Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([CH2:17][CH2:18][CH3:19])=[N:14][C:15]=2[CH3:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[OH-:20].[K+].Cl[CH2:23]Cl.O>CO>[F:12][C:7]1[CH:6]=[C:5]2[C:10]([N:11]=[C:2]([O:20][CH3:23])[C:3]3[N:4]2[C:13]([CH2:17][CH2:18][CH3:19])=[N:14][C:15]=3[CH3:16])=[CH:9][CH:8]=1
Reactant: ClCCl
Reactant: [OH-]
Reactant: CCCc1nc(C)c2c(Cl)nc3ccc(F)cc3n12
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCc1nc(C)c2c(OC)nc3ccc(F)cc3n12

Procedure:
560 mg 4-Chloro-8-fluoro-3-methyl-1-propyl-imidazo(1,5-a)quinoxaline (2 mmol) were dissolved in 10 ml methanol and 500 mg potassium hydroxide were added. The reaction was heated to reflux for 2 hours, cooled, and distributed between 50 ml dichloromethane and 20 ml water. The separated water phase was extracted again with 50 ml dichloromethane. The combined organic layers were washed with 25 ml water and distilled to dryness.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[CH2:10]([OH:13])[C:11]#[CH:12]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:13][CH2:10][C:11]#[C:12][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6]
Reactant: NCc1cccc(I)c1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: NCc1cccc(C#CCO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Cuprous iodide (1.06 mg, 0.0056 mmol) was added to a mixture of (PPh3)2PdCl2 (7.84 mg, 0.011 mmol) and 3-iodobenzylamine (262 mg, 1.12 mmol) in dry diethylamine (7 mL) under a nitrogen atmosphere. Then a solution of propargyl alcohol (41.2 μL, 0.73 mmol) in dry diethylamine (3 mL) was added. The resulting solution was stirred at room temperature for 3 h. The solvent was concentrated in vacuo and the residue was partitioned between water (20 mL) and CHCl3 (20 mL). The aqueous phase was separated and extracted with CHCl3 (20 mL×2). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by PTLC (chloroform/methanol 9:1) to give 72 (106 mg, 90% yield). 1H NMR (CDCl3, 300 MHz) δ 7.39-7.26 (m, 4H), 4.48 (s, 2H), 3.85 (s, 2H), 1.73 (br s,22H). MS (m/e) (positive FAB) 162.1 (M+H)+.
Reaction SMILES: CN(C)C=O.[CH3:6][C@@:7]1([CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[N:13]=[C:12]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:9][O:8]1.[N:31]1([C:37]([O:39][CH2:40][CH:41]=[CH:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.O>C(OCC)(=O)C>[N+:16]([C:14]1[N:13]=[C:12]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[N:11]([CH2:10][C@:7]([OH:8])([CH3:6])[CH2:9][N:34]2[CH2:33][CH2:32][N:31]([C:37]([O:39][CH2:40][CH:41]=[CH:42][C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:51])([F:52])[F:50])=[CH:45][CH:44]=3)=[O:38])[CH2:36][CH2:35]2)[CH:15]=1)([O-:18])=[O:17]
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CO1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 67.4 %

Procedure:
N,N-Dimethylformamide (0.18 ml) solution of (R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrobenzenesulfonyl)imidazole (36 mg) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazin-1-carboxylate (34 mg) was stirred at 60° C. for 1 day. To the reaction mixture was added water and ethyl acetate, the organic layer was taken by separation. The ethyl acetate layer was washed with water and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfonate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/methanol=30/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(4-nitrobenzenesulfonyl)imidazol-1-yl]-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (45 mg, yield: 67%) as pale yellow amorphous product.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][C:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].[NH2:44][CH2:45][CH2:46][C:47]1[N:51]=[CH:50][NH:49][CH:48]=1.[OH-].[Na+]>ClCCl.CN(C)C=O.O>[CH:16]1([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:32]([NH:44][CH2:45][CH2:46][C:47]3[N:51]=[CH:50][NH:49][CH:48]=3)=[O:33])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:10][CH2:9]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCc1c[nH]cn1
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(Cl)c(Cl)c2)NC(=O)NCCc2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
60 mg (11 mmol) of ethyl 1-[(R)-2-amino-3-(3,4-dichlorophenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate and 29 mg (0.12 mmol) of para-nitrophenyl chloroformate are dissolved in 5 ml of dichloromethane. The mixture is stirred for 1 hour at room temperature and the solution is then poured into water and extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated. The colourless oil obtained is diluted in 5 ml of dimethylformamide, the mixture is heated to 80° C., and 18 mg (0.12 mmol) of histamine are added and the solution is stirred for 5 minutes at 80° C. and overnight at room temperature. The reaction is stopped by adding aqueous 1N sodium hydroxide solution and the organic compounds are extracted with dichloromethane. The organic phase is washed with water and then dried over sodium sulfate, filtered and concentrated. The oil obtained is chromatographed on silica gel (eluent: 90/10 DCM/MeOH). 25 mg of ethyl 4-cyclohexyl-1-((R)-3-(3,4-dichlorophenyl)-2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-propionyl)piperidine-4-carboxylate in the form of a colourless oil are obtained in a yield of 38%.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[OH:24].C[O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][CH:28]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[F:16])[CH:6]=[N:5]2)[C:27]([OH:26])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Oc1cc(F)ccc1F
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cc(F)ccc2F)cc1=O
Yield: 59 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,5-difluoro-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2,5-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (10.4 g, 59%) as a white solid; LC-MS 365 [M+H+]; HPLC (0.17% trifluoroacetic acid in acetonitrile/water, 50%-100% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), purity>95%. 1H-NMR (300 MHz, DMSO-d6) δ 13.01 (bs, 1H), 8.16 (s, 1H), 7.53 (m, 1H), 7.26 (m, 1H), 6.00 (s, 1H), 5.30 (m, 1H), 1.01-2.19 (m, 11H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10](O)[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](=O)([O-])[O-].[K+].[K+].S([O:27][CH3:28])(OC)(=O)=O>C(#N)C>[CH:13]([C:9]1[C:10]([O:27][CH3:28])=[CH:11][C:2]([O:1][CH3:16])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])([CH3:15])[CH3:14]
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C(C)C)c(O)cc1O
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(C)C)c(OC)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (662 mg, 4.8 mmol) in acetonitrile (10 ml) was treated with dimethyl sulphate (0.4 ml, 4.2 mmol) and the mixture was stirred at room temperature for 16 hours and then held at reflux for 6 hours. Upon cooling to room temperature the solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford methyl 5-isopropyl-2,4-dimethoxybenzoate (350 mg, 74%) as a colourless solid. 1H NMR (DMSO-d6) 7.53 (1H, s), 6.67 (1H, s), 3.92 (3H, s), 3.86 (3H, s), 3.75 (3H, s), 3.13 (1H, m), 1.14 (6H, d). MS: [M+Na]+ 261.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11]CC)=O)=[C:4]([CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:3]=1[F:31].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCOCC>[Cl:1][C:2]1[CH:20]=[C:19]2[C:5](=[C:4]([CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:29])([CH3:28])[CH3:30])([CH3:26])[CH3:25])[C:3]=1[F:31])[N:6]=[CH:7][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]2[OH:11]
Reactant: CCOC(=O)C(=CNc1ccc(Cl)c(F)c1CCO[Si](C)(C)C(C)(C)C)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)c1cnc2c(CCO[Si](C)(C)C(C)(C)C)c(F)c(Cl)cc2c1O
Temperature: 200 °C
Yield: 76.8 %

Procedure:
To 8.35 g (17.1 mmol) of the compound (128), 80 ml of Dowtherm A (Trademark) was added, and the solution was heated until a fraction of 200° C. was taken out. The solution was further heated at reflux for 5 minutes. After air-cooling, 50 ml of ether was added to the solution, and the crystals were filtered off to obtain 5.62 g of the subject compound (129) in a 74% yield.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Br:9][CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>C(#N)C>[Br-:9].[CH3:13][C:12]([CH3:15])([CH3:14])[C:11](=[O:16])[CH2:10][N+:6]1[C:5]([CH3:7])=[C:4]([CH3:8])[S:3][C:2]=1[CH3:1]
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cc1nc(C)c(C)s1
Solvent: CC#N
Product: Cc1sc(C)[n+](CC(=O)C(C)(C)C)c1C
Product: [Br-]
Temperature: 60 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
A mixture of 2,4,5-trimethylthiazole (640 mg, 5 mmol) and 1-bromo-3,3-dimethylbutan-2-one (1.8 g, 10 mmol) in anhydrous acetonitrile (20 mL) was stirred at 60° C. for 5 h. The mixture was then concentrated under reduced pressure, the residue was triturated with anhydrous ethyl ether and the solid was filtered and dried under reduced pressure to provide 1.4 g of the crude title compound.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH3:5]OCOC.[CH2:10]([S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:11]>ClCCCl>[CH2:10]([S:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:5][Cl:1])=[CH:15][CH:14]=1)[CH3:11]
Reactant: COCOC
Reactant: CCSc1ccccc1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCCl
Product: CCSc1ccc(CCl)cc1
Temperature: 5 °C

Procedure:
Aluminum chloride (2 g, 15 mmol) was suspended in 8 mL 1,2-dichloroethane and the solution was cooled to 5° C. Dimethoxymethane (0.69 mL, 7.8 mmol) over 10 min. Ethylphenylsulfide (0.88 mL, 6.5 mmol) was added and the mixture was warmed to rt. After 15 h ice water was added and the mixture was extracted with methylene chloride (3×). The combined organic fractions were dried over magnesium sulfate and concentrated. The crude material was used directly in the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[CH2:15]([O:11][C:9]1[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]([CH:5]=[O:6])=[C:3]([CH2:1][CH3:2])[CH:10]=1)[CH3:16]
Reactant: CCI
Reactant: CCc1cc(O)cc(CC)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cc(CC)c(C=O)c(CC)c1
Temperature: 50 °C
Yield: 89.5 %

Procedure:
To a solution of 0.30 g (1.68 mmol) 2,6-diethyl-4-hydroxy-benzaldehyde in 8 ml N,N-dimethylformamide in a pressure tube were added 0.16 ml (2.02 mmol) iodoethane and 0.35 g (2.52 mmol) potassium carbonate. The tube was sealed and the reaction mixture was heated at 50° C. for 16 h. The reaction mixture was then cooled to room temperature, diluted with diethyl ether, and washed sequentially with water and saturated brine. The phases were separated, and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane 1:30) to afford 0.31 g (88%) of the title compound as a yellow oil. MS (ISP): 207.3 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]#[N:7].Cl.[CH3:15][NH:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][N:16]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]#[N:7])[CH3:17]
Reactant: N#Cc1cc(CBr)cc([N+](=O)[O-])c1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1cc(C#N)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a stirred mixture of 3-(bromomethyl)-5-nitrobenzonitrile (1.50 g, 6.22 mmol) (prepared according to the method described in J. Org. Chem. 55: 1040-1043 (1990)) and dimethylamine hydrochloride (1.01 g, 12.44 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.88 g, 18.66 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 3 h and evaporated to dryness under reduced pressure. The residue was diluted with water (15 mL) and extracted with EtOAc (3×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-((dimethylamino)methyl)-5-nitrobenzonitrile (1.10 g, 87%) as a viscous liquid. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1 H), 8.40 (d, 1H, J=1.6 Hz), 8.01 (s, 1H), 3.59 (s, 2H), 2.30 (s, 6H).
Reaction SMILES: [S:1]1[C:5]2[S:6](=[O:10])(=[O:9])[CH2:7][CH2:8][C:4]=2[CH:3]=[C:2]1C(O)=O>N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C.[Cu]>[S:6]1(=[O:10])(=[O:9])[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:8][CH2:7]1
Reactant: O=C(O)c1cc2c(s1)S(=O)(=O)CC2
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: O=S1(=O)CCc2ccsc21
Temperature: 180 °C
Yield: 94.7 %

Procedure:
Copper dust (13.4 g. 0.20 mol) was added to a solution of 4,5-dihydrothieno[2,3-b]thiophene-2-carboxylic acid-6,6-dioxide (45 g, 0.20 mol) in quinoline (500 mL) in a reaction vessel fitted with an efficient condenser. The well stirred reaction mixture was heated to 180° C. for 1.5 hours under a nitrogen atmosphere. The dark solution was cooled to room temperature and diluted with ethyl acetate (2 L). The solution was washed with 6N HCl, water, saturated sodium bicarbonate, and saturated brine. The organic phase was dried over magnesium sulfate and treated with decolorizing carbon. Filtration and evaporation of solvent gave the title compound as a solid (33 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH2:9][OH:10]
Reactant: OCc1c(O)cccc1Cl
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1c(Cl)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-chloro-2-(hydroxymethyl)phenol (for a preparation see Intermediate 6)(1.37 g, 8.62 mmol) in absolute ethanol (30 ml) was added 2 M sodium hydroxide (4.74 ml, 9.49 mmol) and then benzyl bromide (1.03 ml, 8.62 mmol, Aldrich). The solution was stirred at ambient temperature for 3 days under nitrogen. The solvent was removed under reduced pressure to leave an aqueous suspension. The aqueous residue was partitioned between 2 M aqueous sodium hydroxide (40 ml) and ethyl acetate (60 ml). The phases were separated and the aqueous phase extracted with ethyl acetate (40 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound as a very pale brown oil (1.87 g); LCMS: (System 1) (M-H)−=247, tRET=3.20 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS-No. 335255-65-7] (227 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow viscous oil (356 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([O:13][C:14]([O:16]C3C=CC=CC=3)=O)[C:11]3[S:23][CH2:24][CH2:25][S:26][C:10]=3[C:9]2=[O:27])=[N:6][CH:7]=1.[CH:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:30])[CH3:29]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([O:13][C:14]([N:34]3[CH2:35][CH2:36][N:31]([CH:28]([CH3:30])[CH3:29])[CH2:32][CH2:33]3)=[O:16])[C:11]3[S:23][CH2:24][CH2:25][S:26][C:10]=3[C:9]2=[O:27])=[N:6][CH:7]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(Oc1ccccc1)OC1C2=C(SCCS2)C(=O)N1c1ccc(Cl)cn1
Solvent: CC#N
Product: CC(C)N1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc(Cl)cn2)CC1
Temperature: 2 °C
Yield: 63.8 %

Procedure:
6-(5-Chloropyrid-2-yl)-7-oxo-5-phenoxycarbonyloxy-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (10.0 g.) and 1-isopropylpiperazine (6.1 g.) in anhydrous acetonitrile (100 cc.) is stirred for 20 hours at a temperature of about 25° C. The reaction mixture is filtered and then evaporated under reduced pressure (20 mm. Hg). The residue is dissolved in methylene chloride (250 cc.). The organic solution is washed twice with N sodium hydroxide solution (total 160 cc.) and once with distilled water (80 cc.) and then evaporated. The residue is dissolved in an ice-cold 0.5N aqueous solution of methanesulphonic acid (200 cc.). The aqueous acid solution is washed twice with diethyl ether (total 100 cc.) and then rendered alkaline by adding 10N sodium hydroxide solution. The oil which separates out is extracted twice with methylene chloride (total 240 cc.). The organic solution is washed three times with distilled water (total 240 cc.) dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.2 g.) and evaporated. The crystals obtained (10.3 g.; m.p. 130°-135° C.) are dissolved in boiling acetonitrile (26 cc.). After filtering the boiling solution and then cooling it for 2 hours at 2° C, the crystals which have appeared are filtered off, washed twice with ice-cold acetonitrile (total 15 cc.) and dried under reduced pressure (20 mm. Hg). 6-(5-Chloropyrid-2-yl)-5-(4-isopropylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (6.9 g.), melting at 156° C, is thus obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8].[NH2:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([Cl:18])[N:12]=1.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[NH2:10][C:11]1[N:16]=[C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH:2]2[C:7]([NH2:9])=[O:8])[CH:14]=[C:13]([Cl:18])[N:12]=1
Reactant: NC(=O)C1COCCN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC(=O)C1COCCN1c1cc(Cl)nc(N)n1
Temperature: 100 °C
Reaction time: 40 h
Yield: 50 %

Procedure:
A mixture of 3-morpholinecarboxamide (830 mg, 3.40 mmol), 2-amino-4,6-dichloropyrimidine (502 mg, 3.06 mmol), and Hunig's base (1.6 mL, 9.16 mmol) in CH3CN (12 mL) was stirred at 100° C. in a sealed tube for 40 hours. The mixture was diluted with EtOAc (100 mL), and washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL). The combined aqueous phases were further extracted with CH2Cl2 (3×50 mL) and EtOAc (3×50 mL). All of the organic phases were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (34 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (394 mg) as a white solid. LC-MS (ES) m/z=258, 260 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc(C=O)cc1
Yield: 46.6 %

Procedure:
The reaction between 61.0 g (0.50 mole) of 4-hydroxybenzaldehyde, 24.0 g of 50% NaH, and 341 ml of 2.2 N (0.75 mole) 2-dimethylaminoethyl chloride in toluene in a procedure described for Example 2,part A, gives 45.0 g (46%) of colorless product, bp 140°-142°/2 mm. Lit. bp 185°-187°/15 mm.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Ca+2].[Br-:21].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:21][C:10]1[C:11]([CH2:13][OH:14])=[CH:12][C:3]([N:2]([CH3:1])[CH3:15])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(CO)cc1N(C)C
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Br)c(CO)cc1N(C)C
Yield: 83.5 %

Procedure:
After dissolving methyl 2-(dimethylamino)-4-(hydroxymethyl)benzoate (1.023 g, 4.9 mmol) in a methylene chloride (15 ml) and methanol (6 ml) mixed solvent, calcium carbonate (2 g) was added, the mixture was stirred, and then benzyltrimethylammonium tribromide (2.100 g, 5.4 mmol) was gradually added and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was filtered and the solvent was distilled off under reduced pressure. Water was added to the residue, extraction was performed with ethyl acetate and the ethyl acetate layer was washed with water and brine. The aqueous layer was then extracted with a methylene chloride and methanol mixed solvent, combined with the ethyl acetate layer, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.179 g) as a white solid. (84% yield)