Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:36]=[C:35]5[C:30]([CH2:31][CH2:32][NH:33][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40].C(N(CC)CC)C>C1COCC1>[CH3:37][N:38]([CH3:42])[C:39]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][C:27]([C:19]3[N:20]4[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[C:17]([C:12]4[CH:13]=[CH:14][C:15]5[C:10]([CH:11]=4)=[N:9][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:16]=5)[CH:18]=3)=[CH:28][CH:29]=2)[CH2:34]1)=[O:40]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ncnn2c(-c3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCc2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2C1
Temperature: 40 °C

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (150 mg, 0.3 mmol) in THF (2 mL) was added dimethylcarbamyl chloride (44 mg, 0.4 mmol) and triethylamine (64 mg), and the mixture was heated to 40° C. for 4 hours. The mixture was concentrated in vacuo and the residue was dissolved in methanol and purified by preparative HPLC to provide the title compound, 53 mg (31%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.4 (m, 2 H), 3.5 (m, 2 H), 2.9 (m, 2 H), 2.8 (s, 6 H); ES-MS m/z 543.47 [M+H]+, HPLC RT (min) 3.16.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][C:7]1[C:12]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:11][N:10]=[C:9]([NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[NH:23][C@H:22]([CH2:32][CH3:33])[CH2:21]2)[N:8]=1.[H-].[Na+].I[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]>CN(C)C=O>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=1)[CH2:6][C:7]1[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:11][N:10]=[C:9]([NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[N:23]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[C@H:22]([CH2:32][CH3:33])[CH2:21]2)[N:8]=1
Reactant: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c2nc(OC)ccc2N1
Reactant: CCOC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-[1,5]naphthyridine (300 mg) is dissolved in N,N-dimethylformamide (3 ml), and thereto is added sodium hydride (62.7%, 21 mg) under ice-cooling, then after 1 hour added ethyl iodoacetate (71 μl). The mixture is stirred at room temperature for 24 hours. The reaction solution is partitioned by adding water and ethyl acetate. The organic layer is washed with saturated brine, then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by NH-column chromatography (silica gel; hexane:ethyl acetate=9:1→4:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-1-ethoxycarbonylmethyl-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine (107 mg). MS (m/z): 683 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.B.O1CCCC1>O1CCCC1.C(OCC)C.O>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1c(F)c(F)c(F)c(-c2ccccc2)c1F
Agent: B
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1c(F)c(F)c(F)c(-c2ccccc2)c1F

Procedure:
Under a dry argon atmosphere 2,4,5,6-tetrafluoro-[1,1'-biphenyl]-3-carboxylic acid (21.6 g, 0.08 mole) was dissolved in 150 ml of tetrahydrofuran with stirring. During a 45 minute period 6.9 g of a borane-tetrahydrofuran complex (1.00 molar solution in tetrahydrofuran) was added to the reaction mixture. After complete addition, the reaction mixture was stirred at room temperature for approximately 23 hours. Water (5 ml) was added slowly to the reaction mixture, and the resultant mixture was stirred for two hours. The mixture was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was dissolved in diethyl ether and water. The organic phase was separated, washed with three 200 ml portions of 2N aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Filtration of the mixture and evaporation of the solvent from the filtrate gave 2,4,5,6-tetrafluoro-[1,1'-biphenyl]-3-methanol as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.P([S-])(OCC)(OCC)=[S:12].O>Cl.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH2:8])=[S:12])=[CH:5][CH:4]=1
Reactant: CCOP(=S)([S-])OCC
Reactant: CSc1ccc(C#N)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(N)=S)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 67 %

Procedure:
4-Methylthiobenzonitrile (12 g) was dissolved in a solution (130 mL) of 4N hydrogen chloride in ethyl acetate. To this solution was added O,O-diethyl dithiophosphate (15 mL) and the mixture was stirred at room temperature for 22 h. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate. The insoluble material was filtered off and the filtrate was washed with saturated brine, dried and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give the title compound (10 g, yield 67%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.Cl[CH2:48][C:49]([N:51]([CH3:53])[CH3:52])=[O:50]>>[CH3:52][N:51]([CH3:53])[C:49](=[O:50])[CH2:48][O:46][C:43]1[CH:42]=[CH:41][C:40]([C:17]2[C:16]([C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[CH:8][N:9]=4)[CH:12]=3)=[CH:20][N:19]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:18]=2)=[CH:45][CH:44]=1
Reactant: Oc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)COc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Yield: 77.8 %

Procedure:
90 mg 4-{4-[3-(pyridin-2-yl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazol-3-yl}phenol (compound in Example 353) and 28 mg 2-chloro-N,N-dimethylacetamide were reacted under the same conditions as in Example 190, to give 80 mg of the title compound as a pale yellow amorphous matter.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][CH2:11][CH2:12][O:13][C@H:14]1[O:33][C@H:32]([CH2:34][O:35][C@H:36]2[O:44][C@H:43]([CH2:45][OH:46])[C@@H:41]([OH:42])[C@H:39]([OH:40])[C@@H:37]2[OH:38])[C@@H:30]([OH:31])[C@H:17]([O:18][C@H:19]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]([OH:23])[C@@H:20]2[OH:21])[C@@H:15]1[OH:16])=[O:9])[C:3]([OH:5])=[O:4].[O:47]=[C:48]([NH:62][CH2:63][CH2:64][O:65][C@@H:66]1[O:74][C@@H:73]([CH3:75])[C@@H:71]([OH:72])[C@@H:69]([OH:70])[C@@H:67]1[OH:68])[CH2:49][CH2:50][CH2:51][C:52](ON1C(=O)CCC1=O)=[O:53].C(OC(=O)CCCCC(O)=O)C1C=CC=CC=1>CN(C=O)C>[C@H:19]1([O:18][C@H:17]2[C@H:30]([OH:31])[C@@H:32]([CH2:34][O:35][C@H:36]3[O:44][C@H:43]([CH2:45][OH:46])[C@@H:41]([OH:42])[C@H:39]([OH:40])[C@@H:37]3[OH:38])[O:33][C@H:14]([O:13][CH2:12][CH2:11][NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@H:2]([NH:1][C:52](=[O:53])[CH2:51][CH2:50][CH2:49][C:48](=[O:47])[NH:62][CH2:63][CH2:64][O:65][C@@H:66]3[O:74][C@@H:73]([CH3:75])[C@@H:71]([OH:72])[C@@H:69]([OH:70])[C@@H:67]3[OH:68])[C:3]([OH:5])=[O:4])[C@H:15]2[OH:16])[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]([OH:23])[C@@H:20]1[OH:21]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCC(=O)ON2C(=O)CCC2=O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: N[C@@H](CCC(=O)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O)C(=O)O
Agent: O=C(O)CCCCC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCC(=O)N[C@@H](CCC(=O)NCCO[C@H]2O[C@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H](O)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H]2O)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-amino-5-[(2-{[α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl]oxy}ethyl)amino]-5-oxopentanoic acid (350 mg, 4.75 mmol) in DMF (5 mL) at 0° C. was added 2,5-dioxopyrrolidin-1-yl 5-oxo-5-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)pentanoate (216 mg, 0.517 mmol, prepared according to Example 4, ML-4, Step A, substituting 5-(benzyloxy)-5-oxopentanoic acid for 6-(benzyloxy)-6-oxohexanoic acid and TEA (0.2 mL, 1.435 mmol). After stirring at 0° C. for 2 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 silica gel (150 g), eluting with 5-40% AcCN in H2O to give the title compound. UPLC Method B: calculated for C38H65N3O26 979.39, observed m/e: 980.31 [M+1]; Rt=0.92 min.
Reaction SMILES: C(OC(=N[O:7][CH2:8][CH2:9][N:10]([CH3:30])[CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[C:18]2[CH3:27])[C@H:14]([OH:28])[C@@H:13]1[OH:29])C)C.CNC[C@H]1[O:38][C@@H:37](N2C3N=CN=C(N)C=3N=C2C)[C@H:36](O)[C@@H]1O.ClCC(OCC)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[C:8]([CH2:9][N:10]([CH3:30])[CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[C:18]2[CH3:27])[C@H:14]([OH:28])[C@@H:13]1[OH:29])([O:38][CH2:37][CH3:36])=[O:7]
Reactant: CCOC(C)=NOCCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(=O)CCl
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 35 was prepared by the same procedure as described for the preparation of 6a using 4a (415 mg, 1.41 mm), ethyl chloroacetate (207 mg, 0.18 ml, 1.68 mm), DIEA (91 mg, 0.12 ml, 0.70 mm), and DMF (5 ml): yield 204 mg (38%), MS: m/z 381 (M+H)+; 1HNMR (DMSO-d6) δ 8.06 (s, 1H, H-2), 7.11 (bs, 2H, 6-NH2), 5.73 (d, 1H, H-1′, J1′,2′=5.4 Hz), 5.33 (bd, 1H, OH-2′, J2′-2′OH=4.7 Hz), 5.19 (bd, 1H, OH-3′, J3′-3′OH=4.9 Hz), 5.03 (ddd, 1H, H-2′, J1′,2′=5.4 Hz, J2′,3′=5.7 Hz, J2′-2′OH=4.7 Hz), 4.17 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.4 Hz, J3′-3′OH=4.9 Hz), 4.02 (q, 2H, CH3—CH2), 3.92-3.99 (m, 1H, H-4′), 3.27 (bs, 2H, NCH3—CH2), 2.83-2.90 (m, 1H, 5′-CH2), 2.70-2.79 (m, 1H, 5′-CH2), 2.53 (s, 3H, 8-CH3), 2.31 (s, 3H, N—CH3), 1.13 (t, 3H, OCH2—CH3); UV λmax, nm, pH 1, 258.9 (∈ 16,100), pH 7, 260 (∈ 15,900), pH 13, 260.1 (∈ 16,200).
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:5].[OH:20][CH2:21][CH2:22][O:23][C:24]1[C:31]([CH3:32])=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[CH3:33]>C(O)C.[Cu](Cl)Cl>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][CH:14]=3)[N:1]=[C:28]2[C:27]2[CH:30]=[C:31]([CH3:32])[C:24]([O:23][CH2:22][CH2:21][OH:20])=[C:25]([CH3:33])[CH:26]=2)=[CH:12][CH:11]=1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: COc1cccc(C(=O)Nc2ccc(Br)cc2)c1N
Agent: Cl[Cu]Cl
Solvent: CCO
Product: COc1cccc2c(=O)n(-c3ccc(Br)cc3)c(-c3cc(C)c(OCCO)c(C)c3)nc12

Procedure:
To a solution of 2-amino-N-(4-bromo-phenyl)-3-methoxy-benzamide (0.600 g, 1.86 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.360 g, 1.86 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.750 g, 5.58 mmol). The reaction mixture was stirred at reflux for 16 hours under nitrogen. The solvent was removed and the residue was diluted with ethyl acetate (100 mL) and water (100 mL). After separation, the organic phase was further backwashed with water (100 mL), then brine (100 mL), dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (SiO2, hexane/ethyl acetate=1:1) to give the title compound as a white solid. Yield: 250 mg (27%). MP 100-102° C. 1H-NMR (400 Hz, CDCl3): δ 7.90 (d, 1H), 7.47 (m, 3H), 7.25 (m, 1H), 7.03 (d, 2H), 7.00 (s, 2H), 4.02 (s, 3H), 3.91 (m, 2H), 3.80 (t, 2H), 2.15 (s, 6H), 2.06 (t, 1H). MS (ES+) m/z: 497.41 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>C(#N)C>[CH3:24][O:23][C:21]([CH2:20][O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc2c1CCCC2=O
Reaction time: 3.5 h

Procedure:
A mixture of 1-hydroxy-5-oxo-5,6,7,8-tetrahydronaphthalene (10 g), potassium carbonate (9.4 g), methyl bromoacetate (6.2 ml) in acetonitrile (250 ml) was refluxed with stirring for 3.5 hours. The mixture was filtered off and the filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The separated organic layer was washed with 1N-hydrochloric acid, 1N-sodium hydroxide, brine, dried over magnesium sulfate and evaporated in vacuo. The residue was suspended in n-hexane and then the solid was collected by filtration to give 1-methoxycarbonylmethoxy-5-oxo-5,6,7,8-tetrahydronaphthalene (13.90 g).
Reaction SMILES: [C:1]1([N:7]2[C:13](=[O:14])[CH2:12][C:11](=[O:15])[NH:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:23][C:24]([N:26]([CH:33]1[CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>CN(C=O)C>[CH:33]1([N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](=[O:25])[CH2:23][N:10]2[C:11](=[O:15])[CH2:12][C:13](=[O:14])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:19]=[CH:18][CH:17]=[CH:16][C:9]2=3)[CH2:35][CH2:34]1
Reactant: O=C(CBr)N(c1ccccc1)C1CC1
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1CC(=O)N(c1ccccc1)C1CC1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a stirred solution of 500 mg (1.98 mmol) 1-Phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2,4-dione in 15 mL DMF is added 103 mg (2.58 mmol, 1.3 equiv) 60 wt % NaH at ambient temperature and stirred 0.5 h. To this solution is added 504 mg (1.98 mmol, 1.0 equiv) 2-Bromo-N-cyclopropyl-N-phenyl-acetamide, prepared as in Part A, in 1 mL DMF and stirred 18 h at ambient temperature. The solvent is removed in vacuo and the residue taken into 50 mL EtOAc, washed successively with H2O (30 mL), 1N HCl (30 mL), satd. NaHCO3 (30 mL), and brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to a brown oil. The crude product is purified by flash chromatography on 15 g silica gel eluted with EtOAc/Hexanes (1:1, 450 mL). Appropriate fractions were combined and concentrated in vacuo to give 572 mg (1.34 mmol) of N-Cyclopropyl-2-(2,4-dioxo-5-phenyl-2,3,4,5,tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-phenyl-acetamide as a white foam: 1H NMR (CDCl3, 300 MHz) δ7.50-7.07 (m, 13H), 6.92 (d, 1H, J=7.3), 3.60 (d, 1H, J=11.9), 3.51 (d, 1H, J=12.0), 3.30 (m, 1H), 0.86 (m, 2H), 0.60 (m, 2H); TLC Rf =0.35 (EtOAc/Hexanes, 2:1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[Br:22]Br>C(O)(=O)C>[Br:22][C:16]1[CH:17]=[N:18][C:19]2[C:14]([CH:15]=1)=[CH:13][C:12]([S:11][C:8]1[N:6]3[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=1)=[CH:21][CH:20]=2
Reactant: Cc1ccc2nnc(Sc3ccc4ncccc4c3)n2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1ccc2nnc(Sc3ccc4ncc(Br)cc4c3)n2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (370 mg, 1.26 mmol) in glacial acetic acid (10 mL) was added bromine (0.324 mL, 6.31 mmol) dropwise. The reaction mixture was stirred at room temperature for 5 min then at 100° C. for 2 h. The reaction was cooled to room temperature, and the mixture was concentrated in vacuo. The residue was partitioned between 10% aqueous NaOH and 10% methanol/dichloromethane. The organic layer was separated, washed with 5% aqueous Na2SO3, and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-5% methanol/dichloromethane afforded 422 mg of 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a beige solid (90% yield): 1H NMR (DMSO-d6): δ 2.53 (s, 3H), 7.41 (d, 1H), 7.70 (dd, 1H), 7.87 (d, 1H), 7.99 (d, 1H), 8.41 (d, 1H), 8.66 (d, 1H), 8.93 (d, 1H); MS (m/z) 372, 374 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=[N:10]2)=[C:4]([N+:20]([O-])=O)[C:3]=1[O:23][CH3:24].O>C(O)(=O)C.[Fe]>[CH2:11]([C:24]1[O:23][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([F:8])=[C:5]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=[N:10]3)[C:4]=2[N:20]=1)[CH:12]([CH3:16])[CH3:13]
Reactant: COc1c(Cl)cc(F)c(-n2ncc(C(F)(F)F)cc2=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Cc1nc2c(-n3ncc(C(F)(F)F)cc3=O)c(F)cc(Cl)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 166.9 %

Procedure:
A mixture of 2-(4-chloro-6-fluoro-3-methoxy-2-nitrophenyl)-5-trifluoromethylpyridazin-3-one (0.52 g) and iron powder (0.4 g) in acetic acid (30 ml) was stirred overnight at ambient temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with brine (×3) and dried over anhydrous sodium sulfate. The solvent was removed to give the title compound (0.46 g). 1H NMR (CDCl3, 300 MHz) 3.88 (3H, s), 4.19 (2H, br s), 6.67 (1H, d, J=9.6 Hz), 7.31 (1H, m), 8.10 (1H, d, J=2.2 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[Cl:14][C:15]1[NH2+:16][S:17][S:18][C:19]=1Cl>C(Cl)Cl>[Br:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2](/[N:1]=[C:19]2\[C:15]([Cl:14])=[N:16][S:17][S:18]\2)[CH:11]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: ClC1=C(Cl)SS[NH2+]1
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)cc1/N=c1/ssnc1Cl

Procedure:
A solution of methyl 2-amino-4-bromobenzoate (1.0 g, 4.34 mmol, 1 eq) and 4,5-dichloro-1,2,3-dithiazolium chloride (2.0 g, 9.6 mmol, 2.2 eq) in DCM (20 mL) was stirred at rt under N2 for 5 days. The reaction mixture was quenched with water and filtered. The filtrate was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 365, 367 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:40][CH2:41][CH2:42][O:43]C)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.BrCC(OC(C)(C)C)=[O:50].BrCCOC>>[C:42]([CH2:41][O:40][C:9]1[CH:10]=[C:11]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]4[N:26]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[C:25]5[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=5[N:23]=4)[CH:18]=3)[N:13]=2)[C:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:46][CH:45]=2)=[CH:7][CH:8]=1)([OH:50])=[O:43]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COCCOc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: COCCBr
Product: O=C(O)COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1

Procedure:
The title compound was synthesized as described for Compound 475, except tert-butyl bromoacetate was used for alkylation instead of 1-bromo-2-methoxy ethane. The tert-butyl group was removed in a separate step before saponification by a 1 h treatment with TFA.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([NH2:17])=[C:12]([CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:3].[H][H]>C(O)(C)(C)C>[NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([CH:10]1[CH2:15][CH:14]([CH3:16])[CH:13]([NH2:17])[CH:12]([CH3:18])[CH2:11]1)([CH3:9])[CH3:8])[CH3:3]
Reactant: [H][H]
Reactant: Cc1cc(C(C)(C)CCCC(C)N)cc(C)c1N
Solvent: CC(C)(C)O
Product: CC(N)CCCC(C)(C)C1CC(C)C(N)C(C)C1

Procedure:
58 Parts of 2-amino-6-(4-amino-3,5-dimethylphenyl)-6-methylheptane, 640 parts of tert-butanol, and 12 parts of 5% Rh/Al2O2 were heated in an autoclave at 150°-60° C. with hydrogen at a pressure of 200 bar. After 15 hours hydrogen uptake was complete and the reaction mixture was then filtered free of catalyst. Distillation of the filtrate after removal of the tert-butanol gave 47 parts of 2-amino-6-(4-amino-3,5-dimethylcyclohexyl)-6-methylheptane b0.2 116°-8° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=O.[OH-].[Na+]>O>[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]1[NH:8][C:7]2[C:2](=[N:3][CH:4]=[N:5][CH:6]=2)[N:1]=1
Reactant: Nc1cncnc1N
Reactant: O=C(O)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccccc1-c1nc2ncncc2[nH]1
Temperature: 180 °C
Yield: 88.5 %

Procedure:
A mixture of 4,5-diaminopyrimidine (0.500 g), 2-fluorobenzoic acid (0.700 g) and polyphosphoric acid (25 mL) was heated at 180° C. for 3 hours. Then the reaction mixture was cooled and poured into water (500 mL). The solution was adjusted to pH=8-9 by addition of solid NaOH and the resulting precipitate was collected by filtration, washed with water and dried to give 8-(2-fluorophenyl)-purine (off-white powder, 88.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH3:17])=[CH:5][CH:4]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:11]([C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH3:17])[CH2:10][C:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:18])=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COc1ccc(C(=O)/C=C/c2scnc2C)cn1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: O
Solvent: C1=CCCC=CCC1
Solvent: C1COCCO1
Product: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2scnc2C)cn1

Procedure:
In analogy to example 203, step 1, (E)-1-(6-methoxypyridin-3-yl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one was reacted with 4-bromophenylboronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a yellow solid, MS (ESI+): m/z=419.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1[O:11][N:12]=[C:13]2[CH:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[CH:15][C:14]=12>>[CH2:1]([N:8]([CH3:9])[C:19]([C:17]1[CH:16]=[CH:15][C:14]2=[N:10][O:11][N:12]=[C:13]2[CH:18]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=O)c1ccc2nonc2c1

Procedure:
Prepared from N-benzyl-N-methylamine and [2,1,3]-benzoxadiazole-5-carbonylchloride according to the procedure previously described. N-Benzyl-N-methyl-[2,1,3]-benzoxadiazole-5-carboxamide was isolated as a white solid. Mp=105-106° C., LC-MS, MH+=268; 1H NMR (300 MHz, CDCl3, 2 rotamers) δ 7.96-7.86 (m, 1H); 7.90 (d, 1H, J=9.6 Hz); 7.43-7.30 (m, 5H); 7.19-7.13 (m, 1H); 4.78+4.56 (s+s, 2H); 3.11 and 2.94 ppm (s+s, 3H).