Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[CH:7](=O)[C:8]1[C:9]([O:14][CH3:15])=[CH:10][CH:11]=[CH:12][CH:13]=1>O>[CH:7](=[CH:3][C:4](=[O:5])[CH3:6])[C:8]1[C:9]([O:14][CH3:15])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)=O
Reactant: COc1ccccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1C=CC(C)=O
Reaction time: 2 h

Procedure:
O-Anisalacetone is prepared by adding 70 ml of 10% aqueous sodium hydroxide to 7.7 moles of acetone, 280 ml of water, and 2.8 moles of o-anisaldehyde, slowly with cooling to maintain the temperature in the range of 25°-31° C. Another 2 hours stirring followed by acidification, separation of layers, dehydration with acid in benzene at reflux, and finally distillation at reduced pressure gives the crude o-anisalacetone.
Reaction SMILES: [CH2:1]([S:4][C@:5]1([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25]([O:27]C)=[O:26])[CH2:6]1)[CH:2]=[CH2:3].O.[OH-].[Li+]>C1COCC1.CO.O>[OH2:18].[CH2:1]([S:4][C@:5]1([C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:33][CH:34]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([CH3:13])([CH3:14])[CH3:15])[C@H:7]([C:25]([OH:27])=[O:26])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Reaction time: 24 h
Yield: 173.1 %

Procedure:
To a solution of (2S,4R)-methyl 4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylate (362 mg, 0.639 mmol) in THF (5 mL) and MeOH (5.00 mL) was added pre-made solution of lithium hydroxide hydrate (80 mg, 1.916 mmol) in Water (5 mL). The resulting cloudy solution was stirred at room for 24 h. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid (312 mg, 0.553 mmol, 87% yield) as a white solid. LC-MS (retention time: 2.96 min, method B), MS m/z 553 (M+H).
Reaction SMILES: [Li]CCCC.CCCCCC.[F:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].CC(C)([O-])C.[K+].[C:32](=[O:34])=[O:33]>C1COCC1.O>[F:12][C:13]1[C:21]([C:32]([OH:34])=[O:33])=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][C:14]=1[C:22]([F:25])([F:23])[F:24]
Reactant: O=C=O
Reactant: Fc1cc2[nH]ccc2cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C(O)c1c(F)c(C(F)(F)F)cc2cc[nH]c12
Temperature: -78 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A 1.6 molar solution of n-BuLi in hexane (1.38 ml, 2.2 mmol) was diluted with 3 ml THF and cooled to −78° C. Then, a solution of 203 mg of 6-fluoro-5-trifluoromethyl-1H-indole (1 mmol) in 1 ml THF was added dropwise, keeping the internal temperature below −70° C. After 5 min a solution of 269 mg potassium tert-butoxide (2.4 mmol) in 1 ml THF was added, again keeping the internal temperature below −70° C. The reaction mixture was then stirred for 2 h. Then dry ice was added and the mixture was allowed to warm to 10° C. Water was added and the phases were separated. The aqueous phase was washed twice with ether, then acidified with 1 N HCl solution and extracted several times with DCM. The combined DCM extracts were dried with magnesium sulfate, filtered and the solvent was evaporated. The remaining residue was triturated with pentane. Final filtration yielded 105 mg (42%) of 6-fluoro-5-trifluoromethyl-1H-indole-7-carboxylic acid as an off-white solid. 1H-NMR (DMSO-d6, 300 MHz): δ 6.63 (m, 1H), 7.43 (t, J=3 Hz, 1H), 8.15 (d, J=7 Hz, 1H), 11.49 (br s, 1H), 13.70 (br s, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[Br:20][C:21]1[C:22]([O:31][CH3:32])=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=[O:25]>>[Br:20][C:21]1[C:22]([O:31][CH3:32])=[C:23]([CH:24]([OH:25])[C:9]#[C:8][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C=O)c(OC)c1Br
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1ccc(C(O)C#Cc2ccccc2)c(OC)c1Br
Yield: 59 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 3-bromo-2,4-dimethoxy-benzaldehyde (0.80 g, 3.26 mmol) [prepared as described in Helv. Chim, Acta, 1990, 73, 48], was reacted to give the title compound (0.67 g, 59%). 1H NMR (400 MHz, DMSO-d6): δ 7.67-7.62 (d, 1H), 7.45-7.35 (m, 5H), 7.01-6.96 (d, 1H), 6.14-6.11 (d, 1H), 5.78-5.74 (d, 1H), 3.88-3.84 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([O:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[C:22]2[C:29]([CH3:30])=[C:28]([C:31](O)=[O:32])[S:27][C:23]=2[N:24]=[CH:25][N:26]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C.C1COCC1.CO>[F:19][C:17]1[CH:16]=[CH:15][C:14]([NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31](=[O:32])[NH:35][CH3:34])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)=[C:13]([CH:18]=1)[O:12][CH:10]([CH3:11])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC(C)CNC(=O)OC(C)(C)C)c12
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)CNC(=O)OC(C)(C)C)c2c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(2-(1-(tert-Butoxycarbonylamino)propan-2-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (80 mg) in DMF (1 ml), TBTU (54 mg) and triethylamine (60 μl) were added. The mixture was stirred at room temperature for 5 min then methylamine in THF (2M; 420 μl) was added and the reaction stirred at room temperature overnight. The mixture was diluted with methanol and purified directly by RP-chromatography (water with 0.2% trifluoroacetic acid/methanol 72-100%) to give the title compound.
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10](=O)[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[NH2:2][C:1]1[S:29][C:10]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[N:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C#N)NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2c(F)cccc2F)sc1N
Temperature: 95 °C
Reaction time: 48 h

Procedure:
To a solution of the ethyl 2-cyano-2-(2,6-difluorobenzamido)acetate (1 eq) in 10 mL of toluene was added Lawesson reagent. The mixture was stirred at 95° C. for 2 days. Solvents were removed under reduced pressure. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to give the ethyl 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylate, which was dissolved in 5 mL of methanol and 5 mL of THF. Then the mixture was added 1M sodium hydroxide (2 eq). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated to remove most of solvents. The residue was extracted with ethyl acetate. The aqueous layer was acidified to pH=4-5 by 1N HCl. The resulting mixture was extracted by ethyl acetate. The organic layer was separated, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. to give the pure titled compound (34%). LC/MS (m/z): 257.1 (MH+), Rt:0.61 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=2)[CH2:9][O:10][CH2:11][C:12]#[C:13][CH2:14][OH:15])=[CH:2]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=2)[CH2:9][O:10][CH2:11]/[CH:12]=[CH:13]/[CH2:14][OH:15])=[CH:2]1
Reactant: OCC#CCOCc1cccc(-c2ccsc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OC/C=C/COCc1cccc(-c2ccsc2)c1
Reaction time: 2 h
Yield: 57.9 %

Procedure:
0.48 g of the resulting alcohol compound was dissolved in 5 ml of tetarahydrofuran, and under a nitrogen atmosphere, a tetrahydrofuran solution (5 ml) of 78 mg of lithium aluminum hydride was added. The mixture was stirred under ice cooling for 2 hours, and then at room temperature for 1 hour. Ethyl acetate and water were added, and the organic layer separated was worked up in a customary manner. The product was purified by silica gel column chromatography [hexane / ethyl acetate=4/1] to give 0.28 g of the captioned compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](/[N:8]=[CH:9]/N(C)C)=[N:6][CH:7]=1.Cl[CH2:14][C:15](=[O:17])[CH3:16].C([O-])(O)=O.[Na+]>CC(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:14]([C:15](=[O:17])[CH3:16])=[CH:9][N:8]=2)[CH:7]=1
Reactant: CC(=O)CCl
Reactant: CN(C)/C=N/c1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)c1cnc2ccc(Br)cn12
Yield: 47.5 %

Procedure:
(E)-N′-(5-Bromopyridin-2-yl)-N,N-dimethylformimidamide (2.0 g, 8.8 mmol), 1-chloropropan-2-one (1.2 mL, 1.4 g, 15 mmol), NaHCO3 (1.3 g, 15.5 mmol) in 2-propanol (30 mL) were heated at 90° C. under nitrogen for 12 h. The dark reaction mixture was cooled and the dense heterogeneous suspension was diluted with water. The solid was collected by filtration, washed with water and dried to obtain 1.0 g of 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)ethan-1-one. 1H NMR (300 MHz, DMSO-d6) δ 9.62 (d, J=1.9 Hz, 1H), 8.61 (s, 1H), 7.81 (d, J=9.5 Hz, 1H), 7.75 (dd, J=9.5, 1.9 Hz, 1H), 2.55 (s, 3H). See Bioorg. Med. Chem. Lett. 15(1), 403-412 (2007); Int'l Pat. App. Pub, no. 2009/158011.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[CH3:14][O:15][C:16]1[CH:41]=[CH:40][C:19]([CH2:20][N:21]([C:35]2[S:36][CH:37]=[CH:38][N:39]=2)[S:22]([C:25]2[CH:26]=[CH:27][C:28]3[NH:33][CH2:32][CH2:31][O:30][C:29]=3[CH:34]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.BrC1N=C(N(CC2C=CC(OC)=CC=2)S(C2C=CC3N(C4C=CC(C(F)(F)F)=CC=4Cl)CCOC=3C=2)(=O)=O)SN=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:6]([C:5]([O:4][C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[N:33]1[CH2:32][CH2:31][O:30][C:29]2[CH:34]=[C:25]([S:22]([N:21]([CH2:20][C:19]3[CH:40]=[CH:41][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[C:35]3[S:36][CH:37]=[CH:38][N:39]=3)(=[O:23])=[O:24])[CH:26]=[CH:27][C:28]1=2)([CH3:9])[CH3:8])#[N:7]
Reactant: CC(C)(C#N)Oc1ccccc1Br
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: COc1ccc(CN(c2nc(Br)ns2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2Cl)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OC(C)(C)C#N)cc1
Yield: 15.9 %

Procedure:
A microwave vial containing a suspension of 2-(2-bromophenoxy)-2-methylpropanenitrile (0.173 g, 0.719 mmol), N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 0.2 g, 0.479 mmol), sodium t-butoxide (0.117 ml, 0.958 mmol), Xantphos (0.111 g, 0.192 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.088 g, 0.096 mmol) in toluene (9.58 ml) was purged with nitrogen and was microwave irradiated at 110° C. for 30 min. Reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaCl solution. Organic layer was concentrated and purified by preperative LC/MS-2 System Column: XBridge 19×100 mm 12230326114 03 Mobile phase: 0.1% NH4OH in water/acetonitrile Flow rate: 40 ml/min Inj: 2200 uL. Gradient: 10 min5-50% shallow; 10 min10-60% shallow to obtain 4-(2-((2-cyanopropan-2-yl)oxy)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (44 mg, 0.076 mmol, 16% yield). To the material was then added DCM (1 mL) and TFA (4 drops) and stirred at ambient temperature for 2 h The reaction mixture was concentrated and purified by preperative LC/MS-2 System Column: XBridge 19×100 mm 12230326114 03 Mobile phase: 0.1% NH4OH in water/acetonitrile Flow rate: 40 ml/min Inj: 2200 uL. Gradient: 10 min5-50% shallow; 10 min10-60% shallow to obtain 4-(2-((2-cyanopropan-2-yl)oxy)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (3.8 mg, 0.008 mmol, 1.6% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.43 (dd, J=8.12, 1.28 Hz, 1 H) 7.39 (dd, J=7.85, 1.55 Hz, 1 H) 7.31-7.37 (m, 1 H) 7.21-7.27 (m, 1 H) 7.11-7.14 (m, 2 H) 7.08 (dd, J=8.55, 2.14 Hz, 1 H) 6.66 (d, J=4.38 Hz, 1 H) 6.34 (d, J=8.44 Hz, 1 H) 5.75 (s, 1 H) 4.26-4.32 (m, 2 H) 3.60-3.65 (m, 2 H) 1.55 (br. s., 6 H); MS (ESI, positive ion) m/z; 457.0 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].O>O1CCOCC1.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>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(Cl)nc1Cl
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: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2ccc(N)cc2)nc1Cl
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
2.89 mmol (500 mg) of 2,6-dichloronicotinonitrile and 3.18 mmol (551 mg, 1.1 eq.) of 4-aminophenylboronic acid are dissolved under an inert atmosphere in 33.3 ml of dioxane. 680 mg (8.09 mmol, 2.8 eq.) of sodium bicarbonate and then 8.3 ml of water are subsequently added. The mixture is stirred for 5 minutes under an inert atmosphere and then 334 mg (0.29 mmol, 0.1 eq.) of tetrakis(triphenylphosphine)palladium are added. The reaction mixture is brought to reflux (100° C.) for 2 hours and is then cooled to ambient temperature. The reaction medium is filtered and then extracted four times with ethyl acetate. The organic phases are combined, washed twice with a saturated aqueous sodium chloride solution, dried with magnesium sulphate, and concentrated. A yellow solid is then obtained. This crude is purified on a column of 90 g of silica, with an eluent gradient of 20% to 50% of ethyl acetate in heptane. The expected product is obtained in the form of a yellow solid (531 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:26](=[O:27])[N:25]([CH3:29])[CH3:24])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(CNC(=O)N(C)C)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) in acetonitrile (10 mL), was added dimethyl carbamyl chloride (0.21 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-1,1-dimethyl-urea as an off-white solid (290 mg, 52% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min. 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 4.66 min (98.7%); mp, 264-268° C.; 1HNMR (DMSO-d6) 2.14-2.20 (m, 1H, CH), 2.56-2.86 (m, 12H, N(CH3)2, CHCH2, CH3), 4.31 (d, J=5 Hz, 2H, CH—NH), 5.26 (dd, J=6, 11 Hz, 1H, C H, 7.00 (t, f=5 Hz, 1H, CH2NH), 7.54-7.89 (m, 3H, Ar), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ20.95, 23.38, 30.61, 35.85, 43.20, 56.49, 119.88, 123.54, 126.30, 133.91, 139.98, 145.59, 154.27, 158.09, 160.50, 169.49, 172.62. LCMS MH=372; Anal Calcd For C18H21N5O4+0.5H2O: C, 56.83; H, 5.83; N, 18.41. Found: C, 56.71; H, 5.81; N, 18.18.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:11])[O:7][CH2:8]2)=[CH:4][C:3]=1[O:12][C:13](=[O:15])[CH3:14].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[OH:1][C:2]1[C:10]([N+:16]([O-:18])=[O:17])=[C:9]2[C:5]([C:6](=[O:11])[O:7][CH2:8]2)=[CH:4][C:3]=1[O:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)Oc1cc2c(cc1O)COC2=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Oc1cc2c(c([N+](=O)[O-])c1O)COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic acid 6-hydroxy-3-oxo-1,3-dihydro-isobenzofuran-5-yl ester (3.8 g) was mixed with acetic acid (150 ml) followed by addition of 65% nitric acid (2.5 ml). After dissolution the mixture was stirred at room temperature for 2 hours followed by removal of the acetic acid and water in vacuo. The remainder was filtered through silica gel using a mixture of toluene, ethyl acetate and methanol (8:1:1) as eluent. Appropriate fractions were collected and evaporated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10](OS(C(F)(F)F)(=O)=O)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].B1([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)OC(C)(C)C(C)(C)O1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:52]2[CH:53]=[CH:54][N:55]=[CH:56][CH:57]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccncc1
Temperature: 95 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(trifluoromethanesulfonyl)oxybenzoate (1.43 g, 2.8149 mmol) in toluene (32 ml) were added tetrakistriphenylphosphine palladium (98 mg, 0.0848 mmol), aqueous solution of sodium carbonate (2M aqueous solution, 3.66 ml), lithium chloride (239 mg, 5.6381 mmol) and ethanolic solution (5.9 ml) of pyridine-4-boronic acid pinacol cyclic ester (866 mg, 4.2243 mmol) and the mixture was heated with stirring at 95° C. for 16 hours. The reaction solution was diluted with ethyl acetate (200 ml), washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (910 mg, 2.0823 mmol, 74%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: CC1Cc2ccccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 59 %

Procedure:
The product is prepared according to the procedure described in example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 510 mg of 2-methyl-2,3-dihydro-1H-indole, and 487 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.308 ml of pyridine and 8 ml of N,N-dimethylformamide. 400 mg of 2-[2-(2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:8]([C:11]#[N:12])=[N:9][CH:10]=1)=[O:5])C.[OH-:21].[K+].Cl>CCO.O>[C:11]([C:8]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]([C:4]([OH:3])=[O:5])=[CH:10][N:9]=1)(=[O:21])[NH2:12]
Reactant: CCOC(=O)c1cnc(C#N)n1COCC[Si](C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1c(C(=O)O)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-cyano-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carboxylic acid ethyl ester (prepared in the previous step)(0.28 g, 0.95 mmol) in 10 mL of 50% EtOH/H2O was added a 2 N KOH soln (0.95 mL, 1.9 mmol) and the mixture stirred for 8 h at RT. The pH was adjusted to 4 with 3 N HCl and the ppt was collected and dried to give 0.24 g (88%) of a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 13.39 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 6.29 (s, 2H), 3.57 (t, J=7.8 Hz, 2H), 0.87 (t, J=7.8 Hz, 2H), 0.00 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C11H19N3O4Si, 286.1 (M+H), found 285.8.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]([CH:26](O)[CH2:27][CH3:28])[C:10]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>O1CCCC1.ClCCl.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:9](=[CH:26][CH2:27][CH3:28])[C:10]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:7]1
Reactant: CCC(O)C1C(N2CCN(C)CC2)=Nc2ccccc2N=C1N1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC=C1C(N2CCN(C)CC2)=Nc2ccccc2N=C1N1CCN(C)CC1
Temperature: 0 °C
Yield: 85.1 %

Procedure:
To a suspension of 1-[2,4-bis(4-methyl-1-piperazinyl)-3H-[1,5]benzodiazepin-3-yl]-1-propanol (1.195 g, 3 mmol), triethylamine (2.50 ml, 18 mmol) and pyridine (0.024 ml, 0.3 mmol) in tetrahydrofuran (10 ml) under constant flow of argon, at 0° C., a solution of trifluoroacetic anhydride (1.26 ml, 9 mmol) in tetrahydrofuran (5 ml) was added dropwise. The reaction mixture was stirred for another hour at 0° C. Methanol (5 ml) was added. The solution was allowed to warm to 10° C., while strongly agitated NaOH (1 M, 20 ml) was added dropwise. Dichloromethane (30 ml) was added and the phases were separated. The organic phase was dried over anhydrous Na2SO4 and the solvent was evaporated at reduced pressure. The crude product was suspended in isopropyl ether (8 ml) and filtered off. The filtrate was evaporated at reduced pressure to give 0.971 g (84%) of the title compound as a yellow resin. The product obtained was characterized using 1H-NMR spectroscopy and was found to be identical to the product obtained by method A.