Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH3:10])[N:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[N:20]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[N:24][C:19]2=[N:18][CH:17]=1)CCC>>[CH2:9]([O:8][C:4]1[N:3]=[C:2]([C:16]2[N:20]3[CH:21]=[CH:22][C:23]([C:25]([F:26])([F:27])[F:28])=[N:24][C:19]3=[N:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:10]
Reactant: CCOc1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: CCOc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 25.8 %

Procedure:
2-Bromo-6-ethoxypyridine (0.30 g, 1.48 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-40%) and trituration with isohexane gave 3-(6-ethoxypyridin-2-yl)-7-(trifluoromethyl)imidazo[1,2-α]pyrimidine (90 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 1.50 (3H, t, J 7), 4.45 (2H, quartet, J 7), 6.73 (1H, d, J 8), 7.34 (1H, d, J 7), 7.41 (1H, d, J 7), 7.71 (1H, dd, J 8 and 7), 8.46 (1H, s), 10.31 (1H, d, J 7); m/z (ES+) 309 (M++H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([O:21][CH3:22])=[CH:19][N:18]=[C:17]([Cl:23])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.Cl.O1CCOCC1>[ClH:23].[ClH:23].[Cl:23][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:20]([O:21][CH3:22])=[CH:19][N:18]=1
Reactant: COc1cnc(Cl)nc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cnc(Cl)nc1NC1CCNCC1

Procedure:
A solution of 4-(2-chloro-5-methoxy-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.43 g, 4.17 mmol) in dichloromethane (10 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 243.3 [M+H]+.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][C:28]=1[C:36]([F:39])([F:38])[F:37].Cl>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:35])=[CH:29][C:28]=1[C:36]([F:37])([F:38])[F:39]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)ccc3C2=O)C(=O)N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.5 g, 1.4 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.31 g, 1.4 mmol) in DMF (30 mL) at 0° C. The mixture stirred at 0° C. for 3 h, and then 4% aqueous HCl (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 1-(4-chloro-3-trifluoromethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid, (0.57 g, 86% yield); mp 261-263° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 8.57 (98.52%); 1H NMR (DMSO-d6) δ 1.98-2.02 (m, 1H), 2.13-2.46 (m, 1H), 2.58-2.63 (m, 1H), 2.86-2.98 (m, 1H), 4.28-4.48 (m, 4H), 5.11 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 6.98 (t, 1H, J=6.0 Hz), 7.45 (d, 1H, J=8.1 Hz), 7.54 (d, 2H, J=11.7 Hz), 7.61 (dd, 1H, J=8.7 Hz, J=2.1 Hz), 7.70 (d, 1H, J=7.8 Hz), 8.09 (d, 1H, J=2.4 Hz), 9.18 (s, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.6, 116.2 (q, J=5.6 Hz), 121.5, 121.9, 122.4, 122.8 (q, J=271 Hz), 122.9, 126.6 (q, J=30 Hz), 126.9, 130.3, 131.8, 140.0, 142.4, 144.5, 154.9, 167.9, 171.0, 172.8; LCMS: MH=495, 497; Anal. Calcd for C22H18ClF3N4O4+0.1H2O: C, 53.20; H, 3.69; N, 11.28. Found: C, 52.83; H, 3.47; N, 11.15.
Reaction SMILES: [F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13]([NH2:15])=[O:14])=[CH:10][C:4]=2[O:3]1.[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:15]=[C:13]([CH:12]=[CH:11][C:9]2[CH:8]=[CH:7][C:5]3[O:6][C:2]([F:1])([F:16])[O:3][C:4]=3[CH:10]=2)[O:14][CH:21]=1
Reactant: NC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Product: FC1(F)Oc2ccc(C=Cc3nc(CCl)co3)cc2O1

Procedure:
6.90 g (30.4 mmol) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylamide, 4.76 g (37.5 mmol) 1,3-dichloroacetone and 50 ml toluene were kept at reflux temperature for 48 h with continuous removal of water by applying a Dean-Stark trap. After removal of solvents in vacuo, the residue was treated with 60 ml of a 1:1 mixture of water/isopropanol. After filtration the precipitate was washed first with isopropanol, then with heptane. Drying at 40° C. in vacuo gave 4-Chloromethyl-2-[2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-vinyl]-oxazole.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:3]=1[OH:21].C([O-])(=O)C.[Na+]>[Pd].CO>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([C:4]1[C:3]([OH:21])=[CH:2][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=1)=[O:20]
Reactant: Cc1ccccc1C(=O)c1cc2c(c(Br)c1O)CCCC2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1C(=O)c1cc2c(cc1O)CCCC2
Yield: 95.4 %

Procedure:
A mixture of 1-bromo-3-(2-methylbenzoyl)-5,6,7,8-tetrahydro-2-naphthol (3.33 g), sodium acetate (0.82 g), 5% palladium-on-carbon (50% hydrate, 1.0 g) and methanol (10 ml) was subjected to catalytic reduction. After the theoretical amount of hydrogen had been absorbed, the catalyst was filtered off. The solvent was then distilled off and the residue was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off to give 3-(2-methylbenzoyl)-5,6,7,8-tetrahydro-2-naphthol as an oil (2.45 g, 96.5%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH2:9][C:10]2([CH2:13][C:14]#[N:15])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][C:18]([C:20]1[S:29][C:23]2[N:24]=[C:25](Cl)[N:26]=[CH:27][C:22]=2[C:21]=1[CH3:30])=[O:19]>>[C:14]([CH2:13][C:10]1([CH2:9][O:8][C:3]2[C:2]([NH:1][C:27]3[C:22]4[C:21]([CH3:30])=[C:20]([C:18]([O:17][CH3:16])=[O:19])[S:29][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:12][CH2:11]1)#[N:15]
Reactant: N#CCC1(COc2ncccc2N)CC1
Reactant: COC(=O)c1sc2nc(Cl)ncc2c1C
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OCC3(CC#N)CC3)c2c1C

Procedure:
Prepared analogously to example 32.1 using 2-(1-((3-aminopyridin-2-yloxy)methyl)cyclopropyl)acetonitrile (264 mg) and chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (152 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[N+:14]([CH3:17])([O-:16])=[O:15].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:11][O:10][C:8](=[O:9])[CH2:7][CH:6]([C:5]1[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:17][N+:14]([O-:16])=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=Cc1ccc(C)cc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture to 300 g of p-methylcinnamic acid, methyl ester, 500 g of nitromethane and 39 g of tetramethylguanidine is allowed to stir at room temperature for 72 hours. The solution is diluted with diethyl ether and (1 liter, 1 N) aqueous hydrochloric acid solution added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(4-methylphenyl) butanoic acid methyl ester.
Reaction SMILES: C([O:5][C:6](=[O:23])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[S:18][C:19]([Br:22])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:22][C:19]1[S:18][C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:23])=[O:5])=[CH:10]2)(=[O:15])=[O:16])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
A mixture of 4.5 g (E)-3-[1-(5-bromo-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester with 85.0 ml dichloromethane and 13.0 ml TFA is stirred at ambient temperature for 24 h. The dichloromethane and TEA is evaporated and the residue is coevaporated with toluene for 3 times. By this method 3.8 g light pink solid is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=O.[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[CH:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH3:21]
Reactant: COc1ccc2ccccc2c1C=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1c(OC)ccc2ccccc12)C(=O)OCC

Procedure:
2-Methoxy-1-naphthaldehyde (25 g, 1.34.10−1 mol) in benzene (200 ml) is heated for 20 hours at reflux in the presence of diethyl malonate (25 ml, 1.65.10−1 mol, 1.23 eq.) and piperidine (2 ml, 2.02.10−2 mol, 0.15 eq.) in a Dean-Stark apparatus. After adding a few additional drops of piperidine, the mixture is returned to reflux for 20 hours. The reaction mixture is diluted with toluene (200 ml) and washed with water (125 ml). After separation of the phases, the organic phase is treated with a 1N hydrochloric acid solution (190 ml), then with a saturated NaHCO3 solution (125 ml) and with a saturated NaCl solution (125 ml). After drying over MgSO4 and evaporation under reduced pressure, the oil obtained is recrystallised from cyclohexane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[F:18]>>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[F:18])[O:19][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccc(F)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 3,4-difluorobenzaldehyde and 3,4-difluorophenol. LC-MS (ESI): m/z 253 [M+H]+; 3.39 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>C(Cl)Cl>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)nc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2-chloropyridine (162 mg, 1262 μmol) and DIEA (275 μL, 1578 mmol) in DCM (6.0 mL) was added 4-nitrophenyl chloroformate (212 mg, 1052 μmol). The resulting mixture was then stirred at RT for overnight. A yellow precipitation was observed. The yellow solid was collected by filtration to give the title compound as a light yellow solid, which was used in the next step without purification requirement.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Mg+2].[Cl-].[Cl-].[CH2:14]=[O:15].Cl>C(#N)C>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[CH:14]=[O:15]
Reactant: COc1ccc(O)c(Cl)c1
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: COc1cc(Cl)c(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of 2-chloro-4-methoxyphenol (25.0 g, 158 mmole) in anhydrous acetonitrile (625 mL) under a dry N2 atmosphere was added MgCl2 (22.5 g, 236 mmole) and TEA (82.3 mL, 591 mmole). The mixture warmed slightly as the MgCl2 was added. Paraformaldehyde (32.0 g, 1.06 mmiole) was then added, the mixture was refluxed for 4.5 h and allowed to stand at room temperature overnight. Additional paraformaldehyde (14.2 g, 474 mmole) was added and reflux was resumed. After 4 h, the mixture was cooled, additional paraformaldehyde (32.0 g, 1.06 mmole) was added and reflux was resumed for another 2.25 h. The mixture was then cooled to room temperature, acidified with 1 N HCl and extracted with ethyl ether (4×500 mL). The combined extracts were washed with brine (250 mL), dried over MgSO4, filtered and concentrated in vacuo to give 30.3 g of a yellow crystalline solid. Recrystallization from isopropanol-H2O gave 11.9 g (41% yield) of the product as a yellow crystalline solid: 1H NMR (dmso-d6/300MHz) 10.47 (brs, 1H, 10.11 (s, 1H), 7.36 (d, 1H, J=3.0 Hz), 7.19 (d, 1H, J=3.0 Hz), 3.73 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])[N:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[CH3:12])[CH:6]=1.[OH-].[Na+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[N:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[CH3:12])[CH:6]=1
Reactant: CCOC(=O)/C=C/c1cc(Br)cn1[C@@H]1CCC[C@@H]1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1CCC[C@H]1n1cc(Br)cc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a solution of ethyl (2E)-3-(4-bromo-1-(cis-2-methylcyclopentyl)-1H-pyrrol-2-yl)acrylate (800 mg) in THF (7.36 mL) were added 1N aqueous sodium hydroxide solution (7.36 mL) and methanol (10 mL) at room temperature, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure to evaporate the methanol and THF, and the remaining aqueous solution was washed with diethyl ether (100 mL). The obtained aqueous layer was acidified with 1N hydrochloric acid (7.36 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (711 mg).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[C:25]([CH3:34])=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=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.O>[F:23][C:24]1[C:25]([CH3:34])=[C:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[N:18][C:19]=5[NH2:21])[N:14]([CH3:22])[N:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1c(F)cccc1CC(=O)O
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)cccc1CC(=O)N1CCc2cc(-c3nn(C)c4ncnc(N)c34)ccc21
Reaction time: 8 h
Yield: 85.1 %

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (3-fluoro-2-methylphenyl)acetic acid (34.7 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred overnight. The reaction was poured into water, and an off-white solid formed. The solid was filtered to give the title compound (73 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (d, J=1.52 Hz, 3H), 3.24-3.31 (m, 2H), 3.94 (s, 3H), 3.97 (s, 2H), 4.27-4.34 (m, 2H), 7.04-7.11 (m, 2H), 7.19 (d, J=6.32 Hz, 1H), 7.44 (d, J=8.08 Hz, 1H), 7.53 (s, 1H), 8.16 (d, J=8.08 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[NH2:17])=[N:6][CH:7]=1.[CH3:19][S:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[NH:17][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([S:20][CH3:19])=[CH:22][C:23]=2[O:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:33][CH2:32]2)=[N:6][CH:7]=1
Reactant: CSc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: Nc1cc(I)ccc1C(=O)Nc1ccc(Cl)cn1
Product: CSc1ccc(C(=O)Nc2cc(I)ccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 84 %

Procedure:
Using a procedure analogous to Example 4-E, N-(5-chloropyridin-2-yl)-4-iodo-2-aminobenzamide and 4-methylthio-2-(1-t-butoxycarbonylpiperidin-4-yloxy)benzoic acid gave the title compound as a white solid (3.03 g, 84%).
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=O)(C)(C)C.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH2:27])=[CH:25][C:20]=2[O:19][CH2:18]1>>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C:10]([C@@H:9]3[CH2:13][C:14](=[O:16])[CH2:15][NH:8]3)=[O:12])=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: NCc1ccc2c(c1)OCO2
Product: O=C1CN[C@H](C(=O)NCc2ccc3c(c2)OCO3)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-oxoproline, and 1,3-benzodioxol-5-ylmethylamine the title compound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=263.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]2[N:13]=[N:12][C:11](N)=[N:10][CH:9]=2)[CH:7]=1.N(OCCC(C)C)=O.C(Br)(Br)[Br:25]>>[Br:25][C:11]1[N:12]=[N:13][C:8]([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:15])=[CH:9][N:10]=1
Reactant: Nc1ncc(-c2cc(Br)ccc2F)nn1
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Product: Fc1ccc(Br)cc1-c1cnc(Br)nn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-(5-Bromo-2-fluorophenyl)-1,2,4-triazin-3-amine (4.5 g, 16.7 mmol) was dissolved in 25 mL of bromoform and heated to 80° C. Isoamyl nitrite (9.8 g, 83.5 mmol) was then added and stirred at 85° C. for 1 h. The reaction mixture was then concentrated and silica gel chromatography afforded a yellow solid (4.4 g), m/z=331.1 [M+H].
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[C:19]([CH2:23][C:24](Cl)=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:24](=[O:25])[CH2:23][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A mixture of 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.27 g, 1.1 mmol), t-butylacetyl chloride (0.18 mL, 1.3 mmol) and poly-(4-vinylpyridine) (700 mg) in dichloromethane (18 mL) was stirred at room temperature overnight. The resin was removed by filtration and washed with dichloromethane. The filtrate was concentrated and the product was purified by flash column chromatography (elution with 30% ethyl acetate-hexane) to provide 0.20 g of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-yl-3,3-dimethylbutanamide as a white solid. MS (ESI) m/z 339.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10](OC)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>CCOCC.O>[CH2:1]([C:7]1[CH:8]=[C:9]([CH2:10][OH:11])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(C(=O)OC)ccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCCCc1cc(CO)ccc1OC
Reaction time: 1 h

Procedure:
Methyl 3-hexyl-4-methoxybenzoate (93.2 mg, 0.372 mmol) and THF (2 ml) were mixed in a stream of argon. To this solution was added LAH (19 mg, 0.5 mmol) under ice-cooling, and the mixture was stirred for 1 hour. To this reaction mixture were successively added dropwise water (0.019 ml), a 1N aqueous sodium hydroxide solution (0.019 ml) and water (0.06 ml). Ether (20 ml) was added, and the mixture was vigorously stirred for 1 hour. The inorganic salt was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of (3-hexyl4-methoxyphenyl)methanol. The obtained product was not further purified, and used in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[Cl:17]Cl>C(O)(=O)C>[Cl:17][C:3]1[C:4]2[C:5](=[O:16])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:14]=[CH:15][C:2]=1[OH:1]
Reactant: ClCl
Reactant: O=c1c2ccccc2[nH]c2ccc(O)cc12
Solvent: CC(=O)O
Product: O=c1c2ccccc2[nH]c2ccc(O)c(Cl)c12
Temperature: 15 °C
Reaction time: 8 h

Procedure:
2-Hydroxyacridone (3.17 grams; 0.015 mole) and acetic acid were charged into a glass reaction vessel equipped with a stirrer and thermometer. The mixture was cooled to 15° C. and a solution of chlorine (0.015 mole) in acetic acid (2.5 ml) was added dropwise with stirring. After the addition was completed stirring was continued at room temperature overnight. After this time the reaction mixture was filtered to recover product. The product was then washed, dried and dissolved in tetrahydrofuran (50 ml). The solution was treated with triethylamine (2 ml). The treated solution was then filtered and the filtrate treated with activated charcoal. The filtrate was then stripped of solvent in a rotary evaporator to yield chloro-2-hydroxyacridone m.p. 184°-191° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1>>[C:22]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])[CH:21]=1
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 3-(bromomethyl)-1,1′-biphenyl. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 402.16 g/mol.