Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH:10]=[O:11])=[CH:8][CH:9]=1)=[O:4].C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][OH:11])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C=O)o1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)o1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A solution of 5-formyl-2-furancarboxylic acid methyl ester in 65 ml of tetrahydrofuran was treated with 14 ml of a 3M solution of methyl magnesium bromide in ether at 0°-5° C. The reaction mixture was stirred at the same temperature for 1 hour, poured into a saturated solution of ammonium chloride and extracted with ether. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated giving 6.3 g (87.8%) of 5-(1-hydroxymethyl)-2-furan carboxylic acid methyl ester as a pale yellow oil after chromatographic purification. The oxidation of this secondary alcohol was carried out by using the Swern oxidation conditions. Thus, 6.3 g of 5-(1-hydroxy- methyl) -2-furancarboxylic acid methyl ester in 60 ml of methylene chloride was added to a stirred solution of 5 g of oxalyl chloride, 7.1 g of dimethyl sulfoxide in 80 ml of methylene chloride at -60° C. The reaction mixture was stirred 15 minutes at the same temperature, then 17.5 ml of triethylamine was added. The cooling bath was removed allowing the temperature to rise to 25° C. The reaction mixture was then treated with 25 ml of water, stirred for 10 minutes and extracted with methylene chloride. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 6.7 g of a brown oil. Chromatographic purification of this material on a silica gel column followed by crystallization from ethyl acetate-hexane gave 3.5 g (56.2%) of 5-acetyl-2-furancarboxylic acid methyl ester as a white solid, mp 101°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4](O)[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1.CCN(S(F)(F)[F:36])CC>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([F:36])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)[C@H](O)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](F)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
To a solution of (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-hydroxy-butyric acid methyl ester (220 mg, 0.524 mmol) is added DAST (0.083 mL, 0.629 mmol) at 0° C. The reaction mixture is gradually warmed to room temperature and stirred for 1 h. Additional DAST (0.083 mL, 0.629 mmol) is added and stirred at room temperature for 2 h. The reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 aqueous solution and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, eluent; heptane/EtOAc=100:0 to 0:100) to give (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-fluoro-butyric acid methyl ester (63 mg). HPLC retention time=1.36 minutes (condition B): MS (m+1-Boc)=322. 1H-NMR (400 MHz, CDCl3) δ ppm 1.39 (s, 9 H), 2.84-2.95 (m, 2 H), 3.06 (bs, 0.5 H), 3.69 (s, 3 H), 4.43-4.61 (m, 1 H), 4.72-4.80 (m, 0.5 H), 5.00 (s, 0.5 H), 5.12 (s, 0.5 H), 7.28-7.34 (m, 3 H), 7.37 (t, 1 H, J=7.58 Hz), 7.42-7.47 (m, 1 H), 7.48-7.53 (m, 1 H), 7.55 (t, 1 H, J=2.02 Hz). 19F-NMR (377 MHz, CDCl3) δ ppm −204.18.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([OH:30])=[C:25]([Br:31])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:33][C:34](=[O:45])[C@H:35](O)[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([O:30][C@@H:35]([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:34]([OH:45])=[O:33])=[C:25]([Br:31])[CH:24]=2)=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](O)CCc1ccccc1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Product: O=C(O)[C@H](CCc1ccccc1)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3,5-dibromo-biphenyl-4-ol, and (R)-(−)-2-hydroxy-4-phenylbutyric acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 85-87° C.; MS m/e 709 (M−H)+;
Reaction SMILES: C(O[CH:4]=[C:5]1[C:9](=[O:10])[O:8][C:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[N:6]1)C.[CH:21](=[N:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH:21](=[N:28][CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([CH:4]=[C:5]2[C:9](=[O:10])[O:8][C:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)=[N:6]2)[CH2:34][CH2:35]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C(=NCC1CCNCC1)c1ccccc1
Reactant: CCOC=C1N=C(c2cccc3ccccc23)OC1=O
Solvent: C1CCOC1
Product: O=C1OC(c2cccc3ccccc23)=NC1=CN1CCC(CN=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-ethoxymethylene-2-naphthalen-1-yl-4H-oxazol-5-one (11.40 g, 43 mmol) in tetrahydrofuran, benzylidene-piperidin-4-ylmethyl-amine (8.60 g, 43 mmol) was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure to yield 4-{4-[(benzylidene-amino)-methyl]-piperidin-1-ylmethylene}-2-naphthalen-1-yl-4H-oxazol-5-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:5]=[CH:6][CH:7]=O.[C:13]([CH2:15][C:16]([N-:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])#[N:14].N1CCCCC1.Cl>C(O)C.O>[CH2:19]([NH:18][C:16](/[C:15](=[CH:7]/[CH:6]=[CH:5]/[C:4]1[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=1)/[C:13]#[N:14])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=CC=Cc1ccc(O)c(O)c1
Reactant: N#CCC(=O)[N-]Cc1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: N#C/C(=C\C=C\c1ccc(O)c(O)c1)C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 68 %

Procedure:
To 3,4-dihydroxycinnamaldehyde A12 (example 59) (32 mg, 0.2 mmol) and amide A3 (Example 4) (32 mg, 0.2 mmol) in 8 mL of ethanol 40 μl of piperidine was added and the mixture was kept at room temperature for 1 h. 2N HCl and water were added and the precipitated solid was recrystallized from ethanol-water to give 44 mg (68%) of an orange solid. The analytical data were identical to the compound prepared as described in Example 8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH: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:6][CH:7]=1.[F-].[Cs+].CS(O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(=O)=O>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
4-[(3-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-ol (3, 500 mg, 1.565 mmol) was dissolved in DMA (20 ml). tert-Butyl(4-methanesulfonyloxy)piperidine-1-carboxylate (436.6 mg, 1.565 mmol) and cesium fluoride (236.3 mg, 1.565 mmol) were added, and the mixture was heated to 60° C. with stirring. After 18 hours, tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride were again added in the same quantities to the reaction mixture and heating was continued at 60° C. for a further 18 hours. The solvent was evaporated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and EtOAc (2×50 mL). The organics were combined, dried over MgSO4 and evaporated. The crudes were then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/EtOAc (100/0 to 0/100). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-({4-[(3-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate as a colourless foam (757 mg, 96%); 1H NMR Spectrum: (DMSO-d6): 1.52 (s, 9H), 1.60-1.80 (m, 2H), 2.02-2.20 (m, 2H), 3.20-3.45 (m, 2H), 3.75-3.92 (m, 2H), 4.05 (s, 3H), 4.95 (m, 1H), 7.32-7.45 (m, 2H), 7.55-7.70 (m, 2H), 7.92 (s, 1H), 8.50 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H)+ 503.08.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([Cl:25])[CH:21]=1)[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: Clc1cc(Cl)cc(OC2CCN(Cc3ccccc3)C2)c1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2cc(Cl)cc(Cl)c2)C1
Temperature: 5 °C

Procedure:
To a stirred solution of 200 ml of 2 molar phosgene in benzene under nitrogen gas was added dropwise over a 3 hr period, a solution of 115 g (0.358 mole) of 1-benzyl-3-(3,5-dichlorophenoxy)pyrrolidine in 100 ml of benzene. The resulting solution was concentrated on a rotary evaporator to give an oil. The oil was triturated three times with boiling 30/60 petroleum ether, decanting each time. The oil residue solidified on cooling. The solid was taken up in benzene and the solution filtered, charcoaled and filtered. Crystalline product was obtained by adding ligroin and cooling to 5° C. in the amount of 92.7 g (87.9%), m.p. 105°-107° C. A purer 3 g sample, m.p. 106°-108° C. was obtained from the petroleum ether on standing.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14]#[CH:15])[CH3:5].C(O)(=O)C>C(OCC)C>[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14]1[CH:15]=[CH:3][NH:1][N:2]=1)[CH3:5]
Reactant: C=[N+]=[N-]
Reactant: C#Cc1ncccc1C(=O)OCC
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1cccnc1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An excess of diazomethane in diethylether at 0° is added to 3.91 g of 2-ethynylnicotinic acid ethyl ester and the solution allowed to warm to RT and let stand overnight. Acetic acid is added until no further gas evolves and the mixture is extracted with brine, dried over MgSO4, filtered and the solvent removed by evaporation under vacuum to yield the title compound as an oil.
Reaction SMILES: O.Cl.[CH2:3]([NH:7][NH2:8])[CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14]>O1CCCC1>[CH2:11]([NH:15][C:16]([N:7]([CH2:3][CH2:4][CH2:5][CH3:6])[NH2:8])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNN
Reactant: CCCCN=C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCNC(=O)N(N)CCCC
Yield: 53.4 %

Procedure:
To a cooled (water bath), stirred mixture of 2.42 g n-butylhydrazine hydrochloride in 15 mL tetrahydrofuran was added 1.7 g powdered potassium hydroxide. The resulting mixture was stirred and maintained under a nitrogen atmosphere as n-butyl isocyanate (1.49 g, 0.015 moles) in 30 mL tetrahydrofuran was added dropwise. After addition, the solution was stirred overnight at ambient temperature. Work up as in Example 5 above yielded 1.5 g N,1-dibutylhydrazinecarboxamide b.p. 135°-6° C. at 0.08 torr, m.p. 34°-36° C. This structure was confirmed by NMR analysis.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:11])([CH3:10])[C:5](=[O:9])[CH2:6][C:7]#[N:8].[OH-].[Na+].Cl.[NH2:15]O.Cl>C(O)C.O>[CH3:1][O:2][CH2:3][C:4]([C:5]1[O:9][N:8]=[C:7]([NH2:15])[CH:6]=1)([CH3:11])[CH3:10]
Reactant: NO
Reactant: COCC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCC(C)(C)c1cc(N)no1
Temperature: 25 °C
Yield: 31.6 %

Procedure:
To a mixture of 5-methoxy-4,4-dimethyl-3-oxopentanenitrile (1 g, 6.5 mmol) in ethanol (100 mL), was added 96% sodium hydroxide (308 mg, 7.70 mmol). To this was added a solution of hydroxylamine hydrochloride (537 mg, 7.70 mmol) in water (100 mL). The resulting solution (pH 7.8) was stirred at 60° C. for 22 h, then cooled to room temperature. To this was added concentrated hydrochloric acid (3 mL, 36 mmol) and the mixture refluxed (80° C.) for 1 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and the residue was mixed with 30% sodium hydroxide (2.1 g). The mixture was shaken with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. Purification via silica gel chromatography afforded 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine as a colorless solid (350 mg, 32%). 1H NMR (300 MHz, CDCl3) δ 5.60 (s, 1H), 3.39 (s, 2H), 3.32 (s, 3H), 2.94 (brs, 2H), 1.28 (s, 6H); LC-MS (ESI) m/z 171 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=3[CH:12]=2)=[CH:7][CH:6]=1.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.B(Cl)(Cl)Cl>CO.C(Cl)Cl>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=3[C:12]=2[C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Yield: 89.6 %

Procedure:
A 250 mL, 3 neck, round bottomed flask fitted with a mechanical agitator and connected to a sodium hydroxide scrubber is purged with nitrogen and charged with 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene (5.3 g, 19.6 mmol), p-anisoyl chloride (3.68 g, 21.56 mmol), and 100 mL of methylene chloride. To this slurry at 20° C. is added boron trichloride (3.4 mL, 39.8 mmol) which had been condensed in a graduated cylinder. The reaction mixture is quenched after 40 minutes by the slow addition of 50 mL of methanol over approximately 5 minutes followed by addition of 50 mL of water over 5 minutes. The organic phase is washed with 50 mL brine, dried over sodium sulfate, filtered, and concentrated affording a dark orange oil. Addition of 10 mL of methanol followed by sonication for 5 minutes resulted in crystallization of 7.1 g of crude product as a yellow solid. The crude material is recrystallized from 3:1 hexanes/toluene affording 5.9 g of product as pale yellow crystals. (75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH3:13])[CH:6]=[CH:5]2.Br[CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[CH:16][CH:15]=1)[CH3:13])[CH:6]=[CH:5]2
Reactant: COC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1ccc2cc(Cl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(N(C)c2ccc3cc(Cl)ccc3n2)cc1
Reaction time: 16 h

Procedure:
A mixture of 4-[N-(6-chloro-2-quinolinyl)-N-methylamino]phenol (1.1 g), methyl 2-bromopropionate (1.3 ml), anhydrous potassium carbonate (0.7 g) and acetone (20 ml) was heated under reflux with stirring for a period of 16 hours. The acetone was removed by distillation under reduced pressure and the residue was partitioned between water and chloroform. The chloroform extracts were dried (anhydrous MgSO4) and the solvent was evaporated. The residue was chromatographed over silica gel (40 g) with chloroform elution to give methyl 2-{4-[N-(6-chloro-2-quinolinyl)-N-methylamino]-phenoxy}propionate (1.05 g) as a colourless oil. Proton magnetic resonance spectrum (CDCl3 ; δ ppm); 8.0-6.6 (9H, m, quinoline and phenoxy protons); 4.9 (1H, q, CH--CH3); 3.9 (3H, s, OCH3); 3.6 (3H, s, N--CH3); 1.6 (3H, d, CHCH3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[S:21][C:22]([CH3:24])=[CH:23][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[N:26]1([C:32]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1N2CCN(CC2)C1.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[S:21][C:22]([CH3:24])=[CH:23][C:8]=2[C:7]=1[N:29]1[CH2:30][CH2:31][N:26]([C:32]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:33])[CH2:27][CH2:28]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(C)sc2n(Cc2cccc(F)c2)c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(C)sc2n(Cc2cccc(F)c2)c1=O
Yield: 65.8 %

Procedure:
A solution of 4-chloro-7-(3-fluoro-benzyl)-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester (70) (3.0 g, 7.89 mmol), piperazin-1-yl-thiophen-2-yl-methanone (1.78 g, 9.09 mmol), and DABCO (1.02 g, 9.09 mmol) in anhydrous DMF was heated overnight at 110° C. The solution was cooled and poured into a 2% ammonium chloride aqueous solution. The precipitated solid was collected by vacuum filtration. The solid was redissolved in dichloromethane and filtered. The filtrate was concentrated under vacuum and the residue was purified by flash chromatography eluting with 0-5% MeOH in CH2Cl2 gradient to yield 2.8 g (65%) of 7-(3-fluoro-benzyl)-2-methyl-6-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6) δ 1.29 (t, J=7.2 Hz, 3H), 2.43 (s, 3H), 3.29 (m, 4H), 3.81 (m, 4H), 4.26 (q, J=7.2 Hz, 2H), 5.23 (s, 2H), 6.99 (d, J=1.2 Hz, 1H), 7.06-7.16 (m, 4H), 7.41 (m, 1H), 7.46 (dd, J=1.2, 4.0 Hz, 1H), 7.79 (dd, J=1.2, 4.8 Hz, 1H); EIMS m/z 540(M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccc2ccccc2n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc3ccccc3n2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-aminomethyl-quinoline dihydrochloride and DBU in DME. ES-MS m/e (%): 343 (M+H+, 100).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH:5]([C:7]([O:9]C)=[O:8])[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.O.[OH-].[Li+]>C1COCC1.O>[C:14]([O:13][C:11]([N:4]1[CH:5]([C:7]([OH:9])=[O:8])[CH2:6][S:2](=[O:1])(=[O:18])[CH2:3]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1CS(=O)(=O)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CS(=O)(=O)CC1C(=O)O
Yield: 92 %

Procedure:
A solution of O3-tert-butyl O4-methyl 1,1-dioxo-1,3-thiazolidine-3,4-dicarboxylate (Example 127 a, 0.35 g, 1.25 mmol) and lithium hydroxide hydrate (63.1 mg, 1.5 mmol) in THF (3.5 mL) and water (1.05 mL) was stirred for 20 h at ambient temperature. The reaction mixture was poured onto ice/0.1N HCl (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/brine (1×25 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the title compound (306 mg, 92%) as colorless foam, MS (ESI) m/e=264.05 [M−H−].
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])[CH:2]=[CH2:3].C1N2CN3CN(C2)CN1C3.Cl.[C:23](O)(=[O:25])C>>[CH2:1]([C:4]1[CH:9]=[C:8]([CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])[CH:23]=[O:25])[CH:2]=[CH2:3]
Reactant: C=CCc1cccc(C)c1O
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: C=CCc1cc(C=O)cc(C)c1O
Temperature: 25 °C

Procedure:
2-Allyl-6-methylphenol (7.6 g, 0.051 mol) and urotropin (hexamethylenetetramine, 11.9 g, 0.085 mol) were heated under reflux in 50 ml of 50% conc. acetic acid for 4½ hours. Subsequently, 56 ml of half-concentrated hydrochloric acid were then added to the hot reaction solution. The solution was heated under reflux for a further half hour. After cooling to room temperature, the precipitated solid was filtered off, washed with a little water and dried at room temperature under vacuum.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[NH:16][C:15]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[NH:16][C:15]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1[nH]c2cc(N3CCCC3)c(F)cc2c(=O)n1OCc1ccccc1
Yield: 86.6 %

Procedure:
Pyrrolidine (0.065 mL, 0.8 mmol) was added to a solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 0.2 g, 0.65 mmol) and triethylamine (0.18 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 18 hours, cooled, and filtered to give 0.2 g of the title compound as a solid, mp>250° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH:22]=[CH:21][C:11]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][C:8]1=[O:9])=[O:5])C.[OH-].[Na+].Cl>O>[C:4]([CH2:6][N:7]1[CH:22]=[CH:21][C:11]([NH:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:10][C:8]1=[O:9])([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Compound 7 (1.38 g, 4.6 mmol) and NaOH (0.36 g, 9.2 mmol) were dissolved in water (10 mL) and the solution was stirred at room temperature for 2 h. Then the pH was adjusted to 3 using 1M HCl. The precipitate formed was separated by filtration, washed with 5 mL water and dried in vacuo to afford 3 as a white solid (1.16 g, 92%); ESI-MS m/z 274 [M+H]+; 1H NMR (400 MHz, D2O, sodium salt): δ7.78 (d, 1H, J=7.2 Hz), 7.75 (d, 2H, J=7.2H), 7.55 (t, 1H, J=7.2 Hz), 7.39 (t, 2H, J=7.2 Hz), 7.19 (d, 1H, J=7.2 Hz), 4.31 (s, 2H).