Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([CH:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>O>[O:13]1[C:17]2([CH2:18][CH2:19][CH:20]([CH:23]3[CH2:28][CH2:27][C:26]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)=[CH:25][CH2:24]3)[CH2:21][CH2:22]2)[O:16][CH2:15][CH2:14]1
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Reactant: C1CCNC1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)CCC(C2CCC3(CC2)OCCO3)C1
Temperature: 25 °C

Procedure:
Toluene (200 ml) and pyrrolidine (90 ml) were added to 4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone (100 g) in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 3 hours while the water formed was removed by a Dean-Stark apparatus. After the reaction mixture had been cooled to a room temperature, it was washed with brine, and dried over anhydrous magnesium sulfate. The toluene was distilled off to give 1-(4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohex-1-enyl)pyrrolidine (105.8 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1)C.[CH3:30][NH2:31]>C(O)C.O>[CH3:30][NH:31][C:4](=[O:3])[CH2:5][C:6]1[N:7]=[C:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][S:12][C:10]=2[N:11]=1
Reactant: CN
Reactant: CCOC(=O)Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Solvent: O
Solvent: CCO
Product: CNC(=O)Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Reaction time: 0.5 h

Procedure:
In a 10 ml glass tube were placed (5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}acetic acid ethyl ester (35 mg, 0.088 mmol) and a saturated solution of methylamine in ethanol (2.0 ml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200 W was used, the temperature being ramped from room temperature to 100° C. Once 100° C. was reached, the reaction mixture was held at this temperature for 30 minutes. The temperature was then ramped up to 150° C. and the reaction mixture was held at this temperature for a further 30 minutes. The resultant mixture was diluted with water (50 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give a residue which was purified by flash chromatography (silica) eluting with 5% methanol in dichloromethane to give N-methyl-2-{5-phenyl-4-[{pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}acetamide (2 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](B(O)O)[CH:38]=2)[C:33]([CH3:43])=[N:32]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:37]3[CH:38]=[C:39]4[C:34]([C:33]([CH3:43])=[N:32][N:31]4[CH3:30])=[CH:35][CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nn(C)c2cc(B(O)O)ccc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.202 mmol), 1,3-dimethyl-1H-indazol-6-ylboronic acid (76 mg, 0.4 mmol), Pd(PPh3)4 (23 mg, 20 μmol), and K2CO3 (83 mg, 0.6 mmol). De-gassed dioxane (1.6 mL) and water (0.4 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to 23° C., the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 30% EtOAc in hexanes) to give the product. LCMS-ESI+: calc'd for C31H33ClN3O3S: 562.2 (M+H+); Found: 562.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]1[NH:7][CH:8]=[CH:9][C:10](=[O:12])[CH:11]=1)([CH3:5])[CH3:4].OS(O)(=O)=O.[N+:20]([O-])([OH:22])=[O:21].[OH-].[Na+]>>[N+:20]([C:9]1[C:10](=[O:12])[CH:11]=[C:6]([C:3]([CH3:5])([CH3:4])[C:2]([F:1])([F:13])[F:14])[NH:7][CH:8]=1)([O-:22])=[O:21]
Reactant: CC(C)(c1cc(=O)cc[nH]1)C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(c1cc(=O)c([N+](=O)[O-])c[nH]1)C(F)(F)F
Temperature: 90 °C
Reaction time: 15 h
Yield: 26 %

Procedure:
To a mixture of 2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one (300 mg, 1.462 mmol) in H2SO4 (8 mL, 150 mmol) was added nitric acid (3.27 mL, 73.1 mmol). The mixture was stirred at 90° C. for 15 h. Then the mixture was added to ice water and basified by aqueous NaOH solution. The mixture was filtered. The filtrate was concentrated and purified by preparative TLC (DCM/MeOH=9:1, Rf=0.1) to yield a light yellow solid of 5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one (100 mg, 0.380 mmol, 26.0% yield): 1H NMR (400 MHz, CD3OD): δ 8.82 (s, 1H), 6.95 (s, 1H), 1.64 (s, 6H). ES-LCMS m/z 251.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([CH2:23][O:24][CH3:25])=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1.N1C=CC=CC=1.[C:32](Cl)([CH3:34])=[O:33].[OH-].[Na+]>C1COCC1>[CH3:25][O:24][CH2:23][C:7]1[C:6]2[C:2]([NH:1][C:32](=[O:33])[CH3:34])=[N:3][NH:4][C:5]=2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[N:8]=1
Reactant: CC(=O)Cl
Reactant: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(NC(C)=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-1-(3-amino-4-(methoxymethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (30 mg, 0.088 mmol) in THF (1 ml) was charged with pyridine (72 μl, 0.890 mmol) and AcCl (62 μl, 0.872 mmol). The mixture was stirred at RT for 17 hr before 1N NaOH (1.2 ml, 1.200 mmol) was added and stirred at RT for 2 hr and then heated to 50° C. for 1 hr. The reaction was quenched with sat aq NH4Cl and extracted into EtOAc. The mixture was washed with sat aq NH4Cl followed by brine, dried over MgSO4, filtered, concentrated in vacuo and purified via flash chromatography (0-20% MeOH/DCM) to give (R)—N-(4-(methoxymethyl)-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd for C19H23N6O3 [M+H]+ 383. found 383. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.01 (s, 1H), 9.13 (s, 1H), 7.33 (m, 5H), 7.22 (m, 1H), 4.89 (t, J=6.8 Hz), 4.59 (s, 2H), 3.28 (s, 3H), 2.06 (s, 3H), 1.39 (d, 5.1 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.[CH3:15]O>Cl>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2c(c1)CCCC2=O
Yield: 86 %

Procedure:
A solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (5.14 g, 27.0 mmol) (Peakdale Molecular) in 4N hydrochloric acid in methanol was heated to reflux for eighteen hours. The solution was returned to ambient temperature and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride and dried over magnesium sulfate. Filtration followed by concentration in vacuo provided methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a brown solid (4.76 g, 86% yield). Reversed-phase HPLC on 4.6×50 mm C-18 column, tR=1.90 minutes (10 to 90% acetonitrile/water over 4 minutes at 4 mL/minute with detection 254 nm, at 20° C.); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.99-2.08 (m, 2H), 2.58-2.66 (m, 2H), 2.99 (t, J=6.04 Hz, 2H), 3.85 (s, 3H), 7.83-7.87 (m, 1H), 7.91 (d, J=0.81 Hz, 1H), 7.92-7.97 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][N:3]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH2:17]([O:16][C:14]([C:13]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][N:3]2[CH:12]=1)=[O:15])[CH3:18].[CH:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:1]=2)[CH:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccc(N)nc1
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2cc(C(C)C)ccc2n1

Procedure:
15.1 Ethyl 6-isopropylimidazo[1,2-a]pyridine-2-carboxylate Ethyl 6-isopropylimidazo[1,2-a]pyridine-2-carboxylate is prepared by condensing 2-amino-5-isopropylpyridine (PCT Int. Appl. WO 2005028444) with ethyl 3-bromopyruvate according to the method described by J. G. Lombardino in J. Org. Chem. (1965), 30(7), 2403.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]=1[N+:16]([O-:18])=[O:17])[O:8][CH2:9][C:10](Cl)=[O:11])([O:3][CH3:4])=[O:2].[CH2:23]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]=1[N+:16]([O-:18])=[O:17])[O:8][CH2:9][C:10]([N:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc(OCC(=O)Cl)cc(C(=O)OC)c1[N+](=O)[O-]
Reactant: CCCCCCNCCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCN(CCCCCC)C(=O)COc1cc(C(=O)OC)c([N+](=O)[O-])c(C(=O)OC)c1

Procedure:
A stirred solution of (3,5-dicarbomethoxy-4-nitrophenoxy)acetyl chloride in tetrahydrofuran, cooled in an ice bath, is treated dropwise with a tetrahydrofuran solution containing 1 equivalent each of dihexylamine and triethylamine. After the addition, the precipitated amino hydrochloride is removed by filtration and the tetrahydrofuran filtrate is concentrated under reduced pressure to an oil which is used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][N:19]([CH3:25])[C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>CN(C)C=O>[CH3:18][N:19]([CH3:25])[C@H:20]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH2:21]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Nc1ccnc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1CCN(c2nccc(N)n2)C1
Temperature: 220 °C
Yield: 64.1 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (200 mg, 1.544 mmol), Hunig's base (539 μl, 3.09 mmol) and (3S)—N,N-dimethyl-3-pyrrolidinamine (294 μl, 2.316 mmol) in N,N-dimethylformamide (DMF) (2 ml) was heated to 220° C. via a microwave reactor for 30 min. The reaction mixture was purified by RP-HPLC to yield 2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinamine (205 mg, 0.989 mmol, 64% yield). MS (ES+) m/z 208.0 (MH+).
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.CC1CCC[NH:30]1>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:30]
Reactant: CC1CCCN1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 252.2 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.350 g, 0.900 mmol, 1 eq, Example 56, Step D) was suspended in dioxane (20 mL) under Ar. 2-Methyl-pyrrolidine (0.207 g, 1.800 mmol, 2 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.300 g (88%) of the indole-amine was obtained as a white solid. This was converted to the HCl. salt. LC/MS (ESI+) 377 (M+1); Anal. Calcd for C24H28N2O2.1HCl.0.75H2O: C, 67.59; H, 7.21; N, 6.57; Found: C, 67.79; H, 7.16; N, 6.50.
Reaction SMILES: [Cl-].[CH3:2][N:3]([S:7]([CH3:10])(=[O:9])=[O:8])[CH2:4][CH2:5][NH3+:6].F[C:12]1[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C>CS(C)=O>[C:18]([C:13]1[C:12]([NH:6][CH2:5][CH2:4][N:3]([CH3:2])[S:7]([CH3:10])(=[O:9])=[O:8])=[CH:17][CH:16]=[CH:15][N:14]=1)#[N:19]
Reactant: N#Cc1ncccc1F
Reactant: CN(CC[NH3+])S(C)(=O)=O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(CCNc1cccnc1C#N)S(C)(=O)=O

Procedure:
In a manner similar to that described for Example 2, 2-[methyl(methylsulfonyl)amino]ethanaminium chloride (4 g, 25.4 mmol) was dissolved in DMSO (20 mL) and treated with 3-fluoro-2-cyanopyridine (2.5 g, 21.2 mmol) and Hunig's base (4.4 mL, 25.4 mmol) and heated to 90 degrees under pressure. The product was isolated as an oily off-white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].[NH2:24][CH2:25][CH2:26][CH:27]1[O:31][CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:28]1[CH2:29][CH2:30][O:31][CH:27]1[CH2:26][CH2:25][NH:24][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCC2OCCO2)c1
Yield: 98 %

Procedure:
A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide prepared according to Example A1 (1.86 g, 1 eq), 2-(2-aminoethyl)-1,3-dioxolane (0.8 g, 1.2 eq) and potassium carbonate (1.58 g, 2 eq) in acetonitrile (150 ml) is heated under reflux for 3 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (150 ml) and water (60 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 7:3) produces the expected compound in the form of an orange-yellow oil (2.4 g; 98% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.N1C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].C(=O)([O-])O.[Na+]>ClCCl>[CH2:11]([C:4]1[CH:3]=[C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:24]=[C:23]([O:22][CH3:21])[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=2)[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1cc(N)n2nccc2n1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n2nccc2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.5 %

Procedure:
7-Amino-5-n-butylpyrazolo[1,5-a]pyrimidine (1.90 g) and pyridine (20 ml) were dissolved in 20 ml of dry dichloromethane. A dry dichloromethane solution (10 ml) containing 2.6 g of 3,4,5-trimethoxybenzoyl chloride was slowly added dropwise thereto and stirred at room temperature for 10 hours. After addition of 50 ml of a 10% aqueous sodium hydrogen carbonate solution, the reaction mixture was extracted with chloroform. The organic layer was collected, washed with 10% aqueous hydrochloric acid and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane=1:2) and recrystallized from diethyl ether-n-hexane to provide 2.4 g of the object compound as colorless crystals. Table 1 shows the structure and melting point of the compound obtained.
Reaction SMILES: Cl.[CH:2]12[O:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][NH:4][CH2:3]2.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.CC(C)=O>[CH:6]12[O:9][CH:2]([CH2:8][CH2:7]1)[CH2:3][N:4]([C:15]1[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]3)[N:14]=1)[CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Reactant: C1CC2CNCC1O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
Temperature: 72.5 °C
Reaction time: 2 h

Procedure:
To a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.49 g, 3.3 mmol) in water (18 mL) was added a suspension of tert-butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (1.0 g, 3.0 mmol) in acetone (about 10 mL). The suspension was stirred magnetically while solid sodium carbonate (0.70 g, 6.6 mmol) was added in a single portion. The mixture was stirred for two hours while heating in a 70-75° C. in an oil bath. After allowing the mixture to cool to room temperature, the title compound was removed by filtration, washed with water, and dried under vacuum.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[F:13].[CH3:14][S:15]([O-:17])=[O:16].[Na+]>C(O)(C)C>[F:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(CCBr)c(F)c1
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)CCc1ccc([N+](=O)[O-])cc1F
Temperature: 70 °C
Yield: 70.3 %

Procedure:
To a stirred solution of 1-(2-bromoethyl)-2-fluoro-4-nitrobenzene (1 g, 4.03 mmol) in isopropanol (15 mL) was added sodium methane sulfinate (2.05 g, 20.16 mmol) at room temperature. The reaction mixture was heated to 70° C. for 10 h. The reaction mixture was cooled to room temperature and was concentrated under reduced pressure to obtain a crude compound which was filtered out and the residue was washed with water (2×5 mL) to obtain pure 2-fluoro-1-(2-(methylsulfonyl)ethyl)-4-nitrobenzene (700 mg, 70%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][CH2:24][CH2:25][NH2:26])[CH:15]=3)=[CH:13][C:6]=12.C(N(CC)CC)C>ClCCl>[N:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][CH2:24][CH2:25][NH:26][C:1](=[O:3])[CH3:2])[CH:15]=3)=[CH:13][C:6]=12
Reactant: NCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetyl chloride (31 μl) was added dropwise to a solution of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propylamine [100 mg, Example 3(a)] and triethylamine (52.2 μl) and dichloromethane (20 mL) at ambient temperature under a nitrogen atmosphere. After stirring for 24 hours at ambient temperature the reaction mixture was evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (9:1, v/v) to give the title compound (82 mg) as a yellow solid, m.p. 260° C. MS: 334 (MH+).
Reaction SMILES: C([NH:11][C:12](=[N:46]C(OCC1C=CC=CC=1)=O)[NH:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:34]([NH:36][C@H:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][OH:39])=[O:35])[NH:18][C:19](=[O:33])[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C=CC=CC=1)=O.CC(O)=O.[ClH:61]>[Pd].CO>[ClH:61].[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]([NH:18][C@H:17]([C:34]([NH:36][C@H:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][OH:39])=[O:35])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:11])[NH2:46])=[O:33])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(N=C(NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(g) above from (R)-Nω,Nω '-bis(Cbz)-N2 -(diphenylacetyl)-(S)-N-(2-hydroxy-1-phenylethyl)-arginine amide (0.250 g; from step (e) above), 10% Pd/C (200 mg) and, instead of HOAc, 50 mL of MeOH with 1 mL of concentrated HCl, yielding 78 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][S:18][CH2:17]3)=[O:15])[O:11][C:10]=2[C:21]2[CH:22]=[C:23]([C:27]#[N:28])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][S:18](=[O:37])[CH2:17]3)=[O:15])[O:11][C:10]=2[C:21]2[CH:22]=[C:23]([C:27]#[N:28])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1cccc(-c2oc(C(=O)N3CCSC3)cc2-c2cc(F)cc(Cl)c2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cccc(-c2oc(C(=O)N3CCS(=O)C3)cc2-c2cc(F)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
95.0 mg (0.23 mmol) of the compound from Example 1 are provided in 3 ml of dichloromethane, and 51.6 mg (0.23 mmol) of meta-chloroperbenzoic acid are added. The mixture is stirred at room temperature overnight, a saturated aqueous sodium thiosulfate solution is subsequently added and the reaction mixture is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient). 63.0 mg (64% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[S:26][C:16]=2[N:17]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.