Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.Cl.[N:39]1([CH2:44]/[CH:45]=[CH:46]/[C:47](O)=[O:48])[CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:47](=[O:48])/[CH:46]=[CH:45]/[CH2:44][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: O=C(O)/C=C/CN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1nccn2c([C@@H]3CCCN3C(=O)/C=C/CN3CCCC3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 2b, 19.7 mg, 0.049 mmol), triethylamine (20 mg, 0.197 mmol, 0.027 mL) and (E)-4-(pyrrolidin-1-yl)but-2-enoic acid hydrochloride (9.45 mg, 0.049 mmol) in dichloromethane (2 mL) was added HATU (18.75 mg, 0.049 mmol). The mixture was stirred for 30 min at room temperature. The mixture was washed with water dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing product were collected and reduced to dryness to afford 7.1 mg of (S,E)-4-(8-amino-3-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (26.8% yield). Data: UPLC (C) Rt: 1.25 min; m/z 537.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])=[CH:16][C:15]=3[CH3:27])=[CH:7][C:6]=2[C:5]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:4]=2[N:3]=1.BrCCOCCO[CH2:40][CH2:41][CH2:42][P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:40][CH2:41][CH2:42][P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])=[CH:16][C:15]=3[CH3:27])=[CH:7][C:6]=2[C:5]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCO)cc3C)cc12
Reactant: CCOP(=O)(CCCOCCOCCBr)OCC
Product: CCOP(=O)(CCCOCCOCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC

Procedure:
Diethyl 3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)propylphosphonate was prepared from following the procedure described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 148) and diethyl 3-(2-(2-bromoethoxy)ethoxy)propylphosphonate 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.70 (s, 1H), 8.26 (d, 1H), 7.42 (s, 1H), 7.16 (d, 1H), 7.09 (d, 1H), 6.77 (s, 1H), 6.71 (d, 1H), 6.58 (br, 2H), 3.95-4.11 (m, 6H), 3.76-3.80 (m, 2H), 3.63-3.67 (m, 2H), 3.55-3.58 (m, 2H), 3.57-3.51 (m, 2H), 3.14-3.18 (m, 2H), 3.04-3.05 (m, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 1.71-1.87 (m, 4H), 1.22-1.29 (m, 8H). LRMS [M+H]=610.3.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH2:42]([C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1)[CH3:43]>C(#N)C>[CH2:42]([C:44]1[CH:45]=[CH:46][C:47]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])=[CH:48][CH:49]=1)[CH3:43]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1
Yield: 51 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0322 g, 0.0698 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0580 mL, 0.419 mmol) and 4-ethylbenzene-1-sulfonyl chloride (0.0430 g, 0.209 mmol) to obtain 4-(4-ethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0224 g, yield 51%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.[CH2:23]([S:30](Cl)(=[O:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>N1C=CC=CC=1>[CH2:8]([C:7]1[C:2]([NH:1][S:30]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(NS(=O)(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Yield: 36.8 %

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-(4-methoxyphenyl)pyrazine (c-11) (prepared by the method described in Adamczyk M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (99.5 mg, 342 μmol) was dissolved in pyridine (1 mL) and cooled to 0° C. To this was added benzylsulfonyl chloride (84.7 mg, 444 μmol) and stirred for an hour after warming to room temperature. To this was added benzylsulfonyl chloride (13.8 mg, 72.3 μmol) and the mixture was stirred for 2.5 h. To this was further added benzylsulfonyl chloride (13.9 mg, 72.9 pimp and the mixture was stirred for 15 h. To this was further added benzylsulfonyl chloride (13.1 mg, 68.7 μmol) and the mixture was stirred for 5.5 h. To this was added 2 M hydrochloric acid to stop the reaction, and after separating the aqueous layer and organic layer, it was extracted 3 times with dichloromethane. The organic layer was washed with saturated aqueous solution of sodium sulfate and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (7 g, n-hexane/ethyl acetate=7/3→ethyl acetate). The resulting solid was recrystallized from ethyl acetate to give 3-benzyl-2-benzylsulfonylamino-5-(4-methoxyphenyl)pyrazine (c-18) as a colorless solid (56.0 mg, 36.8%). Rf=0.32 (n-hexane/ethyl acetate=7/3). Mp. 213-215° C. UV (MeOH, 0.3% DMSO) λmax (log ε) 334.5 (4.04), 290 (4.21), 276.5 (4.23). UV (pH 7.4 PB, 0.3% DMSO) λmax (log ε) 348.5 (3.90), 293 (3.95). 1H NMR (400 MHz, DMSO-d6) δ 3.80 (s, 3H), 4.22 (s, 2H), 4.91 (s, 2H), 7.02-7.07 (AA′BB′, 2H), 7.14-7.21 (m, 1H), 7.24-7.27 (m, 4H), 7.36 (s, 5H), 7.99 (d, J=7.3 Hz, 2H), 8.88 (s, 1H), 10.46 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 38.0, 55.3, 59.6, 114.4 (2C), 126.3, 127.6 (2C), 128.1, 128.3 (2C), 128.4, 128.5 (2C), 129.0 (2C), 129.9, 130.9 (2C), 136.2, 138.1, 144.6, 145.8, 146.0, 160.3. IR (KBr, cm−1) 459, 538, 586, 698, 748, 785, 831, 893, 912, 926, 1032, 1121, 1132, 1177, 1215, 1256, 1287, 1319, 1395, 1452, 1495, 1516, 1609, 3231. HRMS (FAB+) m/z 446.1548 (M+H, C25H24N3O3S requires 446.1548).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][CH2:6][CH2:5]2>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: Cc1cc2c(cc1[N+](=O)[O-])NCC2
Solvent: C1COCCO1
Product: Cc1cc2cc[nH]c2cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 67.4 %

Procedure:
5-Methyl-6-nitroindoline (0.75 gr) was dissolved in 20 mL dioxane and treated with 1.5 g of dichloro dicyano quinone. The solution was heated at 80° C. for two hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography to give 0.5 g of 5-methyl-6-nitroindole (e/z (M+H) 177).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cccc(NC(=O)C(C)(C)C)c1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of 20 g (162 mmol) 3-methoxy-phenylamine in 400 ml diethylether is added 24.9 ml (178 mmol) triethylamine and slowly within 30 minutes 23.9 ml (195 mmol) pivaloyl chloride. Due to the exothermic reaction the temperature rises despite cooling to 15° C. The temperature is left rising to room temperature, after 1 hour the reaction mixture is poured on ice and extracted with ethyl acetate, washed 2× with water and 1× with brine, dried with Na2SO4 and evaporated to give a crude product which is purified by two crystallizations from CH2Cl2/hexane to yield N-(3-methoxy-phenyl)-2,2-dimethyl-propionamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C@H:5]([OH:30])[CH2:6][N:7]([C:14](=[O:29])[C@@H:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([Cl:28])[CH:19]=1)[CH3:16])[CH2:8][CH:9](OC)OC.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(N(CC)CC)C.OS([O-])(=O)=O.[K+].CCOC(C)=O>ClCCl>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C@H:5]([OH:30])[CH2:6][N:7]1[CH2:8][CH2:9][N:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[C:20]([Cl:28])[CH:19]=2)[C@@H:15]([CH3:16])[C:14]1=[O:29]
Reactant: COC(=O)C[C@H](O)CN(CC(OC)OC)C(=O)[C@H](C)Nc1ccc(C(F)(F)F)c(Cl)c1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](O)CN1CCN(c2ccc(C(F)(F)F)c(Cl)c2)[C@@H](C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 7.2 %

Procedure:
1.82 g (3.9 mmol) of (S)-4-[[(S)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propionyl]-(2,2-dimethoxy-ethyl)-amino]-3-hydroxy-butyric acid methyl ester were dissolved at RT in 39.0 ml of dichloromethane, cooled (0° C.) and treated with 4.4 ml of trifluoroacetic acid. After 30 min at 0° C. and 2.5 h at RT 3.2 ml (19.3 mmol) of triethylsilane were added and stirred over night at RT. The reaction was neutralized with 8.1 ml (58 mmol) of triethylamine at 0° C. and after 10 min poured on aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous 10% KHSO4, saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield after flash chromatography (SiO2, EtOAc/Heptan from 1:1 to 4:1) 0.114 g (7%) of the titled compound as yellow oil. MS: 409.2 (MH+).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[O:6].[OH:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[C:14]([C:13]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:17][CH:18]=[CH:19][C:12]=1[O:11][CH2:2]/[CH:3]=[CH:4]/[C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[O:6])#[N:15]
Reactant: CCCNC(=O)/C=C/CBr
Reactant: N#Cc1c(O)cccc1[N+](=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCNC(=O)/C=C/COc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Yield: 79 %

Procedure:
(E)-4-Bromo-N-propylbut-2-enamide (Elliott, M.; Farnham, A. W.; Janes, N. F.; Johnson, D. M.; Pulman, D. A. Pesticide Science 1987 18(4) 229) (0.14 g, 0.70 mmol), 2-hydroxy-6-nitrobenzonitrile (0.14 g, 0.88 mmol), potassium carbonate (0.39 g, 2.81 mmol), and 18-crown-6 (0.11 g, 0.42 mmol) were refluxed in acetone (6 mL) for 2 h, and then poured into ice water (45 mL). The resultant precipitate was collected by filtration to give 0.16 g (79%) of the title compound as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.84 (t, J=7.2 Hz, 3H), 1.42 (hex, J=7.2 Hz, 2H), 3.06 (q, J=6.8 Hz, 2H), 5.07 (d, J=2.8 Hz, 2H), 6.16 (d, J=16.0 Hz, 1H), 6.71-6.78 (m, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.88-7.96 (m, 2H), 8.11-8.14 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.O.[NH2:25][NH2:26]>C(O)C>[NH:25]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1)[NH2:26]
Reactant: FC(F)(F)c1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Yield: 97.1 %

Procedure:
4-Chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (1.8 g, 5.3 mmol) (synthesized according to the procedure described in example 1) was stirred in ethanol (10 ml) containing hydrazine hydrate (0.64 g, 12.8 mmol) for 2 hours at 35° C. The crystals thus obtained in the reaction mixture was filtered under vacuum, washed with ethanol (5 ml) and dried to yield the title compound (1.7 g, 95.7%, HPLC purity 99.2%), mp: 182-186° C.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>Cl>[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:9][C:8](=[O:10])[C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C1=COCCC1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: O=C(OC1CCCCO1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
10 g (35 mmol) of triphenylacetic acid are mixed with 8.8 g (104 mmol) of 3,4-dihydro-2H-pyran and 2 drops of concentrated hydrochloric acid are added to the mixture. The solution is then stirred at 70° C. for 3 hours and working up is thereafter effected in accordance with the general procedure described in Example A. Recrystallisation from n-hexane gives a product which melts at 115° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:9][C:8]([CH2:10][CH2:11][CH3:12])=[N:7][C:6]=2[CH:13]=1.C([Sn](CCCC)(CCCC)[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)CCC.O>C1(C)C=CC=CC=1.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>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:9][C:8]([CH2:10][CH2:11][CH3:12])=[N:7][C:6]=2[CH:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CCCc1nc2cc(Br)cc(C)c2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1nc2cc(-c3ccco3)cc(C)c2[nH]1
Temperature: 100 °C
Reaction time: 72 h
Yield: 30.1 %

Procedure:
Under a nitrogen atmosphere, 6-bromo-4-methyl-2-propylbenzimidazole (WO2004082621; 200 mg, 0.83 mmol) was dissolved in toluene (4 mL), tributyl(2-furanyl)tin (0.78 mL, 2.49 mmol) and tetrakis(triphenylphosphine)palladium (288 mg, 0.25 mmol) were added, and the mixture was stirred at 100° C. for 3 days. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/2 to 1/9) to give the title compound (60 mg, 30%).
Reaction SMILES: O.[ClH:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[O:25]([CH2:32][CH2:33][CH2:34]Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[OH2:25].[ClH:2].[ClH:2].[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:34][CH2:33][CH2:32][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:14][CH2:13]2)=[CH:8][CH:9]=1.[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:34][CH2:33][CH2:32][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:14][CH2:13]2)=[CH:8][CH:9]=1.[ClH:2].[ClH:2]
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: BrCCCOc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
A mixture of 3.92 g (10.5 mmol) of N,α-bis(4-fluorophenyl)-4-piperidinemethanamine hydrochloride hydrate, 2.77 g (13.0 mmol) of 3-phenoxy propyl bromide, 3.80 g (36.0 mmol) of sodium carbonate, and 0.61 g (3.7 mmol) of KI in 400 mL of 1-butanol was heated at reflux for 69 h. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (Na2SO4), and the solvent was removed in vacuo. The residue was subjected to flash column chromatography (silica gel, elution with 1 to 3% CH3OH in CH2Cl2) to give the free base of the title compound. This was converted to the HCl salt, and the salt was recrystallized from CH3OH/ether to give 3.59 g (65.9%) of the title compound as a white crystalline solid, mp 222°-226° C.
Reaction SMILES: [CH:1]12[O:8][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:3][CH2:2]2.[NH3:19]>>[CH2:12]([O:11][C:9]([N:4]1[CH2:5][CH2:6][CH:7]([OH:8])[CH:1]([NH2:19])[CH2:2][CH2:3]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N
Reactant: O=C(OCc1ccccc1)N1CCC2OC2CC1
Product: NC1CCN(C(=O)OCc2ccccc2)CCC1O

Procedure:
3 g benzyl 8-oxa-4-azabicyclo[5.1.0]octane-4-carboxylate in 70 mL 30% aqueous ammonia was stirred at 65° C. in a sealed vessel overnight. The reaction was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate filtered and concentrated to yield 3.1 g of the desired product. (M+H)+: 265
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Product: CCOC(=O)c1cnn2ccc(Cl)nc12
Yield: 97.6 %

Procedure:
Ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (22.7 g, 110 mmol) was suspended in phosphoryl trichloride (100 mL) and heated to reflux. After heating for 2 hours, the reaction mixture was cooled and concentrated to remove the excess POCl3. The residue was diluted in DCM (100 mL) and slowly added to a flask containing ice water. The mixture was separated and the aqueous layer extracted with DCM. The combined organics were dried with MgSO4, filtered and concentrated to afford ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (24.2 g, 97.6% yield) as a pale yellow solid. MS (apci) m/z=225.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[N:5]=2.[Cl:34][CH2:35][C:36](Cl)=[O:37]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][CH2:35][C:36]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[N:5]=2)=[O:37]
Reactant: O=C(Cl)CCl
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-ethylphenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.327 mmol) in N,N-dimethylformamide (4.0 mL) was added chloroacetyl chloride (34 μL, 0.425 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-ethylphenyl]-3-(1-cyano-1-methylethyl)benzamide as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:36])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccc2F)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccc2F)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(2-fluorobenzoyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.050 g, 0.12 mmol) and ammonium acetate (0.0936 g, 1.21 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.30 mL, 0.30 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C22H23ClFN4O (M+H)+: m/z=413.2; Found: 413.2.