Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:9])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CN1CCC(N)CC1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NC2CCN(C)CC2)cc1[N+](=O)[O-]
Yield: 76.5 %

Procedure:
3-Nitro-4-methoxybenzoic acid (Aldrich; 300 mg, 1.52 mmol), 1-methyl-4-aminopiperidine (Fluorochem; 174 mg, 1.52 mmol), HATU (868 mg, 2.28 mmol) and DIPEA (796 uL, 4.56 mmol) were stirred in DMF (6 mL) at room temperature for 2 hours. The reaction mixture was loaded onto an SCX-3 column pre-washed with methanol. The column was washed with methanol and then eluted with 2% 7N ammonia/methanol. Product containing fractions were combined and evaporated to give the title compound as an orange solid (341 mg, 76.4%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](N2CCOCC2)[N:8]=1.Cl.C(N)(=N)[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:8]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)n2)s1
Reactant: N=C(N)c1cccnc1
Agent: Cl
Product: CC(=O)Nc1nc(C)c(-c2ccnc(-c3cccnc3)n2)s1

Procedure:
The titled compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with nicotinamidine hydrochloride.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:24][CH:25]2[CH2:28][CH2:27]C2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.[CH:30]1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(F)=C(F)C=2)CCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:24]1([N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[C:13](=[O:14])[N:12]([CH3:30])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:29])=[CH:8][N:9]=2)[CH2:25][CH2:28][CH2:27]1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCC2)c2ccc(F)c(F)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: Fc1ccc(NCC2CCC2)cc1F
Product: CN(C(=O)N(c1ccc(F)c(F)c1)C1CCC1)c1ncc(SCC(=O)O)s1

Procedure:
The title compound was prepared via {2-[3-cyclobutylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclobutylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].FC(F)(F)C(O)=O.[CH2:22]([O:24][C:25](=[O:50])[CH2:26][NH:27][C:28]([CH:30]1[NH:35][CH2:34][CH2:33][N:32]([S:36]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[C:44]([Cl:49])[CH:45]=3)[CH:40]=2)(=[O:38])=[O:37])[CH2:31]1)=[O:29])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:50])[CH2:26][NH:27][C:28]([CH:30]1[CH2:31][N:32]([S:36]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[C:44]([Cl:49])[CH:45]=3)[CH:40]=2)(=[O:38])=[O:37])[CH2:33][CH2:34][N:35]1[C:11]([C:9]1[S:8][C:5]2[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=2[N:10]=1)=[O:13])=[O:29])[CH3:23]
Reactant: CCOC(=O)CNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, N-[[1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]carbonyl]glycine ethyl ester trifluoroacetate
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][C:5]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]1=[O:19])=O.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1.C1(C)C=CC=CC=1>[CH3:2][O:3][CH2:4][C:5](=[C:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]1=[O:19])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: COCC(=O)C1CCN(C(=O)OC(C)(C)C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [K]
Solvent: C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COCC(Nc1ccccc1)=C1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
Into a 200 mL four-mouthed flask were added tert-butyl 3-(2-methoxyacetyl)-2-oxopyrrolidine-1-carboxylate potassium salt (9.00 g) [mw. 295.37, 30.47 mmol], 1 mol/L aqueous hydrochloric acid solution (50 mL) and toluene (90 mL), and the mixture was stirred at room temperature for 10 min. After partitioning, the organic layer was washed with water (50 mL), and dried over magnesium sulfate. After filtration, aniline (2.84 g) [mw. 93.13, 30.50 mmol], p-toluenesulfonic acid monohydrate (0.58 g) [mw. 190.22, 3.05 mmol] and cyclohexane (50 mL) were added. Dean-Stark trap was set, and distillation by thermal dehydration was performed for 1 hr. After cooling to room temperature, 5 w/w % aqueous acetic acid solution (50 mL) was added to allow for partitioning. The organic layer was washed successively with 5 w/w % aqueous sodium bicarbonate solution (50 mL) and water (50 mL), further washed with water (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the concentrate were added methanol (78 mL) and activated carbon (0.78 g), and the mixture was stirred at room temperature for 1 hr. After filtration, the mother liquor was concentrated under reduced pressure, and the solvent was replaced with ethyl acetate. To the concentrate was added diisopropyl ether (22 mL) to allow for crystallization, and the crystals were aged for 1 hr. After filtration under reduced pressure, the crystals were washed with diisopropyl ether (8 mL), and dried at 40° C. under reduced pressure to give the object compound. Pale-yellow crystals, 3.47 g, yield 34.3%, 1H-NMR (500 MHz, DMSO-d6, TMS) δ 1.47 (s, 9H), 2.70 (t, J=7.7 Hz, 2H), 3.26 (s, 3H), 3.65 (t, J=8.1 Hz, 2H), 4.06 (s, 2H), 7.07-7.14 (m, 3H), 7.31-7.35 (m, 2H), 10.34 (s, 1H). 13C-NMR (125 MHz, DMSO-d6) δ 20.29, 27.74, 43.23, 57.83, 67.40, 89.97, 100.10, 121.40, 123.48, 129.20, 139.43, 148.97, 150.33, 169.16. MS (ESI) m/z 333.1776 [M+H]+, 355.1629 [M+Na]+, 331.1672 [M−H]−. Found: C, 65.04; H, 7.28; N, 8.43%. Calcd for C18H24N2O4: C, 64.97; H, 7.20; N, 8.37%.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3([C:29]([O:31]C)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:19][CH2:18]2)=[O:14])[C:5]1=[O:33])([CH3:3])[CH3:2].Cl>C(O)(=O)C>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]3([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:21][CH2:22]2)=[O:14])[C:5]1=[O:33])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(CN2CCC(CNC(=O)n3c(=O)n(C(C)C)c4ccccc43)CC2)CCCC1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(C(=O)O)CCCC3)CC2)c2ccccc21
Yield: 87.3 %

Procedure:
A mixture of Methyl 1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylate (1.33 g, 2.90 mmol, Step 4) in 4N—HCl (6 mL) and acetic acid (6 mL) was stirred at reflux for 18 h. After cooling, the reaction mixture was concentrated and basified with sat. NaHCO3 aq. (100 mL), extracted with CH2Cl2 (150 mL) for three times. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a column of silica gel eluted with MeOH/CH2Cl2 (1:10) to give 1.12 g (85%) of title compound as white solid. The crude compound was recrystallized from EtOAc×2 and dried in vacuo at 50° C. for 2 days to give 610 mg of title compound as white crystal.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:10]([C:14]1[NH:15][C:16]([Cl:21])=[C:17]([CH:19]=O)[N:18]=1)[CH2:11][CH2:12][CH3:13].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH2:10]([C:14]1[NH:18][C:17]([CH2:19][NH:1][C:2]2[N:3]=[CH:4][NH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[C:16]([Cl:21])[N:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc(C=O)c(Cl)[nH]1
Reactant: NC(=O)c1[nH]cnc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1nc(Cl)c(CNc2nc[nH]c2C(N)=O)[nH]1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
A reaction mixture of 4-amino-5-imidazolecarboxamide (0.50 g, 3.96 mmol), 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde (0.89 g, 4.76 mmol), and NaCNBH3 (0.25 g, 3.96 mmol) in methanol (5 mL) was stirred at r.t. over night. Acetic acid (0.24 g, 3.96 mmol) was added and the mixture was heated at 50° C. for 5 h. The mixture was concentrated in vacuo and dissolved in ethyl acetate and washed with water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (CH2Cl2/methanol gradient; 0 to 20% methanol), obtaining 0.30 g (26%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].[CH:22]([S:25](Cl)(=[O:27])=[O:26])([CH3:24])[CH3:23]>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:25]([CH:22]([CH3:24])[CH3:23])(=[O:27])=[O:26])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: c1ccncc1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNS(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.9 %

Procedure:
A solution of the compound of Example 51, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.50 mmol) in 30 mL of pyridine was chilled in an ice water bath. The stirred solution was treated dropwise with isopropylsulfonyl chloride (0.39 mL, 3.50 mmol) and the reaction was allowed to gradually warm to room temperature. After 18 h, the reaction was concentrated. The crude product was purified by column chromatography (SiO2, 90:10:0.5 CHCl3:MeOH:NH4OH) and then triturated in hexanes to give 314 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}propane-2-sulfonamide as a white solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)=[O:3].Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:16][CH:15]=1>>[NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(N)=O)cc3)cc2)CC1
Yield: 18.9 %

Procedure:
The title compound (15 mg, 15%) was prepared from [4-(aminocarbonyl)phenyl]boronic acid (33 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3 and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.86 (d, 2H, J=8.1 Hz), 7.63 (d, 2H, J=8.1 Hz), 7.55 (d, 2H, J=8.8 Hz), 6.97 (d, 2H, J=8.9 Hz), 6.09 (s, 2H), 4.99-4.86 (m, 1H), 4.28-4.14 (m, 2H), 3.85 (d, 2H, J=6.4 Hz), 2.84-2.74 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.34-1.18 (m, 8H); LRMS (ESI), m/z 419 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[F-].[K+].Cl[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(C)cc1
Yield: 94.8 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), 2-methoxyphenylboronic acid (228 mg, 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 4-chlorotoluene (0.144 mL, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at 65° C. until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 188 mg (95%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[H-].[Na+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl.Cl>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: ClCc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(NCc2cccc(Cl)c2)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(Cc2cccc(Cl)c2)Cc2cccc(Cl)c2)cn1

Procedure:
To the solution of 1.38 g of 5-(m-chlorobenzylamino)-pyridine-2-carboxylic acid methyl ester in 15 ml of dimethylformamide, 0.12 g of sodium hydride in 2 ml of dimethylformamide are added and the mixture is stirred several minutes. Then 0.97 g of m-chlorobenzyl chloride are added and the mixture is stirred at room temperature for 18 hours. It is made acidic with diluted hydrochloric acid and extracted with diethyl ether. The extract is washed with 10% aqueous potassium bicarbonate and water, dried and evaporated, to yield the 5-[di-(m-chlorobenzyl)-amino]-pyridine-2-carboxylic acid methyl ester.
Reaction SMILES: [CH:1](=[C:5]1/[C:6]([O:11]C)=[CH:7][C:8](=[O:10])[NH:9]/1)\[CH:2]([CH3:4])[CH3:3].Cl>[OH-].[Na+]>[CH:1](=[C:5]1/[C:6](=[O:11])[CH2:7][C:8](=[O:10])[NH:9]/1)\[CH:2]([CH3:4])[CH3:3]
Reactant: COC1=CC(=O)N/C1=C\C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)/C=C1\NC(=O)CC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
50 g of finely powdered (Z)-5-isobutylidene-4-methoxy-3-pyrroline-2-one was stirred with 500 ml of concentrated hydrochloric acid for 5 hours at room temperature. The mixture was then stirred 5 hours at room temperature and slowly mixed with 1 liter of 14 percent sodium hydroxide solution. The precipitated yellow product was filtered off, washed with cold water and dried in a vacuum drying cabinet. The yield of the title compound was 42.0 g (92 percent of theory). The title compound had a melting point of 134° to 136° C. (THF/hexane).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)#[CH:10].C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:10]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Clc1ncc(I)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cnc(Cl)nc2)cc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A solution of 2-chloro-5-iodopyrimidine (600 mg, 2.5 mmol), 1-ethynyl-4-fluorobenzene (330 mg, 2.75 mmol), triethylamine (556 mg, 761 μl, 5.49 mmol), and bis(triphenyl-phosphine)palladium (II) chloride (175 mg, 250 μmol) in 7 ml of THF was purged with argon. Then copper (I) iodide (23.8 mg, 125 μmol) was added and the reaction was heated for 2 h at room temperature. The dark solution was filtered and the solids were washed with THF. The residue was taken up in ethyl acetate, adsorbed onto 3 g of silicagel which was loaded onto a 50 g prepacked flash chromatography column. After elution with a 0% to 20% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 505 mg (87%) of the title compound as an crystalline light yellow solid, MS: m/e=233.1, 235.1 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]([CH3:25])=[C:18]([CH:22]=[CH:23][N:24]=3)[C:19](O)=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH:33]=[CH2:34]>>[CH2:32]([N:35]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][N:24]=[C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH:7]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[C:17]=1[CH3:25])[CH:33]=[CH2:34]
Reactant: Cc1c(C(=O)O)ccnc1N1CCN(CCC(c2ccccc2)c2ccccc2)CC1
Reactant: C=CCNC1CCCCC1
Product: C=CCN(C(=O)c1ccnc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1C)C1CCCCC1
Yield: 68.1 %

Procedure:
Step (d) of Example 107 was repeated, except that the compound (50 mg) prepared in step (c) of Example 109 and allylcyclohexylamine (34 mg) were used as the starting compounds. Thus, the title compound (44 mg) was obtained.
Reaction SMILES: C([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[N:6][CH:7]=[C:8](Br)[N:9]=2)[N:4]=1)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:34]=[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[C:32](B4OC(C)(C)C(C)(C)O4)=[CH:31][C:25]=3[C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:34]=[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])[C:32]([C:8]4[N:9]=[C:10]5[C:5](=[N:6][CH:7]=4)[N:4]=[CH:3][NH:12][C:11]5=[O:13])=[CH:31][C:25]=3[C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[CH:18][CH:17]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CCc1nc2ncc(Br)nc2c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4nc[nH]c(=O)c4n3)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a stirring mixture of ethyl 6-bromopteridin-4(3H)-one (50 mg, 0.22 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (110 mg, 0.22 mmol) and Na2CO3 (35 mg, 0.33 mmol) in dioxane/H2O (2 mL/0.2 mL) was added Pd(dppf)Cl2 (10 mg) under N2 protection. The mixture was stirred at 100° C. overnight. The mixture was concentrated in vacuo and extracted with EtOAc. After the organic layer was washed with brine, dried over Na2SO4, filtered and evaporated, the crude product was purified by prep-HPLC to give the product of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4-oxo-3,4-dihydropteridin-6-yl)benzofuran-3-carboxamide (30 mg, yield: 26%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.19 (s, 1H), 8.61 (d, J=4.8 Hz, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 7.97˜7.99 (m, 3H), 7.42 (t, J=8.4 Hz, 2H), 3.37 (s, 3H), 3.00 (s, 3H), 2.83 (d, J=4.0 Hz, 3H). MS (M+H)+: 523.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].[O:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: c1ccoc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1)c1ccco1

Procedure:
This compound is prepared by method C using compound 12j and furane
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:19](=[O:27])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([CH2:23][CH:24]2[CH2:25][CH2:26]2)[C:19](=[O:27])[C:18]=1[I:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1CC1CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: O=c1c(I)c(OCc2ccccc2)ccn1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Iodosuccinimide (2.64 g, 11.74 mmol) was added to a solution of intermediate D1 (3.0 g, 11.74 mmol) in acetic acid (40 ml). The reaction mixture was stirred at room temperature for 1 hour, after which it was concentrated in vacuo, purified by flash chromatography (silica gel; 0-3% methanol/DCM as eluent) and finally recrystallized from diethyl ether to afford intermediate D10 (4.12 g, 92%) as a solid.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[C:42]1(=[O:52])[O:47][C:45](=[O:46])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12>ClCCCl>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:42]([C:43]5[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=5[C:45]([OH:47])=[O:46])=[O:52])[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II (25.3 mg, 0.05 mmol) in 1,2-dichloroethane (3 mL) was added triethyl amine (14 μL, 0.1 mmol) and phthalic anhydride (7.4 mg, 0.05 mmol). The resulting mixture was stirred at ambient temperature for 4 hours. After evaporation of the solvents, the residue was purified by flash chromatography on silical gel, eluting with a gradient of 10-30% methanol in ethyl acetate to afford 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid as amorphous solid (29 mg, quant.). 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J=6.6 Hz, 1H), 7.53-7.50 (m, 1H), 7.48-7.36 (m, 7H), 7.25-7.21 (m, 1H), 7.17-7.09 (m, 3H), 4.61-4.54 (m, 1H), 3.26 (br, 4H), 3.95 (br, 1H), 3.09 (br, 1H), 2.46 (s, 3H), 2.42-2.32 (m, 3H), 2.24-2.06 (m, 1H), 2.00-1.86 (m, 5H), 1.86-1.76 (m, 5H), 1.61 (d, J=7.7 Hz, 2H). HRMS m/z (M+H)+ calcd 577.3179; obsd 577.3176.