Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.CCCCCC.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.[CH3:28][Si:29]([CH3:38])([CH3:37])[C:30]1[O:34][CH:33]=[C:32]([CH:35]=[O:36])[CH:31]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>O1CCCC1>[C:39]([O:36][CH:35]([C:32]1[CH:31]=[C:30]([Si:29]([CH3:38])([CH3:37])[CH3:28])[O:34][CH:33]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: BrCCCCCc1cccc2ccccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)OC(CCCCCc1cccc2ccccc12)c1coc([Si](C)(C)C)c1
Reaction time: 0.5 h

Procedure:
Tert-butyl lithium (a 1.7M solution in hexane (1.27 ml, 2.16 mmol) was added to a -78° solution of 1-bromo-5-(1-naphthyl)-pentane (300 mg, 1.08 mmol) in tetrahydrofuran (2 ml) under nitrogen. After stirring for 30 minutes at -78°, a solution of 5-trimethylsilyl-3-furaldehyde (182 mg, 1.08 mmol) in tetrahydrofuran (0.5 ml) was added and the solution was stirred 2 hours at room temperature. Acetic anhydride (20 mg, 0.2 mmol) was added and the solution stirred at room temperature overnight. The reaction was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulfate) extracts gave an oil. Purification of the crude material by preparative TLC (developed with 10% ethyl ether/hexane) gave the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]=[C:34]=[S:35])[CH2:27][CH2:26]2)=[CH:10][CH:9]=1>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][NH:33][C:34]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[S:35])[CH2:29][CH2:30]2)=[CH:10][CH:9]=1
Reactant: C1CCNCC1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCNC(=S)N4CCCCC4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
A mixture of 0.9 parts of piperidine, 4.1 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 135 parts of tetrahydrofuran was stirred for 2 hours at room temperature. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1 part (20.2%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-1-piperidinecarbothioamide; mp. 175.6° C. (compound 29).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([O:31][CH2:32][CH2:33][N:34]([CH3:41])[CH:35]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:47][C:48](Cl)=[O:49]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:48](=[O:49])[CH2:47][C:43]5[S:42][CH:46]=[CH:45][CH:44]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)=[CH:25][C:26]=1[O:31][CH2:32][CH2:33][N:34]([CH3:41])[CH:35]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36]1
Reactant: CN1CCC(N(C)CCOc2cc(Nc3nccc(-c4c(-c5cccc(N)c5)nn5ccccc45)n3)ccc2Cl)C1
Reactant: O=C(Cl)Cc1cccs1
Product: CN1CCC(N(C)CCOc2cc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)ccc2Cl)C1
Yield: 55 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[4-chloro-3-({2-[methyl(1-methyl-3-pyrrolidinyl)amino]ethyl}oxy)phenyl]-2-pyrimidinamine using 2-thienylacetyl chloride as described in Example 10, Step E to give a brown solid in 55% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.7 (s, 2H) 2.8 (m, 5H) 3.0 (d, J=14.5 Hz, 4H) 3.1 (s, 2H) 3.8 (s, 1H) 3.9 (s, 1H) 3.9 (s, 2H) 4.0 (s, 1H) 6.5 (d, J=5.3 Hz, 1H) 6.9 (s, 2H) 6.9 (s, 3H) 7.1 (m, 2H) 7.2 (m, 3H) 7.4 (m, 2H) 7.5 (d, J=8.6 Hz, 1H) 7.7 (d, J=20.0 Hz, 1H) 7.9 (s, 1H) 8.3 (d, J=5.1 Hz, 1H) 8.8 (d, J=6.4 Hz, 1H) 9.7 (s, 1H) 10.4 (s, 1H). ES-LC/MS m/z 693 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[I:12]N1C(=O)CCC1=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:12])=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C1CCC(=O)N1I
Product: Nc1ccc(I)cc1S(N)(=O)=O

Procedure:
Commercially available 2-aminobenzenesulfonamide can be treated with N-iodosuccinimide (NIS) to afford 2-amino-5-iodo-benzenesulfonamide. Acylation with a malonyl halide monoester, such as ethyl 3-chloro-3-oxo-propionate, or with a dialkyl malonate, such as diethyl malonate, affords the corresponding amide, which can simultaneously be cyclized to the thiadiazine-dioxide and hydrolyzed to the desired acid intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[CH:8]=[N:9][NH:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19]C(C)(C)C)=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:35]([C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1)=C=O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[N:9][NH:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([NH:35][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=2)=[O:19])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1[nH]ncc1Cc1ccc(Cl)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCC[C@@H]1c1[nH]ncc1Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 27.8 %

Procedure:
A solution of (R)-tert-butyl 2-(4-(4-chlorobenzyl)-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate (30 mg, 0.8 mmol) was dissolved in 4M HCl in 1,4-dioxane (1 mL), stirred for 2 h and then concentrated in vacuo. The resulting residue was suspended in dicloromethane (2 mL) and DIEA (56 μL, 0.32 mmol) before 1-isocyanato-4-(trifluoromethyl)benzene (8.5 μL, 0.08 mmol) was added. After 10 min of stirring the reaction mixture was concentrated in vacuo. Purification of the resulting residue by semi-preparative HPLC afforded (R)-2-(4-(4-chlorobenzyl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxamide (10 mg, 28%). LCMS: calculated: 448, found (MH+): 449.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[CH:8][N:7]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>ClCCl.CCOCC>[Cl:24][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A mixture of 1.9 g (6.456 mmol) of [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol and 0.515 ml (7.1 mmol) thionylchloride in 20 ml dichloromethane was stirred for 1 h at RT. The reaction mixture was taken up in ether and washed with sodium bicarbonate solution and water. The ether phase was concentrated under reduced pressure to give 1.97 g of pure 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22](C)[CH:21]=1.[C:31](O)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]([NH2:18])=[O:17])=[C:2]2[NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][C:29]=1[CH3:31]
Reactant: CC(=O)O
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: COC(=O)c1ccc(N)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2c(C(N)=O)cnc3cc(OC)c(OC)cc23)c(C)c1
Temperature: 100 °C
Yield: 47 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.35 mmol), methyl 4-amino-2-methylbenzoate acid (0.076 g, 0.46 mmol) and acetic acid (100 μl) in DMF (0.8 ml) was heated at 100° C. for 9 h. After cooling, the mixture was combined with two similar reaction mixtures (starting from 92 and 46 mg 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide respectively) and diluted with water. The mixture was made alkaline with saturated NaHCO3 and the gummy precipitate was collected, washed with water and re-crystallized from methanol to give the title compound (130 mg, 47%).
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[CH:13]1([C:19](=[S:21])[NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[BrH:1].[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:20]=[C:19]([CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[S:21][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: NC(=S)C1CCCCC1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Product: Br
Product: OC12N=C(C3CCCCC3)SC1Cc1cc(Cl)ccc12

Procedure:
This compound is prepared analogously to the process described in Example 1c using 2-bromo-5-chloroindan-1-one and cyclohexanethiocarboxamide; melting point: 170-175° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[C:22]([CH2:26][C:27](Cl)=O)([CH3:25])([CH3:24])[CH3:23].[OH-].[Na+].C(O)C>C(OCC)(=O)C>[CH3:23][C:22]([CH3:25])([CH3:24])[CH2:26][C:27]1[N:14]([CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:9])=[O:10])=[CH:7][C:2]=2[N:1]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)S(=O)(=O)c1ccc(NCCN2CCCC2)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 2-amino-4-(isopropylsulfonyl)-1-(N-2-pyrrolidine-1-ylethylamino)benzene (122.9 mg, 0.39 mmol) in ethyl acetate (8 mL) was added tert-butylacetyl chloride (60 μL, 0.43 mmol) at room temperature, and the mixture was stirred for 1 h at room temperature. 2N—NaOH (1 mL) and ethanol (3 mL) were then added to the reaction mixture at room temperature, and stirred for 6 h at 80° C. The reaction was quenched with water, and extracted with three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by amine coated silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound as an orange solid (107.9 mg, 70%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>C1COCC1>[N:48]1([CH2:47][CH2:46][O:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropyl azodicarboxylate (1.1 equivalents) was added dropwise to a stirred solution of 4-amino-3-nitrophenol (1.0 equivalent), triphenylphosphine (1.1 equivalents), and N-(2-hydroxyethyl)morpholine (1.0 equivalent), in THF at 0° C. The mixture was allowed to warm to room temperature and left to stir for 18 hours. The solvent was evaporated and the product was purified by silica gel chromatography (98:2 CH2Cl2:MeOH) to yield a dark reddish-brown oil. LC/MS m/z 268.0 (MH+), Rt 1.01 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[CH:7][C:6]=1[F:13])[CH3:2].[CH2:15]([N:17](CC)[CH2:18][CH3:19])[CH3:16].N1CCCC1>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:17]2[CH2:18][CH2:19][CH2:16][CH2:15]2)=[CH:7][C:6]=1[F:13])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(F)cc1F
Reactant: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: CCOC(=O)c1cc(F)c(N2CCCC2)cc1F
Reaction time: 24 h
Yield: 97 %

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e, 4.32 g, 21.2 mmol) in acetonitrile (25 mL) is added triethylamine (5.9 mL, 42.3 mmol) and pyrrolidine (2.2 mL, 25.4 mmol). After 24 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound as an oil (5.25 g). MS CI: m/z 256 (MH+).
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[CH3:15][O:9][C:8]([C:2]1([NH2:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: NC1(C(=O)O)CCCCC1
Product: COC(=O)C1(N)CCCCC1
Product: Cl
Reaction time: 4 h

Procedure:
1-Amino-cyclohexanecarboxylic acid (49 g, 342 mmol) was added to a solution, cooled to 0° C., of thionyl chloride (49.6 ml, 684 mmol) in methanol (750 ml). The reaction mixture was stirred for 4 h under reflux and then overnight at room temperature. Then the mixture was heated again for 3 h under reflux and stirred overnight again at room temperature. The reaction solution was concentrated and the thionyl chloride residues were removed by dragging out with methanol and diethyl ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([NH:9][C:4]2[C:5]([Br:8])=[CH:6][CH:7]=[CH:2][N:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccc(Br)nc1
Product: Brc1cccnc1Nc1ccccc1
Yield: 67 %

Procedure:
A mixture of 2,5-dibromopyridine (10.2 g, 43 mmole) in aniline (25 mL) was stirred and heated at reflux for 3 h. The reaction was cooled to RT and most of the aniline was distilled off under vacuum. The remaining residue was taken up in ethyl acetate and the solution was washed with 1.0 N Na2CO3 then with brine, dried (Na2SO4), and concentrated under vacuum. Trituration with petroleum ether, filtration and drying under vacuum gave the title compound (7.20 g, 67%) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=2.4 Hz, 1H), 7.58 (dd,1H), 7.3 1-7.39 (m, 4H), 7.11 (m,1H), 6.79 (br s, 1 H); MS (ES) m/e 249.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH2:7][N:8]([CH3:25])[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[C:14]([C:23]#[N:24])[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[C:28]([C:31]1[CH:32]=[C:33]([NH:37][CH:38](C2C=CC(CCNC)=CC=2)[C:39]([OH:41])=[O:40])[CH:34]=[CH:35][CH:36]=1)(=[O:30])[NH2:29].[CH2:52]([O:59][C:60](NCC1C=C(N(C2C=CC=CC=2)C(=O)O)C=CC=1S(CC)(=O)=O)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[CH2:52]([O:59][C:60]([NH:24][CH2:23][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[N:8]([CH2:7][CH2:6][C:5]2[CH:26]=[CH:27][C:2]([CH:38]([NH:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([C:28](=[O:30])[NH2:29])[CH:32]=3)[C:39]([OH:41])=[O:40])=[CH:3][CH:4]=2)[CH3:25])[CH:17]=[CH:16][C:15]=1[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(Br)cc2)cc1C#N
Reactant: CNCCc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1
Reactant: CCS(=O)(=O)c1ccc(N(C(=O)O)c2ccccc2)cc1CNC(=O)OCc1ccccc1
Product: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(C(Nc3cccc(C(N)=O)c3)C(=O)O)cc2)cc1CNC(=O)OCc1ccccc1
Yield: 49 %

Procedure:
Using a procedure analogous to that used to synthesize 25B, 28F (227 mg, 0.69 mmol) was reacted with 28B to yield 28G (230 mg, 49%) as a yellow solid. MS (ESI) m/z 702.44 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Br)cc1
Reaction time: 8 h
Yield: 74 %

Procedure:
4-Bromophenylacetic acid, 7-c, (30 g, 0.14 mol) was dissolved in ethanol (150 mL) at reflux along with p-toluenesulphonic acid (2.4 g, 0.014 mol). The reaction mixture was then stirred overnight. The ethanol was the removed in vacuo and the residue was taken up in EA. Combined organic layers were washed with water and the aqueous layer was re-extracted with EA. Combined organic layers were then dried over Na2SO4 and concentrated to afford the titled compound, 12-a, (25 g, 74%). 1H NMR (300 MHz, CDCl3) δ 1.23-1.29 (m, 3H), 3.56 (s, 2H), 4.11-4.18 (m, 2H), 7.16 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H). LC-MS (M+H)+ 243, 245.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH2:21][CH3:22])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH2:21][CH3:22])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]([C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=2)=[CH:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCS(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCS(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 71.7 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (80 mg, 0.134 mmol), 4-methylsulfonyl phenylboronic acid (80 mg, 0.401 mmol) and dichlorobis(triphenylphosphine)palladium (II) (9.4 mg, 0.013 mmol) in dioxane (1 mL) was added an aqueous sodium carbonate solution (2 M, 0.2 mL, 0.4 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (10 mL), washed with a saturated aqueous sodium bicarbonate solution (2×3 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-ethanesulfinyl-1H-pyrrolo[2,3-b]pyridine (56 mg, 72%) as a light yellow solid: LC/MS m/e calcd for C29H30N2O5S3 [M+H]+ 583.76, observed 583.2.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:7]2[C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3].[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](N)[N:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:7]3[C:8](=[O:16])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:3])[N:26]=[CH:25][N:24]=1
Reactant: N#Cc1c(N)ncnc1N
Reactant: Cc1cccc2nc(C(C)N)c(-c3ccccc3)c(=O)n12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2nc(C(C)Nc3ncnc(N)c3C#N)c(-c3ccccc3)c(=O)n12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(1-aminoethyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.178 g, 0.637 mmol) and 4,6-diaminopyrimidine-5-carbonitrile (0.090 g, 0.67 mmol) in butan-1-ol (4 mL) was added diisopropylethyl amine (0.33 mL, 1.91 mmol). After stirring at 120° C. for 3 h, the solution was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-8% MeOH in DCM) to afford 4-amino-6-(1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethylamino)pyrimidine-5-carbonitrile as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (d, J=6.65 Hz, 3 H) 2.91 (s, 3 H) 5.09 (quin, J=6.85 Hz, 1 H) 6.97 (d, J=7.04 Hz, 1 H) 7.03 (d, J=7.24 Hz, 1 H) 7.32 (br. s., 2 H) 7.35-7.50 (m, 6 H) 7.72 (dd, J=8.80, 6.85 Hz, 1 H) 7.98 (s, 1 H) Mass Spectrum (ESI) m/e=398.1 (M+1). The racemic mixture (0.210 g) was separated by chiral separation using SFC to give 2 fractions. First-eluting enantiomer on AD-H column: 4-amino-6-(((1S)-1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26 (d, 3 H) 2.90 (s, 3 H) 5.09 (qd, J=6.89, 6.72 Hz, 1 H) 6.97 (d, J=6.85 Hz, 1 H) 7.04 (d, J=7.34 Hz, 1 H) 7.33 (br. s., 2 H) 7.35-7.50 (m, 6 H) 7.71 (dd, J=8.93, 6.97 Hz, 1 H) 7.97 (s, 1H) Mass Spectrum (ESI) m/e=398.1 (M+1). Second-eluting enantiomer on AD-H column: Concentration of product fractions gave a solid that was triturated in water and filtered to afford 4-amino-6-(((1R)-1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a light yellow solid. Mass Spectrum (ESI) m/e=398.1 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.C([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])(=O)C.O>C1COCC1.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)/[CH:8]=[C:24]1/[C:23](=[O:28])[NH:22][CH2:27][CH2:26][CH2:25]/1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CC(=O)N1CCCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(/C=C2\CCCNC2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To a sodium hydride suspension (40% mineral oil content, 2.77 g) in THF (50 mL) and DMF (200 mL), a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (10 g) obtained in Example 1 and 1-acetylpiperidin-2-one (7.17 g) in THF (50 mL) and DMF (200 mL) were added dropwise over 20 minutes at 5° C. This reaction solution was agitated at 0° C. for 2 hours. The reaction solution was added to iced water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The deposited solids were separated by filtering and 5.0 g of the title compound was obtained by washing with diethyl ether. The physical properties of the compound are as follows.