Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[N:4][C:5]([CH3:14])=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CN(C)C1C=CC=CC=1.[Br:29][CH2:30][C:31](Br)=[O:32]>ClCCl>[Br:29][CH2:30][C:31]([NH:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[N:4][C:5]([CH3:14])=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[O:32]
Reactant: O=C(Br)CBr
Reactant: COCCOc1nc(C)cc(OCC(F)(F)F)c1N
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: COCCOc1nc(C)cc(OCC(F)(F)F)c1NC(=O)CBr

Procedure:
3-Amino-2-[(2-methoxyethyl)oxy]-6-methyl-4-[(2,2,2-trifluoroethyl)oxy]pyridine (1.39 g, 4.96 mmol) was dissolved in dichloromethane (15 mL). N,N-dimethylaniline (0.76 g, 6.27 mmol) was added to the solution. Under stirring on an ice bath, bromoacetyl bromide (1.16 g, 5.75 mmol) in dichloromethane (5 mL) was added dropwise to the mixture, followed by stirring at the same temperature for 30 minutes. The reacion mixture was directly subjected to silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1→n-hexane/acetone=1/1) for purification, to thereby yield 2-bromo-N-[2-[(2-methoxyethyl)oxy]-6-methyl-4-[(2,2,2-trifluoroethyl)oxy]pyridin-3-yl]acetamide as a colorless solid (1.98 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:16].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>C(#N)C.[I-].[Na+]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)=[O:9])=[CH:4][C:3]=1[Cl:16]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(C(=O)N2CCNCC2)cc1Cl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1Cl
Reaction time: 24 h
Yield: 50.2 %

Procedure:
A mixture of (4-amino-3-chlorophenyl)(piperazin-1-yl)methanone (6.67 mmol, 1.6 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (6.67 mmol, 2.250 g), sodium hydrogencarbonate (20.02 mmol, 1.682 g) and sodium iodide (0.334 mmol, 0.050 g) in acetonitrile (50 mL) was stirred for 24 hours. The reaction was concentrated under reduced pressure and dichloromethane was added. The mixture was filtered and the filtrate was chromatographed on silica eluting with dichloromethane to dichloromethane/ethyl acetate to give the title compound (1.66 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:40])[C:8]1[N:12]([C:13]2[N:14]=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:16]3[N:21]=[N:20][N:19]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:17]=3[N:18]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:40][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:14]=[C:15]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[C:16]3[N:21]=[N:20][N:19]([CH:22]4[CH2:23][CH2:24][N:25]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:26][CH2:27]4)[C:17]=3[N:18]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCNCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCN(S(C)(=O)=O)CC3)c2n1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 87.1 %

Procedure:
Methanesulfonyl chloride (0.09 mL, 1.16 mmol) was added dropwise to a mixture of the above amine (107 mg, 0.220 mmol) and powdered K2CO3 (274 mg, 1.98 mmol) in CH2Cl2 (10 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred for 16.5 hrs. Water was added, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (1×). The combined organic extracts were dried (Na2SO4) and the solvent removed under vacuum. Recrystallization from CH2Cl2/MeOH gave 5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-3-[1-(methylsulfonyl)-4-piperidinyl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (108 mg, 87%): mp 258-259° C.; 1H NMR (CDCl3) δ 7.81 (dd, J=8.4, 0.5 Hz, 1H), 7.41 (t, JHF=53.5 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.93 (tt, J=10.5, 4.2 Hz, 1H), 4.79 (br s, 2H), 4.16 (br s, 2H), 4.07 (s, 3H), 4.01-3.90 (m, 6H), 3.14 (m, 2H), 2.89 (s, 3H), 2.60 (m, 2H), 2.35 (m, 2H); Anal. Calcd. for C23H27F2N9O4S: C, 49.0; H, 4.8; N, 22.4. Found: C, 48.9; H, 4.8; N, 22.2%.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH3:44])[C:8]([C:10]1([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[CH:12]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:24]=3[S:23](=[O:37])(=[O:36])[N:22]=2)[C:11]1=[O:38])=[O:9])(=O)C.C(OC[C@H]1CCCN1C([C@@]1(CCC(C)C)C2C(=CC=CC=2)C(O)=C(C2NC3C=CC(NS(C)(=O)=O)=CC=3S(=O)(=O)N=2)C1=O)=O)(=O)C>>[OH:4][CH2:5][CH2:6][N:7]([CH3:44])[C:8]([C:10]1([CH2:39][CH2:40][CH:41]([CH3:42])[CH3:43])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[CH:12]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][C:24]=3[S:23](=[O:36])(=[O:37])[N:22]=2)[C:11]1=[O:38])=[O:9]
Reactant: CC(=O)OCCN(C)C(=O)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)C(=O)c2ccccc21
Agent: CC(=O)OC[C@H]1CCCN1C(=O)[C@]1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Product: CC(C)CCC1(C(=O)N(C)CCO)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)C(=O)c2ccccc21

Procedure:
The title compound was prepared using the procedure described for Example 172 substituting the product of Example 176G for the product of Example 171G. The title compound was purified by column chromatography on silica gel using a solvent gradient of 2-6% methanol in chloroform, and was obtained as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 0.49 (m, 1H), 0.62 (d, J=6.62 Hz, 3H), 0.67 (d, J=6.62 Hz, 3H), 0.92 (m, 2H), 1.27 (m, 1H), 1.86 (m, 1H), 2.15 (m, 1H), 2.33 (s, 3H), 3.00 (s, 3H), 3.14 (m, 1H), 3.47 (m, 2H), 6.96 (m, 1H), 7.42 (m, 5H), 8.08 (m, 1H), 9.90 (s, 1H), 14.99 (br s, 1H); MS (ESI) m/z=605 [M+H].
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[N:9]2[CH2:10][CH2:11][CH2:12][N:13]=[C:8]2[S:7][C:6]=1[C:14]([OH:16])=O)([CH3:4])[CH3:3].C(OCC)C>S(Cl)(Cl)=O>[ClH:1].[CH:2]([C:5]1[N:9]2[CH2:10][CH2:11][CH2:12][N:13]=[C:8]2[S:7][C:6]=1[C:14]([Cl:1])=[O:16])([CH3:4])[CH3:3]
Reactant: CC(C)C1=C(C(=O)O)SC2=NCCCN21
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CC(C)C1=C(C(=O)Cl)SC2=NCCCN21
Yield: 201.3 %

Procedure:
In 50 ml of thionylchloride was suspended 6.5 g of 3-isopropyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid hydrochloride obtained in Example 46, followed by reflux under heating for 1 hour. To the reaction mixture was added dry diethylether. The precipitated crystals were collected by filtration and washed with diethylether to obtain 7.0 g of 3-isopropyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride. In the mixture 5 ml of pyridine and 5 ml of dimethylformamide was dissolved 500 mg of this compound. To the solution was added 291 mg of 2,5-dimethoxyaniline, followed by stirring at 80uÅ for 12 hours. The solvent was removed under reduced pressure. The residue was crystallized from isopropylalcohol and diethylether. The resulting crystals were recrystallized from isopropylalcohol and saturated hydrogenchloride diethylether solution to obtain 200 mg of the titled compound.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[OH:1][C:2]1[C:9]([O:10][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=Cc1cccc(O)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1cccc(C=O)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A suspension of 2,3-dihydroxybenzaldehyde (15 g, 109 mmole) in CH2Cl2 (70 ml) was cooled to -10° C. Triethyl amine (5.49 g, 54.3 mmol) was added followed by pivaloyl chloride (6.49 g, 53.9 mmol). The reaction was allowed to stir for 1 hour at -10° C. and then warmed to ambient temperature. The reaction mixture was stirred at ambient temperature overnight, then washed with water, 1N aqueous HCl, saturated aqueous NaHCO3 and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl acetate/hexane) to give 2-hydroxy-3-pivaloyloxybenzaldehyde: (10.15 g, 84%).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]1[O:21][C:20]2[CH:19]=[CH:18][C:9]([CH2:10][C:11]3[O:17][C:14]([CH2:15]O)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[O:6]1.[OH-].[Na+]>CCOCC>[CH2:5]1[O:21][C:20]2[CH:19]=[CH:18][C:9]([CH2:10][C:11]3[O:17][C:14]([CH2:15][Br:2])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[O:6]1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Cc2ccc3c(c2)OCO3)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: BrCc1ccc(Cc2ccc3c(c2)OCO3)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6.6 g. of phosphorus tribromide in 50 ml. of ether was added dropwise to a solution of 15 g. of 5-(3,4-methylenedioxybenzyl)furfuryl alcohol in 150 ml. of ether held at 0° C. After the addition was completed, the mixture was stirred for one hour at room temperature and then shaken with 20 ml. of 50% aqueous sodium hydroxide for 15 minutes. The organic layer was separated, washed with water, dried over potassium hydroxide and concentrated. The resulting product was used directly in the next reaction.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]([O-:18])=O)[C:3]1=[O:19].[Li+].[NH2:21][C:22]1[CH:23]=[C:24]2[C:38](=[CH:39][CH:40]=1)[CH2:37][C:26]1([O:31][C:30](=[O:32])[NH:29][C:28]3[N:33]=[CH:34][CH:35]=[CH:36][C:27]1=3)[CH2:25]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:4]([CH2:15][C:16]([NH:21][C:22]2[CH:23]=[C:24]3[C:38](=[CH:39][CH:40]=2)[CH2:37][C:26]2([O:31][C:30](=[O:32])[NH:29][C:28]4[N:33]=[CH:34][CH:35]=[CH:36][C:27]2=4)[CH2:25]3)=[O:18])[C:3]1=[O:19]
Reactant: Nc1ccc2c(c1)CC1(C2)OC(=O)Nc2ncccc21
Reactant: CC1C(=O)N(CC(=O)[O-])C(c2ccccc2)CN1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC1C(=O)N(CC(=O)Nc2ccc3c(c2)CC2(C3)OC(=O)Nc3ncccc32)C(c2ccccc2)CN1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of lithium(3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yl)acetate (30 mg, 0.11 mmol) [Wood et al. US 2007/0265225], 5-amino-1,3-dihydrospiro[indene-2,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one (Intermediate 2, 27 mg, 0.10 mmol) and HATU (42 mg, 0.11 mmol) in DMF (1 mL) is treated with N-methylmorpholine (0.036 mL, 0.33 mmol). The mixture is stirred at rt for 18 h and is then purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and lyophilized to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][NH:16][C@@H:15]([C:19](=[O:31])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH3:30])=[CH:24][CH:23]=3)[CH2:14]2)=[N:10][C:9]=1[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:39]=[C:38]([O:40][C:41]([F:44])([F:43])[F:42])[CH:37]=[CH:36][C:35]=1[S:45](Cl)(=[O:47])=[O:46]>N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:45]([C:35]3[CH:36]=[CH:37][C:38]([O:40][C:41]([F:42])([F:43])[F:44])=[CH:39][C:34]=3[F:33])(=[O:47])=[O:46])[C@@H:15]([C:19](=[O:31])[NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH3:30])=[CH:26][CH:27]=3)[CH2:14]2)=[N:10][C:9]=1[CH3:32])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1F
Reactant: CCCc1ccc(CNC(=O)[C@H]2CN(c3nc(C)c(C(=O)OC(C)(C)C)s3)CCN2)cc1
Solvent: c1ccncc1
Product: CCCc1ccc(CNC(=O)[C@H]2CN(c3nc(C)c(C(=O)OC(C)(C)C)s3)CCN2S(=O)(=O)c2ccc(OC(F)(F)F)cc2F)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
To a solution of the compound (50 mg) obtained in Step 6 in pyridine (0.5 ml) was added, with stirring at room temperature, 2-fluoro-4-trifluoromethoxybenzenesulfonyl chloride (46 mg). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned by adding ethyl acetate and water. The organic layer was washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (59 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH:17]=1)[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11].[O-][Cl:30].[Na+]>>[Cl:30][N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[C:10](=[O:11])[C:9]1[CH:17]=[C:5]([O:4][C:3]2[CH:21]=[CH:22][C:23]([C:25]([F:27])([F:26])[F:28])=[CH:24][C:2]=2[Cl:1])[CH:6]=[CH:7][C:8]=1[N+:18]([O-:20])=[O:19]
Reactant: [O-]Cl
Reactant: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Product: CS(=O)(=O)N(Cl)C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitro-N-methanesulfonyl benzamide, m.p. 215°-218° C. was chlorinated with "Clorox" (aqueous NaClO), following procedure I, to yield a product, m.p. 160°-161° (crystallizes from chloroform/ether).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:25]([O-])=O)[C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([NH2:25])[C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)OC(COS(=O)(=O)c1ccc(C)cc1)CO2

Procedure:
To a mixture of 3.74 g (9.40 mmole) of [(2S)-7-nitro-6-methoxy-2,3-dihydro-1,4-benzodioxin-2y]methyl 4-methylbenzenesulfonate and 2.5 mL of 4 N isopropanolic HCl in 200 mL of ethyl acetate was added 0.45 g of 10% palladium on carbon and the mixture treated with 50 psi of hydrogen on a Parr apparatus for 15 hours. The catalyst was then removed by filtration through celite and the filtrate concentrated in vacuum to give 3.41 g of the (R)-enantiomer of the title compound as beige solid hydrochloride salt. 1H-NMR (DSMO-d6): broad singlet 9.8 δ (2 H); doublet 7.8 δ (2 H); doublet 7.45 δ (2 H); singlet 6.85 δ (1 H); singlet 6.75 δ (1 H); multiplet 4.2-4.45 δ (4 H); multiplet 4.0 δ (1 H); singlet 3.8 δ (3 H); singlet 2.5 δ (3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C@@H:19]([NH2:21])[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:21][C@H:19]([C:10]2[N:9]([C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=2)[CH3:20])[N:26]=[CH:25][N:24]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Temperature: 90 °C
Yield: 39 %

Procedure:
A mixture of (S)-1-[1-(3,5-difluorophenyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (245 mg, 0.84 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (137 mg, 0.88 mmol) and DIPEA (0.44 mL, 2.5 mmol) in IPA (1.7 mL) was heated in a sealed tube for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 25-75% EtOAc/cyclohexane) to give colourless oil. The residue was taken up in EtOAc and the product triturated with cyclohexane. The solid was filtered to afford 349 as a white solid (134 mg, 39%). LCMS (Method K): RT 4.10 min [M+H]+ 410. 1H NMR (DMSO-d6, 400 MHz): δ 7.87 (1H, s), 7.76-7.7 (2H, m), 7.36-7.31 (3H, m), 7.18 (2H, bs), 7.13 (1H, ddd, J=10.0, 8.5, 2.5 Hz), 7.05 (1H, dd, J=9.0, 2.5 Hz), 5.64 (1H, dq, J=7.0, 7.0 Hz), 1.56 (3H, d, J=7.0 Hz)
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:8]=[CH:9][C:10]=1[F:11].[C:36]([O-:39])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=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>[F:11][C:10]1[C:5]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:36]=[O:39])[CH:10]=2)=[CH:6][C:7]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[CH:19]=[CH:20][CH:21]=2)=[O:15])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)NCc3ccc(F)c(Br)c3)c2)CC1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)NCc3ccc(F)c(-c4cccc(C=O)c4)c3)c2)CC1
Yield: 161.5 %

Procedure:
To a solution of 3-formylphenyl)boronic acid (21 mg, 0.14 mmol) in dioxane (3 mL) and water (1 mL) was added 1,1-dimethylethyl 4-{[3-({[(3-bromo-4-fluorophenyl)methyl]amino}carbonyl)phenyl]methyl)-1-piperidinecarboxylate (70 mg, 0.14 mmol), K2CO3 (97 mg, 0.7 mmol) and Pd(PPh3)4 (8 mg, 0.007 mmol). The resulting solution was irradiated in a microwave reactor at 150° C. for 20 minutes then diluted with EtOAc (5 mL). The organic layer was separated and the aqueous layer was further extracted by EtOAc (2×5 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by Gilson HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 90/10, v/v, over 12 min), to give the title compound (60 mg, 81%). LC/MS: m/z, 531 (M+H), 2.83 min.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[C:5]([C@@:9]2([CH3:19])[NH:14][C:13](=S)[CH2:12][N:11]3[N:16]=[CH:17][CH:18]=[C:10]23)[CH:6]=[CH:7][CH:8]=1.CO>O.C([O-])([O-])=O.[Na+].[Na+]>[Br:2][C:3]1[CH:4]=[C:5]([C@@:9]2([CH3:19])[N:14]=[C:13]([NH2:1])[CH2:12][N:11]3[N:16]=[CH:17][CH:18]=[C:10]23)[CH:6]=[CH:7][CH:8]=1
Reactant: C[C@]1(c2cccc(Br)c2)NC(=S)Cn2nccc21
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@]1(c2cccc(Br)c2)N=C(N)Cn2nccc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
32% aqueous ammonia solution (11.9 mL, 201.1 mmol) was added to a stirred mixture of (R)-4-(3-bromo-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazine-6-thione (1.8 g, 5.59 mmol) in 7 N solution of ammonia in methanol (11.97 mL, 83.79 mmol) in a sealed tube. The mixture was stirred at 60° C. for 90 minutes. After cooling to room temperature the mixture was diluted with water and Na2CO3 (aq. sat. solution) and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M solution of ammonia in methanol in DCM 0/100 to 2/98 to 3/97 to 10/90). The desired fractions were collected and concentrated in vacuo to yield (R)-4-(3-bromo-phenyl)-4-methyl-4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-ylamine (1.4 g, 82% yield) as a yellow solid.
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.[Br-].[CH:32]1([Zn+])[CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[CH:32]1([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9](=[O:14])[CH:8]=[C:7]3[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: [Zn+]C1CCCC1
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(C3CCCC3)ccc2o1
Temperature: 160 °C
Yield: 22.3 %

Procedure:
Into a dry microwave vial under N2 was added 6-Bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(dppf)Cl2 (about 5 mol %), and CuI (about 6 mol %) in dry THF (0.5 mL) followed by cyclopentyl zinc bromide (0.273 mL, 0.138 mmol (0.5M in THF)) dropwise. The solution was heated in the microwave for 10 minutes at 160° C., filtered, and was purified by Prep HPLC to give 4.4 mg (18%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 429 (M+H)+; 1H NMR (300 MHz, MeOH) δ ppm. 1.62-2.13 (m, 10H), 2.40 (br d, 2H), 3.06-3.12 (m, 1H), 3.24(br t, 2H), 3.72 (br d, 2H), 3.96 (m, 3H), 5.42 (s, 1H), 6.31-6.40 (m, 1H), 6.96 (d, 1H), 7.23-7.54 (m. 8H), 7.90 (d, 1H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].Br[CH2:17][CH2:18][CH:19]=[CH2:20].O>CS(C)=O>[CH2:20]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH2:19][CH:18]=[CH2:17]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
This example illustrates a synthesis of 1-(3,4-Oxidobutyl)-3,7-dimethylxanthine (inventive compound no. 2513). Sodium hydride (95%) (1.26 g, 50 mmol) was added to a solution of theobromine (7.2 g, 40 mmol) in dimethylsulfoxide (300 mL). After 20 minutes of stirring, 4-bromobutene (5.4 g, 40 mmol) was added. After 16 hours of stirring at room temperature, the reaction was poured into a separatory funnel containing 1 L of water and extracted with dichloromethane (5×200 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using a 20% petroleum ether/ethyl acetate eluant to yield 6.3 g (67.7% yield) 1-(3-Butenyl)-3,7-dimethylxanthine (inventive compound no. 2503) as a white solid.