Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:20][CH2:21]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.34 g) obtained in Example 1d) in dichloromethane (24 ml) was added benzoyl chloride (0.14 ml) under ice-cooling, and the mixture was stirred for 30 min and at room temperature for 3 hr. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the precipitated solid was washed with ethyl acetate to give the title compound as a white powder (0.36 g, 78%).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([CH2:17][NH2:18])=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=O)=[CH:23][CH:22]=1.C1COCC1.C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl.O>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]([C:24]2[CH:35]=[CH:36][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[N:18][CH2:17][C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[CH:16][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8]3)=[CH:13][CH:12]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: NCc1ccc2ccc(-c3ccccc3)nc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=NCc2ccc3ccc(-c4ccccc4)nc3c2)c2ccc(OC)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
C-(2-Phenylquinolin-7-yl)methylamine (170 mg, 0.73 mmol) and 4,4′-dimethoxybenzophenone (176 mg, 0.73 mmol) were added to a flask under nitrogen. THF (4 mL) and triethylamine (0.30 mL, 2.2 mmol) were then added. The mixture was cooled to −78° C. and titanium tetrachloride (0.080 mL, 0.73 mmol) was added. The reaction mixture was allowed to warm to room temperature. After stirring for 30 minutes the mixture was cooled to −78° C. and triethylamine (2 mL) was added followed by water (3 mL). The mixture was warmed to room temperature and DCM was added. The organic solution was washed with water, dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The resultant yellow oil was purified by silica gel chromatography (eluted with DCM/heptane 2:1). A light yellow solid (0.247 g, yield 74%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:24]=[C:17]2[C:18](OC(=O)[NH:22][C:16]2=[CH:15][CH:14]=1)=O)(=[O:12])=[O:11].C(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:42]([NH:50][NH2:51])(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([NH2:22])=[C:17]([C:18]2[O:49][C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[N:50][N:51]=2)[CH:24]=1)(=[O:11])=[O:12]
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3Cl)cc2c(=O)o1
Reactant: NNC(=O)c1ccccc1
Agent: O=C=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN1CCCC1=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cl)cc1-c1nnc(-c2ccccc2)o1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
97 Parts of this isatoic anhydride are dissolved in 200 parts of N-methylpyrrolidone and 35 parts of benzhydrazide are added. The mixture is stirred at 120° C. until the evolution of CO2 is ceased, 35 parts of phosphorus pentoxide are then added and the batch is stirred for a further 4 hours at 120° C. After cooling, the product is precipitated with water, filtered off, rinsed with water and dried. This gives 107 parts of 4-[2,4-dichlorophenyl-sulfamoyl]-2 [5-phenyl-1,3,4-oxdiazolyl]-aniline of meltingpoint 215°-220° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:19])/[CH:16]=[CH:17]/[CH3:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[CH3:21][S+](C)(C)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH:16]2[CH2:18][CH:17]2[CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C/C(=O)c1cccc(OCc2ccccc2)c1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1CC1C(=O)c1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a solution of 93.C (5.33 g, 21.1 mmol) in ACN (200 mL) were added trimethylsulfoxonium iodide (available from Aldrich) (5.58 g, 25.3 mmol) and DBU (4.11 mL, 27.5 mmol). The mixture was stirred overnight at 60° C. under N2, cooled to room temperature, and concentrated. The crude product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford 93.D (2.04 g, 36% yield) as a colorless oil.
Reaction SMILES: C([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])(C)(C)C.C1(O)C=CC=CC=1.C1(S(O)(=O)=O)C=CC=C(S(O)(=O)=O)C=1>>[C:11]([C:9]1[CH:10]=[CH:5][C:6]([OH:15])=[CH:7][CH:8]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)c1cccc(S(=O)(=O)O)c1
Solvent: Oc1ccccc1
Product: CC(C)(C)c1ccc(O)cc1
Yield: 81.2 %

Procedure:
Thus, to 2.06 grams of 2,4-ditertiary-butyl phenol was added 0.94 grams of phenol. Then 1% of meta-benzenedisulfonic acid was stirred in with warming and the final mixture was heated to 150°C. for 1.5 hours. Analysis gave 81.2% para-tertiary-butyl phenol. The remaining components were its isomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Yield: 74.4 %

Procedure:
4-nitro-2-phenylbenzoyl methionine methyl ester (0.35 g, 0.90 mmol) was taken up in ethyl acetate (9.0 ml). To this mixture was added SnCl2 -2H2O (1.02 g, 4.50 mmol) and the reaction was heated under nitrogen at reflux for 1h. The mixture was poured onto ice, the solution was made basic using NaHCO3 and the product was extracted into ethyl acetate several times (7-8). The ethyl acetate fractions were combined washed with brine and dried over Na2SO4 and the solvent was removed in vacuo to give 0.24 g (73.4%) of yellow solid. 1H NMR (CDC13) 1.58-1.70 (1 H, m), 1.80-1.92 (1 H, m), 1.98 (3 H, s), 2.06 (2 H, t, J=7.7 Hz), 3.62 (3 H, s), 4.00 (2 H, br s), 4.56-4.63 (1 H, m), 5.84 (1 H, d, J=7.7 Hz), 6.50 (1 H, s), 6.61 (1 H, d, J=8.4 Hz), 7.29-7.42 (5 H, m), 7.58 (1 H, d, J=8.3 Hz); 13C NMR (CDCl3) 15.02, 29.25, 31.25, 51.57, 52.15, 113.27, 115.88, 123.52, 127.56, 128.37, 128.44, 130.92, 140.66, 141.44, 148.53, 168.58, 171.91.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][OH:11])=[C:6]([F:12])[C:5]([F:13])=[CH:4][CH:3]=1.[CH:14](O)=O>>[F:13][C:5]1[CH:4]=[CH:3][C:2]2[N:1]=[CH:14][N:8]([CH2:9][CH2:10][OH:11])[C:7]=2[C:6]=1[F:12]
Reactant: Nc1ccc(F)c(F)c1NCCO
Reactant: O=CO
Product: OCCn1cnc2ccc(F)c(F)c21
Reaction time: 2.5 h

Procedure:
A solution of 2-[(6-amino-2,3-difluorophenyl)amino]ethanol in 100 ml of formic acid is heated at 100° C. for 2 hours. The reaction is concentrated to dryness, taken into 100 ml of 2 N NH3 in ethanol and stirred for 2.5 hrs. The reaction is concentrated and taken into ethyl acetate. The resulting precipitate is collected by filtration and rinsed with cold ethyl acetate. The mother liquor is concentrated and purified by silica gel flash chromatography using ethyl acetate/heptane. The combined yield is 3.2 g or 93% for two steps based on 3.8 g of 2-[(2,3-difluoro-6-nitrophenyl)amino]ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:30]2[CH2:35][CH2:34][CH2:33][CH:32]=[CH:31]2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C([O-])(O)=O.[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:30]2[CH2:35][CH2:34][CH2:33][CH:32]=[CH:31]2)=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])[CH:20]1[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]1)=[O:4]
Reactant: COC(=O)c1sc(C2C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(C2C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-cyclohex-2-enyl-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (50 mg, 0.1 mmol) in DCM (4 mL), trifluoroacetic acid (0.4 mL) and water (20 μl) was stirred for 16 h at room temperature. Trifluoroacetic acid ((0.2 mL) was added and it was stirred for another 3 h. Saturated NaHCO3 solution was added and it was extracted with DCM. The extract was washed with brine, dried over MgSO4 and evaporated yielding crude 5-cyclohex-2-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (40 mg) which was used in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([F:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:30])[CH3:29].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:28](=[O:30])[CH3:29])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([F:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)c(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)c(F)cc3F)nc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2,4-difluorophenyl}carbamate (3.94 g, 10.0 mmol) and N,N-dimethylpyridine-4-amine (1.22 g, 10 mmol) in pyridine (20 mL) was added dropwise acetyl chloride (0.94 g, 12 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (4.36 g, quantitatively) as a pale-yellow amorphous.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=O)[C:36]([F:39])([F:38])[F:37])=[CH:30][C:29]=1[I:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO[CH:44](OC)[CH2:45][NH2:46]>C(Cl)(Cl)(Cl)Cl>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:44]=[CH:45][N:46]=[C:35]2[C:36]([F:39])([F:38])[F:37])=[CH:30][C:29]=1[I:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)c(I)c1)C(F)(F)F
Reactant: COC(CN)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1nccn1-c1ccc(OCc2ccccc2)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Triphenylphosphine (3.11 g, 11.88 mmol) was added to a suspension of N-(4-benzyloxy-3-iodophenyl)trifluoroacetamide (Description 15; 2.5 g, 5.94 mmol) in carbon tetrachloride (35 ml) and the mixture was heated under reflux for 24 hours. The mixture was then allowed to cool and the solvent was evaporated under reduced pressure. Hexane was then added and the mixture was heated under reflux for 1 hour. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (20 ml), aminoacetaldehyde dimethyl acetal (2.5 ml, 22.9 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and acetic acid was added. The mixture was heated under reflux for 3 hours, cooled and diluted with water. The mixture was basified and extracted with ethyl acetate. The organic extract was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (75:25) to give the title compound as a pale yellow oil (900 mg, 34%). 1H NMR (360 MHz, CDCl3) δ 7.80 (1H, d, J 2.5 Hz), 7.50 (2H, m), 7.44−7.43 (3H, m), 7.30 (1H, dd, J 2.5, 8.7 Hz), 7.20 (1H, s), 7.10 (1H, s), 6.91 (1H, d, J 8.7 Hz), and 5.22 (2H, s). m/z (ES+) 445 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[S:8]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:33][CH3:34]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([CH2:33][CH3:34])[C:24]3=[O:27])=[CH:19][CH:18]=2)[S:8]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)(=[O:9])=[O:10])=[CH:28][CH:29]=1
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2ccc3c(c2)C(=O)NCC3)n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2ccc(N(Cc3ccc(Cl)cc3)S(=O)(=O)c3ccn(C)n3)cc2C1=O
Temperature: 110 °C
Yield: 23.7 %

Procedure:
To a suspension of 1-methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide (20 mg, 0.046 mmol) and sodium hydride (3 mg, 0.055 mmol) in anhydrous THF (1 ml) was added iodoethane (8 μl, 0.055 mmol) and the reaction heated to 110° C. in a microwave for 0.5 h. The solvent was evaporated in vacuo and the resulting residue purified by preparative HPLC (Method B) to yield the title compound as a colourless solid (5 mg, 24%). HPLC retention time 4.34 min. Mass spectrum (ES+) m/z 459 (M+H).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:10]=[C:11]1[N:16]2[CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:15]2[CH2:14][NH:13][CH2:12]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]1([C:7]([N:13]2[CH2:12][C:11](=[S:10])[N:16]3[CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH:15]3[CH2:14]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C1CNCC2c3ccccc3CCCN12
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N1CC(=S)N2CCCc3ccccc3C2C1
Reaction time: 5 h
Yield: 15.5 %

Procedure:
Cyclohexanoyl chloride (0.16 g) was added to a mixture of 4-thioxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.24 g) and triethylamine (0.25 ml) in chloroform (20 ml, ethanol-free) at 0°. The mixture was maintained at 0° for 30 min then at room temperature for 5 hr. The solution was washed with, first, dilute hydrochloric acid, and secondly with sodium bicarbonate solution. The chloroform solution was dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, Et2O) and recrystallised from dichloromethane/40°-60° C. petroleum ether to give white crystals of the title compound (55 mg, 16%) m.p. 150°-151° C.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][N:4]1[C:9](=[O:10])[CH:8]=[C:7]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:6]=[C:5]1[CH2:17][C:18]([O:20]CC)=[O:19]>O1CCCC1>[CH3:3][N:4]1[C:9](=[O:10])[CH:8]=[C:7]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:6]=[C:5]1[CH2:17][C:18]([O-:20])=[O:19].[Na+:2]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.88 ml of 2M sodium hydroxide are added to a solution of 1.62 g of ethyl [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 20 ml of tetrahydrofuran. The reaction mixture is stirred for 48 hours at ambient temperature. The precipitate formed is filtered off through sintered glass, washed with ethyl acetate, rinsed with diethyl ether and dried, so as to give 730 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4]([CH3:6])=[CH2:5].CCOCC.S(=O)(=O)(O)O.[CH2:18](O)[CH2:19][CH2:20]C>>[C:3]([O:2][CH2:1][CH2:18][CH2:19][CH3:20])(=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: CCCCO
Reactant: C=C(C)C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: C=C(C)C(=O)OCCCC
Reaction time: 6 h
Yield: 88.2 %

Procedure:
A 148.2g (2.0 mols) amount of n-butanol, 400.5g (4.0 mols) of methylmethacrylate, 0.5g of hydroquinonemonomethyl ether and 2.45g (0.025 mol) of concentrated sulfuric acid were added to a flask to conduct a reaction in the same manner described in Example 1. The reaction was carried out for 6 hours. The reaction results obtained were an 89.9% conversion of n-butanol and an 88.2% yield of n-butyl methacrylate. However, it was found by gas chromatography that a high boiling point by-product was present and 0.004 mol of methacrylic acid (2740 ppm. on n-butyl methacrylate) was produced as a by-product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[Cl:12]C1C=CC(C(O)=O)=C(F)C=1>>[Cl:12][C:3]1[CH:2]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([F:11])[CH:4]=1
Reactant: O=C(O)c1ccc(Cl)cc1F
Reactant: NC(=O)c1cc(Cl)ccc1F
Product: NC(=O)c1ccc(Cl)cc1F

Procedure:
A method similar to the preparation of 5-chloro-2-fluorobenzamide (see page 17 above) was followed using 4-chloro-2-fluorobenzoic acid (500 mg, 5.73 mmol). The title compound was isolated as an off-white solid (465 mg, 94%).
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1.CCOCC>[CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOCC
Solvent: c1ccccc1
Product: C=C[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 22.1 %

Procedure:
Pregna-4,20-dien-3-one (1, 1.19 g. 3.99 mmol) was refluxed for 24 h with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 2.72 g, 12.1 mmol) in 40 mL of benzene under Argon. The cooled suspension was diluted with ether and washed with two 100 mL portions of 5i (w/w) sodium hydroxide, two 100 mL portions of water and once with 100 mL of brine. Ether (100 mL) was added to the resulting emulsion, which was dried over sodium sulfate and then filtered through a column of sodium sulfate (20 g). After washing the residue twice with 50 mL portions of ether the combined filtrates were concentrated under reduced pressure and then flash chromatographed (25% ethyl acetate/hexanes on silica gel) to give a slightly yellow crystalline solid (0.26 g, 0.88 mmol, 22%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].Cl.[N:14]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[NH:17][CH2:16][CH2:15]2.C(N(CC)CC)C.CC(C)([O-])C.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCCC1>[N:14]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[N:17]([C:2]1[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]3=[O:12])[CH2:16][CH2:15]2
Reactant: C1CN2CCC(CC2)N1
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]cnc2ccc(N3CCN4CCC3CC4)cc12
Temperature: 120 °C
Yield: 3.2 %

Procedure:
A mixture of 6-bromoquinazolin-4(3H)-one (0.50 g, 2.22 mmol), 1,4-diazabicyclo[3.2.2]nonane hydrochloride (0.44 g, 2.22 mmol), triethylamine (0.45 g, 4.44 mmol), potassium tert-butoxide (0.25 g, 2.22 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (1.06 g, 2.22 mmol) and tris(dibenzyllideneacetone)dipalladium (0) (0.41 g, 0.44 mmol) in Tetrahydrofuran (15 mL) was heated in the microwave at 120° C. for 30 mins. The solvent was evaporated off and to the residue was added methanol and the mixture acidified with acetic acid then loaded on to a 5 g SCX column. The mixture was purified on silica (25 g SNAP column on SP4) eluting with dichloromethane to 60/40 dichloromethane/(2M ammonia in methanol) to afford 6-(1,4-diazabicyclo[3.2.2]nonan-4-yl)quinazolin-4(3H)-one (18.5 mg, 0.07 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[OH-].[Na+].CN1CCN(C)C1=O.Cl[CH:23]([F:25])[F:24]>O>[Br:1][C:2]1[C:3]([O:11][CH:23]([F:25])[F:24])=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=[N+]([O-])c1cccc(Br)c1OC(F)F
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
Into a 1-liter four-necked flask provided with a reflux condenser, a stirrer and a thermometer were fed 53.0 g (0.24 mol) of 2-bromo-6-nitrophenol, 40.5 g (0.49 mol) of 48% sodium hydroxide, 240 ml of 1,3-dimethylimidazolidine-2-one and 40.5 g of water. The mixture was heated to 80° C. and stirred at the same temperature for 1.5 hours with heating while chlorodifluoromethane (flon 22) was blown thereinto from a bomb. Then, while 20.0 g of 48% sodium hydroxide was added in seven portions, blowing of flon gas was continued at the same temperature for 7.5 hours. The total amount of flon gas blown was 242.3 g (2.80 mol). The reaction mixture was cooled. Thereto were added 26.0 g of 48% sodium hydroxide, 1 liter of water and 500 ml of ether, and extraction and layer separation was conducted. The organic layer was separated, and the water layer was subjected to reextraction using 500 ml of ether. The ether layers were combined and washed with 500 ml of water two times. The resulting organic layer was dried over anhydrous sodium sulfate and subjected to distillation to remove the solvent and obtain 45.4 g of 3-bromo-2-difluoromethoxynitrobenzene (yield: 70.6%, purity: 98.1%).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:32][C:33](=[O:49])[C@@H:34]([NH2:48])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>>[C:39]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:41][C:36]([CH2:35][C@H:34]([NH:48][C:26]([C:15]2[N:16]=[C:17]([CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:18]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[C:10]([O:9][C:8]2[CH:29]=[CH:30][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=2)[CH:19]=3)=[O:27])[C:33]([OH:32])=[O:49])=[CH:37][CH:38]=1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@@H](Cc4ccc(-c5ccccc5)cc4)C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 93.1 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid was reacted with (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (34.8 mg, 0.13 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 70 mg of the title compound as a white solid.