Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH3:6][O:7][CH2:8][CH2:9]Br.C(N(CC)CC)C>C(#N)C>[CH3:6][O:7][CH2:8][CH2:9][N:2]([CH2:3][CH2:4][OH:5])[CH3:1]
Reactant: COCCBr
Reactant: CNCCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCN(C)CCO
Temperature: 25 °C
Yield: 31.3 %

Procedure:
A mixture of 2-methylaminoethanol (5.4 g), 2-bromoethyl methyl ether (10 g), triethylamine (10 ml) and acetonitrile (70 ml) was stirred and heated to reflux for 16 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was triturated under diethyl ether. The organic solution was separated and evaporated to give 2-[N-(2-methoxyethyl)-N-methylamino]ethanol (3 g, 31%); NMR Spectrum: (CDCl3) 2.35 (s, 3H), 2.6 (t, 2H), 2.65 (t, 2H), 3.35 (s, 3H), 3.5 (t, 2H), 3.6 (t, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][C:8]([OH:10])=[O:9].[CH2:17](O)[CH3:18]>>[ClH:3].[NH2:5][CH:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][C:8]([O:10][CH2:17][CH3:18])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: NC(CC(=O)O)c1cccnc1
Reactant: CCO
Product: CCOC(=O)CC(N)c1cccnc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To 40 mL of stirred ethanol at 0° C. under nitrogen was slowly added thionyl chloride (3.3 mL, 45 mmol) followed by addition of 3-amino-3-(3-pyridyl)propionic acid (2.65 g, 15 mmol). The reaction mixture was allowed to slowly warm to room temperature and then refluxed for 3 hours. After 2 hours at reflux all of the solid had dissolved. The reaction mixture was allowed to cool to room temperature and stirred overnight. The slurry was filtered and the solid was washed with copious amounts of ethanol. The solid was dried in vacuo (60° C., <1 mm) to afford 3.17 g (79%) of ethyl 3-amino-3-(3-pyridyl)propionate hydrochloride as a white powder: 1H NMR (DMSO-d6, 250 MHz) δ9.32 (br s, 3H), 9.21 (br s, 1H), 8.87-8.95 (m, 2H), 8.09-8.14 (m, 1H), 4.93 (br s, 1H), 3.90-4.15 (m, 2H), 3.20-3.38 (m, 2H), 1.11 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ168.8, 144.5, 142.8, 142.6, 136.2, 126.7, 60.7, 47.9, 37.2, 13.9.
Reaction SMILES: C(O[CH:7]([CH2:32][O:33]C1C=CC(C(=O)C(F)(F)F)=CC=1)[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](SCCC(O)=O)[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)CCCC.[O:46]1[CH:51]=[CH:50][CH2:49][CH2:48][CH2:47]1.CC1C=CC(S([O-])(=O)=[O:60])=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[O:33]1[CH2:32][CH:7]1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:60][CH:51]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:15]=1
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCCCCOC(COc1ccc(C(=O)C(F)(F)F)cc1)COc1ccc(C(CCCc2ccccc2)SCCC(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: c1ccc(CCCC(OC2CCCCO2)c2ccc(OCC3CO3)cc2)cc1
Reaction time: 4 h

Procedure:
A solution of the product (5 g) of Step 1 in 150 mL of CH2Cl2 was treated with 10 mL of dihydropyran and 20 mg of PPTS. The mixture was stirred for 4 hrs. at r.t. and then quenched with 0.2 mL of Et3N. Evaporation of solvent gave 5.5 g of the crude title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[C:5]([C:7]#[N:8])[N:6]=1.O.[Sn](Cl)[Cl:21]>C(O)(C)C.Cl>[ClH:21].[CH3:1][C:2]1[S:3][C:4]2[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:7]([NH2:8])[C:5]=2[N:6]=1
Reactant: Cl[Sn]Cl
Reactant: Cc1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Cc1nc2c(s1)Nc1ccccc1N=C2N
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
Combine a suspension of 2-methyl-5-(2-nitroanilino)thiazole-4-nitrile (36 g,; 138.5 mmol) in isopropanol (400 ml) in a 2.0 liter 3-necked RB flask equipped with a reflux condenser, thermometer, magnetic stirrer bar and heat with stirring to 65° C. (orange solution obtained). Add tin (II) chloride hydrate (78.7 g; 415.4 mmol) in hydrochloric acid (400 ml; 5M) and heat the resulting solution at reflux. After 2.5 h., cool the reaction to 15° C., filter the suspension, wash with isopropanol/water (2:1) and dry at 50° C. under reduced pressure to leave a yellow solid (36.7 g). Evaporate the filtrate to around 200 mL to form a yellow slurry. Filter the slurry again and dry at 50° C. under reduced pressure to leave a yellow solid (10 g). Combine the solid and suspend in 1 N HCl (700 mL) and heat to reflux for 20 min, cool to 15° C. Filter the resulting yellow slurry and dry at 50° C. under reduced pressure to leave a yellow solid (32.4 g, 88%): mass spectrum (m/e): 231 (M+1); 1HNMR(300 MHz, DMSO, ppm): 2.5 (s, 3H), 6.78 (dd, 1H), 6.85 (dd, 1H), 6.98 (t, 1H), 7.02 (t, 1H), 8.80 (s, 1H), 9.10 (s, 1H), 9.98 (s, 1H), 10.78 (s, 1H). 13CNMR(75 MHz, DMSO, ppm): 19.6, 120.1, 120.8, 123.6, 125.8, 127.8, 129.2, 137.6, 154.4, 159.3, 160.4. Formula C11H11N4S.
Reaction SMILES: [CH2:1]([Si:4]([Cl:7])(Cl)Cl)[CH:2]=[CH2:3].N12CCCN=C1CCCCC2.[CH3:19][O:20][C:21]([CH3:32])([C@H:23]([OH:31])[C@@H:24]([OH:30])[C:25]([O:28][CH3:29])([CH3:27])[CH3:26])[CH3:22]>C(Cl)Cl>[CH2:1]([Si:4]1([Cl:7])[O:30][C@@H:24]([C:25]([O:28][CH3:29])([CH3:26])[CH3:27])[C@H:23]([C:21]([CH3:32])([O:20][CH3:19])[CH3:22])[O:31]1)[CH:2]=[CH2:3]
Reactant: C=CC[Si](Cl)(Cl)Cl
Reactant: COC(C)(C)[C@H](O)[C@@H](O)C(C)(C)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CC[Si]1(Cl)O[C@@H](C(C)(C)OC)[C@H](C(C)(C)OC)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
Preparation of (4R,5R)-2-allyl-2-chloro-4,5-bis-(1-methoxy-1-methyl-[1,3,2]dioxasilolane: To a cooled (0° C.) solution of allyltrichlorosilane (7.0 mL; 48 mmol) in CH2Cl2 (80 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (15 mL; 102 mmol). A solution of (3R,4R)-2,5-dimethoxy-2,5-dimethyl-hexane-3,4-diol (10.0 g; 48 mmol) in CH2Cl2 (80 mL) was then added and the mixture was allowed to warm to ambient temperature and stirred for 12 hours. The solution was concentrated and the residue was treated with diethylether (100 mL). The mixture was stirred for 1 hour. The mixture was then filtered and the filtrate was concentrated. The residue was distilled under reduced pressure to give 6.6 g (44%) of (4R,5R)-2-allyl-2-chloro-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolane as a clear, colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH2:21])=O)[CH:14]=3)[O:9][CH:8]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:7]2)[N:6]=1.CCN(C(C)C)C(C)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH2:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:21])[CH:14]=3)[O:9][CH:8]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:7]2)[N:6]=1
Reactant: NC(=O)c1cccc(-c2ccc3c(c2)C2(CSC(N)=N2)CC(c2ccccc2)O3)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CSC(N)=N2)CC(c2ccccc2)O3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To a solution of 3-(2′-amino-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzamide (20 mg, 0.048 mmol) and DIEA (21 mg, 0.096 mmol) in CH2Cl2 was added TFAA (0.2 mL) at 0. The mixture was stirred at room temperature for 1 h and concentrated to give the residue, which was purified by preparative TLC to give 3-(2′-amino-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzonitrile (1.53 mg, 8%). 1H-NMR (MeOD): 2.27 (m, 2H), 3.36 (m, 1H), 3.84 (m, 1H), 5.24 (m, 1H), 6.92 (m, 1H), 7.31 (m, 4H), 7.48 (m, 4H), 7.81 (m, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]([C:12]1[CH:28]=[CH:27][C:15]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)C(C)C)C>C1C=CC=CC=1>[O:5]([C:12]1[CH:28]=[CH:27][C:15]([N:16]([C:1](=[O:3])[CH3:2])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: c1ccc(Oc2ccc(NCc3ccc4c(c3)OCO4)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CC(=O)N(Cc1ccc2c(c1)OCO2)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.2 ml of acetyl chloride dissolved in 10 ml of anhydrous benzene is added dropwise at 0°-5° C. in the course of one hour, with stirring, to a solution of 12.7 g of 4-phenoxy-N-(3,4-methylenedioxybenzyl)-aniline and 6 g of N-ethyl-diisopropylamine in 100 ml of anhydrous benzene. The whole is subsequently heated to room temperature and stirred for a further 8 hours. The precipitated N-ethyl-diisopropylamine-hydrochloride is separated by filtration; the filtrate is washed with 10% sodium carbonate solution and then with water. After drying of the organic phase by means of sodium sulphate, the benzene is distilled off in vacuo, and the residue recrystallised in hexane to obtain 4-phenoxy-N-acetyl-N-(3,4-methylenedioxybenzyl)-aniline, M.P. 75°-76° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:16])[CH:11]=2)[CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].C(S([C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])=[CH:30][N:29]=1)(=O)=O)C.CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])=[CH:30][N:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:16])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c2cc(Br)ccc2c1
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(Oc2cc(C(=O)OC)cc3ccc(Br)cc23)nc1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of 6-bromo-4-hydroxy-naphthalene-2-carboxylic acid methyl ester (423 mg, 1.5 mmol), potassium carbonate (414 mg, 3 mmol), 2,5-bis-ethanesulfonyl-pyridine (420 mg, 1.6 mmol) and N,N-dimethylformamide (4 mL) was vigorously stirred and heated at 100° C. overnight under an argon atmosphere, then cooled to room temperature, and diluted with ethyl acetate (10 mL). The resulting mixture was washed with water (10 mL×3). The combined aqueous layers were extracted with ethyl acetate (10 mL). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel, 100-200 mesh, 30% ethyl acetate in petroleum ether) to give 6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalene-2-carboxylic acid methyl ester (280 mg, 41%, crude yield) as a yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]2[CH:20]=[CH:21][CH:22]=[C:8]2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([O-:28])=[O:27].[Na+]>COCCO>[CH2:13]([N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])=[C:7]([OH:23])[C:8]2=[CH:22][CH:21]=[CH:20][N:9]12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccccc2)c1=O
Yield: 75.3 %

Procedure:
A mixture of 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (78 mg, 0.249 mmol) and sodium glycinate (122 mg, 1.25 mmol) in 2-methoxyethanol (5 mL) was refluxed for 20 h; subsequently, the reaction was cooled and solvent was removed by rotovaping; the residue was dissolved in water and then acidified with 2 M HCl solution; the precipitates were collected via filtration, washed with water and vacuum dried at 50° C. to give the desired product (64 mg) as yellow solid. ESI (m/z): 342 (M+H)+.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:12]=[C:11]([CH:13]=[CH:14][O:15][CH3:16])[CH:10]=[CH:9][C:8]=1[CH:17]([CH3:19])[CH3:18].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[CH:17]([C:8]1[CH:9]=[CH:10][C:11]([CH:13]=[CH:14][O:15][CH3:16])=[CH:12][C:7]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:19])[CH3:18]
Reactant: COC=Cc1ccc(C(C)C)c(Br)c1
Reactant: CCOC(=O)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C=COC)ccc1C(C)C
Reaction time: 1 h
Yield: 220.9 %

Procedure:
tert-BuLi solution (1.7 M in pentane, 800 mL; 1.59 M in pentane, 2L; 4.5 mol total) was added via cannula over 135 minutes under nitrogen into a solution of 1-Bromo-6-isopropyl-3-(2-methoxyvinyl)benzene (C) (500 g, 1.96 mol) in anhydrous THF (3 L) at −50 to −75° C. The mixture was stirred for 1 hour after addition was complete. The solution was then transferred via cannula into a chilled (kept below −50° C.) solution of ethyl chloroformate (562 mL, 5.88 moles) in anhydrous THF (2 L), and the resultant solution was stirred for 68 minutes. The reaction was quenched by addition of 1 L of saturated aqueous NH4Cl with stirring, followed by the addition of 2 L of water. The organic phase was separated, washed with a 10% NaCl solution. The solution was concentrated under vacuum to approximately. Evaporation furnished the crude product as a light yellow or greenish yellow liquid. A total of 3 batches were produced according to the above procedures, and 1.7 kg of crude product was obtained. The crude liquid product was distilled under high vacuum (0.9 mm Hg) and distillates in the range of 158 to 165° C. were collected to obtain 1075 g (yield 73%) of product. The following values were obtained by nuclear magnetic resonance spectroscopy:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][CH2:9][N+:10]([O-:12])=O)([CH3:4])([CH3:3])[CH3:2].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C.C1(N=C=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][C:9]1[CH2:16][CH:15]([C:14]([O:18][CH3:19])=[O:17])[O:12][N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCC[N+](=O)[O-]
Reactant: C=CC(=O)OC
Solvent: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(CCC(=O)OC(C)(C)C)=NO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 18.9 g of 4-nitrobutyric acid t-butyl ester, 8.6 g of methyl acrylate, 0.2 g triethyl amine in 200 ml of toluene is stirred and treated dropwise with 27.4 g of phenyl isocyanate. The mixture is stirred for 72 hours at room temperature and heated at 90° C. for two hours. The mixture is cooled, filtered to remove the diphenyl urea, and concentrated under reduced pressure. The resulting oil is chromatographed on SiO2 (elution with hexane:ethylacetate; 75:25) to yield 4,5-dihydro-5-(methoxycarbonyl)-3-isoxazolepropanoic acid t-butyl ester as a colorless oil. NMR (CDCl3) and 5.00 (t, J=9 Hz, 1H), 3.77 (s, 3HO, 3.28 (d, J=9 Hz, 2H), 2.58 (s, 4H), 1.42 (s, 9H). IR (cm-1) 2955, 2910, 1728, 1545, 1437, 1385, 1370, 1340, 12155, 1215.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCl>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(c1ccc(CBr)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.5 %

Procedure:
A solution of 4-(bromomethyl)benzoic acid (2.43 g, 11.3 mmol) in dichloromethane (40 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (1.83 g, 11.3 mmol). This mixture was allowed to stir at room temperature for 15 minutes. Pyrrolidine (0.8 g, 11.3 mmol) was then added and the stirring continued for 1 hour at room temperature. The reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate and evaporated in vaccuo (i.e under reduced pressure) to give a yellow oil which was added to a 20 g pre-packed silica column and eluted from 20-50% ethyl acetate in petroleum ether to give the title compound as a colourless solid (0.5 g, 17%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[C:5]([C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:4]=1.O.[NH2:25][NH2:26].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[CH2:9][C:10](=[O:11])[NH:25][N:26]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[C:5]=2[CH:4]=1
Reactant: NN
Reactant: COc1ccc(CC(=O)O)c(C(=O)c2ccc([N+](=O)[O-])cc2)c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(c1ccc([N+](=O)[O-])cc1)=NNC(=O)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
7.8 g of 2-(4-methoxy-2-(4-nitrobenzoyl)phenyl)acetic acid is mixed in 200 ml of tetrahydrofuran with 2.3 ml of 80% hydrazine hydrate and stirred for 6 hours at room temperature. After standing overnight, it is mixed with 50 ml of water, and the tetrahydrofuran is drawn off in a rotary evaporator. The precipitated 2-(4-methoxy-2-(4-nitrobenzoyl)phenyl)acetic acid hydrazide (4.9 g) is suctioned off and stirred in 37 ml of glacial acetic acid at room temperature for 2 hours. It is diluted with 37 ml of water and suctioned off. 4.37 g of 8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepin-4-one with a melting point of 282° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]([O:24][CH3:25])[C:13](=[O:23])[CH:14]=[C:15]2[C:19](=[O:20])OC(C)(C)[O:16]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C=O.[CH3:28][NH2:29].[CH3:30]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]([O:24][CH3:25])[C:13]([C:14]2[CH2:28][N:29]([CH3:30])[C:19](=[O:20])[C:15]=2[OH:16])=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN
Reactant: CO
Reactant: CON(CCCc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Agent: C=O
Product: CON(CCCc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 58 %

Procedure:
Reaction of N-[3-(3,4-dichlorophenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide (0.480 g, 1.16 mmol) with the paraformaldehyde-methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.250 g (58% yield) of the title compound as white crystals; mp 106–108° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 2.01 (2H, m, CH2), 2.65 (2H, t, J=7.6 Hz, CH2), 3.14 (3H, s, NCH3), 3.73 (3H, s, OCH3), 3.77 (2H, t, J=7.0 Hz, NCH2), 4.11 (2H, s, NCH2), 7.04 (1H, dd, J=2.0 Hz and J=8.1 Hz, aromatic), 7.30 (1H, d, J=2.0 Hz, aromatic), 7.36 (1H, d, J=8.1 Hz, aromatic), 11.67 (1H, broad s, OH). Anal. Calcd for C16H18Cl2N2O4: C, 51.49; H, 4.86; N, 7.51. Found: C, 51.65; H, 4.90; N, 7.45.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=O)[C:9]([CH3:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][NH2:22].O1CCC[CH2:24]1.C([O-])(O)=O.[Na+]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]3[C:10]([C:9]([CH3:14])([CH3:13])[CH2:8][N:7]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[C:6]=2[N:20]=1)=[N:22][N:21]=[CH:24]3
Reactant: C1CCOC1
Reactant: NN
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2-n2cnnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
2-Chloro-9-cyclopentyl-8,9-dihydro-7,7-dimethyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (0.21 g, 0.73 mmol) in phosphorus oxychloride (6 ml) was heated at 110° C. for 4 hours. The reaction mixture was concentrated in vacuo and redissolved in dichloromethane (4 ml). This latest solution was then added dropwise to a 1M solution of hydrazine in tetrahydrofuran (7.27 ml, 7.27 mmol). The reaction mixture was stirred overnight at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting mixture was dissolved in trimethylorthoformate (4 ml) and heated to 110° C. for 90 minutes. The reactionnel mixture was evaporated in vacuo and purified by silica gel chromatography eluting with ethyl acetate to give the title compound as an off-white solid (0.16 g, 69% yield). NMR DMSO D6 1.37 (6H, s), 1.52-1.88 (8H, m), 3.44 (2H, s), 5.23 (1H, quint.), 8.56 (1H, s), 9.02 (1H, s); MS (ES+) 319.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:4]1[C:5](=[O:16])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:9][C:7]=2[N:8]=[C:3]1[CH2:2][N:29]1[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]1
Reactant: NS(=O)(=O)c1cc2c(=O)n(-c3ccccc3Cl)c(CBr)nc2s1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2nc3sc(S(N)(=O)=O)cc3c(=O)n2-c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3 g of 3,4-dihydro-2-bromomethyl-3-(2-chlorophenyl)-4-oxo-6-sulfamoylthieno[2,3-d]pyrimidine were added 40 ml of dimethylformamide, 0.8 ml of 1-ethylpiperazine and 2.7 g of potassium carbonate, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured onto water, and the mixture was extracted with chloroform. The concentrated residue was purified by silica gel column chromatography, crystallized from ethyl acetate and recrystallized from ethanol to give 320 mg of the title compound, m.p. 203°-204° C. (decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][NH:16][CH3:17]>CO.CN(C=O)C>[CH3:15][N:16]([CH2:11][CH:10]([OH:12])[CH2:9][O:8][C:7]1[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Reactant: CNC
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CC(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Nitrophenoxy)-2,3-epoxypropane (Reference Example 1-B, 4.3 g) was dissolved in methanol (30 ml) and DMF (10 ml). Dimethylamine (2M solution in methanol, 17 ml) was added and the mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in saturated sodium bicarbonate solution and ethyl acetate. The ethyl acetate layer was separated and washed twice with saturated brine, dried over anhydrous sodium sulphate, filtered and evaporated to yield an oil that slowly crystallised under high vacuum (4.79 g, 89.9%). NMR: (CDCl3, 300 MHz) 2.33 (s, 6H), 2.98 (m, 1H), 2.54 (m, 1H), 4.00 (m,3 H), 7.00 (d, 2H), 8.20 (d, 2H); M.S.: (ES+) 241 (MH+).
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[CH2:13]([OH:19])[CH2:14][O:15][CH2:16][CH2:17][OH:18]>ClCCl>[Cl:12][CH2:11][O:10][C:8]([O:19][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:8]([O:10][CH2:11][Cl:12])=[O:9])=[O:9]
Reactant: OCCOCCO
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCl)OCCOCCOC(=O)OCCl
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of chloromethyl chloroformate (1.32 ml, 14.83 mmol) and diethylene glycol (0.47 ml, 5.00 mmol) in dichloromethane (10 ml) at 7° C. with good stirring under a dry N2 atmosphere. After 10 min. at 7° C. and 6 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure (10 mm Hg) to give 1.26 g (86%) title product. 1H NMR (300 MHz, CDCl3): δ 3.72 (m, 2×CH2 --O), 4.34 (m, 2×CH2 --O--C=O), 5.71 (s, 2×Cl--CH2 --O). 13C NMR (75 MHz, CDCl3): δ 67.6 (2×CH2 --O), 68.5 (2×CH2 --O--C=O), 72.1 (2×Cl--CH2 --O), 153.2 (2×C=O).