Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC)=O.C([O:10][CH2:11][C:12]([OH:14])=O)(=O)C.C(N(CC)CC)C.[NH:22]([C:24]1[N:25]=[N:26][C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:28]([CH3:30])[N:29]=1)[NH2:23]>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:10][CH2:11][C:12]([NH:23][NH:22][C:24]1[N:25]=[N:26][C:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:28]([CH3:30])[N:29]=1)=[O:14]
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Reactant: CC(=O)OCC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(NNC(=O)CO)nnc1-c1ccccc1
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
A solution of ethyl chloroformate (1.628 g) in methylene chloride (6 ml) was added dropwise to a stirred solution of acetoxyacetic acid (1.77 g) and triethylamine (1.515 g) in methylene chloride (30 ml) under ice cooling in 3 minutes, and the stirring was continued for 10 minutes under ice cooling. To the mixture was added quickly a solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (2.01 g) in chloroform (28 ml) with stirring under ice cooling, and then the stirring was continued for 20 minutes. The solution was washed with water, dried over sodium sulfate, and concentrated. The resultant residue was dissolved in methanol (50 ml), and a solution of sodium hydroxide (0.8 g) in water (10 ml) was added thereto under ice cooling. After stirring for 0.5 hours, the solution was evaporated under reduced pressure and the residue was dissolved in water. To the solution was added dry ice and then the solution was concentrated under reduced pressure. The resultant precipitates were collected by filtration, washed with cold water and dried. On the other hand, the filtrate was salted out and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to give a solid residue. The residue was combined with the substance obtained above, and recrystallized from a mixture of ethyl acetate and ethanol to give colorless crystals of 3-(2-hydroxyacetylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (1.852 g).
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH:17]([OH:50])[CH2:18][O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[C:28]([O:30][CH2:31][CH:32]([OH:49])[CH2:33][N:34]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:35]1[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]1)=[O:29])=[O:21])[CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[C:51]1([N:57]=[C:58]=[O:59])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1C=CC=CC=1>[CH2:1]([N:5]([CH2:16][CH:17]([O:50][C:58](=[O:59])[NH:57][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:18][O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[C:28]([O:30][CH2:31][CH:32]([O:49][C:58](=[O:59])[NH:57][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:33][N:34]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:35]1[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]1)=[O:29])=[O:21])[CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:14])([CH3:15])[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC(O)COC(=O)C1CCCCC1C(=O)OCC(O)CN(CCCC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: CCCCN(CC(COC(=O)C1CCCCC1C(=O)OCC(CN(CCCC)C1CC(C)(C)NC(C)(C)C1)OC(=O)Nc1ccccc1)OC(=O)Nc1ccccc1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 3 h

Procedure:
A mixture of 2.4 g of bis{3-[N-butyl-N-(2,2,6,6-tetramethyl-4-piperidyl)amino]-2-hydroxypropyl}1,2-cyclohexanedicarboxylate, obtained as described in Example 18, and 2.4 g of phenylisocyanate in 30 ml of benzene was refluxed, with stirring, for 3 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel eluted with a 20:1 by volume mixture of ethyl acetate and triethylamine. The desired compound was obtained in the form of a vitreous mass having an Rf value of 0.58 on thin layer chromatography on silica gel developed with a 5:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:14]([O:18][P:19]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[CH2:15][CH2:16][CH3:17]>>[CH2:22]([O:21][P:19]([O-:26])([O:18][CH2:14][CH2:15][CH2:16][CH3:17])=[O:20])[CH2:23][CH2:24][CH3:25].[CH2:10]([P+:5]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCP(CCCC)CCCC
Reactant: CCCCOP(=O)(OCCCC)OCCCC
Product: CCCCOP(=O)([O-])OCCCC
Product: CCCC[P+](CCCC)(CCCC)CCCC
Temperature: 200 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
Tri-n-butylphosphine (215 g, 94%, 1.0 mole) was added dropwise over a period of 4 hours to a flask containing 272 g (98%, 1.0 mole) of tributylphosphate at 170° C. When the addition was complete, the reaction mixture was heated to 200° C. and stirred at this temperature for 24 hours. The viscous liquid was dried in a rotary evaporator at 160° C./5 mm Hg for 5 hours. The product (363 g, yield 77.5%) was pure according to NMR. At room temperature the product was a white, wax-like solid (m.p. from DSC measurement: 28.0° C.). 1H-NMR (CDCl3, 300.13 MHz, δ): 3.84 (q, 4H, 2×CH3CH2CH2—CH2—O—), 2.38 (m, 8H, 4×CH3CH2CH2—CH2P+), 1.53 (m, 16H, 4×CH3—CH2CH2—CH2P+), 1.40 (m, 8H, 2×CH3—CH2CH2—CH2O—), 0.97 (m, 12H, 4×CH3—CH2CH2CH2P+), 0.90 (m, 6H, 2×CH3—CH2CH2CH2O—). 31P-NMR (CDCl3, 81.015 MHz, δ): 33.72 (P+), 0.94 [m, (RO)2—P(═O)—O−].
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])[CH2:26][CH3:27]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: CCC(N)CO
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC(CC)CO)s1
Yield: 52 %

Procedure:
As described for example 102, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using rac-2-amino-1-butanol instead of 1,1-dimethylhydrazine, to the title compound (98 mg, 52%) which was obtained as a white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane). MS: m/e=378.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[N:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].O1CCCC1.C(O)C.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:9]([CH2:10][OH:11])=[CH:12][CH:13]=[CH:14][N:15]=1
Reactant: COc1cc(COc2ncccc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(COc2ncccc2CO)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a mixture of 2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinaldehyde (620 mg), tetrahydrofuran (10 ml) and ethanol (10 mL) was added sodium borohydride (54 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (615 mg, 99%) of [2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol. The crystals were recrystallized from ethyl acetate-hexane. melting point: 143-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[CH2:31][C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][C:32]5[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: Cn1cncc1CO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: Cn1cncc1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1-methyl-1H-imidazol-5-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 5-hydroxymethyl-1-methyl-1H-imidazole following General Procedure J.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[S:26][C:25]([C@@:27]3([OH:39])[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[C:29]([CH3:38])([CH3:37])[CH2:28]3)=[N:24][CH:23]=2)[CH:8]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=2)[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[S:26][C:25]([C@@:27]3([OH:39])[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[C:29]([CH3:37])([CH3:38])[CH2:28]3)=[N:24][CH:23]=2)[CH:8]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][N:13]=2)[CH:10]=1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CN=[N+]=[N-])cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CN)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 23 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
To a solution of the product from Step 2 (220 mg, 0.392 mmol) in THF (4 ml) and water (2 ml), was added resin-bound triphenylphosphine (154 mg, 0.588 mmol, 1.5 equiv). The resulting mixture was stirred at 23° C. for 18 h. The resin-bound triphenylphosphine was removed by filtration, and the residual biphasic, orange-maroon mixture was partitioned between EtOAc (45 ml) and water (55 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated. The crude orange oil was purified via reverse-phase HPLC (acetonitrile/water gradient with 0.1% TFA present). The TFA salt was converted to the free base by partitioning between EtOAc (55 ml) and saturated aqueous NaHCO3 (45 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The organic layer was filtered and concentrated, yielding methyl(1S,4R)-4-{5-[3-(aminomethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (55 mg, 25%), as an orange oil. MS ESI: [M+H]+ m/z 536.2
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[C:27]1([CH:33]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36](O)([C:43]3[C:51]([OH:52])=[CH:50][C:46]4[O:47][CH2:48][O:49][C:45]=4[CH:44]=3)[C:35]2=[O:54])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:55]1([CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]([C:43]3[C:51]([OH:52])=[CH:50][C:46]4[O:47][CH2:48][O:49][C:45]=4[CH:44]=3)[C:35]2=[O:54])[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: O=C1C(c2cc3c(cc2O)OCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 2C, and making the variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (84%) as an off-white solid: MS (ES+) m/z 458.4 (M+23).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.Cl[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:4]([O:3][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:13])=[N:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: ClCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCc3cccnc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An oily suspension (50% by weight; 1.2 g) of sodium hydride is added in small portions at a temperature in the region of 0° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (6.2 g) in anhydrous dimethylformamide (100 cc). The suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. and a 1.4M solution (16 cc) of 3-chloromethylpyridine in toluene is then added. The reaction mixture is heated with stirring to a temperature of 70° C. for 1 hour, then cooled to a temperature in the region of 10° C., poured into distilled water (600 cc) and extracted with dichloromethane (3×200 cc). The organic phases are combined, washed with distilled water (4×50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 1N aqueous hydrochloric acid solution (30 cc) is added to the residue obtained. After removal of a solid by filtration, the filtrate is alkalinized with 10N aqueous sodium hydroxide solution to a pH in the region of 11, and extracted with dichloromethane (3×150 cc). The organic phases are combined, washed with distilled water (3×25 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-[(3-pyridyl)methoxy]-1-isoindolinone (3.7 g), m.p. 175° C., is obtained.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8].[CH:13]1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[H][H]>CO>[C:4]1([CH:5]([CH3:13])[CH2:6][C:7]([OH:9])=[O:8])[CH:3]=[CH:2][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(/C=C\C(=O)O)c1
Reactant: [H][H]
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Product: CC(CC(=O)O)c1ccccc1
Yield: 100 %

Procedure:
In a 100 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 0.32 g (2 mmoles) of (Z)-3-methylcinnamic acid and 20 ml of methanol. Then, 2.9 mg (0.0034 mmole) of Ru((+)BINAP)-(O2CCH3)2 prepared according to the same manner as in Referential Example 3 except using (+)-BINAP in place of (-)-BINAP was added to the mixture to perform hydrogenation for 70 hours at a hydrogen pressure of 104 kg/cm2 and at a reaction temperature of 25° C. Thereafter, the solvent was distilled off to provide 0.32 g of 3-phenylbutyric acid. The yield was 100%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][N:13]([CH:16]3[CH2:18][CH2:17]3)[CH:14]=O)[CH:11]=1)[O:8][C:7]([CH3:20])([CH3:19])[CH2:6][C:5]2([CH3:22])[CH3:21].[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C(N(CC)CC)C.O1CCCC1.C(OCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:16]1([N:13]([CH2:12][C:10]2[CH:11]=[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:3]=[C:4]3[C:9]=2[O:8][C:7]([CH3:20])([CH3:19])[CH2:6][C:5]3([CH3:22])[CH3:21])[CH3:14])[CH2:18][CH2:17]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(CN(C=O)C3CC3)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C)C1CC1
Temperature: 70 °C

Procedure:
A solution of 6-bromo-8-[(cyclopropyl-formyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman (Intermediate 9, 1.5 g, 4.2 mmol) in triethyl amine (5 mL) and anhydrous tetrahydrofuran (10 mL) was treated with copper(I)iodide (0.32 g, 1.68 mmol) and sparged with argon for 5 minutes. Trimethylsilyl acetylene (2.5 mL, 17.6 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (0.737 g, 1.05 mmol). The resulting reaction mixture was heated at 70° C. for 17 h. It was then cooled to ambient temperature, diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) to afford the title compound as a brown oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([Cl:11])=[C:9]([CH3:12])[N:8]=[C:7]([C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[N:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1>[CH2:1]([O:4][C:5]1[C:10]([Cl:11])=[C:9]([CH3:12])[N:8]=[C:7]([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:29](=[O:30])[CH2:28][Cl:27])=[CH:15][CH:14]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1nc(-c2ccc(N)cn2)nc(C)c1Cl
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCOc1nc(-c2ccc(NC(=O)CCl)cn2)nc(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 55 (0.064 g, 0.231 mmol) in THF (4 mL), at 0° C. was added triethylamine (0.035 g, 0.346 mmol) and chloroacetylchloride (0.039 g, 0.346 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and the reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[N:10]=[C:6]2[C:5]([Br:15])=[N:4][CH:3]=1.C[Si](C)(C)[NH:18][C:19]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=[CH:21][C:20]=1[F:29].CS(C)=O>C(#N)C>[F:29][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[C:19]=1[NH:18][S:11]([C:9]1[N:10]=[C:6]2[C:5]([Br:15])=[N:4][CH:3]=[C:2]([Br:1])[N:7]2[N:8]=1)(=[O:13])=[O:12]
Reactant: COC(=O)c1cccc(F)c1N[Si](C)(C)C
Reactant: O=S(=O)(Cl)c1nc2c(Br)ncc(Br)n2n1
Solvent: CS(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc(F)c1NS(=O)(=O)c1nc2c(Br)ncc(Br)n2n1
Reaction time: 1 h

Procedure:
A solution of 0.75 g (20 mmol) of 5,8-dibromo-2-chlorosulfonyl[1,2,4]triazolo[1,5-a]pyrazine in 8 mL of dry acetonitrile was placed in a flask equipped with a drying tube and was treated sequentially with 6.0 mL (6.0 mmol) of a 1M solution of N-trimethylsilyl-2-fluoro-6-methoxycarbonylaniline in acetonitrile and 25 μL (0.35 mmol) of dimethyl sulfoxide at room temperature with stirring. The reaction became progressively darker and after 1 hour, the volatiles were removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by flash column chromatography on silica gel using a 0.5 to 4 percent ethanol/dichloromethane gradient as eluent to obtain 715 mg (70 percent of theory) of the desired product as an orange glassy solid melting at 190°-195° C.; Mass Spectrum, m/e 510 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)[O:13][C:12]3=[O:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47].[Na+].[I-]>C1COCC1>[CH3:49][O:48][C:46](=[O:47])[CH2:45][CH2:44][N:18]([CH2:17][CH2:16][CH:14]1[O:13][C:12](=[O:33])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:15]1)[CH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1ccc2nccc(CCNCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Reactant: COC(=O)CCBr
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(CCc1ccnc2ccc(OC)nc12)CCC1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 80 °C
Yield: 42.4 %

Procedure:
A solution of the compound of Example 72 (0.2 g, 0.44 mmol) in THF (3 mL) was treated with DIPEA (0.147 mL, 2 eq.), methyl 3-bromopropionate (0.074 g, 1 eq.) and NaI (0.067 g, 1 eq.). The mixture was heated at 80° C. for 2 h, partitioned between EA and water. The org. phase was dried over MgSO4 and concentrated. The residue was purified by FC (EA) to give the title compound as a yellowish oil (0.1 g, 42% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[CH3:22][C:23](=[CH2:31])[CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:31][C:23](=[CH2:22])[CH2:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:27][CH2:26]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Reactant: C=C(C)CN1CCNCC1
Product: C=C(C)CN1CCN(CCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 45 %

Procedure:
Using the procedure of Example 2, 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one was reacted with 1-(2-methyl-allyl)-piperazine to obtain a 45% yield of 5,11-dihydro-11-{3-[4-(2-methyl-allyl)-1-piperazinyl]-propionyl}-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 210°-211° C. after crystallization from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[C:35](Cl)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCC(=O)Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)N1CCN(c2ccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.120 g, 0.32 mmol) in CH2Cl2 (10 mL) was added Et3N (0.06 mL, 0.48 mmol) and hexanoyl chloride (0.03 mL, 0.28 mmol). The resulting solution was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The material was purified by flash chromatography, eluting with 2% to 10% of MeOH/CH2Cl2, to afford the title compound (0.050 g, 38%). 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.11 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.75-4.05 (m, 6H), 3.47-3.73 (m, 4H), 3.17-3.43 (m, 4H), 2.20-2.40 (m, 2H), 1.41-1.62 (m, 2H), 1.15-1.38 (m, 4H), 0.76-0.98 (m, 3H); APCI MS m/z 465 [M+H]+.