Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.Cl[CH2:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([CH2:69][CH3:70])=[CH:65][CH:64]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C(O)(=O)C(O)=O>C(O)CCC>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:69]([C:66]1[CH:67]=[CH:68][C:63]([O:62][CH2:61][CH2:60][CH2:59][N:48]2[CH2:47][CH2:46][CH:45]([C:43]([C:51]3[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=3)([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)[OH:44])[CH2:50][CH2:49]2)=[CH:64][CH:65]=1)[CH3:70]
Reactant: CCc1ccc(OCCCCl)cc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: CCc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 54 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [α,α-bis(4-fluorophenyl)]-4-piperidinemethanol, 2.0 g (0.01 mole) of 1-chloro-3-(4-ethylphenoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a solid as residue. This solid was converted to the oxalic acid salt and the salt was recrystallized from 2-propanol to yield 3.0 g (54%) of the title compound as a white solid, mp 132°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si](C(C)C)(C(C)C)C(C)C)=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2([OH:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2([OH:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:41][CH:42]=1
Reactant: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2(O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A mixture of 14 (27 mg, 0.046 mmol) in THF (0.46 mL) and tetrabutyl ammonium fluoride (50 μL, 0.050 mmol) was stirred at room temperature under a N2 atmosphere for 2 hours when reaction was complete as demonstrated by LCMS analysis. The organic solvent was removed in vacuo and the residue was suspended in EtOAc. The organic layer was washed with water and dried. The solid was washed with hexane and dried to provide 15 mg (76%) of the product 15 as a light orange solid. 1H NMR (300 MHz, CD3OD) δ 3.54 (s, 3H), 4.36 (d, 1H, J=15 Hz), 4.48 (d, 1H, J=15 Hz), 6.84 (t, 2H, J=9 Hz), 7.17-7.23 (m, 2H), 7.24-7.26 (m, 3H), 7.35-7.46 (m, 2H), 7.62 (dd, 1H, J=4, 9 Hz), 8.44 (d, 1H, J=9 Hz), 8.89 (d, 1H, J=3 Hz); 19F NMR (282.6 MHz, CDCl3) δ 58.5; EI MS (m/z) 431.2 [MH+], 453.2 [M+Na].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH:40]([CH3:42])[CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]5[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:39][CH:40]([CH3:42])[CH3:41])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CC(C)Oc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)Oc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 71.1 %

Procedure:
A mixture of 0.10 g (0.32 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.11 g (0.38 mmole) of 4-amino-3-isopropoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.090 g (0.48 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight, then cooled and diluted with dichloromethane and saturated sodium carbonate. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 0.13 g 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-isopropoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-180) as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Br:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][C:46]=1[O:52][CH3:53]>>[Br:44][C:45]1[C:46]([O:52][CH3:53])=[CH:47][C:48]([OH:51])=[C:49]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])[CH:50]=1
Reactant: COc1cc(O)ccc1Br
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(Br)c(OC)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-bromo-3-methoxyphenol, the title compound was obtained (48%): 1H NMR (300 MHz, CDCl3) δ 9.85 (s, 1H), 7.52-7.38 (m, 2H), 7.22 (td, 1H), 6.94 (d, 1H), 6.89 (s, 1H), 6.63 (s, 1H), 4.13-4.03 (br, 1H), 3.86 (s, 3H), 3.80-3.57 (m, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 402 (M−17), 404 (M−17), 442 (M+23), 444 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 89.1 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate (27 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 34 mg of the titled compound (yield, 83%). 1H NMR (300 MHz, CDCl3): δ 3.28-3.31 (m, 4H), 3.75-3.78 (m, 4H), 4.15 (s, 4H), 6.90-6.97 (m, 3H), 7.24-7.42 (m, 5H), 7.80 (dd, J=9.0 and 6.0 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)SC=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][S:29]([NH:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:31])=[O:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[O:21][C:19]([C:37]5[CH:38]=[C:33]([NH:32][S:29]([CH3:28])(=[O:30])=[O:31])[CH:34]=[CH:35][CH:36]=5)=[CH:17][C:18]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CS(=O)(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3o2)c1

Procedure:
2-Chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine 45 from Example 27 was reacted with 3-(methylsulfonylamino)phenylboronic acid via General Procedure A to give the corresponding intermediate, after purification by flash chromatography, which was then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to give, after purification by reverse phase HPLC, 327. MS (Q1) 491 (M+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:24]3[C:11]([CH2:12][C:13]4[C:21]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[N:15]([CH3:22])[C:14]=4[CH2:23]3)=[C:10]([C:25](OC)=[O:26])[C:9]=2[C:29](OC)=[O:30])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:24]3[C:11]([CH2:12][C:13]4[C:21]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[N:15]([CH3:22])[C:14]=4[CH2:23]3)=[C:10]([CH2:25][OH:26])[C:9]=2[CH2:29][OH:30])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(Cl)cc2)n2c1Cc1c(n(C)c3ccccc13)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c2c(c3ccccc31)Cc1c(CO)c(CO)c(-c3ccc(Cl)cc3)n1C2
Reaction time: 0.25 h

Procedure:
A solution of dimethyl 3-(4-chlorophenyl)-6-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate (3.2 g, 7 mmol) in anhydrous dichloromethane (35 mL) was added dropwise into a stirred suspension of LiAlH4 (0.6 g, 17.8 mmol) in anhydrous diethyl ether (20 mL) at 0 to −5° C. The reaction mixture was further stirred for 15 min after the addition was completed. The excess hydride was destroyed by the sequential addition of water (1 mL), 15% aqueous NaOH (1 mL), and water (1 mL) at 0° C. The mixture was filtered through a pad of Celite and the solid was washed with dichloromethane. The combined filtrate and washings were evaporated to dryness in vacuo. The residue was triturated with ether to give (3-(4-chlorophenyl)-6-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-diyl)-dimethanol (BO-1934), 2.2 g (77%); mp 238-239° C. 1H NMR (DMSO-d6) δ 3.62 (3H, s, Me), 4.10 (2H, s, CH2), 4.29 (2H, m, CH2), 4.55 (2H, s, CH2) 4.59 (2H, brs, exchangeable, 2×OH), 5.16 (2H, s, CH2), 7.04-7.08 (1H, m, ArH), 7.14-7.18 (1H, m, ArH), 7.43-7.45 (1H, m, ArH), 7.53-7.59 (5H, m, 5×ArH). Anal. Calcd for (C23H21ClN2O2.0.5H2O): C, 68.74; H, 5.52; N, 6.97. Found: C, 68.72; H, 5.16; N, 6.94.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][NH:13]2.[C:25](O)(=[O:27])[CH3:26].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(OCC)(=O)C.C1(C)C=CC=CC=1.CN(C)C=O>[C:25]([N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([O:18][C:17]2[C:9]([CH3:8])=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[CH2:20]1)(=[O:27])[CH3:26]
Reactant: Cc1c(OC2CCCNC2)ccc2[nH]ncc12
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC(Oc2ccc3[nH]ncc3c2C)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.8 %

Procedure:
Triethylamine (0.14 ml, 1.0 mmol) was added to a mixture of the 4-methyl-5-(piperidin-3-yloxy)-1H-indazole (92 mg, 0.40 mmol) obtained in Example 422, acetic acid (24 mg, 0.40 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (77 mg, 0.40 mmol), 1-hydroxybenzo-triazole (54 mg, 0.40 mmol) and N,N-dimethylformamide (1.5 ml), and the resulting mixture was stirred at room temperature for 19 hours. The mixture was diluted with a mixed solution of ethyl acetate (10 ml)/toluene (10 ml) and washed with water and then a saturated aqueous sodium hydrogencarbonate solution. The mixture washed was dried over potassium carbonate and then concentrated to dryness to obtain 5-[(1-acetylpiperidin-3-yl)oxy]-4-methyl-1H-indazole (84 mg, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[CH:29][C:28]([C:32](O)=[O:33])=[N:27]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:32]([C:28]5[CH:29]=[C:30]([CH3:31])[N:26]([CH3:25])[N:27]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)O)nn1C
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)nn1C
Temperature: 60 °C
Reaction time: 36 h
Yield: 26.3 %

Procedure:
To a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) in N,N-dimethylformamide (4.0 mL) were added 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (171 mg, 1.22 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (351 mg, 1.83 mmol), 1-hydroxybenzotriazole (248 mg, 1.83 mmol) and triethylamine (256 μL, 1.83 mmol), and the mixture was stirred at 60° C. for 36 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) to give the title compound (72 mg, 26%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([O:33]CC)=O)[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:37][NH2:38]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:38][CH3:37])=[O:33])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Solvent: CCO
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-methylamine in ethanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (d, J=4.42 Hz, 4 H), 1.61-1.77 (m, 4 H), 2.35-2.44 (m, 2 H), 2.91 (d, J=4.84 Hz, 3 H), 3.34-3.42 (m, 4 H), 4.14-4.23 (m, 4 H), 7.14 (t, J=8.95 Hz, 2 H), 7.40 (dd, J=8.84, 5.48 Hz, 2 H), 7.99 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.14 (d, J=4.63 Hz, 1 H), 17.22 (s, 1 H); ES+ MS: 481 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:19]=1[C:20]#[N:21]>>[CH3:27][O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:18]([NH:17][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[C:19]=1[C:20]#[N:21]
Reactant: COc1cccc(N)c1C#N
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: COc1cccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c1C#N
Yield: 87 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 113 using Compound 83 (100 mg, 0.43 mmol) and 2-amino-6-methoxy-benzonitrile (77 mg, 0.52 mmol) to provide 157 (128 mg, 86% yield) as a yellow solid. LC-MS (M+H=343, obsd.=343).
Reaction SMILES: FC1C=CC(CNC)=CC=1.[CH3:11][NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[F:21][C:22]1[CH:44]=[CH:43][C:25]([CH2:26][NH:27][C:28]([C:30]2[S:34][C:33]([C:35]3[CH:40]=[N:39][CH:38]=[C:37](I)[N:36]=3)=[N:32][C:31]=2[CH3:42])=[O:29])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:44]=[CH:43][C:25]([CH2:26][NH:27][C:28]([C:30]2[S:34][C:33]([C:35]3[CH:40]=[N:39][CH:38]=[C:37]([N:12]([CH3:11])[CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[N:36]=3)=[N:32][C:31]=2[CH3:42])=[O:29])=[CH:24][CH:23]=1
Reactant: CNCCc1ccccn1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Agent: CNCc1ccc(F)cc1
Product: Cc1nc(-c2cncc(N(C)CCc3ccccn3)n2)sc1C(=O)NCc1ccc(F)cc1
Yield: 75 %

Procedure:
Following the procedure described in Example 14, making variations as required to replace 4-fluoro-N-methyl-benzylamine with methyl-(2-pyridin-2-yl-ethyl)-amine to react with 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro benzylamide, the title compound was obtained in 75% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.40-8.52 (m, 2H), 8.03 (s, 1H), 7.36-7.43 (m, 3H), 7.11-7.35 (m, 3H), 7.00-7.10 (m, 2H), 4.55 (d, J=4.0 Hz, 2H), 4.00-4.15 (m, 2H), 3.15-3.40 (m, 2H), 3.12 (bs, 3H), 2.70 (s, 3H); MS (ES+) m/z 463.1 (M+1), Rt=1.39 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:19]2=[CH:20][CH:21]=[N:22][CH:23]=[C:18]2[C:5]2[C:6]([OH:17])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:17][C:6]1[C:5]2[C:18]3[C:19]([C:2]([CH3:1])([CH3:24])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:11])[CH:7]=1)=[CH:20][CH:21]=[N:22][CH:23]=3)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Solvent: c1ccncc1
Product: CCCCCC(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-(2-heptyl)-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-(2-heptyl)-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:12])[C:9]=1[CH:10]=[O:11])[NH:5][CH3:6].[BH4-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:12])[C:9]=1[CH2:10][OH:11])[NH:5][CH3:6]
Reactant: CNc1cc(Cl)c(C=O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(Cl)c(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
To a solution of 3,5-dichloro-4-formyl-N-methylaniline (242 mg) in methanol (3 ml) and tetrahydrofuran (3 ml) was added sodium borohydride (45 mg) and the mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was quenched with aqueous saturated ammonium chloride solution and ethyl acetate was added thereto. The separated organic layer was washed with aqueous saturated ammonium chloride solution, dried and concentrated in vacuo to give 3,5-dichloro-4-hydroxymethyl-N-methylaniline (246 mg).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])[CH3:3].[CH3:18][C:19]([O:22][C:23]([NH:25]/[C:26](/N1N=CC=C1)=[N:27]/[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:31]([O:30][C:28]([N:27]=[C:26]([NH:25][C:23]([O:22][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:24])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:15]([OH:17])=[O:16])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Reactant: CC(C)(C)OC(=O)NC(CCCCN)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 111 %

Procedure:
A solution of N-α-Boc-L-lysine 18 (5.00 g, 20.3 mmol) in CH2Cl2 (100 mL) was charged with N,N′-bis-Boc-1-guanylpyrazole (5.10 g, 16.6 mmol) and triethylamine (5.54 mL, 40.6 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was washed with 10% aqueous citric acid (2×80 mL) and the solvent was removed under reduced pressure. The residue was dissolved in 1 N NaOH (200 mL), the pH of solution was adjusted to 5-6 with 1 N HCl, and the mixture was extracted with CH2Cl2 (300 ml). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (2×200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford compound 10 (9.00 g, 91%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 4.10-4.02 (m, 1H), 3.36 (t, J=6.8 Hz, 2H), 1.90-1.78 (m, 1H), 1.73-1.56 (m, 3H), 1.52 (s, 9H), 1.45-1.31 (m, 2H), 1.47 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:21])=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1.[C:23](Cl)(=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>ClCCl>[CH2:39]([C:40]1[N:13]([CH2:12][CH2:11][CH2:10][N:9]([CH3:8])[CH3:22])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[N:21]=1)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Cc1ccc(NCCCN(C)C)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 31.3 %

Procedure:
Triethylamine (0.557 g) was added to a solution containing N1-[3-(dimethylamino)propyl]4-methyl-1,2-benzenediamine (1.037 g) in dichloromethane (5 ml), and then a solution containing stearoyl chloride (1.515 g) in dichloromethane (5 mnl) was added thereto while being cooled with ice. After being stirred for 4.5 hours at room temperature, the reaction mixture was diluted with dichloromethane, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (3.5 ml) was added to a solution containing the residue (1.97 g) in ethanol (20 ml). After being stiffed for 5.5 hours at 90° C., the reaction mixture was concentrated. The residue, with chloroform added thereto, was washed with 0.5N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (1.03 g) was purified by silica gel column chromatography (silica gel 30 g, chloroform:methanol=50:1-1:1), thereby yielding the entitled compound (0.714 g) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:25])([F:24])[CH2:17][N:18]1[CH:22]=[N:21][NH:20][C:19]1=[O:23]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:20]1[C:19](=[O:23])[N:18]([CH2:17][C:16]([F:15])([F:25])[F:24])[CH:22]=[N:21]1)[CH3:13]
Reactant: O=c1[nH]ncn1CC(F)(F)F
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(CC(F)(F)F)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 65.7 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.36 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.91 g of 4-(2,2,2-trifluoroethyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(2,2,2-trifluoroethyl)-3(2H,4H)-1,2,4-triazolone (1.25 g) was obtained as a colorless oil. IR ν cm-1 (film): 1716, 1704, 1652, 1616, 1558, 1508.