Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[CH:5][N:4]=1)[NH2:2].[F:14][C:15]([F:20])([F:19])[C:16](O)=O>>[F:14][C:15]([F:20])([F:19])[C:16]1[N:4]2[CH:5]=[C:6]([CH3:13])[C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cnc(NN)c2ccccc12
Product: Cc1cn2c(C(F)(F)F)nnc2c2ccccc12
Yield: 65 %

Procedure:
1-Hydrazino-4-methylisoquinoline (5.0 g.) and trifluoroacetic acid (70 ml.)were heated at reflux for three hours. After removal of the excess trifluoroacetic acid, the residue was dissolved in chloroform and extracted with sodium carbonate solution. The organic layer was dried and concentrated and the residue was recrystallized from a cyclohexane-benzene(70/30) mixture to provide the product in a yield of 65%, m.p. 162°-164°C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=3[F:30])[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH3:32][NH:33][CH3:34].CO>CCO>[CH3:32][N:33]([CH3:34])[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:31])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=3[F:30])[CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Reactant: CNC
Solvent: CO
Solvent: CCO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CN(C)C)c3c2)c1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 40.4 %

Procedure:
N-(3-(2-Chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.181 mL, 0.0361 mmol), EtOH (0.2 mL), and dimethylamine as a solution in MeOH (0.181 mL, 0.361 mmol) was charged to a 2 dram vial. The vial was capped and stirred at 60° C. for 4 hours. The mixture was concentrated under reduced pressure. The residue was taken up in 1M HCL (1 mL) and washed with EtOAc (2×1 mL). The aqueous portion was neutralized and extracted with 25% isopropyl alcohol (“IPA”)-DCM (3×2 mL), which was concentrated to provide N-(3-(2-(dimethylamino)acetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (7 mg, 40.4%) as a solid. 1H NMR (400 MHz, CD3OD) δ 9.03-9.06 (m, 1H), 8.56-8.58 (m, 1H), 8.46 (s, 1H), 7.63-7.69 (m, 1H), 7.12-7.16 (m, 1H), 3.11-3.14 (m, 2H), 3.03 (s, 6H), 2.90 (s, 2H), 1.85-1.90 (m, 2H), 1.05-1.08 (m, 3H); m/z (APCI-pos) M+1=480.1.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=[S:13])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.Cl.[SH:15][CH2:16][CH2:17][NH2:18].[OH-].[K+]>O>[NH2:18][CH2:17][CH2:16][S:15][CH2:2][CH2:3][NH:4][C:5](=[S:13])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1
Reactant: NCCS
Reactant: S=C(CC1CCCCO1)NCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NCCSCCNC(=S)CC1CCCCO1
Yield: 190.5 %

Procedure:
N-(2-Chloroethyl)-tetrahydropyran-2-ylthioacetamide (0.48 g, 2 mmol), 2-mercaptoethylamine hydrochloride (0.34 g, 3 mmol), potassium hydroxide (0.34 g, 6 mmol) methanol (5 cm3) and water (1 cm3) were mixed and heated at 75 C for 2 h. After cooling, 111acetone (50 cm3) was added and the resulting mixture filtered. Volatile components were removed from the filtrate under reduced pressure to give a pale yellow residue. This material was purified firstly by chromatography on silica using a mixture of ethyl acetate, methanol, and aqueous ammonia (90:9:1) as the eluant and then by reverse phase h.p.l.c. using aqueous acetonitrile as the eluant. The purified N-[2-(2-aminoethylthio)ethyl]-tetrahydropyran-2-ylthioacetamid e (1 g, 32%) was obtained as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Cl:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]([C:13]4[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=4[F:19])=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:31][CH:30]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: OB(O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)nc4)cc23)c1F
Reaction time: 0.27 h

Procedure:
Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (56, 10 mg, 0.022 mmol) was weighed into a 5 mL microwave vial and combined with 6-chloro-pyridine-3-boronic acid (72, 4.4 mg, 0.028 mmol), followed by the addition of 600 μL of acetonitrile and 500 μL of 1M potassium carbonate and a spatula tip (˜1 mg) of [1,1″-bis(diphenylphosphino)-ferrocene]dichloropalladium(II). The reaction mixture was irradiated in a microwave at 160° C. for 5 minutes. The solution was neutralized with 100 μL of acetic acid and all material was transferred to a 4 mL vial and the solvents were removed under vacuum. The crude material was dissolved in 400 μL of dimtheylsulfoxide and purified by reverse phase HPLC, eluting with 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile, 20-100% acetonitrile over 16 minutes at 6 mL per minute. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound. MS (ESI) [M+H+]+=491.1.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:24])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH2:25]=[O:26].[OH-].[Na+]>O1CCCC1.O>[OH:1][C:2]1[C:3]([C:11]2([CH2:25][OH:26])[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:24])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=C1Nc2c(cccc2C(F)(F)F)C1c1cc2c(cc1O)OCO2
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Nc2c(C(F)(F)F)cccc2C1(CO)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a suspension of 3-(6-hydroxy-1,3-benzodioxol-5-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one (5.64 g, 16.7 mmol), para-formaldehyde (1.78 g, 59.4 mmol) in tetrahydrofuran (20.0 mL) and water (50.0 mL) was added the aqueous solution of sodium hydroxide (2.68 g, 66.9 mmol) in water (30.0 mL). The reaction mixture was stirred at 0° C. for 1 h and quenched with 10% hydrochloric acid (50.0 mL). The mixture was extracted with ethyl acetate (3×50.0 mL). The combined organic solution was washed with saturated ammonium chloride (3×50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography to afford 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one (4.56 g, 73%) as a fluffy solid: 1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.16 (s, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 7.01 (s, 1H), 6.94 (dd, J=7.7, 7.7 Hz, 1H), 6.18 (s, 1H), 5.88 (s, 2H), 5.03 (br, 1H), 3.97 (ABq, J=9.9 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 180.5, 150.3, 146.8, 141.5, 140.0, 136.0, 127.5, 123.8, 121.0, 117.7, 109.7, 108.4, 101.2, 97.9, 60.2, 55.2; MS (ES+) m/z 390.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][C:30]([CH3:39])([CH3:38])[CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([NH:37][C:34]2[CH:35]=[CH:36][N:32]([CH2:31][C:30]([O:29][CH3:28])([CH3:38])[CH3:39])[N:33]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: COC(C)(C)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CC(=O)C2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 50.8 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionic acid (65 mg, 0.20 mmol) in methylene chloride (8 mL) was cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 120 μL, 0.24 mmol) and N,N-dimethylfomamide (one drop) which was then stirred at 0° C. for 20 minutes and 40 min at 25° C. After this time, the reaction was concentrated in vacuo and azeotroped with methylene chloride (10 ml). In a separate flask a solution of 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (36 mg, 0.22 mmol), 2,6-lutidine (34 μL, 0.29 mmol) in methylene chloride (8 mL) was cooled to 0° C. in an ice bath. To this solution was then added the solution of the prepared acid chloride in methylene chloride (5 mL) dropwise. After addition was complete the reaction was then stirred at 0° C. for 15 min and at 25° C. for 18 h. After this time the reaction was concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(3-oxo-cyclobutyl)-propionamide (49 mg, 52%) as an off-white solid: [α]29589=−14.0° (c=0.55, CHCl3); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04, 1.05 (2×s, 6H, 2×CH3), 1.93-2.40 (m, 3H, CH and CH2), 2.69-2.84 (m, 2H, 2×CH or 2×CH2), 2.99-3.12 (m, 2H, 2×CH or 2×CH2), 3.14 (s, 3H, OCH3), 3.34 (s, 3H, SO2CH3), 3.88 (t, J=7.8 Hz, 1H, ArCHCO2), 3.98 (s, 2H, NCH2), 6.47 (d, J=2.3 Hz, 1H, Ar), 7.49 (d, J=2.3 Hz, 1H, Ar), 7.61 (dd, Jm=1.2 Hz, Jo=8.3 Hz, 1H, Ar), 7.73 (d, Jm=1.2 Hz, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=2)[CH:19]=1)[CH2:16][OH:17])(C)(C)C>C(Cl)Cl>[NH2:14][C@H:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=2)[CH:19]=1)[CH2:16][OH:17]
Reactant: COc1ccc2ccc([C@H](CO)NC(=O)OC(C)(C)C)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ccc([C@@H](N)CO)cc2c1
Yield: 99.1 %

Procedure:
A solution of TFA (8 mL) and (R)-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-carbamic acid tert-butyl ester (1.268 g) in methylene chloride (24 mL) was stirred for 2 h. After concentration, the residue was neutralized with 10 N NaOH and extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the title compound as a solid (860 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23]1([C:28]#[C:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(#N)C.N12CCCN=C1CCCCC2.Cl>>[CH:23]1(/[C:28](/[N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)=[CH:29]\[C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)C#CC1CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)/C=C(\C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a stirred suspension of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (17, 12.08 g, 38.31 mmol) and methyl 3-cyclopentylprop-2-ynoate (18, 8.970 g, 45.97 mmol, 1.2 equiv) in acetonitrile (76 mL, 1400 mmol) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.92 mL, 19.2 mmol, 0.5 equiv). The resulting reaction mixture was stirred at room temperature for 2 h. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (50 mL) and 1 N aqueous HCl solution (20 mL). The quenched reaction mixture was adjusted to pH 4 after treatment with 1 N aqueous HCl solution. The mixture was then extracted with EtOAc (2×100 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2, 0-50% EtOAc/hexane gradient elution) to afford (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21, 6.838 g, 17.92 g theoretical, 38% in yield) as a colorless, very viscous oil. For 19: 1H NMR (CDCl3, 400 MHz) δ ppm 8.93 (s, 1H), 8.55 (bs, 1H), 8.44 (s, 1H), 7.49 (d, 1H, J=3.5 Hz), 6.86 (d, 1H, J=3.5 Hz), 6.34 (s, 1H), 5.74 (s, 2H), 4.56 (m, 1H), 3.84 (s, 3H), 3.60 (t, 2H, J=8.2 Hz), 2.01 (m, 2H), 1.96 (m, 4H), 1.77 (m, 2H), 0.98 (t, 2H, J=8.2 Hz), 0.00 (s, 9H); C24H33N5O3Si (MW, 467.64), LCMS (EI) m/e 468.2 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:11][CH3:12])=[N:4][CH:5]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([O:10][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:11][CH3:12])=[N:4][CH:5]=1)[CH3:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1ncc(C(C)O)cc1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc(C(C)OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
3-Chloro-5-(1-hydroxyethyl)-2-methylthiopyridine (21.9 g, 0.108 mol) was dissolved with stirring in anhydrous DMF (250 mL) and 60% sodium hydride (5 g, 0.125 mol) added in portions. The mixture was stirred at room temperature for 30 minutes and benzyl bromide (17.6 g, 0.103 mol) added dropwise. The mixture was then stirred at room temperature for four hours, diluted with water (400 mL) and extracted three times with ethyl acetate (100 mL). The combined organic extracts were washed twice with water (200 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulphate, and evaporated to dryness. Purification of the residue by chromatography over silica (0-5% ethyl acetate:hexane) gave the desired product (25.0 g, 79%) as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][C:16]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:17]
Reactant: O=C(Cl)CCCl
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCCl)N1CCCC1
Reaction time: 0.25 h

Procedure:
A solution of pyrrolidine (35 grams; 0.5 mol) and triethylamine (50 grams; 0.5 mol) in benzene (500 ml) is placed in a glass reaction flask equipped with a mechanical stirrer and reflux condenser. β-Chloropropionyl chloride (64 grams; 0.5 mol) is then slowly added with stirring over a period of about 15 minutes. Stirring is continued for a period of about 30 minutes. After this time the reaction mixture is first filtered to remove triethylamine hydrochloride nd is the stripped of benzene to yield 1-(β-chloropropionyl) pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[Mg].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=O.[Cl-].[NH4+]>C(OCC)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[C:13](/[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)\[CH3:12]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C/C(=C\c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Yield: 71.9 %

Procedure:
118 g of 2,4-dichlorobenzyl chloride were added dropwise to 14.6 g of magnesium turnings in 400 ml of dry diethyl ether at the boiling point. After the reaction was complete, a solution of 77.3 g of 4-chloroacetophenone in 400 ml of dry diethyl ether was added. Thereafter, decomposition was effected with aqueous ammonium chloride solution, the organic phase was separated off, washed neutral, dried over sodium sulfate and evaporated down under reduced pressure, the residue was taken up in 1 liter of toluene and the solution was refluxed with 4 g of 4-methylbenzenesulfonic acid, in a water separator. After dehydration was compelete, the toluene phase was washed with sodium carbonate solution and water and dried over sodium sulfate, the solvent was evaproated off and the residue was recrystallized from methanol to give 107 g (81.9%) of E-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)-prop-1-ene of melting point 84°-85° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][CH:10]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1)[CH3:11]>C(Cl)(Cl)Cl>[Br:1][C:18]1[N:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:20]2[C:16]([N:17]=1)=[C:15]([NH2:28])[N:14]=[C:13]([O:12][CH:10]([CH3:9])[CH3:11])[N:21]=2
Reactant: CC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
N-Bromosuccinimide (604 mg, 3.39 mmol) was added to a solution of 2-[(1-methylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (888 mg, 3.20 mmol) in chloroform (30 ml) at 0-5° C. under nitrogen. The mixture was stirred at 0-5° C. for 1 hour during which time it became reddish brown in colour and it was then warmed to room temperature and stirred for a further 4 hours. LCMS indicated the reaction to be incomplete and more N-bromosuccinimide (114 mg, 0.641 mmol) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was then diluted with chloroform (30 ml), washed with water (2×20 ml) and the layers were separated using a hydrophobic frit and the organic layer was evaporated to give a red solid (1.16 g). This material was dissolved in dichloromethane and purified by silica gel chromatography on an SPE cartridge (50 g) using a 0-100% ethyl acetate in cyclohexane gradient as eluent. The appropriate fractions were combined and evaporated to give the title compound as a pale yellow solid 712 mg.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:39])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:16]=[C:15]([N:25]3[CH2:31][CH:30]4[O:32][CH:27]([CH2:28][CH2:29]4)[CH2:26]3)[N:14]=2)[C:11]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:39][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21][CH2:20]3)[N:16]=[C:15]([N:25]3[CH2:31][CH:30]4[O:32][CH:27]([CH2:28][CH2:29]4)[CH2:26]3)[N:14]=2)[C:11]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:10]=2[N:9]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CC3CCC(C2)O3)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCN(S(C)(=O)=O)CC2)nc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.5 %

Procedure:
Methanesulfonyl chloride (0.12 mL, 1.55 mmol) was added dropwise to a stirred suspension of 3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-8-oxa-3-azabicyclo[3.2.1]octane (165 mg, 0.349 mmol) and powdered K2CO3 (434 mg, 3.15 mmol) in CH2Cl2 (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 days. Water was added, the phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4) and the solvent removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (99:1), followed by recrystallization from CH2Cl2/MeOH gave 170 mg (89% yield) of 3-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octane: mp (CH2Cl2/MeOH) 312-314° C.; 1H NMR (CDCl3) δ7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.45 (t, JHF=53.6 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 4.49 (br s, 2H), 4.32 (d, J=13.2 Hz, 2H), 4.05 (s, 3H), 4.02 (br s, 4H), 3.30 (m, 6H), 2.81 (s, 3H), 1.99 (m, 2H), 1.79 (m, 2H); Anal. Calcd. for C23H28F2N8O4S: C, 50.2; H, 5.1; N, 20.35. Found: C, 50.3; H, 5.1; N, 20.5.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[O:12][CH2:13][C:14](=[O:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:13]2[O:12][C:11]([N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]2=[O:21])=[CH:23]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N2CCc3ccccc3C2)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(N2CCc3ccccc3C2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 14.8 %

Procedure:
To a solution of ethyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.60 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.091 g, 0.60 mmol) in ethanol (5.0 mL), L-proline (0.0070 g, 0.060 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.037 g, y. 14%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:4]=1.[N:38]1([CH2:44][CH2:45][O:46][CH2:47][CH2:48][OH:49])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C1COCC1.CCOC(C)=O>[OH:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][N:38]1[CH2:43][CH2:42][N:41]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]3[CH:17]=[C:16]([C:18]#[C:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]5[O:30][CH:31]=[CH:32][C:33]=5[CH3:34])=[O:28])[CH:21]=4)[CH:15]=[N:14][CH:13]=3)=[CH:5][CH:4]=2)[CH2:40][CH2:39]1
Reactant: OCCOCCN1CCNCC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CBr)cc3)c2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CN4CCN(CCOCCO)CC4)cc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Crude N-{[4-(Bromomethyl)phenyl] (methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide was dissolved in THF (2 mL). 2-(2-piperazin-1-yl-ethoxy)-ethanol (0.064 g, 0.390 mmol) and TEA (0.054 mL, 0.390 mmol) were then added to the solution and the resulting reaction mixture was allowed to stir for 1 h at rt. The reaction mixture, subsequently, was dissolved in EtOAc and then extracted with H2O (2× mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was purified via column chromatography (gradient eluant mixture of MeOH in EtOAc: 0% to 20% MeOH) to afford the title compound (0.064 g, 49% overall for step 1 and 2).