Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.CCCCCC.O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: O=C(O)c1ccc(CBr)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
In 840 ml of carbon tetrachloride were suspended 100 g of 5-methyl-2-thiophenecarboxylic acid, 125.2 g of N-bromosuccinimide and 7 g of benzoyl peroxide. The suspension was heated to 90° C. with vigorous agitation. After the reaction started, the reaction temperature was raised to 100° C. and agitation was continued for 2 hours at the same temperature. The reaction mixture was cooled to 0° C., and 500 ml of n-hexane was added thereto. Precipitated crystals were collected by filtration and washed with 100 ml of n-hexane. The obtained crude crystals were suspended in 2 of water and the suspension was stirred at room temperature for 10 minutes. The suspended crystals were collected again by filtration and washed with 200 ml of water. The obtained crystals were recrystallized from ethanol-water to give 84 g of the desired 5-bromomethyl-2-thiophenecarboxylic acid as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH:6]=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1.C([O-])=O.[NH4+].C(N(CC)CC)C.CCCCCC>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:16])=[O:8])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(C=C2OC(=O)c3ccccc32)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COc1cccc(CCc2ccccc2C(=O)O)c1
Temperature: 70 °C
Yield: 50.3 %

Procedure:
A solution of 15.6 g of 1 (62 mmol) in 300 ml of THF was added 30 g of 10% Pd-C, 40 g of ammonium formate and 17.2 ml of triethyl amine. The reaction mixture was heated at 70° C. for 6 hours and filtered. The filtrate was concentrated and redissolved in 500 ml of ethyl acetate and washed with 2×150 ml of 3% aqueous HCl and 2×100 ml of brine. The organic layer was concentrated and triturated with 1:1 ethyl acetate:hexane to give 8 g (31.2 mmol, 51%) of 2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1.[H][H]>CCOC(C)=O.CO.[Pd]>[NH:10]1[CH2:11][CH2:12][CH:7]([C@H:5]2[CH2:6][C@H:4]2[CH2:3][CH2:2][OH:1])[CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCC[C@@H]1C[C@@H]1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl 4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (10 g, 33 mmol) was dissolved in 100 mL of EtOAc/MeOH (1:1 v/v), to which was added 1 g of 5% Pd/C and apply hydrogen balloon. After stirring at rt for 1 h, the reaction mixture was filtered through Celite to give the product that was used in the next step without further purification. Rf was 0 @ 50% EtOAc in hexanes (blue spot on CAM stain).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[F:24][C:25]([F:34])([F:33])[CH:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH:29]4[CH2:30][CH2:31][CH:26]([C:25]([F:34])([F:33])[F:24])[CH2:27][CH2:28]4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: OC1CCC(C(F)(F)F)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3cc(OC4CCC(C(F)(F)F)CC4)ccc3c2)COC(=O)N1

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (0.1042 g, 0.0004284 mol) was dissolved in tetrahydrofuran (5.00 mL, 0.0616 mol) in a capped 40 mL vial. 4-Trifluoromethylcyclohexanol (0.101 g, 0.000600 mol) was added, followed by triphenylphosphine (0.180 g, 0.000685 mol) and the mixture was refluxed for 5 minutes. Diisopropyl azodicarboxylate (0.135 mL, 0.000685 mol) was then added and the mixture was heated at reflux overnight. TLC analysis showed that the reaction was complete. The mixture was concentrated to dryness under vacuum and purified by flash chromatography (0-20% EtOAc in methylene chloride).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[O:21])[N:10]=1.Cl.C(O[C:31](=[NH:33])[CH3:32])C.C(N(CC)CC)C>C(O)C>[C:31]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[O:21])[N:10]=1)(=[NH:33])[CH3:32]
Reactant: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2N)c2cc(C)ccc2n1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(C)=N)c2cc(C)ccc2n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of 450 mg of 4-{[(1S,2R)-2-aminocyclohexyl]amino}-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide and 467 mg of ethylacetoimidate hydrochloride in 10 ml of ethanol, 764 mg of triethylamine was added, and the mixture was stirred at 80° C. for 8 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (chloroform:methanol=20:1), whereby 391 mg of a desired compound was obtained as a pale yellow powder.
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[S:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:13]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=2)[CH:18]=1)[C:14]([OH:16])=[O:15]>>[C:3]([S:10][CH:13]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=2)[CH:18]=1)[C:14]([OH:16])=[O:15])(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC(=S)c1ccccc1
Reactant: COc1ccc2cc(C(Cl)C(=O)O)ccc2c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2cc(C(SC(=O)c3ccccc3)C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To 17.5 ml. of 2N alcoholic potassium hydroxide solution (0.035 mole) is added 4.84 g. (0.035 mole) of thiobenzoic acid. The solution is cooled to room temperature and to this is added in small portions 0.035 mole of α-chloro-6-methoxy-2-naphthylacetic acid. The reaction mixture is stirred at room temperature for 25 hours, then the solvent is removed, the residue dissolved in ether, filtered and washed with cold water. The ethereal solution is then dried over magnesium sulfate and evaporated to dryness to obtain α-benzoylthio-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: [CH2:1]=O.[S:3](=[O:6])([OH:5])[O-:4].[Na+].[C:8]([OH:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].S(=O)(O)[O-].Cl>O>[S:3]([CH2:1][NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:8]([OH:17])=[O:16])([OH:5])(=[O:4])=[O:6]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=S([O-])O
Reactant: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1NCS(=O)(=O)O
Temperature: 60 °C

Procedure:
Formaldehyde solution (37%, 31.6 g, 0.4 mol) and sodium bisulfite (38 g, 0.37 mol) were dissolved in water (200 ml) and the stirred mixture warmed to 60° C. Anthranilic acid (50 g, 0.37 mol) was dissolved in water (200 ml) at pH 7, and this solution was added to the bisulfite adduct solution, maintaining the temperature at 60-70° C. for 2 hours. The reaction mixture was allowed to cool slowly before hydrochloric acid was added to precipitate the product as a white solid. The product was collected by filtration and washed with saturated sodium chloride solution and then acetone. The dried product (34 g) contained 22.5% salt.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.C([Li])CCC.CCCCCC.CN(C)[CH:32]=[O:33]>O1CCCC1.O>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([CH:32]=[O:33])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(C=O)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 8-bromo-2-dipropylamino-1,2,3,4-tetrahydronaphthalene (1.68 gm, 5.4 mMol) in tetrahydrofuran (50 mL) at -78° C. was added a solution of n-butyl lithium in hexane (1.6 M, 5.4 mL, 8.6 mMol), and the solution was stirred for one hour at -78° C. To the solution was then added N,N-dimethylformamide (0.3 mL, 5.94 mMol), and the reaction mixture was allowed to warm gradually to room temperature. The reaction mixture was diluted with water (10 mL) and stirred vigorously for one-half hour. The reaction mixture was then extracted with chloroform. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated in vacuo to give a yellow-green oil. Purification by flash chromatography (3% methanol in dichloromethane+tr. NH4OH) gave the title compound as a colorless oil (700 mg, 50%). The maleate salt was formed and crystallized (ethanol/diethyl ether) to give colorless crystals (m.p.=120°-121° C.).
Reaction SMILES: [OH-:1].[K+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[Na].[CH2:12]=O>O.C(O)(=O)C>[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH2:12][OH:1])[N:5]=1
Reactant: Oc1cccnc1Br
Reactant: C=O
Reactant: [OH-]
Agent: [K+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: OCc1ccc(O)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide (85% assay, 113.8 g, 1.73 mol) was dissolved in distilled water (750 ml) and to the solution was added 2-bromo-3-hydroxypyridine (300 g, 1.72 mol), ethylenediaminetetraaeetic acid sodium salt (2 mol %, 13.1 g, 0.034 mol) and formalin (37-41% w/v 470 ml, 5.95 mol). The stirred mixture was heated at 90°-95° C. until the assay (HPLC) of remaining starting material fell below 3% (approx 5 h). The reaction mixture was then cooled to room temperature and glacial acetic acid (103 ml) added and stirred for a further 2 h. The precipitated solid was filtered from the mixture and the filtrate saturated with sodium chloride (310 g). The resulting solution was extracted with ethyl acetate (4×280 ml). The combined organic extracts were dried and evaporated to dryness keeping the temperature below 85° C. The residue was assayed by HPLC to determine the quantity of contained 2-bromo-3-hydroxy-6-hydroxymethylpyridine. The yield was typically 65%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CC2)CC1
Reaction time: 2 h
Yield: 26.7 %

Procedure:
1-(5-chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.063 g, 0.22 mmol) was combined with cyclopropanecarbonyl chloride (0.029 mL, 0.32 mmol) and triethylamine (0.090 mL, 0.64 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromthane) to give the desired product (21 mg, 27%). LCMS calculated for C19H21ClN3O2 (M+H)+: m/z=358.1; Found: 358.0.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:11].[C:12]([CH:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:16]([O:18][CH3:19])=[O:17])(=O)[CH3:13]>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[C:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:16]([O:18][CH3:19])=[O:17])[CH3:13]
Reactant: Nc1ccc2c(c1)CCCC2
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Product: COC(=O)CC(C(=O)OC)=C(C)Nc1ccc2c(c1)CCCC2
Reaction time: 72 h
Yield: 65.6 %

Procedure:
The 5,6,7,8-tetrahydronaphthalen-2-amine (10 g; 68 mmol) and dimethyl acetylsuccinate (11.6 g; 62 mmol) were mixed together, placed in a dessicator and the homogeneous mixture was stirred under vacuum (3 mbars) for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (1 to 20%) in heptane furnished 12.9 g (60%) of dimethyl 2-(1-(5,6,7,8-tetrahydronaphthalen-2-ylamino)ethylidene)succinate as a deep orange oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 25 h
Yield: 90.8 %

Procedure:
To a solution of 6-(benzyloxy)-4-chloro-7-methoxyquinazoline (3.3 g, 0.01097 mol) and 3-aminophenol (1.2 g, 0.01097 mol) in THF (70 mL), Cs2CO3 (5.36 g, 0.0164 mol) was added at room temperature. The reaction mixture was stirred at 75° C. for 25 hr. The mixture was filtered and the solid was washed with ethyl acetate (100 mL). The organic phase was washed with water, brine and dried over MgSO4. The solvent was evaporated under vacuum and the solid was triturated with ethyl ether (20 mL). The solid was filtered and washed with ethyl ether to afford 3-(6-(benzyloxy)-7-methoxyquinazolin-4-yloxy)aniline (3.72 g, 90% yield). 1HNMR (DMSO-d6): δ 8.55 (s, 1H), 7.66 (s, 1H), 7.46 (m, 8H), 7.08 (t, 1H), 6.49 (d, 1H), 6.40 (m, 2H), 5.30 (s, 2H), 4.02 (s, 3H). LC-MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:13]=2[CH:14]=1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[CH2:9][N:10]([C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24])[CH2:11][CH2:12][C:13]=2[CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c([nH]1)CNCC2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc2c([nH]1)CN(C(=O)OCC(Cl)(Cl)Cl)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 2-ethoxycarbonyl-4,5,6,7-tetrahydro-6-azaindole from Example 2 (8 g, 0.041 mole) in dichloromethane (200 ml) and triethylamine (4.15 g, 0.041 mole) was cooled to 0° C. and treated dropwise over 30 minutes with a solution of 2,2,2-trichloroethyl chloroformate (8.69 g, 0.041 mole) in dichloromethane (50 ml) and stirred subsequently for 30 minutes at room temperature. The mixture was quenched with water (50 ml), the organic layer separated, washed with water (50 ml), dried over sodium sulphate and evaporated to give a yellow oil which was chromatographed on silica gel (150 g) eluting with chloroform and chloroform:methanol (99:1) to give the expected pure product as a colourless solid (13.49 g, 89%), m.p. 126.5°-127° C. (from ether/hexane). Found: C, 42.24; H, 4.09; N, 7.54. C13H15Cl3N2O4 requires C, 42,24; H, 4.09; N, 7.58%.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:26]([C:28]1[CH:42]=[CH:41][C:31]([S:32][C:33]2[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1)[CH3:27]>ClCCl>[CH2:26]([C:28]1[CH:42]=[CH:41][C:31]([S:32][C:33]2[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:8]([C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=3[CH3:7])=[O:10])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1)[CH3:27]
Reactant: Cc1nc(C)c(C(=O)O)o1
Reactant: CCc1ccc(Sc2ccc(CN)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCc1ccc(Sc2ccc(CNC(=O)c3oc(C)nc3C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a stirred mixture of 2,4-dimethyl-1,3-oxazole-5-carboxylic acid (155 mg, 1.1 mM) and dichloromethane (20 ml) was added 1,3-dicyclohexylcarbodiimide (227 mg, 1.1 mM) at 0°-10° C., and the mixture was stirred for 30 min at the same temperature. To this was added dropwise a solution (10 ml) of 4-(4-ethylthiophenoxy)benzylamine (285 mg, 1.1 mM) in dichloromethane, and the mixture was stirred for 12 h at room temperature. The mixture was poured into ice water, and the mixture was extracted with dichloromethane. The extract was washed with saturated ammonium chloride solution and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give N-[4-(4-ethylthiophenoxy)benzyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide (164 mg, 39%) as colorless crystals, m.p. 60.0°-64.5° C.
Reaction SMILES: [CH3:1]O.C[Si](C=[N+]=[N-])(C)C.[Br:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:12]([OH:14])=[O:13]>C1(C)C=CC=CC=1>[CH3:1][O:13][C:12](=[O:14])[CH:11]([Br:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: CO
Reactant: O=C(O)C(Br)c1ccccc1Cl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)C(Br)c1ccccc1Cl
Yield: 86 %

Procedure:
Methanol (1 mL) was added to toluene (10 mL) under an argon atmosphere at room temperature. The flask was cooled in a water bath and 2M (trimethylsilyl)diazomethane (5 mL, 10 mmol) was added, followed by α-bromo-2-chlorophenyl acetic acid (2.2 g, 8.81 mmol) in portions over 5 minutes. After 10 additional minutes, the toluene/methanol was removed under reduced pressure. The crude oil was purified by MPLC (companion) on a silica cartridge (40 g) with a gradient of ethyl acetate in heptane (10% to 50%) over 20 minutes. The product containing fractions were combined, concentrated, and dried under high vacuum for 1 hour at room temperature to provide bromo-(2-chlorophenyl)-acetic acid methyl ester (2.0 g, 86% yield) as a clear liquid that solidified at low temperatures (−10° C.). 1H NMR (300 MHz, CDCl3/TMS): δ=7.75 (d, 11-1, J=6.9 Hz), 7.39-7.26 (m, 3H), 5.91 (s, 1H), 3.80 (s, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ=168.29, 133.82, 133.30, 130.93, 130.47, 129.83, 127.66, 53, 80, 43.08.
Reaction SMILES: ClOC(C)(C)C.[Na].[C:8]([NH:20][NH2:21])(=[O:19])[C:9]1[C:10](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:11](NN)=[O:12]>CC(C)=O>[C:8]1(=[O:19])[C:9]2[C:10](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11](=[O:12])[N:21]=[N:20]1
Reactant: NNC(=O)c1ccccc1C(=O)NN
Agent: CC(C)(C)OCl
Agent: [Na]
Solvent: CC(C)=O
Product: O=C1N=NC(=O)c2ccccc21
Reaction time: 2.5 h

Procedure:
To a solution of t-butyl hypochlorite (3.8 g., 0.038 m.) in acetone (200 ml.), cooled to -60° is added the sodium salt of phthalhydrazide (4.8 g., 0.021 m.). After 2.5 hours at -60° to -50°, the green reaction mixture is filtered to give a solution of 1,4-phthalazinedione. 1,3-Cyclohexadiene (2.0 ml.) is added to the cooled green solution (-50°) and white crystals precipitate almost immediately. After 10 minutes at -50°, the crude product (3.0 g.) is collected by filtration. Recrystallization from chloroform/acetone affords white microprisms of 1,4-ethano-1,4-dihydropyridazino[1,2-b]phthalazine-6,11-dione, mp >250° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:11][C:12](Cl)=[O:13].C(N(CC)CC)C.[NH2:22][C:23]1[CH:44]=[CH:43][C:26]([C:27]([N:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH2:33][N:32]3[CH:40]=[CH:41][CH:42]=[C:31]3[CH2:30]2)=[O:28])=[CH:25][CH:24]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH:42]1[CH:41]=[CH:40][N:32]2[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N:29]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:12](=[O:13])[CH2:11][C:3]4[S:4][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=5[C:2]=4[CH3:1])=[CH:44][CH:43]=3)=[O:28])[CH2:30][C:31]=12
Reactant: Cc1c(CC(=O)Cl)sc2ccccc12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CC(=O)Nc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)sc2ccccc12
Reaction time: 0.05 h
Yield: 39.5 %

Procedure:
To a stirred solution of 0.445 g of 3-methylbenzo[b]thiophene-2-acetyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. An additional 0.445 g of 3-methylbenzo[b]thiophene-2-acetyl chloride, 0.346 g of triethylamine and 30 mg of dimethylaminopyridine is added and stirring continued for an additional 18 hours. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.320 g of the desired product as a yellow foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](Cl)(=[O:9])[CH:7]=[CH2:8]>C(#N)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:6](=[O:9])[CH:7]=[CH2:8]
Reactant: C=CC(=O)Cl
Reactant: NCCCO
Solvent: CC#N
Product: C=CC(=O)NCCCO

Procedure:
To a 250 mL, four-neck round bottom flask equipped with a mechanical stirrer, a thermometer, a 100 mL dropping funnel, and a nitrogen inlet/outlet, 30.0 g of 1-amino-3-propanol (0.4 mole), and 100 mL of acetonitrile were added. The mixture was cooled below 0° C. with an ice/water bath. To this solution, 18.1 g of freshly distilled acryloyl chloride (0.2 mole) in 50 mL of acetonitrile was added through the dropping funnel. The addition rate was controlled so that the reaction temperature was kept below 0° C. After the addition was finished and the agitation was turned off, the reaction solution separated into two liquid phases. The bottom layer viscous salt solution phase was discarded. To the top layer acetonitrile solution phase, 100 mL of deionized water was added. After removing all acetonitrile by vacuum distillation, the aqueous solution was passed through a mixed bed ion-exchange column packed with 20 g of Dowex MR-3C resin. A total of 76 grams of eluate was collected. The final solution has the following properties: HPLC and FT-IR analysis indicates there is no ester formation; HPAA concentration: 7.2% (wt/wt); pH=5.6 at 25° C; Conductivity=56.6 μS/cm at 25° C.; Viscosity=1.1 cPs at 25° C. The relative low yield of HPAA is due to the fact that HPAA is soluble in the salt phase. HPAA in the salt phase can be recovered by acetone extraction since HPAA is soluble in acetone, and the salt is insoluble.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:11][CH:10]([CH3:13])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][C:6]=2[S:5][CH:4]=1)=[CH2:2]>C1COCC1.CO.[Pd]>[CH2:1]([C:3]1[C:12]2[O:11][CH:10]([CH3:13])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:7][C:6]=2[S:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of tert-butyl 8-ethenyl-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (231 mg) in THF-MeOH (2:1, 15 mL) was added 10% palladium on carbon (50 mg), and the mixture was stirred for 1 hr under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→15% ethyl acetate/hexane) to give the title compound (195 mg, 84%) as a colorless oil.