate (3.0 g, 9.5 mmol) and Cs2CO3 (3.7 g, 11.4 mmol) in DMF (40 mL) was stirred at 100° C. for 4 h. The reaction mixture was concentrated. The residue was treated with EA and filtered. The filtrate was washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give Tert-butyl 2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethylcarbamate 101b (650 mg, 15% for two steps) as a yellow solid. A mixture of 101b (700 mg, 1.6 mmol) in HCl (5 mL, 4M in 1,4-dioxane, 20 mmol) was stirred at rt overnight. The reaction mixture was concentrated to give 103a (550 mg, 83%) as yellow solid. MS-ESI: [M+H]+ 341.0
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[N:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:10]=3[CH2:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:7]=2[C:34]=1[CH3:35])#[N:2].O.[OH-].[Li+].[O:39]1CCOCC1.O>CCOC(C)=O>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([S:21]([N:8]2[C:7]3[C:34]([CH3:35])=[C:3]([C:1]([NH2:2])=[O:39])[CH:4]=[CH:5][C:6]=3[NH:12][C:11]3[N:13]=[C:14]([C:17]([F:19])([F:20])[F:18])[CH:15]=[CH:16][C:10]=3[CH2:9]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: C1COCCO1
Reactant: Cc1c(C#N)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(N)=O)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8-cyano-6-[(4-tert-butylphenyl)sulfonyl]-7-methyl-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (199 mg, 0.398 mmol) and lithium hydroxide monohydrate (50.1 mg, 2.295 mmol) in 1:1 dioxane-water was heated in a microwave reactor for 15 min at 100° C., followed by 30 min at 120° C. The reaction mixture was cooled to room temperature, diluted with EtOAc, and the organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via reverse-phase HPLC to provide the title compound. LC/MS: m/e 519.1 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 7.60 (1H, d), 7.35 (1H, d), 7.15 (2H, d), 7.03-7.10 (3H, m), 6.93 (1H, d), 5.19 (1H, d), 4.40 (1H, d), 2.60 (3H, s), 1.25 (9H, s).
Reaction SMILES: C1([S:7]([NH2:10])(=[O:9])=[O:8])CCCCC1.[CH2:11]([Mg]Cl)[C:12]([CH3:15])([CH3:14])[CH3:13]>C(OCC)C>[CH2:11]([S:7]([NH2:10])(=[O:9])=[O:8])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: NS(=O)(=O)C1CCCCC1
Solvent: CCOCC
Product: CC(C)(C)CS(N)(=O)=O
Yield: 27 %

Procedure:
Following the procedure for the preparation of cyclohexylsulfonamide, 49 mL (37 mmol) of 0.75M neopentylmagnesium chloride (Alfa) in diethyl ether was converted to 1.52 g (27%) of the desired product as a white solid. 1H NMR (CDCl3) δ 1.17 (s, 9H), 3.12 (s, 2H), 4.74 (brs, 2H); 13C NMR (CDCl3) δ 29.46, 31.51, 67.38; MS m/e 150 (M−1)−.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1)[CH2:2][CH3:3].[CH2:16]([S:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])[CH3:17].CCN=C=NCCCN(C)C.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[CH2:16]([S:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:11][C:10]1[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][CH:7]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:9]=1)=[O:22])[CH3:17]
Reactant: CCCNc1ncc(C(F)(F)F)cc1N
Reactant: CCSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCNc1ncc(C(F)(F)F)cc1NC(=O)c1ccccc1SCC
Temperature: 95 °C
Yield: 31.3 %

Procedure:
A mixture of N-propyl-5-trifluoromethylpyridin-2,3-diamine (770 mg), 2-ethylsulfanyl-benzoic acid (700 mg), WSC (740 mg), and pyridine (20 ml) was stirred with heating at 95° C. for 7 hours. Into the reaction mixture cooled to room temperature, saturated aqueous sodium carbonate solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 422 mg of 2-ethylsulfanyl-N-(2-propylamino-5-trifluoromethylpyridin-3-yl)-benzamide (Compound (1B)-513).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1C=CC=CC=1.C(OCC)C>[CH3:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: Cc1cccc(CBr)c1
Solvent: c1ccccc1
Solvent: CCOCC
Product: Cc1cccc(CN2CCNCC2)c1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
α-Bromo-m-xylene (10 ml, 74 mmole) was added to a solution of 75 g (11.8 equiv.) of anhydrous piperazine in 500 ml of benzene and the reaction was heated to reflux for two hours. After cooling to room temperature, the reaction was diluted with 300 ml of diethyl ether and washed with 500 ml of 0.2 M sodium hydroxide followed by two 500 ml portions of water. The organic solution was dried over sodium sulfate and the solvent removed to give 11.0 g (78%) of crude 1-(3-methylbenzyl)piperazine as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[CH3:27][Si:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][O:23][CH2:22][N:19]1[C:16]2=[N:17][CH:18]=[C:13]([C:12]3[C:7]([NH:6][C@H:3]4[CH2:4][CH2:5][N:1]([C:30](=[O:32])[CH3:31])[CH2:2]4)=[N:8][CH:9]=[CH:10][CH:11]=3)[N:14]=[C:15]2[CH:21]=[CH:20]1
Reactant: CC(=O)OC(C)=O
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@H]3CCNC3)cnc21
Product: CC(=O)N1CC[C@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-((S)-3-{3-[5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidin-1-yl)-ethanone was prepared from (S)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and acetic anhydride following the general synthetic procedures described in the above Examples.
Reaction SMILES: Br[C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[OH:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:3]2[C:2]([C:35]3[CH:36]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:24][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[CH2:26]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 185 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethoxy)phenyl)nicotinamide (Stage 220.1) and pyrimidin-5-ylboronic acid to afford an off-white solid. HPLC (Condition 4) tR=5.17 min, UPLC-MS (Condition 3) tR=0.99 min, m/z=496.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.77 (m, 1H) 1.79-1.91 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m, J=11.10, 4.90 Hz, 2H) 3.32-3.44 (m, 1H) 4.20 (d, J=2.35 Hz, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.85 (d, J=9.38 Hz, 2H) 8.08 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.13-9.34 (m, 1H) 10.16 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[C:53](=[O:54])[C:52]([C:55](O)=[O:56])=[CH:51][CH:50]=[N:49]2)=[CH:44][CH:43]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:55]([C:52]2[C:53](=[O:54])[N:48]([C:45]3[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=3)[N:49]=[CH:50][CH:51]=2)=[O:56])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=3)[N:9]=[C:10]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(C3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-1-carboxylate (84.3 mg, 0.1539 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (108.1 mg, 0.4618 mmol, prepared according to Example 19, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (147.6 mg, 0.7697 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (104.0 mg, 0.7697 mmol), N-ethyl-N-isopropylpropan-2-amine (199.0 mg, 1.539 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford the desired product (108.3 mg, 92.11%). LRMS (APCI pos): m/e 664 (M−99).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][F:14])[CH:11]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[CH:34]=[N:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][F:14])[CH:11]([C:15]2[CH:20]=[CH:19][C:18]([C:33]3[CH:34]=[N:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(CF)C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Reactant: N#Cc1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1C(CF)C(c2ccc(-c3cnc(C#N)nc3)cc2)OC1(C)C
Yield: 47.8 %

Procedure:
To the solution of 4-Fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazolidine-3-carboxylic acid tert-butyl ester (1 g, 2.298 mmol, 1.0 eq) in toluene/water (3:1-24 mL) is added 5-Bromo-pyrimidine-2-carbonitrile (0.42 g, 2.282 mmol, 1.20 eq), Na2CO3 (0.48 g, 4.528 mmol) and degassed with nitrogen for 15 minutes followed by addition of Tetrakis(triphenylphosphine)palladium(0) (0.132 g, 0.114 mmol) and heated reaction mixture to 80° C. for 16 hours. Solvent is evaporated in vacuo to get the crude which is purified by column chromatography eluting from 10% ethyl acetate/hexane to give title compound (0.45 g): 1H-NMR (400 MHz, DMSO-d6) 1.43 (s, 9H), 1.51 (s, 3H), 1.63 (s, 3H), 3.85-3.92 (m, 1H), 4.47-4.59 (m, 1H), 4.76-4.96 (m, 1H), 5.17 (d, 1H, J=7.16), 7.67 (d, 2H, J=8.24 Hz), 7.96 (d, 2H, J=8.24 Hz), 9.40 (s, 2H).). m/z M−H 410.8.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])=[CH:21][CH:20]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[CH3:35][NH:36][CH3:37]>CN(C=O)C>[CH3:35][N:36]([CH3:37])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])=[CH:21][CH:20]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: CNC
Reactant: O=C(Nc1ccccc1)Nc1ccc(CCNc2ncnc3cc(OCCCCl)ccc23)cc1
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc2c(NCCc3ccc(NC(=O)Nc4ccccc4)cc3)ncnc2c1
Yield: 49.1 %

Procedure:
A solution of 1-(4-{2-[7-(3-chloro-propoxy)-quinazolin-4-ylamino]-ethyl}-phenyl)-3-phenyl-urea (20 mg, 0.042 mmol) and dimethylamine (94.7 mg, 0.840 mmol) in DMF (1 mL) was heated at 150° C. in CEM microwave for 10 min. The reaction mixture was purified using silica gel preparative thin layer chromatography to provide the title compound (10 mg, 49%). 1H-NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 8.19 (t, 1H, NH), 8.10-8.12 (m, 1H), 7.43-7.45 (m, 2H), 7.36-7.38 (m, 2H), 7.26 (t, 2H), 7.17 (d, J=8.8 Hz, 2H), 7.08-7.11 (m, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.95 (t, 1H), 4.13 (t, 2H), 3.69 (q, 2H), 2.89 (t, 2H), 2.44 (t, 2H), 2.20 (s, 6H), 1.89-1.93 (m, 2H). LC-MS (ESI) m/z 485.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:10][CH2:11][C:12](Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CCl)Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aniline (93.1 g; 1.00 mole) was dissolved in toluene (750 ml), 10 % NaOH (750 ml) was added and the stirred mixture was cooled to 0°C. Chloroacetyl chloride (197 g; 1.75 mole) was added dropwise during 45 minutes while keeping the temperature below 10°C. Stirring was continued at room temperature for about one hour. The precipitated crystalline 2-chloro-N-phenylacetamide was filtered off, washed on the filter with cold toluene and dried in vacuo at 60°C. Yield: 151 g (90.0 %); m.p. 134°-136°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:3]=1.[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:5]([C:11]#[N:12])=[C:6]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:7]=1
Reactant: COc1ccccc1-c1nc(N)nc(S(C)=O)c1C#N
Reactant: OCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COc1ccccc1-c1nc(N)nc(OCc2ccccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-(2-methoxy-phenyl)-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[S:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)Cl.[Br:23]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:23][C:15]1[S:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2csc3ccccc23)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2c(Br)sc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-(methanesulfonyl)phenyl)benzo[b]thiophene (1 g) from Step 2 in CH2Cl2 (70 mL) one equivalent of a 1M Br2 solution in CCl4 was added. The mixture was stirred at 25° C. for 2 hrs, then a 10% Na2S2O3 solution was added. After extraction with EtOAc, the organic layers were washed with a saturated solution of NaHCO3 (3×), brine, and dried over MgSO4, filtered and the solvent evaporated under vacuum. Purification by column chromatography using 5% EtOAc in toluene afforded the title compound.