Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]([F:20])=[C:18]2[C:13]([C:14]([CH3:21])=[CH:15][N:16]=[N:17]2)=[CH:12][C:11]=1[C:22](O)=[O:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[CH:47]([O:49][CH2:50][CH2:51][O:52][NH2:53])=[CH2:48]>CN(C=O)C.CCOC(C)=O>[CH:47]([O:49][CH2:50][CH2:51][O:52][NH:53][C:22]([C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([F:20])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[N:17]=[N:16][CH:15]=[C:14]2[CH3:21])=[O:23])=[CH2:48]
Reactant: C=COCCON
Reactant: Cc1cnnc2c(F)c(Nc3ccc(Cl)cc3Cl)c(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cc2c(C)cnnc2c(F)c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23.2 %

Procedure:
A mixture of 7-(2,4-dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid (31 mg, 0.086 mmol), EDCI (28 mg, 0.14 mmol), and HOBt-H2O (21 mg, 0.14 mmol) in DMF (1 mL) was stirred for 45 minutes at room temperature. O-(2-Vinyloxy-ethyl)-hydroxylamine (18 mg, 0.18 mmol) and TEA (0.030 mL, 0.21 mmol) were added. The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by Biotage (1.5 to 3% MeOH in CH2Cl2) to afford 9 mg (39%) of 7-(2,4-dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid (2-vinyloxy-ethoxy)-amide. A mixture of the vinyl ether (9 mg, 0.020 mmol) and 1 N aqueous HCl (0.040 mL, 0.040 mmol) in EtOH (3 mL) was stirred for 1 hour at room temperature. The pH of the reaction mixture was adjusted to 6 to 7 with 2 N aqueous NaOH. The reaction mixture was diluted with EtOAc, and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 7-(2,4-dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid (2-hydroxyethoxy)-amide (6 mg, 71%). MS APCI (+) m/z 425, 427 (M+, Cl pattern) detected; 1H NMR (400 MHz, CD3OD) δ 9.26 (s, 1H), 8.30 (s 1H), 7.48 (d, 1H), 7.22 (dd, 1H), 6.90 (dd, 1H), 4.08 (t, 2H), 3.99 (t, 2H), 2.80 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>ClCCCl.C(Cl)Cl>[C:42]([NH:46][C:7]1[CH:8]=[C:3]([CH:2]([F:10])[F:1])[CH:4]=[CH:5][N:6]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)N
Reactant: [O-][n+]1ccc(C(F)F)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1cc(C(F)F)ccn1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 64.9 %

Procedure:
A suspension of 4-difluoromethyl-pyridine-N-oxide (4.95 g, 34.1 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (20.7 g, 44.3 mmol), triethylamine (15.6 mL, 111 mmol), and anhydrous tert-butylamine (4.6 mL, 43 mmol) in DCE (100 mL, 0.33 M) was sealed in pressure tube and stirred at 100° C. for 3.5 hr. After cooling to rt, the mixture was diluted with CH2Cl2 and washed with sat. aq. NaHCO3. The organics were dried over MgSO4 and following concentration, the reaction residue was purified by flash column chromatography (100:0-80:20 heptanes/EtOAc) to afford N-tert-butyl-4-(difluoromethyl)pyridin-2-amine as a yellow liquid (4.43 g, 65%); 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=5.2 Hz, 1H), 6.65-6.28 (m, 3H), 4.62 (br s, 1H), 1.44 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[NH:16][CH:15]=[N:14][C:13]=3[C:12](=[O:18])[N:11]3[CH2:19][CH2:20][N:21]=[C:10]23)=[CH:4][CH:3]=1.O.[OH-].[Na+].[CH3:25]I>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[N:16]=[CH:15][N:14]([CH3:25])[C:13]=3[C:12](=[O:18])[N:11]3[CH2:19][CH2:20][N:21]=[C:10]23)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C1c2nc[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cnc2c1C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1
Reaction time: 48 h

Procedure:
4-[(4-Chlorophenyl)methyl]-6,7-dihydro-3H-imidazo-[1,2-a]purin-9(4H)-one (Procedure 3), 6.02 g. (0.02 mole), is dissolved with warming in a mixture of 100 ml. of water and 15 ml. of ethanol containing 1.0 g. (0.25 mole) of sodium hydroxide. Approximately 3 ml. (approximately a molar equivalent) of methyl iodide was added and the mixture was stirred for about 48 hrs. at room temperature. The precipitated solid was collected, air dried, and recrystallized from isopropanol, m.p. 182.5°-184.5°.
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][NH:5][C:6]2[N:7]([N:19]=[CH:20][C:21]=2[C:22]#[N:23])[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[CH3:2].[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([N:5]1[CH2:4][C:3]([CH2:1][CH3:2])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:7]2[N:19]=[CH:20][C:21]([C:22]#[N:23])=[C:6]12)=[O:27]
Reactant: CCC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2NC1
Reactant: O=C(Cl)CCl
Product: CCC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CCl)C1

Procedure:
The reactants were prepared as follows. Using the method of Example 2, 4,5-dihydro-6-ethyl-7 -[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile was reacted with chloroacetyl chloride to give 4-(chloroacetyl)-4,5-dihydro-6-ethyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, m.p. 150°-152° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[N:10][C:9]([C:12]([O:14]CC3CC3)=[O:13])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C1COCC1.[OH-].[Li+].Cl>CO>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[N:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(OCC1CC1)c1ccc(OCC2CC2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCC2CC2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.5 %

Procedure:
To a solution of cyclopropylmethyl 6-(cyclopropylmethoxy)pyridazine-3-carboxylate (0.48 g) in a mixed solvent of THF (5 mL) and methanol (5 mL) was added 1 M aqueous lithium hydroxide solution (5 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.40 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1.Cl.C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[NH:42])[NH2:36])=[CH:31][CH:30]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)S(=O)(=O)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1ccccc1

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-5-[N-(ethoxycarbonylmethyl)-benzenesulphonylamino]-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [NH2:1][C:2](=[N:30]O)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:29])[C:15]=3[NH:19][C:20](=[O:28])[CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[N:10]=2)[CH2:5][CH2:4]1.[C:32](N1C=CN=C1)(N1C=CN=C1)=[S:33].[O:44]1CCCC1>C(Cl)(Cl)Cl.CO>[Cl:29][C:14]1[C:15]([NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:6]1[CH2:7][CH2:8][CH:3]([C:2]3[NH:1][C:32](=[O:44])[S:33][N:30]=3)[CH2:4][CH2:5]1)[CH:18]=[CH:17]2
Reactant: NC(=NO)C1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCC(c4nsc(=O)[nH]4)CC3)ccc12
Reaction time: 1 h

Procedure:
To a stirred solution of N-[2-[4[amino(hydroxyimino)methyl]-1-piperidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide (Example 102(a)) (0.1 g) in tetrahydrofuran (2 mL) was added 1,1′-thiocarbonyldiimidazole (0.042 g). After stirring for 1 hour, silica (1 g) in chloroform:methanol (5:1) (12 mL) was added and the mixture was stirred for a further 12 hours. The solvent was removed under vacuum, the resulting solid was taken up in methanol (20 mL) and was purified by Varian NH2 cartridge (methanol (50 mL) and then acetic acid:methanol 10:90 as eluant) to afford the title product (0.041 g).
Reaction SMILES: C([O:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[S:14]1)[CH:10]=[O:11])C1C=CC=CC=1.C1CC=CCC=1>CCO.[Pd]>[CH:10]([N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[S:14]1)[OH:8])=[O:11]
Reactant: CCCNC(=O)CN1C(=O)C(CN(C=O)OCc2ccccc2)Sc2ccccc21
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CCCNC(=O)CN1C(=O)C(CN(O)C=O)Sc2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-N-propyl-acetamide (0.13 mmol) in 9 ml of EtOH is added Pd/C (10%) (65.6 mg) followed by 1,4-cyclohexadiene (1.29 mL). The reaction mixture is stirred at room temperature for 12 hours and the final product 2-{2-[(formyl-hydroxy-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-N-propyl-acetamide is obtained by preparative LC/MS using 1 to 99% ACN (in the absence of TFA) as gradient. MS: (ES+): 338.2 [M+1].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH-].[Na+].[CH3:17]OS(OC)(=O)=O>>[CH3:17][O:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cc(O)cc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(c(C(=O)O)c1)CCCC2
Reaction time: 24 h

Procedure:
A mixture of 0.02 mole of 3-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid, and 40 ml. of 2 N sodium hydroxide solution is treated with 0.04 mole of dimethylsulfate over a 5 minutes period, and the mixture is stirred for 24 hours. The mixture is washed with 3 × 50 ml. of ether and acidified with dilute hydrochloric acid. The precipitate is collected, washed with water, dried at room temperature and 100μ pressure and recrystallized from cyclohexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Cl.O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:24])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(C(=O)O)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)propionate (22.8 g, 68.6 mmol) in methanol (100 ml) was added 2N aqueous sodium hydride solution (69 ml, 0.137 mol) and the mixture was stirred at room temperature for 4 hrs. The reaction solution was acidified with 6N hydrochloric acid, water (300 ml) was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from a mixture of hexane and diethyl ether to give (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)propionic acid (14.8 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([CH:27]2[CH2:29][CH2:28]2)[CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([CH:27]2[CH2:29][CH2:28]2)[CH:3]=1
Reactant: CN1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C3CC3)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C4CC4)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.Cl.OC[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH2:27])=[NH:26])=[CH:20][CH:19]=1.[OH-].[Na+].[O:30](CCO)[CH3:31]>>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:26]=[C:25]([NH:24][C:21]3[CH:22]=[C:23]([CH2:31][OH:30])[CH:18]=[CH:19][CH:20]=3)[N:27]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: COCCO
Reactant: N=C(N)Nc1ccc(CO)cc1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(C)c(-c2ccnc(Nc3cccc(CO)c3)n2)s1
Yield: 70 %

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (10 mmol, 2.1 g) in 2-methoxylethanol was treated with N-(4-hydroxymethyl-phenyl)-guanidine hydrochloride (1.65 g) in the presence of NaOH (400 mg). The reaction mixture was allowed to reflux for 20 h. After concentration, the precipitates were filtered and washed with EtOAc/MeOH several times. Recrystallisation from MeOH/EtOAc afforded the title compound (2.17 g, 70%). 1H-NMR (300 MHz, d6-DMSO) δ3.00 (s, 3H, CH3), 3.02 (s, 3H, CH3), 4.86 (s, 2H, CH2), 7.30 (m, 1H, Ph-H), 7.44 (d, 1H, J=6.1 Hz, pyrimidinyl-H), 7.61 (m, 1H, Ph-H), 8.01 (m, 1H, Ph-H), 8.13 (s, 1H, Ph-H), 8.88 (d, 1H, J=6.1 Hz, pyrimidinyl-H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.C(OC([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH:27]1[C:39](O)=[O:40])=O)(C)(C)C.Cl.C(N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>ClCCl.O>[CH2:32]([N:29]1[CH2:30][CH2:31][NH:26][CH:27]([C:39]([N:14]([CH2:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]3[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=3[CH:5]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:40])[CH2:28]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1C(=O)O
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C1CN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (84 mg), 4-benzyl-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester (100 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (90 mg), and dimethyl aminopyridine (53 mg) in dichloromethane (8 ml) was stirred at room temperature overnight. After addition of water (8 ml) the reaction mixture was extracted with ethyl acetate (8 ml×3). The organic layers were combined, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (20% ethyl acetate in hexane) to give a resin: MS (m+1)=572.4.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[N:17][OH:18])[C:13]2=[O:16])=[CH:9][CH:8]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>O>[Si:24]([O:18][N:17]=[C:12]1[CH2:11][C:10]2[C:14](=[CH:15][C:7]([CH3:6])=[CH:8][CH:9]=2)[C:13]1=[O:16])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cc1ccc2c(c1)C(=O)C(=NO)C2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)C(=NO[Si](C)(C)C(C)(C)C)C2
Temperature: 95 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To N,N-dimethylformamide (50 ml) were added at room temperature the compound (4.36 g, 24.9 mmol) obtained in step A, imidazole (5.10 g, 74.7 mmol) and tert-butyldimethylsilyl chloride (5.60 g, 37.4 mmol), and the mixture was stirred at 95° C. for 2 hr. After cooling to room temperature, water was added to the reaction solution with stirring and the precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (6.00 g, yield 83%) as a pale-bistered solid.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([NH:32][C:33]([NH:35][C:36]3[N:37]([C:45]4[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=4)[N:38]=[C:39]([C:41]4([CH3:44])[CH2:43][CH2:42]4)[CH:40]=3)=[O:34])=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[ClH:1].[ClH:1].[CH3:44][C:41]1([C:39]2[CH:40]=[C:36]([NH:35][C:33]([NH:32][C:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]([O:21][CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)=[N:23][CH:24]=3)=[O:34])[N:37]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)[N:38]=2)[CH2:43][CH2:42]1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCNCC3)c3ccccc23)cc1
Reaction time: 8 h

Procedure:
Add HCl 4 M in dioxane (2.4 mL, 9.36 mmol) to 4-(4-{3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1.4 g, 2.34 mmol) in dichloromethane (20 mL) at room temperature and stir overnight. Evaporate the solvent under reduced pressure to give the title compound (1.3 g) as a white solid (quantitative). ES+ (m/z): 497.4 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:19])=[CH:7][C:8]([C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])=[CH:9][C:10]=2[I:11])[CH2:3][CH2:2]1.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C1COCC1>[CH:1]1([N:4]2[C:5]3[C:10]([I:11])=[CH:9][C:8]([C:12]4[C:13]([CH3:18])=[N:14][O:15][C:16]=4[CH3:17])=[CH:7][C:6]=3[NH:19][C:25]2=[O:26])[CH2:3][CH2:2]1
Reactant: Cc1noc(C)c1-c1cc(N)c(NC2CC2)c(I)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(I)c2c(c1)[nH]c(=O)n2C1CC1
Temperature: 120 °C

Procedure:
To a mixture of N1-cyclopropyl-4-(3,5-dimethylisoxazol-4-yl)-6-iodobenzene-1,2-diamine (170 mg, 0.46 mmol, 1 equiv.) in a pressure tube was added THF (5 mL) and CDI (223 mg, 1.38 mmol, 3 equiv.). The mixture was heated to 120° C. for 30 minutes in a microwave reactor. The reaction was concentrated in vacuo and purified by HPLC to provide 1-cyclopropyl-5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1H-benzo[d]imidazol-2(3H)-one LCMS (m/z+1) 396.3.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.ClCCl.[C:60]([O:64][C:65]([N:67]1[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][CH2:75][NH2:76])[CH2:69][CH2:68]1)=[O:66])([CH3:63])([CH3:62])[CH3:61]>C(N(CC)CC)C>[C:60]([O:64][C:65]([N:67]1[CH2:68][CH2:69][N:70]([CH2:73][CH2:74][CH2:75][NH:76][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:71][CH2:72]1)=[O:66])([CH3:63])([CH3:62])[CH3:61]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NCCCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
To a mixture of 0.105 g (0.23 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0988 g (0.26 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 1 mL of dichloromethane, 0.2 mL of triethylamine was added followed by 0.0199 g (0.13 mmole) of 4-(3-amino-propyl)-piperazine-1-carboxylic acid tert-butyl ester. After stirring 1.5 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-water (gradient, 5:95-0:100) to give 0.0609 g of 4-{3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (I-94).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10]
Reactant: COP(OC)OC
Reactant: Fc1cccc(CBr)c1
Product: COP(=O)(Cc1cccc(F)c1)OC

Procedure:
Following the procedure of Compound 11, 3-fluorobenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:9]=[C:10](C)[C:11]=1O)[C:5]([O:7][CH3:8])=O.Br[CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:27](OCC)(=O)[CH3:28]>CN(C=O)C>[CH2:8]([O:7][CH2:5][C:4]1[CH:3]=[CH:2][CH:11]=[CH:10][CH:9]=1)[C:15]1[CH:28]=[CH:27][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCBr
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3,5-dimethyl-4-hydroxybenzoate represented by Formula 146 (1.72 g, 9.52 mmol), 1-bromobutane (1.13 mL, 10.47 mmol), potassium carbonate (K2CO3, 1.45 g, 10.47 mmol) and potassium iodide (KI, 158 mg, 0.95 mmol) in DMF (20 mL) was agitated at 80° C. for 24 hours. After decreasing a temperature of the reaction mixture to room temperature, solids were removed through filtration (and washed with acetone) to obtain a filtrate. After adding ethyl acetate to the filtrate, the solution was consecutively washed with water and a 5N HCl solution. After separating an organic layer and drying the same with magnesium sulfate (MgSO4), the solvent was removed under reduced pressure to prepare a concentrate mixture. This mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane, 1:5, v/v) using silica gel (SiO2), resulting in a benzylether compound represented by Formula 147 as a desired product (2.1 g, 93%). Analysis data of the product is provided as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:14])[C:11]=1[O:12][CH3:13])[CH2:5][N:6]=[C:7]=[S:8].[CH:15]([NH:17][NH2:18])=[O:16]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:14])[C:11]=1[O:12][CH3:13])[CH2:5][NH:6][C:7](=[S:8])[NH:18][NH:17][CH:15]=[O:16]
Reactant: NNC=O
Reactant: COc1c(F)cc(CN=C=S)cc1F
Solvent: CCO
Product: COc1c(F)cc(CNC(=S)NNC=O)cc1F
Yield: 104 %

Procedure:
3,5-Difluoro-4-methoxybenzyl isothiocyanate (11.7 g, 25.5 mmole) and formyl hydrazine (1.7 g, 28.7 mole) were refluxed in ethanol (30 ml) for one hour. The reaction was evaporated to dryness, triturated with hexane:ethyl acetate (1:1), filtered, and recrystallized from ethanol-hexane to yield 7.3 g (62%) of crude 4-(3',5'-difluoro-4'-methoxybenzyl)-1-formyl-3-thiosemicarbazide.