Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46]OC)([CH3:33])([CH3:32])[CH3:31].[NH2:49][CH2:50][C:51]1[CH:52]=[C:53]([OH:62])[CH:54]=[CH:55][C:56]=1[C:57]1[CH:61]=[CH:60][O:59][CH:58]=1>>[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46][NH:49][CH2:50][C:51]1[CH:52]=[C:53]([OH:62])[CH:54]=[CH:55][C:56]=1[C:57]1[CH:61]=[CH:60][O:59][CH:58]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COC=C1C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Reactant: NCc1cc(O)ccc1-c1ccoc1
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: CC(C)(C)c1ccc2c(c1)C(=CNCc1cc(O)ccc1-c1ccoc1)C(=O)NC2=O
Yield: 50 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound (purified through chromatography) is prepared from 6-tert-Butyl-4-methoxymethylene-4H-isoquinoline-1,3-dione (˜15 mg, 0.058 mmol) and 3-Aminomethyl-4-furan-3-yl-phenol (40 mg, 0.21 mmol) in 50% yield: MS (ESI): 415.1 (M−1)−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([NH:20][C:21]2[C:22]([N:31]3[CH2:36][C@H:35]([CH3:37])[CH2:34][C@H:33]([NH:38]C(=O)OC(C)(C)C)[CH2:32]3)=[C:23]3[CH2:29][CH2:28][CH:27]([OH:30])[C:24]3=[N:25][CH:26]=2)=[O:19])[CH:15]=[CH:14][C:13]=1[F:46].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][C@H:33]1[CH2:34][C@@H:35]([CH3:37])[CH2:36][N:31]([C:22]2[C:21]([NH:20][C:18]([C:16]3[CH:15]=[CH:14][C:13]([F:46])=[C:12]([C:3]4[C:2]([F:1])=[CH:7][C:6]([CH2:8][O:9][CH3:10])=[CH:5][C:4]=4[F:11])[N:17]=3)=[O:19])=[CH:26][N:25]=[C:24]3[CH:27]([OH:30])[CH2:28][CH2:29][C:23]=23)[CH2:32]1
Reactant: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C3)CCC4O)ccc2F)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](N)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The alcohol intermediated was treated with TFA (6 mL) and DCM (6 mL). The mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The resulting residue was purified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford two diastereoisomers of the title compound as white powders.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[CH2:27][CH2:28][N:29]=[C:30]=[O:31].[H-].[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:27][CH2:28][NH:29][C:30]2=[O:31])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C=NCCCl
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCN2CCNC2=O)Cc2ncccc2C(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a cold (0° C.) solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-{3-isopropyl-pyridin-2-ylmethyl}-butane-1,4-diamine (163 mg, 0.48 mmol) in CH2Cl2 (5 mL) was added 2-chloroethylisocyanate (50 μL, 0.59 mmol) and the resultant mixture was stirred for 80 minutes then concentrated to provide a yellow oil. To a cold (0° C.) solution of the yellow oil in THF (5 mL) was added NaH (95% dry, 39 mg, 0.98 mmol). The cooling bath was removed and the resultant mixture was stirred at room temperature overnight. The mixture was treated with brine (10 mL) and extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 82 mg (41%) of COMPOUND 151 as a colorless oil. 1H NMR (CDCl3) δ 0.98 (d, 6H, J=6.9 Hz), 1.26-1.36 (m, 2H), 1.42-1.52 (m, 2H), 2.19 (s, 3H), 2.28 (s, 3H), 2.53 (dd, 2H, J=7.2, 7.2 Hz), 2.90-3.06 (m, 3H), 3.27-3.39 (m, 4H), 3.72 (s, 4H), 4.21 (br s, 1H), 7.—(dd, 1H, J=7.2, 4.8 Hz), 7.25 (s, 1H), 7.51 (dd, 1H, J=7.8, 1.5 Hz), 8.19 (s, 1H), 8.33 (dd, 1H, J=4.8, 1.5 Hz); 13C NMR (CDCl3) δ 18.27, 18.30, 23.51 (2 carbons), 24.36, 25.98, 27.46, 38.56, 43.75, 45.40, 54.47, 58.99, 59.59, 123.06, 132.12, 133.16, 133.61, 138.92, 144.24, 145.99, 146.57, 154.48, 156.29, 163.37; ES-MS m/z 410 (M+H). Anal. Calcd. For C24H35N5O.0.7H2O: C, 68.28; H, 8.69; N, 16.59. Found: C, 68.24; H, 8.52; N, 16.36.
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>ClCCl>[C:15]([O:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: ON1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)ON1CCCCC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
A few of the inventive 1-hydroxypiperidine (0.96 g, 9.49 mmol) and triethylamine (1.50 mL, 10.8 mmol) were dissolved in anhydrous dichloromethane (40 mL) and cooled to 0° C. Methacryloyl chloride (1 mL, 10.2 mmol) was then added slowly, dropwise. The reaction was then slowly warmed to room temperature. After 2.5 h, the reaction mixture was washed with deionized water (40 mL), 1 M NaOH (20 mL), deionized water (20 mL), 5% citric acid (20 mL), and brine (20 mL). After drying over sodium sulfate and filtering, the product was concentrated by rotary evaporation and dried in vacuo to give and amber liquid. Flash chromatography on silica gel, eluting with dichloromethane, followed by 1-5% methanol:dichloromethane afforded piperidin-1-yl methacrylate as an amber liquid (1.23 g, 76%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].C(#N)C.[OH:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:15][N:16]1[C:20](=[O:21])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]1=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
tert-Butyl(2-bromoethyl)carbamate (5.00 g, 23.5 mmol) was stirred under an argon atmosphere at room temperature with acetonitrile (74 mL). Then, N-hydroxyphthalimide (Pht-OH, 3.83 g) and triethylamine (5.64 g) were added, followed by stirring the reaction mixture at 70° C. for 24 hours. After completion of the reaction, the reaction solution was concentrated, followed by diluting with ethyl acetate and washing with 0.5M hydrochloric acid and saturated sodium bicarbonate aqueous solution, and the organic layer was dried over magnesium sulfate, to the residue resulting from distilling off the solvent under reduced pressure was added ethyl acetate (10 ml), followed by adding hexane, thereby 4.72 g of the title compound was afforded (yield 65.7%). The instrumental data were consistent with those of the compound of Reference Example 7.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[C:4]([OH:12])=[N:3][CH:2]=1.F[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C.C(O)(CC)(C)C>>[F:21][C:20]([F:23])([F:22])[C:19]1[C:14]([N:9]2[CH2:10][CH2:11][C:5]3[C:4]([OH:12])=[N:3][CH:2]=[N:1][C:6]=3[CH2:7][CH2:8]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ncnc2c1CCNCC2
Reactant: Fc1ncccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)(C)O
Product: Oc1ncnc2c1CCN(c1ncccc1C(F)(F)F)CC2
Yield: 33.9 %

Procedure:
A solution of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (353 mg, 1.76 mmol), 2-fluoro-3-trifluoromethyl-pyridine (582 mg, 3.53 mmol), iPr2NEt (0.9 mL, 5.28 mmol), and t-amyl alcohol (5 mL) was heated in a microwave at 180° C. for 5 h. The mixture was concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give the title compound (185 mg, 34%), which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29].CO>N1C=CC=CC=1>[CH2:28]([S:30]([O:26][C:11]1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=1[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:27])[NH:6]2)(=[O:32])=[O:31])[CH3:29]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Solvent: CO
Solvent: c1ccncc1
Product: CCS(=O)(=O)Oc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
133 mg (0.367 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one are suspended in pyridine (5 ml), and 700 (0.73 mmol) of ethanesulfonyl chloride are added. The suspension is stirred at RT for 3 h (during which the precursor dissolves), and then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 63 mg (43% of theory) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](OB(O)O)=[CH:5][CH:4]=1.[CH2:13](N(CC)CC)C.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=C(O)[CH:24]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=[C:1]([S:2][C:3]2[CH:8]=[CH:7][C:6]([CH3:13])=[CH:5][CH:4]=2)[CH:24]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CCN(CC)CC
Reactant: CSc1ccc(OB(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)c1cc(O)cc(Sc2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
After adding 29.0 g of molecular sieves 4A, 22.0 g (0.13 mol) of p-methylthiophenylboric acid, 21.6 g (0.13 mol) of copper (II) acetate and 83.0 ml (0.59 mol) of triethylamine to a solution of 20.0 g (0.12 mol) of 3,5-dihydroxybenzoic acid methyl ester in methylene chloride (1.2 l), the mixture was stirred at room temperature overnight under an oxygen atmosphere. The reaction mixture was filtered and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=2:1) to obtain 12.4 g of 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl ester (yield: 36%) as a yellow solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].I[C:8]1[N:9]=[CH:10][NH:11][CH:12]=1.C(OC([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1B(O)O)=O)(C)(C)C>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.CN(C=O)C>[NH:11]1[CH:12]=[C:8]([C:21]2[NH:20][C:28]3[C:23]([CH:22]=2)=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:9]=[CH:10]1
Reactant: Ic1c[nH]cn1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(-c3c[nH]cn3)cc2c1
Temperature: 85 °C
Yield: 37 %

Procedure:
A mixture of DMF (3 mL) and 2M Na2CO3 (0.75 mL) was purged with nitrogen for 10 minutes. 4-iodo-1H-imidazole (145.5 mg, 0.75 mmol), (1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (235.0 mg, 0.9 mmol) and Pd(PPh3)4 (86.7 mg, 75.0 μmol) were added followed by purging with nitrogen for an additional 2 minutes. The solution was heated at 85° C. over night. The solution was poured into water (20 mL) and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water (2×10 mL), brine and dried. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica gel using 10% MeOH/DCM as the eluent. The BOC protecting group was lost during the reaction sequence. Yield=37%. 1H NMR: 6.66 (s, 1H), 7.07-7.15 (m, 2H), 7.32 (s, 1H), 7.33 (d, 1H, J=7.8 Hz), 7.57 (d, 1H, J=7.5 Hz), 7.63 (s, 1H), 9.47 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:15]=1
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Reactant: OB(O)c1ccccc1Cl
Product: CN1C(=O)OC(C)(C)c2cc(Nc3ccccc3Cl)ccc21

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 2-chlorophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z [M+H]+ (317/319); MS (ESI) m/z [M−H]− (315/317); Anal. calcd for C17H17ClN2O2: C, 64.46; H, 5.41; N8.84. Found: C, 64.42; H, 5.29; N8.76.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[OH:10])=[N:8][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.O[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.[OH-].[K+].[OH-].[Na+]>C1COCC1.N1C=CC=CC=1>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]([O:10][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:20])([F:19])[F:21])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)c1nc2cc(F)ccc2[nH]1
Reactant: Oc1cccnc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Fc1ccc2[nH]c(C(Oc3cccnc3)c3ccc(OC(F)(F)F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
The compound of Example 1 (150 mg) was dissolved in THF (5 mL), and thionyl chloride (60 mg) and pyridine (146 mg) were added thereto. The mixture was stirred for 30 minutes at room temperature, and then 3-hydroxypyridine (87 mg) and potassium hydroxide (65 mg) were added thereto. The mixture was heated to reflux for 30 minutes while being stirred. A 10% aqueous solution of sodium hydroxide was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (60% to 100% ethyl acetate/hexane), and thus the title compound (19 mg) was obtained as a yellow amorphous material.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[H-].[H][H].[CH3:13][C:14]1[CH:19]=[N:18][C:17]([CH2:20]Cl)=[CH:16][N:15]=1>CN(C)C=O.O>[CH3:13][C:14]1[CH:19]=[N:18][C:17]([CH2:20][N:6]2[CH2:7][CH2:8][NH:9][C:5]2=[CH:4][N+:1]([O-:3])=[O:2])=[CH:16][N:15]=1
Reactant: O=[N+]([O-])C=C1NCCN1
Reactant: Cc1cnc(CCl)cn1
Reactant: [H][H]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(CN2CCNC2=C[N+](=O)[O-])cn1
Temperature: 40 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
2-Nitromethyleneimidazolidine (12.9 g) was dissolved in dry dimethylformamide (100 ml), and at room temperature 60% oily soldium hydride (4.4 g) was added. The mixture was stirred at room temperature until the generation of hydrogen ceased. Then, 2-methyl-5-pyrazinylmethyl chloride (14.3 g) was added at room temperature, and the mixture was stirred at 40° C. for 8 hours. After cooling to room temperature, the reaction mixture was added to 200 ml of water, and extracted with dichloromethane. On distilling off dichloromethane from the organic layer under reduced pressure, 1-(2-methyl-5-pyrazinylmethyl)-2-(nitromethylene)imidazolidine (5.4 g) was obtained as yellow crystals having a melting point of 163 to 166° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[C:10]2=[O:26])[CH:6]=[CH:7][CH:8]=1.[N:27]#[C:28][NH2:29]>O1CCOCC1>[ClH:1].[NH:2]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=3)[C:10]2=[O:26])[CH:6]=[CH:7][CH:8]=1)[C:28]([NH2:29])=[NH:27]
Reactant: N#CN
Reactant: COC(=O)CCc1ccc(N2CCN(c3cccc(N)c3)C2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCc1ccc(N2CCN(c3cccc(NC(=N)N)c3)C2=O)cc1

Procedure:
Prepared from 1-(3-amino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl] -imidazolidin-2-one hydrochloride by refluxing for three hours with cyanamide in dioxane.
Reaction SMILES: C[O:2][C:3](=[O:46])[CH2:4][C:5]([CH3:45])([CH3:44])[CH2:6][CH2:7][N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[C:23]2[N:24]=[N:25][N:26]([CH3:28])[N:27]=2)[CH2:11][CH2:10][CH2:9]1.[OH-].[Na+].Cl>CO.O>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:30]([CH:31]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:33]=1)[CH2:29][N:22]([C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1)[C@@H:12]1[C:13]2=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=[C:21]2[N:8]([CH2:7][CH2:6][C:5]([CH3:45])([CH3:44])[CH2:4][C:3]([OH:46])=[O:2])[CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)CC(C)(C)CCN1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc3c(cc21)COC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(CCC(C)(C)CC(=O)O)c3cc4c(cc32)COC4)n1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-5-{9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl}-3,3-dimethyl-pentanoic acid methyl ester (0.113 mmol) in methanol (3 mL), add 5 N NaOH (2 mL) and heat to 60° C. After stirring for 6 h, cool the reaction to room temperature, dilute with water (10 mL) and neutralize with 5 M HCl. Extract the organics with ethyl acetate (2×20 mL). Combine the organic portions, dry over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (20-60%) to afford the title compound as a colorless foam. MS (ES+): 641.3 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)=[O:20])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[N:18])(C)(C)C.[NH:29]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[C:32]=2[CH:31]=[CH:30]1>>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][CH:8]([NH:7][S:38]([C:33]1[C:32]2[CH:31]=[CH:30][NH:29][C:37]=2[CH:36]=[CH:35][CH:34]=1)(=[O:39])=[O:40])[C:19]([N:21]1[CH2:22][CH2:23][CH:24]([CH3:27])[CH2:25][CH2:26]1)=[O:20])#[N:18]
Reactant: CC1CCN(C(=O)C(CCc2ccccc2C#N)NC(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(Cl)c1cccc2[nH]ccc12
Product: CC1CCN(C(=O)C(CCc2ccccc2C#N)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
Example 70 is prepared from tert-butyl{3-(2-cyanophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate and indole-4-sulfonyl chloride in the same manner that Example 5 is synthesized. ESI MS Calc. 464.2; Found: 465.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH2:24][C:25]#[N:26])=[N:7]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH:24]([C:25]#[N:26])[CH2:42][C:43]([O:45][CH3:46])=[O:44])=[N:7]1
Reactant: COc1c2n(c3c(CC#N)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)CC(C#N)c1nn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(OC)c3n(c12)CCN(C)C3=O
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-4-(cyanomethyl)-10-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.11 g, 0.25 mmol; Example 118, step 1) in anhydrous DMF (1 mL), a solution of lithium bis(trimethylsilyl)amide (0.28 mL, 0.28 mmol; 1M) in THF was added over a period of 5 minutes. The reaction solution was stirred at the same temperature for 30 minutes and treated with methyl bromoacetate (43 mg, 0.28 mmol). After stirring at room temperature for two hours, the product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and aqueous ammonium chloride. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0 to 10% methanol in chloroform gradient. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:24][Mg]Br.C(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[CH3:24])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Reactant: C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanone ((xiv), 294 mg, 0.9 mmol) was dissolved in anhydrous THF (70 mL) at 40° C. and methylmagnesium bromide in Et2O (3 M, 0.36 mL) was slowly added and the RM was then allowed to cool down to RT and stirred for 2 h. More methylmagnesium bromide in Et2O (3 M, 0.5 mL) was added and the RM was stirred for 1 h more. It was then taken into DCM and 10% aqueous NaHCO3 solution and extracted. The organic phase was dried on MgSO4. After evaporation of the solvent the crude was purified by flash chromatography to afford the title compound (tR 3.74 min (conditions 5), MH+=343, 1H-NMR in DMSO-d6: 8.87 (dd, 1H); 8.50 (d, 1H); 8.49 (d, 1H); 8.18 (d, 1H); 7.85 (s, 1H); 7.59 (d, 1H); 7.51 (dd, 1H); 7.23 (d, 1H); 6.33 (s, 1H); 2.13 (s, 3H)).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:11].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C1COCC1.CCOC(C)=O>[CH:12]1([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[F:11])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(F)c1NC1CC1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-1-fluoro-3-nitrobenzene (2.0 g, 9.1 mmol), cyclopropanamine (1.26 mL, 18.2 mmol) in THF (10 mL) under N2 was heated at 60° C. for 4 days. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using hexane-EtOAc (8.5:1.5) as eluent to give N-cyclopropyl-2-fluoro-6-nitroaniline.