Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:17])[CH2:13][C:14]([CH3:16])=O)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH2:19][C:20]([NH2:22])=[S:21].S(Cl)(Cl)(=O)=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[C:6]([NH:11][C:12]([C:13]3[S:21][C:20]([NH2:22])=[N:19][C:14]=3[CH3:16])=[O:17])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC(N)=S
Reactant: CC(=O)CC(=O)Nc1cccc2c1CCC2(C)C
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1nc(N)sc1C(=O)Nc1cccc2c1CCC2(C)C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
1.00 g (4.08 mmol) of N-(1,1-dimethyl-4-indanyl)acetoacetamide and 0.62 g (8.16 mmol) of thiourea were dissolved in 10 ml of benzene and to this solution was added dropwise a solution of 0.55 g (4.08 mmol) of sulfuryl chloride in 5 ml of benzene at room temperature. After reacting for 2 hours at this temperature, the reaction mixture was refluxed for 1 hour, and left overnight. Then, the resulting solution was concentrated and dissolved in hot water and thereafter neutralyzed with 28% aqueous ammonia to give a precipitate. This precipitate was filtered, washed with water and dried to obtain 1.00 g of N-(1,1-dimethyl-4-indanyl)-2-amino-4-methylthiazole-5-carboxamide (yield 81%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=1[CH:11]=[O:12].[CH3:14][Mg]Br.C(OCC)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=1[CH:11]([OH:12])[CH3:14]
Reactant: C[Mg]Br
Reactant: CN(C)c1cnn(C)c(=O)c1C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1c(N(C)C)cnn(C)c1=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In THF (10 ml) was dissolved 5-dimethylamino-4-formyl-2-methyl-3(2H)-pyridazinone (362 mg) followed by dropwise addition of 3.0M methylmagnesium bromide/diethyl ether (1.0 ml) with ice-cooling, and the mixture was stirred at 50° C. for 30 minutes. To this reaction mixtrue was added 1N-hydrochloric acid (3 ml) with ice-cooling. Then, saturated aqueous NaHCO3 solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. Yellow oil, 371 mg. 1H-NMR (CDCl3) δ: 1.64(3H,d,J=6.6Hz), 2.94(6H,s), 3.72(3H,s), 4.93(1H,dq,J=6.6&11.4Hz), 5.31(1H,d,J=11.4Hz), 7.66(1H,s).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[CH2:15].C(O)(=O)C>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:14][CH2:15][N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1
Reactant: C=Cc1ccccn1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CCN2CCc3c([nH]c4ccccc34)C2)nc1
Yield: 44 %

Procedure:
A mixture of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.72 g., 0.01 mol), 2-vinylpyridine (1.0 g., 0.01 mol) and 2 ml. of glacial acetic acid were refluxed in 25 ml. of methanol for 24 hours. The solvent was removed in vacuo and the separated solid was suspended in water. The solution was made slightly basic via the addition of solid potassium carbonate and it was extracted with methylene chloride (4×150 ml.). The methylene chloride layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 1.2 g. (44% yield) of 2,3,4,9-tetrahydro-2-[2-(2-pyridinyl)ethyl]-1H-pyrido[3,4-b]indole. This intermediate was dissolved in 50 ml. of dimethylformamide and 0.92 g. (0.04 mol) of sodium hydride was added and stirring was continued for 1 hour. To the stirred solution 0.66 g. (0.004 mol) of benzyl bromide was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the solid residue was suspended in water and extracted with methylene chloride (3×100 ml.). The organic layer was separated, dried and evaporated. The remaining oil was dissolved in ethanol and converted to the dihydrochloride salt; mp 278°-280° C.
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:55]([C:57]1N=C(N)[S:59][N:58]=1)[CH3:56]>ClCCl>[CH2:55]([C:57]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:14])[CH3:15])[S:59][N:58]=1)[CH3:56]
Reactant: CCc1nsc(N)n1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCc1nsc(NC(=O)[C@H](CC(C)C)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 104 mg, 0.32 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) and 1-hydroxybenzotriazole (46 mg, 0.34 mmol). The resulting solution was stirred for 5 min before 3-ethyl-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.39 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (3-ethyl-[1,2,4]thiadiazol-5-yl)-amide (83 mg, 59%) as a light yellow solid: HR-ES-MS m/z calculated for C20H23ClN4O3S [M+H]+ 435.1252, observed 435.1252; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.4 Hz, 3H), 0.91 (d, J=6.4 Hz, 3H), 1.45 (br. s., 1H), 1.53-1.72 (m, 1H), 1.83 (br. s., 1H), 3.69 (s, 3H), 4.04 (s, 2H), 4.26 (d, J=18.4 Hz, 1H), 4.48 (d, J=18.4 Hz, 1H), 4.80 (s, 1H), 4.96 (dd, J=11.2, 4.5 Hz, 1H), 6.84 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 7.35 (td, J=7.8, 1.5 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 13.28 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:17][C:16](=[O:18])[NH:15][C:14]3[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.[CH2:27]([NH:29][C:30]([NH2:32])=[S:31])[CH3:28]>C1COCC1.CCOC(C)=O>[Cl:26][C:20]1[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]2[N:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]4[N:32]=[C:30]([NH:29][CH2:27][CH3:28])[S:31][CH:2]=4)[CH:6]=3)[CH2:17][C:16](=[O:18])[NH:15][C:14]=2[CH:19]=1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Reactant: CCNC(N)=S
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNc1nc(-c2cccc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)c2)cs1
Temperature: 60 °C
Yield: 18.3 %

Procedure:
A mixture of 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (130 mg) (Example 193a) and N-ethyl-thiourea (31 mg) in THF (3 mL) was heated at 60° C. for 15 min. The mixture was diluted with AcOEt and washed with sat. NaHCO3 solution and with brine. The organic layer was dried and evaporated and the residue was purified by chromatography on silica gel using AcOEt/hexane (1:1) as eluent. The purified product was triturated with Et2O to give the title compound (24 mg) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[CH2:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][CH2:13][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:15])=[CH:7]2
Reactant: C=Cc1nc([C@H](C)Nc2ncnc3c2ncn3Cc2ccc(OC)cc2)cc2cccc(Cl)c12
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(CCN5CCOCC5)n4)ncnc32)cc1
Temperature: 25 °C

Procedure:
Compound 2 was then converted to compound 4 in two steps: To a stirred mixture of (S)—N-(1-(8-chloro-1-vinylisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 2 (200 mg, 0.42 mmol, 1 eq) in EtOH (50 mL) at RT, morpholine (183 mg, 2.1 mmol, 5 eq) and triethylamine (213 mg, 2.1 mmol, 5 eq) were added sequentially. The resulting mixture was stirred at reflux for 4 h. The mixture was allowed to cool to RT and then concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 3. The PMB group was then subsequently deprotected using Method L to provide compound 4. ESI-MS m/z: 438.8 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:25][C@@H:24]([F:26])[CH2:23][C@H:22]1[CH2:27][O:28][CH2:29][CH2:30][CH:31]=O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:25][C@@H:24]([F:26])[CH2:23][C@H:22]1[CH2:27][O:28][CH2:29][CH2:30]/[CH:31]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COCCC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/CCOC[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 86.2 %

Procedure:
Trimethyl phosphonoacetate (0.95 ml, 5.88 mmol) was dissolved in THF (40 ml). Under a nitrogen gas stream, sodium hydride (60% in oil, 235 mg, 5.88 mmol) was added in portions to the resulting solution, while stirring at 0° C. After stirring the reaction mixture at the same temperature for 10 minutes, a solution of 3-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinylmethoxy)propionaldehyde (1.35 g, 4.90 mmol) in THF (40 ml) was added dropwise at 0° C. The reaction mixture was further stirred for 2 hours at 0° C. and poured in ice water (50 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (1.40 g, 86%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].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:9][C:4]1[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(Br)cc1F
Reactant: Ic1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Thirty milliliters of a 1.6-M-n-butyllithium hexane solution and a solution of 9.21 g of 4-bromo-2-fluorotoluene in 30 ml of tetrahydrofuran were added in this order to 30 ml of tetrahydrofuran which had been cooled to -78° C. in a nitrogen atmosphere, and the mixture was then stirred at -78° C. for 1 hour. A solution containing 6.64 g of zinc chloride which had been dehydrated through heat-melting under reduced pressure in 30 ml of tetrahydrofuran was added thereto at -78° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to a solution of 6.63 g of iodobenzene and 0.52 g of tetrakis(triphenylphosphine)palladium (0) in 30 ml of tetrahydrofuran at room temperature, and the mixed solution was stirred for 24 hours. The reaction solution was diluted with 300 ml of ethyl acetate, and the dilute solution was extracted with the addition of 10% hydrochloric acid. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, and then concentrated. The residue was purified through silica-gel column chromatography (eluent: hexane) to give 6.00 g of oily 3-fluoro-4-methylbiphenyl.
Reaction SMILES: [C:1](=[N:32]O)([C:8]1[CH:31]=[CH:30][C:11]([C:12](=[N:28]O)[C:13]2[CH:18]=[CH:17][C:16]([C:19](=[N:26]O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.N.[Ni]>[NH2:26][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]1[CH:15]=[CH:14][C:13]([CH:12]([NH2:28])[C:11]2[CH:30]=[CH:31][C:8]([CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH2:32])=[CH:9][CH:10]=2)=[CH:18][CH:17]=1
Reactant: ON=C(c1ccccc1)c1ccc(C(=NO)c2ccc(C(=NO)c3ccccc3)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NC(c1ccccc1)c1ccc(C(N)c2ccc(C(N)c3ccccc3)cc2)cc1

Procedure:
The trioxime from Step 2 (3 g) is dissolved in ethyl alcohol (250 ml) saturated with ammonia gas and Raney nickel W-6 (2 g) added. The mixture is subjected to 500 psi hydrogen pressure and heated to 90° for two hours. The catalyst is removed by filtration and 220 ml ethyl alcohol by distillation. A pale yellow crystalline material is filtered and dried.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:30][C@@H:31]1[C@H:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:34][C:33](=[O:42])[NH:32]1.[Cl-].[Li+]>C1COCC1>[CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:15])[CH2:10][CH2:11][C:12]([N:32]2[C@H:31]([CH3:30])[C@H:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:34][C:33]2=[O:42])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@@H](CCC(=O)O)CCC1CCCCC1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)CCC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask was charged with 4.17 g (19.6 mmol) of (R)-6-cyclohexyl-4-methyl-hexanoic acid, 40 mL of THF, and 8.56 mL (61.4 mmol) of triethylamine. The mixture was cooled in a 0° C. bath, and 2.41 mL (19.6 mmol) of pivaloyl chloride was added. The mixture was stirred for 1 h at 0° C. Then 2.79 g (16.4 mmol) of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and 0.823 g (19.6 mmol) of lithium chloride were added as solids. The mixture was allowed to warm to room temperature and stirred overnight. The resulting solids were filtered off. The solvent was stripped under reduce pressure, and the residue was purified by column chromatography (eluent: 4:1 hexanes/ethyl acetate) to give 6.09 g (quant.) of a clear oil: 1H NMR (400 MHz, CDCl3) δ ppm 0.89 (m, 8H) 1.16 (m, 6H) 1.68 (m, 9H) 2.87 (m, 1H) 2.99 (m, 1H) 4.76 (qd, J=6.83, 6.59 Hz, 1H) 5.66 (d, J=7.32 Hz, 1H) 7.30 (m, 2H) 7.40 (m, 3H). MS (APCI) m+1/z=372.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:22]([Cl:33])(=[O:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([Cl:29])=[O:28])=[CH:25][CH:24]=1.ClCCl.CN(C1C=CC=CN=1)C>C(N(CC)CC)C>[CH2:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:31]3[C:23]([C:22]([Cl:33])=[O:32])=[CH:24][CH:25]=[C:26]([C:27]([Cl:29])=[O:28])[CH:30]=3)=[CH:7][CH:6]=2)=[CH:13][CH:12]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCc1ccc(-c2ccc(O)cc2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(-c2ccc(-c3cc(C(=O)Cl)ccc3C(=O)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 4-hydroxy-4'-octylbiphenyl (0.5 g) and terephthaloyl chloride (0.36 g) in about dichloromethane (30 ml) was added drop by drop triethylamine (0.2 g). To the solution was added dimethylaminopyridine (0.013 g) and the mixture was stirred at the room temperature for 10 hours to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH:15]1([NH:18][C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:2]3[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]4[CH2:12][CH2:11]4)=[O:7])=[CH:4][N:3]=3)[CH:21]=2)=[O:36])[CH2:16][CH2:17]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1)(25.5 mg, 0.10 mmol) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8)(30 mg, 0.110 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetralkis(triphenylphosphine)palladium (4 mg) were heated at 90° C. in DMF (1 ml) for 3 hours. The reaction was absorbed onto silica, applied to a bond-elut (5 g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%) and then acetone. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to 6-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-N-cyclopropylmethyl-nicotinamide as a cream solid. LCMS: retention time 2.70 min, MH+ 350. NMR: δH [2H6]-DMSO 9.11,(1H, s), 8.84,(1H, t), 8.48,(1H, d), 8.31,(1H, dd), 7.88,(1H, s), 7.81,(1H, d), 7.70,(1H, d), 7.41,(1H, d), 3.20,(1H, t), 2.86,(1H, m), 2.37,(3H, s), 1.06,(1H, m), 0.69,(2H, m), 0.57,(2H, m), 0.46,(2H, m), 0.26, (2H, m).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1>>[CH3:13][C:12]1[C:7]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:32])([F:33])[F:23])[CH:26]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1cccc(C(F)(F)F)c1
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccc(C(F)(F)F)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [3-(trifluoromethyl)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.09 (s, 3H), 2.34 (s, 3H), 4.73 (d, J=5.6 Hz, 2H), 5.91 (bs, 1H), 6.47 (bs, 1H), 7.15 (t, J=8.2 Hz, 1H), 7.24-7.40 (m, 3H), 7.57-7.67 (m, 2H), 8.09 (s, 1H), 8.57 (d, J=2.4 Hz, 1H); MS (ESI) m/z 374.7 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH:3]=1.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>C1COCC1>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][NH:37][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:3]=2)=[CH:40][CH:41]=1
Reactant: NCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2cc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
To a solution of tert-butyl 4-((6-chloro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (210 mg, 0.52 mmol), and Hunig's Base (0.18 mL, 1.04 mmol) in THF (3 mL) was added 4-(aminomethyl)phenol (96 mg, 0.78 mmol). The resulting mixture was refluxed for 1 hour. After cooling to rt, the solvent was removed and the crude product was purified by silica gel chromatography using 20-40% EtOAc/Hexanes to give tert-butyl 4-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (117 mg, 46%) as white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][CH3:22]>O1CCOCC1>[Br:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:21]([CH2:20][C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[CH3:22])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: CNCc1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Product: CN(CC(=O)c1cccc(Br)c1)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 1 L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(3-bromophenyl)ethanone (55 g, 199.28 mmol, 1.00 equiv) in 1,4-dioxane (300 mL), TEA (40 g, 396.04 mmol, 1.99 equiv), and (2,4-dichlorophenyl)-N-methylmethanamine (38 g, 201.06 mmol, 1.01 equiv). The resulting solution was stirred for 2 h at 25° C. in an oil bath. The solids were filtered out and the filtrate was used without any further purification.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Br:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]3[N:26]4[CH2:27][CH2:28][CH2:29][N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:25]4=[N:24][C:18]=3[CH:19]=[N+:20]2[O-])=[CH:15][CH:14]=1.[OH-].[NH4+:39]>ClCCl.O>[NH2:39][C:19]1[C:18]2[N:24]=[C:25]3[N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:28][CH2:27][N:26]3[C:17]=2[C:16]2[C:21](=[CH:22][C:13]([Br:12])=[CH:14][CH:15]=2)[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1nc1c[n+]([O-])c3cc(Br)ccc3c12
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCn2c1nc1c(N)nc3cc(Br)ccc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
p-Toluenesulfonyl chloride (441 mg, 2.3 mmol) was added to a mixture of tert-butyl 3-bromo-5-oxido-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate (0.97 g, 2.3 mmol), dichloromethane (30 mL), and concentrated ammonium hydroxide (3 mL), and the reaction was stirred overnight at room temperature. Water and dichloromethane were added. The aqueous layer was separated and extracted four times with dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with a gradient of 2% ammonium hydroxide/methanol in dichloromethane), and the resulting product was recrystallized from 1,2-dichloroethane and hexanes to provide 0.16 g of tert-butyl 6-amino-3-bromo-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate.