Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:25]=[CH:24][C:12]3[O:13][CH2:14][CH2:15][N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]=3[CH:10]=2)O1.Br[C:28]1[N:33]=[C:32]([C:34]([O:36][CH3:37])=[O:35])[C:31]([O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.CCOC(C)=O.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>[CH3:37][O:36][C:34]([C:32]1[N:33]=[C:28]([C:9]2[CH:25]=[CH:24][C:12]3[O:13][CH2:14][CH2:15][N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:11]=3[CH:10]=2)[CH:29]=[CH:30][C:31]=1[O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: COC(=O)c1nc(Br)ccc1OCCCOc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCO3)ccc1OCCCOc1ccccc1
Temperature: 90 °C

Procedure:
A mixture of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (53B) (72 mg, 0.20 mmol), methyl 6-bromo-3-(3-phenoxypropoxy)picolinate (26C) (72 mg, 0.20 mmol), K2CO3 (30 mg, 0.22 mmol in 0.5 mL of water), tetrabutyl ammonium bromide (64 mg, 0.20 mmol) and dichlorobis(triphenylphosphine)palladium (II) (10 mg, catalytic amount) in 1,4-dioxane (5 mL) was heated to 90° C. for 6 hours. The reaction mixture was cooled to rt, diluted with EtOAc, filtered through Celite, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 20% EtOAc in hexanes to provide the desired product tert-butyl 6-(6-(methoxycarbonyl)-5-(3-phenoxypropoxy)pyridin-2-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (53C). 1H NMR (300 MHz, CDCl3): 8.49 (1H, s), 7.74 (1H, d), 7.60 (1H, d), 7.38 (1H, d), 7.24 (2H, m), 6.90 (4H, m), 4.31 (2H, t), 4.18 (2H, t), 4.25 (2H, t), 3.95 (3H, s), 3.85 (2H, t), 2.3 (2H, m), 1.58 (9H, s). LCMS (APCI): m/z 521.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-])=O.[H][H].C(=O)([O-])O.[Na+:23]>O.[Pd]>[Na+:23].[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([O-:16])=[O:15]
Reactant: [H][H]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1ccc(CC(=O)[O-])c(N)c1
Yield: 84.1 %

Procedure:
Five grams of 2,4-dinitrophenylacetic acid were dissolved in a solution of 1.9 gm of sodium hydrogen carbonate in 200 ml water and reduced with hydrogen in the presence of 0.3 gm of palladium on charcoal at room temperature. After completion of the uptake of hydrogen, the catalyst was filtered off, and the filtrate was evaporated in a rotary evaporator at a bath temperature of 30° C. maximum. An amount of 3.5 gm of 2,4-diaminophenylacetic acid sodium salt was obtained.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:12]=[CH:11][C:10]=1[O:24][CH3:25])=[O:7])C>S(=O)(=O)(O)O>[CH3:25][O:24][C:10]1[CH:11]=[CH:12][C:13]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])=[C:14]2[C:9]=1[NH:8][C:6](=[O:7])[CH:5]=[CH:4]2
Reactant: CCOC(CC(=O)Nc1cc(CCNC(=O)C(F)(F)F)ccc1OC)OCC
Agent: O=S(=O)(O)O
Product: COc1ccc(CCNC(=O)C(F)(F)F)c2ccc(=O)[nH]c12
Temperature: 0 °C
Yield: 83.3 %

Procedure:
The product of (a) (17.0 g, 42 mmoles) was added cautiously to concentrated sulphuric acid (50 ml) with stirring. When the addition was complete the dark solution was heated at 100° for 45 min then cooled and poured into ice-water. The suspension was extracted with ethyl acetate, and the extracts washed with sodium bicarbonate solution and water, dried and evaporated to give the sub-title compound as a pale yellow solid (11.0 g) mp 181°-184°. A sample recrystallised from ethanol-cyclohexane formed colourless needles mp 185°-186°.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[OH:14])([CH3:3])[CH3:2]>O=[Pt]=O.CC(O)=O>[CH:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][C@@H:13]([CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1)[OH:14])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C[C@H](O)c2ccncc2)c1OC(C)C
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1cccc(C[C@H](O)C2CCNCC2)c1OC(C)C

Procedure:
Shake a mixture of (S)-2-(2-isopropoxy-3-methylphenyl)-1-(4-pyridinyl)ethanol (21.1 g, 78 mmol), HOAc (400 mL) and PtO2 (370 mg) with H2 (50 psi) for 15 hr. Filter the mixture through celite and evaporate the solvent to give (S)-2-(2-isopropoxy-3-methylphenyl)-1-(4-piperidinyl)ethanol as the acetate salt; 1H-NMR (CDCl3) δ 7.1-6.9 (m, 2H), 4.2 (m, 1H), 3.6 (m, 1H), 3.4 (m, 2H), 2.9-2.7 (m, 4H), 2.3 (s, 3H), 2.0 (s, 3H), 2.1-1.5 (m, 5H), 1.3 (d, 6H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:12])[N:6]([CH3:11])[N:7]=2)[C:3]=1[C:13]([O:15][CH3:16])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:42]([O:46][CH3:47])(=[O:45])[CH:43]=[CH2:44]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:47][O:46][C:42](=[O:45])/[CH:43]=[CH:44]/[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:12])[N:6]([CH3:11])[N:7]=2)[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: C=CC(=O)OC
Reactant: COC(=O)c1c(Br)ccc2nn(C)c(C)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2nn(C)c(C)c2c1C(=O)OC
Temperature: 100 °C
Yield: 54 %

Procedure:
A suspension of methyl 5-bromo-2,3-dimethyl-2H-indazole-4-carboxylate (1.10 g, 3.89 mmol), palladium acetate (87.3 mg, 0.389 mmol), triphenylphosphine (204 mg, 0.778 mmol), potassium carbonate (591 mg, 4.28 mmol) and methyl acrylate (523 μL, 5.83 mmol) in N,N-dimethylformamide (39 mL) was stirred with heating at 100° C. for 4 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→60/40) to give the title compound (606 mg, yield 54%).
Reaction SMILES: C([N:3]1[C:12]2[C:7](=[C:8](N)[C:9](F)=[C:10](F)[C:11]=2F)[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)C.C(NCC1CCNC1)C.C(N(CC)CC)C>C(#N)C>[O:17]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:3][CH:4]=[C:5]1[C:18]([OH:20])=[O:19]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(F)c(F)c21
Agent: CCNCC1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C

Procedure:
A suspension of 3.02 g (10 mmole) of 1-ethyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro quinoline-3-carboxylic acid, 1.93 g (15 mmole) of N-ethyl-3-pyrrolidinemethanamine, 3.0 g (30 mmole) of triethylamine and 100 ml of acetonitrile is refluxed for 18 hours. The reaction mixture is cooled to room temperature and the precipitate is removed by filtration, washed with acetonitrile, ether, and dried in vacuo to give 1-ethyl-5-amino-6,8-difluoro-7-[3-(ethylamino)methyl-1-pyrrolidinyl)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[O:16][CH3:17])(=O)C.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:34][N:35]([CH3:46])[CH2:36][CH2:37][NH:38][C@H:39]1[CH2:44][CH2:43][C@@H:42]([CH3:45])[CH2:41][CH2:40]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:34][N:35]([CH3:46])[CH2:36][CH2:37][N:38]([C@H:39]1[CH2:40][CH2:41][C@@H:42]([CH3:45])[CH2:43][CH2:44]1)[C:11](=[O:13])[CH:10]=[CH:9][C:8]1[CH:14]=[CH:15][C:5]([OH:4])=[C:6]([O:16][CH3:17])[CH:7]=1
Reactant: COc1cc(C=CC(=O)O)ccc1OC(C)=O
Reactant: CN(C)CCN[C@H]1CC[C@@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@@H](C)CC2)ccc1O

Procedure:
Using 2.5 g of 4-acetoxy-3-methoxycinnamic acid, 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3 ml of N-(2-dimethylaminoethyl)-cis-4-methylcyclohexylamine (Example 110), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 75 was carried out. As a result, 1.6 g of N-(2-dimethylaminoethyl)-N-(cis-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[NH2:17][C:18]1[N:23]=[C:22]([CH:24]2[CH2:26][CH2:25]2)[N:21]=[C:20]([O:27][CH3:28])[N:19]=1>C(Cl)Cl>[CH:24]1([C:22]2[N:21]=[C:20]([O:27][CH3:28])[N:19]=[C:18]([NH:17][C:14]([NH:13][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH:2]([F:1])[F:16])(=[O:12])=[O:11])=[O:15])[N:23]=2)[CH2:26][CH2:25]1
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)F
Reactant: COc1nc(N)nc(C2CC2)n1
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(C2CC2)n1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
3.75 g of 2-difluoromethoxybenzenesulfonylisocyanate are added to a solution of 2.5 g of 2-amino-4-cyclopropyl-6-methoxy-1,3,5-triazine in 15 ml of methylene chloride, and the mixture is stirred for 70 hours at room temperature. It is then concentrated by evaporation, and 25 ml of ether are added to the residue. A crystalline precipitate occurs, which is filtered off. The yield is 4.7 g of the above urea, which melts at 121°-124° C.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:12][C:11](=[O:13])[C:10]([CH:14]([NH:16]C(=O)C)[CH3:15])=[N:9][N:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[NH2:16][CH:14]([C:10]1[C:11](=[O:13])[NH:12][C:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:8][N:9]=1)[CH3:15]
Reactant: CC(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1

Procedure:
20 g (69.9 mmol) of N-{1-[3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}acetamide (Example 7A) are stirred under reflux in 200 ml of 2 N hydrochloric acid for 18 h. The cooled mixture is then neutralized using 6 N NaOH and evaporated to dryness in vacuo. The residue is suspended in methanol and the salt is separated off. The concentrated filtrate is flash-chromatographed using dichloromethane/methanol 20/1 and 5/1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.N1C=CC=CC=1.[Br:22]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:22])=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(-c2cnc(N)cn2)cc1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cnc(N)c(Br)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.3 %

Procedure:
To a solution of 2-amino-5-(4-mcthoxyphenyl)pyrazinc 16a (0.35 g, 1.7 mmol) and pyridine (0.20 mL, 2.6 mmol) in chloroform (20 mL), bromine (Br2) (0.13 mL, 2.6 mmol) was added dropwise in chloroform (3 mL) at −10° C. After 6 h stirring at room temperature, the reaction mixture was washed with water, the organic layer dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography using dichloromethane-EtOAc (90:10 v/v) as eluent, to obtain 0.33 g of 17a as an brown solid (mp 166-170° C., 70% yield). 1H-NMR (CDCl3): 3.83 (s, 3H), 5.04 (br s, 2H), 6.92-6.96 (m, 2H), 7.76-7.80 (m, 2H), 8.31 (s, 1H). GC-MS (EI): m/z 279,281 (M1, 100).
Reaction SMILES: [CH2:1]1COCC1.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl.CCCCCC>[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=[CH2:1])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: C1CCOC1
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: CCCCCC
Solvent: ClCCl
Product: C=C1CCC(C(C)(C)C)CC1
Reaction time: 8 h
Yield: 70 %

Procedure:
BDAM (3.00 grams) was suspended in 40 milliliters of methylene chloride and 2 molar equivalents of THF were added at 0° C. After a homogeneous solution was formed, 1 molar equivalent of TEAL in 10 milliliters of hexane was added followed by 2.20 grams of 4-tert-butylcyclohexanone. After overnight stirring, reaction mixture was hydrolyzed and worked up as described in Example 1. A totaI of 1.50 grams of 4-tert-butyl-1-methylenecyclohexane was isolated (70% yield).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:19]1(O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.N1C=CC=CC=1.Cl>C(Cl)Cl>[CH:19]1([O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][C:10]([CH:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: OC1CCCCC1
Reactant: CCCC(c1ccc(C(=O)O)cc1)n1ccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(c1ccc(C(=O)OC2CCCCC2)cc1)n1ccnc1
Yield: 78 %

Procedure:
1 g of 4-[1-(1-imidazolyl)-butyl]-benzoic acid is converted, analogously to example 20, into the acid chloride; it is dissolved in 10 ml of methylene chloride, mixed with 360 mg of cyclohexanol and 3 ml of pyridine, after 20 hours at room temperature it is added to excess 1M hydrochloric acid and extracted with ether. The water phase is alkalized with potassium carbonate and extracted with ethyl acetate. After drying and concentration by evaporation, the residue is distilled on a bulb tube. 915 mg of the title compound is obtained as oil with a boiling point of 200° C./0.03 mbar.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[F:22])[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: NCCc1ccccc1F
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCc2ccccc2F)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 140 °C
Yield: 27.9 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (500 mg, 1.64 mmol), 2-(2-fluorophenyl)ethanamine (500 mg, 2.19 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 4 hours at 140° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC (gradient: 20% CH3CN/H2O to 40% CH3CN/H2O) to afford the title compound (166 mg) as a yellow solid. LC-MS (ES) m/z=364 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.86-2.90 (m, 2H), 3.49-3.51 (m, 2H), 5.35 (s, 2H), 5.98 (s, 2H), 6.25 (s, 1H), 6.97 (s, 1H), 7.12-7.17 (m, 2H), 7.23-7.29 (m, 1H), 7.33-7.41 (m, 2H), 7.68 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH2:1]1[C@H:5]2[C:6](=[O:16])[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[CH3:19][N:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10](=[O:11])[N:4]2[CH2:3][CH2:2][CH2:1][CH:5]2[C:6]1=[O:16]
Reactant: O=C1Nc2ccccc2C(=O)N2CCC[C@@H]12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (S)-(+)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazapine-5,11(10H,11aH)-dione (9.9 g, 45.8 mmol) in DMF (150 ml) at 0° C. was added NaH (2.0 g, 50.4 mmol). The mixture was warmed to room temperature and stirred for 1 h before methyl iodide (8.56 ml, 137 mmol) was added dropwise, After stirring for an additional 1 h, the mixture was dumped into water (1 l) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to a solid which was recrystallized from ethyl acetate-hexane (5.7 g, 54%), m.p. 118-120° C.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12](NCCCC)CCC.C(O)(=O)C.C=O>C1(C)C=CC=CC=1>[CH2:12]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: O=C1CCCc2ccccc21
Reactant: CCCCNCCCC
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C1CCc2ccccc2C1=O
Temperature: 90 °C

Procedure:
A 100-ml pressure-proof glass reaction vessel was charged with 2.92 g (0.02 mole) of 1-tetralone, 2.59 g (0.02 mole) of di-n-butylamine, 1.20 g (0.02 mole) of acetic acid and 15 ml of toluene. To the mixture 0.974 g (0.012 mole) of an 37% aqueous formaldehyde solution was added and the vessel was sealed and heated up to 90° C. After maintaining the temperature at 90° C. for 30 minutes, the vessel was cooled to room temperature. The contents were separated by addition of 5 ml of water, and the water layer was washed off with a 50% aqueous acetic acid solution. The toluene layer was further washed with a 10% aqueous hydrochloric acid, saturated aqueous NaHCO3 solution and saturated aqueous sodium chloride solution, to give a solution of 2-methylene-1-tetralone in toluene. The reaction mixture was analyzed by GLC and its composition was found to be 1.45 g of 2-methylene-1-tetralone and 1.16 g of unreacted 1-tetralone (the conversion of 1-tetralone: 60.2%; selectivity: 82.1%).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:4].C([O-])(O)=O.[Na+]>CC(O)=O.C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][Br:1])=[CH:11][C:10]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1OCC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(C(=O)CBr)cc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Bromine (4.25 ml; 85 mmol) in AcOH:CHCl3 (1:1; 10 ml) was added to a vigorously stirred solution of the compound of example 20b (25.92 g; 80 mmol) in AcOH:CHCl3 (1:1; 110 ml) at 55-60° C. for 15 min. The mixture was stirred at room temperature for 5 min. and poured over crushed ice and NaHCO3 and extracted with EtOAc. The EtOAc layer was washed with water, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 3% CH3CN in chloroform) to obtain the title compound. Yield, 19.34 g, (60%); mp, 84-85° C. (EtOAc-PE 60-80° C.); analysis: C16H19O7Br: requires C, 47.66; H, 4.75; Br, 19.82. found: C, 48.08; H, 4.82; Br, 19.40%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.CN(C=O)C>O>[Si:14]([O:8][C:5]1[CH:4]=[C:3]([F:9])[C:2]([Cl:1])=[N:7][CH:6]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1cnc(Cl)c(F)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1cnc(Cl)c(F)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-5-fluoropyridin-3-ol (13.1 g), tert-butyl (chloro)diphenylsilane (27.7 mL), 1H-imidazole (7.25 g) and DMF (100 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (29.5 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1nc2ccc(O)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc4nc(C)[nH]c4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
Sodium hydride (71 mg, 1.8 mmol) was added to 5-hydroxy-2-methylbenzimidazole (204 mg, 0.89 mmol) in anhydrous DMF (2.5 ml) under an argon atmosphere. The mixture was stirred at ambient temperature for 10 minutes. 4-Chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol) was added and the reaction mixture stirred at 95° C. for 2 hours. Upon cooling to ambient temperature the mixture was poured in water and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), silica was added and the solvent evaporated off. The obtained powder was placed on the top of a disposable silica column (ISOLUTE) and the product eluted off using a gradient of methanol/dichloromethane (3/97, 5/95, 8/92). Evaporation of the solvent gave 6,7-dimethoxy-4-(2-methyl-1H-benzimidazol-6-yloxy)quinazoline (145 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[N:11]([S:14]([C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])=[O:15])=[C:12]=[O:13]>C(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[C:18]1[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=1[S:14]([NH:11][C:12]([NH:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1)=[O:13])(=[O:15])=[O:16])[CH3:23]
Reactant: COc1cc(Cl)nc(N)n1
Reactant: CCOC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(OC)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 1.0 g of 2-amino-4-chloro-6-methoxypyrimidine suspended in 25 ml of dry CH2Cl2 was added 1.53 g of ethyl 2-(isocyanatosulfonyl)benzoate (prepared by procedures taught in U.S. Pat. No. 4,305,884). The reaction mixture was stirred at ambient temperature for three days. The solvent was stripped and the product was recrystallized from butyl chloride to give a white solid with m.p. 198°-201°.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=O)([C:3](OCC)=[O:4])=[O:2]>CN(C)C=O.[Pt]>[C:13]([C:12]1[CH:11]=[C:10]2[C:9]([NH:8][C:1](=[O:2])[C:3](=[O:4])[N:18]2[OH:20])=[CH:17][CH:16]=1)([OH:15])=[O:14]
Reactant: CCOC(=O)C(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2[nH]c(=O)c(=O)n(O)c2c1
Yield: 69.9 %

Procedure:
A solution of 4-ethoxalylamino-3-nitrobenzoic acid (14.0 g, 49.6 mmol) in 800 ml of N,N-dimethylformamide was hydrogenated at room temperature and atmospheric pressure in the presence of 1.3 g of 5% platinum on carbon for 2.5 h. The catalyst was filtered off and washed with N,N-dimethylformamide. The filtrate was evaporated to dryness and the residue was triturated with 500 ml of water and filtered. The crude product was dissolved in 900 ml of 1M potassium dihydrogen phosphate buffer (pH 7.4) , filtered and reprecipitated with 6M hydrochloric acid to yield 7.7 g (70%) of the title compound. 1H-NMR (DMSO-d6): 7.25 (d, J=9 Hz, 1H, ArH), 7.75 (dd, J=9 Hz, 2 Hz, 1H, ArH), 7.98 (d, J=2 Hz, 1H, ArH), 12.3 (br.s, 1H, exchangeable).