Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:28].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:8]1=[O:28]
Reactant: COc1ccc(CC2(CCOS(C)(=O)=O)CCN(Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Product: CCOCCn1c(N2CCCN(CCC3(Cc4ccc(OC)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(4-methoxyphenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][C:10]2[N:11]([CH3:21])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[N:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.[Cu]I>[N:22]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][C:10]3[N:11]([CH3:21])[CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: Cn1cc(-c2ccccc2)nc1C=Cc1cccc(Br)n1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2)nc1C=Cc1cccc(-n2ccnc2)n1
Yield: 58 %

Procedure:
2-Bromo-6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)pyridine (102 mg, 0.3 mmol), imidazole (41 mg, 0.6 mmol), CuI (6 mg, 0.03 mmol), and K2CO3 (124 mg, 0.9 mmol) were mixed in dimethylformamide (2 mL). The resulting solution was heated for 5 h in a microwave reactor held at a constant temperature of 160° C. The crude product was purified using reverse phase column chromatography to give 2-(1H-imidazol-1-yl)-6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-vinyl)pyridine (57 mg). MS (ESI): m/z 328 [M+H]+.
Reaction SMILES: Br.[C:2]1(C2(C3C=CC=CC=3)NC([NH:13][NH2:14])=NC2)C=CC=C[CH:3]=1.[C:21]1([C:27]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:31][NH:30][C:29](=[S:32])[NH:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([Br:41])C>C(O)C>[BrH:41].[C:33]1([C:27]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:28][C:29]([S:32][CH2:2][CH3:3])=[N:30][CH2:31]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1.[NH2:13][NH2:14]
Reactant: S=C1NCC(c2ccccc2)(c2ccccc2)N1
Reactant: CCBr
Reactant: NNC1=NCC(c2ccccc2)(c2ccccc2)N1
Agent: Br
Solvent: CCO
Product: CCSC1=NCC(c2ccccc2)(c2ccccc2)N1
Product: NN

Procedure:
The starting material, 5,5-diphenyl-2-imidazolin-2-ylhydrazine hydrobromide, is prepared as follows: 4,4-diphenylimidazolin-2-thione, prepared by the method of Marshall, J. Am. Chem. Soc. 78 3696 (1956), is treated with ethyl bromide in refluxing ethanol to yield 5,5-diphenyl-2-ethylthio-2-imidazoline hydrobromide, which upon treatment with hydrazine in refluxing ethanol gives the desired intermediate, melting point 227°-⟦8°⟧228° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2Cl)[C:16]([OH:21])=[N:15][CH:14]=[CH:13]3)[CH2:5][CH2:4]1.C(N(CC)CC)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH2:2][C@@H:3]1[CH2:4][CH2:5][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:21])[NH:15][CH:14]=[CH:13]3)[CH2:7][CH2:8]1
Reactant: N[C@H]1CC[C@@H](Oc2cc3ccnc(O)c3cc2Cl)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: N[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Temperature: 25 °C

Procedure:
150 mg (0.46 mmol) of 6-cis-(4-amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one hydrochloride (10) were dissolved in 10 ml of methanol. After addition of molecular sieves 4 A, 92.3 mg (0.57 mmol) of triethyl amine, 273.8 mg (4.56 mmol) of acetic acid and 0.57 mmol of the corresponding aldehyde, a solution of 86.0 mg (1.37 mmol) of sodium cyanoboro hydride is added dropwise and the mixture is stirred at room temperature until complete conversion is achieved. In some cases it was necessary to heat the mixture to 70° C. to achieve complete conversion. For the isolation of the products the solution was filtered and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, washed with 1 N NaOH and sat. sodium chloride solution, dried with magnesium sulfate and evaporated. The mono- or bis alkylated products, if obtained, were purified by preparative HPLC or precipitated from methanolic HCl
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]3[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=3)[CH:9]=2)=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(F)c(Cl)c2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (57.3 mg, 0.209 mmol) in CH2Cl2 (2 mL) was added 3-chloro-4-fluorophenyl isocyanate (0.30 μL, 0.241 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 135 as a colorless solid (66.2 mg, 71%). LCMS m/z (%)=446 (M+H35Cl, 100), 448 (M+H37Cl, 35), 1H NMR (400 MHz, DMSO-d6) δ: 8.87 (bs, 1H), 8.69 (bs, 1H), 7.81-7.77 (m, 1H), 7.47-7.42 (m, 2H), 7.37 (d, J=2.71 Hz, 1H), 7.35-7.26 (m, 2H), 7.09 (d, J=8.98 Hz, 1H), 6.24 (d, J=1.83 Hz, 1H), 3.98 (t, J=6.36 Hz, 2H), 3.65 (s, 3H), 2.19 (t, J=7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[C:25](O)=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:25]([C@@H:23]3[CH2:24][C@H:22]3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:26])[CH2:12][CH2:11]2)=[N:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1cnc(NCC2CCNCC2)nc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1cnc(NCC2CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1

Procedure:
A solution of 5-methyl-N-(piperidin-4-ylmethyl)pyrimidin-2-amine (5.00 g, 0.024 mol), (1R,2R)-2-phenylcyclopropanecarboxylic acid (T. Riley et al., J. Med. Chem., (1972), 15, 1187) (3.93 g, 0.024 mol), EDC (6.97 g, 0.036 mol) and HOBt (4.91 g, 0.036 mol) in DMF (50 mL) was stirred at RT for 2 h. The reaction mixture was diluted with ethyl acetate (400 mL), washed with aqueous saturated NaHCO3 (100 mL), water (5×100 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel 60 (400 g), eluting with 50–100% ethyl acetate in hexane to give 5-methyl-2-{[(1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methyl]amino}pyrimidine. M.S. (M+1): 351.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C([O-])([O-])=O.[Na+].[Na+].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32](C3CC(=O)N(O)C3=O)=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>O1CCOCC1.C(Cl)Cl>[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32](=[O:33])[NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([Br:2])[CH:4]=3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Reactant: NCc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NCc1cccc(Br)c1)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To 3-bromobenzylamine hydrochloride (16.0 g, 71.9 mmol) was added aqueous 9% Na2CO3 (211 mL) followed by 9-fluorenylmethyloxycarbonyl-N-hydroxysuccinimide (25.5 g, 75.5 mmol) in dioxane (211 mL). This was stirred 30 minutes, then diluted with CH2Cl2 (200 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with 1 M HCl, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was purified by recrystallization (ethyl acetate/hexanes) to obtain a fluffy, white solid (24 g, 59 mmol, 82%). 1H NMR (400 MHz, d6-DMSO): δ 7.90 (t, 1H, J=6.2 Hz), 7.88 (d, 2H, J=7.5 Hz), 7.68 (d, 2H, J=7.5 Hz), 7.43 (m, 4H), 7.32 (dd, 2H, J=7.5 Hz, 7.5 Hz), 7.26 (d, 1H, J=7.7 Hz), 7.20 (d, 1H, J=7.3 Hz), 4.35 (d, 2H, J=6.6 Hz), 4.22 (t, 1H, J=6.6 Hz), 4.17 (d, 2H, J=6.2 Hz). ESI/MS: 408 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:22]([OH:27])[C:23]([F:26])([F:24])[F:25])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:28][CH:29]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Reactant: NC1Cc2ccccc2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)NC2Cc3ccccc3C2)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Temperature: 110 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
To a solution of 2,2,2-trichloroethyl 5-tert-butyl-2-methoxy-3-(2,2,2-trifluoro-1-hydroxyethyl)phenylcarbamate (0.150 g, 0.331 mmol) and 2-aminoindane (0.053 g, 0.398 mmol) in acetonitrile (1.0 mL), N,N-diisopropylethylamine (0.173 mL, 0.994 mmol) was added, and the mixture was stirred at 110° C. for 18 hours. The reaction mixture was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-60/40) to obtain 0.133 g of the captioned compound (92% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH:2]=1.[CH3:15][O:16][C:17]1[N:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[CH3:15][O:16][C:17]1[N:22]=[C:21]([C:23]([NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:9]=2)=[O:24])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C(=O)O)n1
Reactant: Nc1cccc(Oc2cccnc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)Nc2cccc(Oc3cccnc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
Compound 5 (25 mg, 0.13 mmol, 1.0 eq), 6-methoxypicolinic acid (23 mg, 0.15 mmol, 1.1 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (56 mg, 0.15 mmol, 1.1 eq) and DIEA (25.7 μL, 0.148 mmol, 1.10 eq) were dissolved in CH2Cl2 (1.5 mL) and stirred at rt overnight. Water was added and the layers separated. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 39 mg (90%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.41 (d, J=2.5 Hz, 1H), 8.38 (dd, J=4.4, 1.5 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.70-7.69 (m, 2H), 7.65 (d, J=8.6 Hz, 1H), 7.48 (ddd, J=8.4, 2.7, 1.6 Hz, 1H), 7.45-7.39 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.84 (dd, J=8.1, 1.9 Hz, 1H), 4.04 (s, 3H); ES-MS [M+1]+: 322.2.
Reaction SMILES: [OH-].[K+].[C:3]([CH:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7]1)(=[O:5])[CH3:4].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[CH2:40](Cl)[C:41](=[CH2:43])[CH3:42]>O.C1(C)C=CC=CC=1>[CH3:12][C:8]1([CH3:13])[CH2:9][CH2:10][CH2:11][CH2:6][CH2:7]1.[C:3]([C:6]1([CH2:42][C:41]([CH3:43])=[CH2:40])[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7]1)(=[O:5])[CH3:4]
Reactant: C=C(C)CCl
Reactant: CC(=O)C1CCCC(C)(C)C1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)CC1(C(C)=O)CCCC(C)(C)C1
Product: CC1(C)CCCCC1
Temperature: 70 °C

Procedure:
A slurry of potassium hydroxide (84 grams, 1.5 moles), 1-acetyl-3,3-dimethylcyclohexane (156 grams, 1 mole), dibenzo-18-crown-6 (3 grams) having the structure: ##STR24## produced by the Aldrich Chemical Company of Metuchen, New Jersey, and toluene (150 ml) is heated to reflux whereupon the reaction mass thickens. The mass is cooled to 70° C., and methallyl chloride (135 grams, 1.5 moles) is added thereto rendering the reaction mixture more fluid. The reaction mixture is heated at reflux for an additional 9 hours whereupon the mass is cooled, and water is added. The aqueous layer is decanted, and the organic layer is distilled to afford 3,3-dimethylcyclohexane (62 gm) and 1-acetyl-3,3-dimethyl-1-(2-methyl-2-propenyl) cyclohexane (83 gm) (NMR spectrum, FIG. 1; IR spectrum, FIG. 2).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:17]=[CH:16][N:15]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH2:27]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:17]=[CH:16][N:15]=[C:14]([NH:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH:7]=2)[CH:19]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Clc1cc(-c2ccccc2OCc2ccccc2)ncn1
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(Nc2cc(-c3ccccc3OCc3ccccc3)ncn2)c1
Temperature: 80 °C

Procedure:
A mixture of 3-methanesulfonyl-phenylamine hydrochloride (4.98 g, 24 mmol) and 4-chloro-6-(2-benzyloxyphenyl)-pyrimidine (6.88 g, 23.2 mmol) in DMFA (50 mL) was stirred at 80° C. till the reaction completion (TLC control). The reaction mixture was diluted with water (200 mL), treated with NaHCO3 (4.2 g, 50 mmol). The resulting precipitate was filtered out, washed with water (2×200 mL), dried and purified by column chromatography on silica (eluent chloroform-ethanol 20:1) to yield [6-(2-benzyloxy-phenyl)-pyrimidin-4-yl]-(3-methanesulfonyl-phenyl)-amine as colorless solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1COCC1.Br[CH2:28][C:29]#[N:30]>O>[C:29]([CH2:28][N:12]([C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9][CH:10]=1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])#[N:30]
Reactant: CC(C)(C)OC(=O)Nc1ccnn1-c1ccccc1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC#N)c1ccnn1-c1ccccc1
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a mixture of tert-butyl (1-phenyl-1H-pyrazol-5-yl)carbamate (3.80 g), 60% NaH (0.422 g) and THF (60.0 mL) was added bromoacetonitrile (1.93 g) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added water, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.38 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH2:6][CH2:7][CH3:8].[N+]([O-])(O)=O.S(=O)(=O)(O)O>S(=O)(=O)(O)O>[N+:1]([C:12]1[CH:11]=[C:10]([C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH:15]=[CH:14][CH:13]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCCC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CCCC(=O)c1cccc([N+](=O)[O-])c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
Concentrated nitric acid (40 ml) was added cautiously with cooling to concentrated sulphuric acid (100 ml) maintaining a temperature of −5° C. Another solution of butyrophenone (59.2 g, 0.47 mol) in concentrated sulphuric acid (140 ml) was made up with shaking, keeping the temperature at −5° C. (+/−5° C.). The former nitric acid/sulphuric acid solution was added portionwise over 45 min to the latter solution of ketone in sulphuric acid keeping the temperature at −10° C.(+/−5° C. during the addition and for a subsequent 30 min. The reaction mixture was poured onto crushed ice (1.5 l) and then extracted with diethyl ether (200 ml and then 3×100 ml). The combined organic extracts were washed with water and then aqueous saturated sodium hydrogen carbonate solution and dried (MgSO4) before concentrating in vacuo. The crude yellow oil crystallised after 16 h and was then purified by chromatography on silica gel (1 kg) eluting with hexane:diethyl ether (9:1) to give the title compound as a white solid (9.1 g, 10%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:25]N1C(C)(C)C(=O)N(Br)C1=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:25])[CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc3c(N)ncnn23)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2cc(Br)c3c(N)ncnn23)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 144.2 %

Procedure:
To a cooled (−20° C.) solution tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxypiperidine-1-carboxylate (1.00 g, 3.00 mmol) in THF (16 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (429 mg, 1.50 mmol) in 3 portions over 10 min. The mixture was allowed warm to 0° C. and stirred for 2 h. The mixture was then stirred at rt for 64 h. Saturated, aqueous Na2SO3 (50 mL) was added and the mixture was warmed to rt. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The crude mixture was purified via ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 892 mg (72%) of the desired product. ES-MS m/z 412.26 [M+H]+, HPLC RT (min) 2.62.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[NH2:10][CH2:11][C:12]([OH:14])=[O:13]>[OH-].[Na+]>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)OCC(Cl)(Cl)Cl
Temperature: 0 °C

Procedure:
2,2,2-Trichloroethyl chloroformate (23,30 g, 0.11 mole) and 4N NaOH (30 ml, 0.12 mole) are added alternately in about 5 equal portions over a period of 30 minutes to an ice-cold, vigorously stirring solution of glycine (7.51 g, 0.1 mole) in 4N NaOH (25 ml). Upon completion of the reaction, the solution is extracted with ether, and the aqueous portion is slurried with EtOAc and acidified in the cold to pH 2.5 with 6N HCl. The EtOAc solution is separated, washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo to give N-(2,2,2-trichloroethyloxycarbonyl)-glycine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=O)[CH:6]=[CH:5]2.C([C:16](CC)(P(=O)([O-])[O-])[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)C.CC(C)([O-])C.[K+]>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:12]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=3)[CH:8]=2)[CH:3]=1
Reactant: CCC(CC)(c1ccc(Br)cc1)P(=O)([O-])[O-]
Reactant: O=Cc1ccc2cc(Br)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Brc1ccc(/C=C/c2ccc3cc(Br)ccc3c2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
6-bromo-2-naphthaldehyde (4.0 g, 17.1 mmol) and diethyl-4-bromobenzylphosphonate (6.3 g, 20.5 mmol) were dissolved in purified dimethylsulfoxide (100 mL) under a nitrogen atmosphere, the reaction solution was cooled down to 0° C., and then potassium t-butoxide (2.5 g, 20.5 mmol) was slowly added thereto. The reaction mixture solution was stirred at room temperature for 12 hours. The reaction mixture solution was subjected to extraction with water and dichloromethane to thereby remove the solvent. The extracted material was sufficiently washed with methanol, and was dried in vacuum to thereby obtain a white solid (6.0 g, yield: 91%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CN1C(=O)CCC1>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:31]3[CH:36]=[C:35]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[N:34]=[CH:33][N:32]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Clc1cc(Cl)ncn1
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(CNc2cc(N3CCCCC3)ncn2)cn(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a stirred solution of 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (30 mg, 0.105 mmol) and N,N-diisopropylethylamine (40.9 mg, 55.2 μL, 0.316 mmol) in NMP (500 μL) was added 4,6-dichloropyrimidine (15.7 mg, 0.105 mmol). The mixture was warmed to 120° C. in a sealed microwave tube. After 1.5 hr, piperidine (35.9 mg, 41.7 μL, 0.421 mmol) was added and heating at 120° C. continued for 9 hr. The reaction mixture was cooled to room temperature. The crude product was purified by preparative reverse-phase HPLC, giving 7-chloro-1-phenyl-3-[(6-piperidin-1-yl-pyrimidin-4-ylamino)-methyl]-1H-quinolin-4-one (25 mg, 53%) as an off-white solid. MS calcd. for C25H24ClN5O [(M+H)+] 446, obsd. 446.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[Cl:25][C:26]1[N:30]([CH3:31])[N:29]=[CH:28][C:27]=1[C@H:32]([NH2:34])[CH3:33].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:25][C:26]1[N:30]([CH3:31])[N:29]=[CH:28][C:27]=1[C@H:32]([NH:34][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:11]=1)=[O:22])[CH3:33]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Reactant: C[C@@H](N)c1cnn(C)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnn(C)c3Cl)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (30 mg, 0.097 mmol), (R)-1-(5-chloro-1-methyl-1H-pyrazol-4-yl)ethanamine hydrochloride (24 mg, 0.12 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (92 mg, 0.24 mmol), N,N-diisopropylethylamine (0.068 mL, 0.39 mmol), and N,N-dimethylformamide (1.0 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to get the product as a light yellow solid.