Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].[C:10]([NH:17][CH2:18][C:19](O)=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][C:19](=[O:20])[CH2:18][NH:17][C:10](=[O:11])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C#Cc1cccc(N)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1cccc(NC(=O)CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3-Ethynylaniline (1.0 g, 8.54 mmol), N-Boc glycine (2.7 g, 15.41 mmol) and PyBOP (8.1 g, 15.41 mmol) were combined in dichloromethane (25 mL). Diisopropylethylamine (3.3 g, 25.61 mmol) was added to the solution and the mixture was allowed to stir at room temperature under argon for 10 h. The reaction mixture was diluted with dichloromethane and then washed successively with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 95:5 hexanes:ethyl acetate to yield tert-butyl 2-(3-ethynylphenylamino)-2-oxoethylcarbamate. 1H NMR (CDCl3): 8.45 (br s, 1H), 7.62 (m, 1H), 7.58 (m, 1H), 7.30 (m, 2H), 5.38 (br s, 1H), 3.95 (d, 2H), 3.08 (s, 1H), 1.48 ppm (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cn1cncc1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cncn2C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.2 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (846 mg, 5.9 mmol) was dissolved in anhydrous DMF (40 mL), then potassium carbonate (2.46 g, 17.8 mmol) and 5-(bromomethyl)-1-methyl-1H-imidazole (1.56 g, 8.9 mmol) were added. The mixture was stirred for 4 hours at room temperature. The solid was removed by filtration, washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford 6-methyl-2-{[(1-methyl-1H-imidazol-5-yl)methyl]sulfanyl}pyrimidin-4-ol (589 mg, 42% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 3.61 (s, 314), 4.44 (s, 2H), 6.02 (s, 1H), 6.88 (s, 1H), 7.56 (s, 1H); LRMS (ES+) m/z 237 (100%, M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:35][O:36][CH2:37][C:38](O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH2:38][CH2:37][O:36][CH3:35])[CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: COCC(=O)O
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Product: COCCN(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O

Procedure:
Similarly to Method B in Example 43 and using 4-(6-chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino}-2-piperazinone (200 mg) and methoxyacetic acid (4 ml) instead of acetic acid, the title compound (123 mg) was obtained as colorless crystals.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][NH:16][CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:33])C.[SH-].[Na+]>O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([OH:33])[CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)NCSC12
Agent: [Na+]
Agent: [SH-]
Solvent: O
Product: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(O)C2C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of benzyl 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (635 mg.) and cupric sulfate pentahydrate (75 mg.) in a mixed solution of acetic acid (4 ml.) and water (0.4 ml.) was stirred at room temperature. After stirring for 100 minutes, an additional cupric sulfate pentahydrate (300 mg.) was added thereto and the mixture was stirred for additional 1.5 hours. The reaction mixture was cooled to 10° C. and sodium bisulfide (86 mg.) was added thereto. The resultant mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was taken up into ethyl acetate, washed with a dilute aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride. Drying over magnesium sulfate and removal of the solvent gave a residue (648 mg.), which was chromatographed on silica gel (20 g.) with a mixed solvent of benzene and ethyl acetate (5:1 to 2:1 by volume) to give an oil (307 mg.), which was crystallized from diethyl ether to afford benzyl 7-phenoxyacetamido-8-oxo-3-hydroxy-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (300 mg.), mp 184°-186° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH2:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])[CH3:9].[CH3:18][S:19][C:20]1[S:21][CH:22]=[C:23]([C:25](Cl)=[O:26])[N:24]=1>C1COCC1>[CH3:9][C:8]([NH:17][C:25]([C:23]1[N:24]=[C:20]([S:19][CH3:18])[S:21][CH:22]=1)=[O:26])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: CC(C)(N)c1ccccc1
Reactant: CSc1nc(C(=O)Cl)cs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1nc(C(=O)NC(C)(C)c2ccccc2)cs1
Reaction time: 0.25 h

Procedure:
Triethylamine (2.24 ml) was added to a solution of cumylamine (3.2 ml) in anhydrous THF (30 ml). After stirring for 15 min, a solution of 2-(methylthio)-4 -thiazolecarbonyl chloride (Intermediate 12; 3.1 g) in anhydrous THF was added and the reaction mixture was concentrated in vacuo after 15 min. The residue was partitioned with EtOAc and water, dried with MgSO4, and concentrated to an orange oil. Flash purification on silica gel with isocratic elution of DCM yielded the product as a yellow oil (3.7 g). MS (ES) MH+: 293 for C14H16N2OS2; NMR: 1.68 (s, 6H), 2.76 (s, 3H), 7.20 (d, J=7.16 Hz, 1H), 7.29 (t, J=7.54 Hz, 2H), 7.36-7.41 (m, 2H), 8.04 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: [C:1](/[N:4]=[CH:5]/[N:6]([CH3:8])[CH3:7])(=[S:3])[NH2:2].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[CH3:7][N:6]([CH3:8])/[CH:5]=[N:4]/[C:1](=[S:3])[NH:2][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)/C=N/C(N)=S
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN(C)/C=N/C(=S)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
(E)-N′-carbamothioyl-N,N-dimethylformimidamide (63) (5 g, 38 mmol), tritylchloride (11.6 g, 41.8 mmol) and trietheylamine (16 mL, 114 mmol) were refluxed in dichloromethane overnight. The reaction mixture was cooled to room temperature and filtered through a plug of celite. The resulting filtrate was washed with saturated sodium bicarbonate solution, followed with brine. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel column (40%-100% EtOAc in hexanes) to afford (E)-N,N-dimethyl-N′-(tritylcarbamothioyl) formimidamide (64) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6](=N)[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[S:20])[N:3]1[CH2:21][CH2:22][CH2:23][OH:24].Cl.C[OH:28]>>[CH3:1][C:2]1([CH3:25])[C:6](=[O:28])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:18])([F:19])[F:17])[CH:9]=2)[C:4](=[S:20])[N:3]1[CH2:21][CH2:22][CH2:23][OH:24]
Reactant: CC1(C)C(=N)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1CCCO
Reactant: CO
Agent: Cl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1CCCO
Temperature: 0 °C
Yield: 68 %

Procedure:
To a solution of compound 4a (627 mg, 1.7 mmol) in methanol (27 mL) was added 2N aqueous hydrogen chloride (5.2 mL). The solution was refluxed for 90 min and then poured in an ice/water solution. The solution was extracted with ethyl acetate (3×30 mL), washed with brine, and dried over magnesium sulphate to give 428 mg (68%) of desired compound 5a. 1H NMR (400 MHz, Acetone-d6) δ: 1.65 (s, 6H), 3.67 (q, 2H, J=5.7 Hz), 3.75 (t, 1H, J=5.01 Hz), 3.90 (m, 2H), 8.03 (d, 1H, J=6.4 Hz), 8.18 (s, 1H), 8.26 (d, 1H, J=8.26 Hz).
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:15])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].Cl[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Cl.[Cl-].[K+]>O1CCCC1.ClCCl>[CH2:9]1[O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:15][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:14][CH2:13][CH2:12][O:11][CH2:10]1
Reactant: OCCOCCOCCOCCO
Reactant: ClCCOCCCl
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C1COCCOCCOCCOCCOCCO1
Reaction time: 18 h
Yield: 119.9 %

Procedure:
A 3 l three-necked round-bottomed flask, fitted with a mechanical stirrer, a reflux condenser and a 250-ml dropping funnel was charged with potassium hydroxide pellets (416 g. containing 6.3 mol KOH), tetraethylene glycol (1.25 mol) and tetrahydrofuran (1000 ml). The reaction vessel was placed in a heating mantle and gently heated. After 15 minutes a solution of bis(2-chloroethyl) ether (3.125 mol) in tetrahydrofuran (150 ml) was added in one stream from the dropping funnel to the vigorously stirred reactants. The reaction mixture was then heated under reflux, with stirring for 18 hours. Subsequently, the reaction mixture was cooled and boiled down under a pressure of 1.9 kPa to give a brown slurry to which dichloromethane (750 ml) was added. The resulting suspension of potassium chloride was filtered and the potassium chloride filtered off was washed with dichloromethane (100 ml). The combined filtrate and washings were dried over anhydrous magnesium sulphate and the solvent was evaporated at a pressure of 1.9 kPa to give a residue of crude 18 -crown-6 (396 g) containing 0.531 mol of 18-crown-6 (yield 42.5%, calculated on starting tetraethylene glycol), potassium chloride and at least eight other compounds among which 1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxacyclohexatriacontane, hexaethylene glycol and unreacted tetraethylene glycol. The crude 18-crown-6 was used as described hereinafter.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][C:60]([F:64])([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[O:24][CH2:61][C:60]([F:64])([F:63])[F:59])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: FC(F)(F)COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (150 mg, 0.355 mmol), 1,1′-(azodicarbonyl)dipiperdine (179 mg, 0.709 mmol) in tetrahydrofuran (7.5 mL) was added tri(n-butyl)phosphine (0.177 mL, 0.709 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2,2-trifluoroethanol (0.259 mL, 3.55 mmol) was added to the reaction mixture. The mixture was stirred at 65° C. for 15 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (102.9 mg, 0.204 mmol, 57%) as colorless crystals.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])(=[O:3])[NH2:2].[C:13]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C>C(O)C.O=[Pt]=O>[C:13]([N:21]1[CH2:26][CH2:25][CH:24]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][C:1](=[O:3])[NH2:2])[CH2:23][CH2:22]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: NC(=O)CCc1ccccc1N
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)CCc1ccccc1NC1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
2-(2-Carbamoylethyl)aniline (37 g) and 1-benzoyl-4-oxopiperidine (67.6 g) are dissolved in ethanol (500 ml) and to the solution is added acetic acid to adjust the pH of the solution to about 5.5. To the solution is further added PtO2 (1 g) and the mixture is stirred under 1 atm. at room temperature under H2 atmosphere. When H2 is absorbed up to 5 liters, the reaction is stopped and the catalyst is separated by filtration. The filtrate is concentrated to give N-(1-benzoyl-4-piperidinyl)-2-(2-carbamoylethyl)aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:22].[OH-].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[O:22])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccc(Sc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A mixture of 4-(4-chlorophenylthio)benzaldehyde (3.63 mmol, 900 mg), 3-chloroperoxybenzoic acid (max 77%, 3.63 mmol, 813 mg) and CH2Cl2 (5.00 mL), was stirred at room temperature for 60 min and poured into a separatory funnel with 5% aqueous KOH solution (10 mL). The phases were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were washed with water (10 mL), brine (50 mL) and dried over MgSO4. Removal of solvents in vacuo gave a light yellow liquid. Purification by flash column chromatography (eluent: 5% EtOAc in Hexane) provided 4-[(4-chlorophenyl)sulfinyl]benzaldehyde (500 mg, 52.2% yield) as a light yellow solid. 1H NMR (CDCl3) δ 10.04 (s, 1H), 7.98 (d, J=8.2 Hz, 2H), 7.82 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][S:25]([CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)(=[O:27])=[O:26]>>[CH:19]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][N:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=5)[CH:23]=[CH:22][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2cnn(CS(C)(=O)=O)c2)OC1(C)C
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CS(C)(=O)=O)c3)ccc1-2

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 was reacted with 1-Methanesulfonylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give 430. MS(ESI+) 471.1. 1H NMR (400 MHz, DMSO) δ 8.36 (m, 2H), 8.19 (s, 1H), 8.10 (s, 1H), 7.49 (dd, J=8.3, 1.8, 1H), 7.36 (d, J=1.7, 1H), 5.84 (m, 1H), 5.75 (s, 2H), 4.40 (t, J=5.0, 2H), 3.46 (t, J=5.0, 2H), 3.06 (s, 3H), 1.56 (d, J=6.6, 6H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[O:21]([CH2:28][CH2:29]O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:29][CH2:28][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(OCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.81 g) in dimethylformamide (25 mL) under argon was treated with 55% sodium hydride (0.437 g), stirred for 15 minutes and treated with the mesylate of 2-phenoxyethanol (2.38 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The crude residue in dichloromethane was passed through a plug of silica gel (5 g) and evaporated and the resulting solids were crystallized from diethyl ether-hexane to give 1.85 g of alpha-oxo-4-[[2-(phenoxy)ethyl]oxy]benzeneacetic acid methyl ester mp 79°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[O:14])[O:12][CH:13]=2)=[CH:5][CH:4]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:10][C:11](=[O:14])[O:12][C:13]=2[CH:16]([CH3:17])[C:15]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(-c2coc(=O)[nH]2)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)C(C)c1oc(=O)[nH]c1-c1ccc(OC)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
4-(4-Methoxyphenyl)-2-oxo-4-oxazoline (1.00 g), methyl acrylate (0.94 mL) was dissolved in toluene (20 mL) and boron trifluoride etherate (1.31 mL) was added. The obtained mixture was heated to 90° C., and after stirring for 2 h, the solvent was concentrated under reduced pressure to give an oily substance. The obtained oily substance was subjected to silica gel column chromatography and eluted with n-hexane-ethyl acetate (1:1). The solvent was evaporated and the obtained oil was crystallized from ethanol. Isopropyl ether (10 mL) was added and the mixture was stirred at not higher than 5° C. for 1 h. The crystals were collected by filtration and washed with isopropyl ether to give the title compound (0.30 g; yield 20.7%) as gray-white crystals.
Reaction SMILES: C1(O[C:8]([N:10]2[C:16]([CH3:17])=[CH:15][C:14]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=3[C:12]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([CH3:32])[CH:24]=3)=[N:11]2)=[O:9])C=CC=CC=1.[CH3:33][NH2:34]>C(O)C>[CH3:33][NH:34][C:8]([N:10]1[C:16]([CH3:17])=[CH:15][C:14]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=2[C:12]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([CH3:32])[CH:24]=2)=[N:11]1)=[O:9]
Reactant: CC1=Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])c(C)c2)=NN1C(=O)Oc1ccccc1
Reactant: CN
Solvent: CCO
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2C=C1C
Yield: 87 %

Procedure:
11.86 g (26.4 mmoles) of 8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3H-2,3-benzodiazepine-3-carboxylic acid phenyl ester are stirred with a solution of 43 ml of methylamine (˜8M) in ethanol at room temperature for 24 hours. The separated crystals are filtered off and washed with ethanol. Thus 8.87 g (87%) of the desired compound (yellow) melting at 196-198° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].C(Br)[CH2:36][CH2:37][CH2:38][CH2:39][Br:40]>CN(C)C=O>[Br:40][CH2:39][CH2:38][CH2:37][CH2:36][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCCBr)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (70 mg), potassium carbonate (30 mg), and pentamethylene bromide (80 μl) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 43 mg (yield 46%) of N-(4-{[7-(4-bromobutoxy)-6-methoxy-4-quinazolinyl]-oxy}-2-chlorophenyl)-N′-propylurea as an intermediate. The intermediate (43 mg), potassium carbonate (30 mg), and morpholine (40 μl) were dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 23 mg (yield 53%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[C:35]([Cl:40])=[C:34]([Cl:41])[CH:33]=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:34]1[CH:33]=[CH:32][C:31]2[N:30]([CH2:42][C:43]([NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=3[CH3:1])=[O:44])[C:29]3[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:39][CH2:38][C:37]=3[C:36]=2[C:35]=1[Cl:40]
Reactant: Cc1cccc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Cn2c3c(c4c(Cl)c(Cl)ccc42)CCN(C(=O)OC(C)(C)C)CC3)c1C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
DMAP (89 mg, 0.73 mmol), 2,3-dimethylaniline (98 mg, 0.81 mmol) and DIC (0.13 mL, 0.81 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.30 g, 0.73 mmol) in dry THF (3.5 mL). After 4 h, additional 2,3-dimethylaniline (0.049 mL, 0.40 mmol) and THF (2 mL) was added. The reaction was diluted with EtOAc after 25 h followed by washing with 10% aqueous citric acid (75 mL), saturated aqueous NaHCO3 (40 mL), and brine (40 mL). A precipitate in the combined organic layers was filtered to yield 0.22 g (58%) white solid: mp 232.5-233.0° C.; 1H NMR (DMSO, 400 MHz) δ 9.77 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.13 (d, J=6.8 Hz, 1H), 7.03 (m, 2H), 5.11 (s, 2H), 3.64 (m, 4H), 3.39 (m, 2H), 3.03 (m, 2H), 2.24 (s, 3H), 2.09 (s, 3H), 1.41 (s, 9H); IR (diffuse reflectance) 2977, 1692, 1659, 1541, 1474, 1451, 1412, 1366, 1303, 1269, 1201, 1174, 1112, 791, 773 cm−1; MS (EI) m/z 515 (M+), 376, 226, 224, 212, 189, 149, 133, 119, 55, 52; HRMS (EI) calcd for C27H31Cl2N3O3 515.1743, found 515.1747.