Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]([CH2:24][CH3:25])=[N:15][N:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18][C:17]=23)=[CH:8][CH:7]=1.[Li+].[OH-].Cl>C1COCC1>[CH2:24]([C:14]1[C:13]([CH2:12][C:9]2[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]([OH:26])=[O:2])=[CH:11][CH:10]=2)=[C:17]2[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]2[N:15]=1)[CH3:25]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(/C=C/C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(/C=C/C(=O)O)cc1
Temperature: 25 °C

Procedure:
(E)-3-[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-acrylic acid methyl ester (4) (2.94 g, 8.4 mmol) was dissolved in 25 ml of THF and 1M LiOH (25 ml) was added. The reaction mixture was stirred over night at rt. Then 0.5M HCl was added until a pH of 3.5 was reached. The mixture was extracted twice with EtOAc, the organic layer was washed with brine and dried over Na2 SO4. After evaporation the product was purified by recrystallisation from EtOAc to give a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Cl[S:18]([OH:21])(=[O:20])=[O:19].S(=O)(=O)([O-])N.C(=O)([O-])[O-].[Na+:31].[Na+]>N1C=CC=CC=1C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:18](=[O:20])(=[O:19])[O-:21])=[CH:7][CH:6]=1.[Na+:31]
Reactant: O=S(=O)(O)Cl
Reactant: Nc1ccc(-c2nc3ccccc3o2)cc1
Agent: NS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccn1
Product: O=S(=O)([O-])Nc1ccc(-c2nc3ccccc3o2)cc1
Yield: 96 %

Procedure:
2(4'-Aminophenyl)benzoxazole was treated with chlorsulphonic acid in 2-picoline and sodium carbonate according to the above-described general procedure for preparation of sulphamate salts. Grey crystals were obtained in 96% yield, m.p. >340° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[C:14]([F:22])[CH:13]=2)=[N:4][C:5]([CH:8]2[CH2:11][O:10][CH2:9]2)=[CH:6][N:7]=1.[Li+].[OH-]>CO.C1COCC1>[NH2:1][C:2]1[C:3]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[C:14]([F:22])[CH:13]=2)=[N:4][C:5]([CH:8]2[CH2:11][O:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3COC3)cnc2N)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc(C2COC2)nc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To methyl 4-(3-amino-6-(oxetan-3-yl)pyrazin-2-yl)-2-fluorobenzoate (13 mg, 0.043 mmol) in MeOH (1 mL) and THF (2 mL) was added LiOH (0.128 mL, 0.128 mmol). The reaction mixture was stirred 2 h at room temperature. The reaction mixtures was adjusted to acidic (pH˜3) and solvent was evaporated on rotovap. The crude was azeotrope with toluene and proceed for next step. LCMS (m/z): 290.1 (MH+), 0.46 min.
Reaction SMILES: COC1C=C(C)C(NC(=O)C)=CC=1.BrC1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].II.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH3:47])[C:34]([N:37](C(=O)C)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:35][CH:36]=1.[OH-].[Na+]>[Cu].O>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH3:47])[C:34]([NH:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:35][CH:36]=1
Reactant: COc1ccc(N(C(C)=O)c2ccccc2)c(C)c1
Agent: [Cu]
Agent: COc1ccc(NC(C)=O)c(C)c1
Agent: II
Solvent: O
Solvent: Brc1ccccc1
Product: COc1ccc(Nc2ccccc2)c(C)c1
Temperature: 180 °C
Yield: 90.5 %

Procedure:
24 g. of 3-methoxy-6-acetylaminotoluene, 31.6 g. of bromobenzene, 10.38 g. of potassium carbonate, 0.6 g. of copper powder and 0.01 g. of iodine were refluxed under ordinary pressure on the oil bath for 48 hours. Then excess bromobenzene was recovered by means of steam distillation, and the reamining reaction mixture was distilled in a vacuum to obtain 29.2 g. (85.0 percent of theoretical yields) of 3-methoxy-6-(N-acetylanilino) toluene as a light yellowish brown solid having a melting point at 86° to 87° C., having the formula: ##STR12## 25 g. of this intermediate was hydrolyzed by heating at 180° C. for 8 hours in the autoclave, together with 130 ml. of water and 9 g. of caustic soda. After cooling, the reaction product was filtered to collect a solid and thereafter recrystallized by using a double amount of ethyl alcohol. 18.8 g. (90.5 percent of theoretical yields) of 3-methoxy-6-anilinotoluene was obtained as light brown crystals having a melting point of 79° to 80.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][C@@H:8]2[CH2:13][O:12][C@@H:11](/[C:14](/[CH3:26])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([C@@H:8]2[CH2:9][O:10][C@@H:11](/[C:14](/[CH3:26])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=3)[O:12][CH2:13]2)=[O:37])=[CH:27][CH:28]=1
Reactant: C/C(=C\c1ccc(C(F)(F)F)cc1)[C@H]1OC[C@H](SCc2ccc(Cl)cc2)CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C/C(=C\c1ccc(C(F)(F)F)cc1)[C@H]1OC[C@H](S(=O)Cc2ccc(Cl)cc2)CO1
Reaction time: 0.25 h

Procedure:
In 10 ml of methylene chloride were dissolved 382 mg (0.89 mmol) of trans-5-[(4-chlorobenzyl)thio]-2-[(E)-1-methyl-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane, and 188 mg (0.92 mmol) of m-chloroperbenzoic acid (purity: 85%) were added to the solution, followed by stirring of the resulting mixture for 15 minutes. The reaction mixture was washed with an aqueous sodium hydrogencarbonate solution and the solid obtained by evaporation of the solvent was washed with a mixed solvent of ethyl acetate-hexane to obtain 328 mg (yield: 83%) having a melting point of 192 to 194° C.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([CH:46]=[CH:47][CH:48]=1)[CH2:10][C@@H:11]1[NH:34][C:33](=[O:35])[C@H:32]([CH:36]([CH3:38])[CH3:37])[NH:31][C:30](=[O:39])[C@H:29]([CH3:40])[C@H:28]([O:41][CH3:42])[CH2:27][CH2:26][CH:25]=[CH:24][CH:23]=[CH:22][CH2:21][CH2:20][O:19][C:18](=[O:43])[C@H:17]2[NH:44][N:13]([CH2:14][CH2:15][CH2:16]2)[C:12]1=[O:45])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:6][C:7]1[CH:8]=[C:9]([CH:46]=[CH:47][CH:48]=1)[CH2:10][C@@H:11]1[NH:34][C:33](=[O:35])[C@H:32]([CH:36]([CH3:38])[CH3:37])[NH:31][C:30](=[O:39])[C@H:29]([CH3:40])[C@H:28]([O:41][CH3:42])[CH2:27][CH2:26][CH:25]=[CH:24][CH:23]=[CH:22][CH2:21][CH2:20][O:19][C:18](=[O:43])[C@H:17]2[NH:44][N:13]([CH2:14][CH2:15][CH2:16]2)[C:12]1=[O:45]
Reactant: CO[C@@H]1CCC=CC=CCCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CO[C@@H]1CC/C=C/C=C/CCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Agent: CO[C@@H]1CC/C=C/C=C/CCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Solvent: C1CCOC1
Product: CO[C@@H]1CCC=CC=CCCOC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of 11b (38 mg, 0.053 mmol.) in anhydrous tetrahydrofuran (10 ml) was cooled to 0° C. under a nitrogen atmosphere before adding a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (265 ul, 0.265 mmol.). The reaction mixture was warmed to room temperature and was stirred under a nitrogen atmosphere for 2.5 hours. The reaction mixture was then treated with saturated aqueous sodium bicarbonate solution (20 ml) and the subsequent mixture was extracted with ethyl acetate (3×15 ml). The combined extract was dried over sodium sulfate, filtered and evaporated. The residue was purified on a silica column eluting with 50% ethyl acetate, 50% hexane then 100% ethyl acetate to yield 11 as a colourless solid (15 mg, 47%). 1H NMR δ (300 MHz NMR, CDCl3) 0.81-0.92 (m, 3H) 0.93-1.01 (m, 4H), 1.34-1.39 (d, 3H, J=7.4 Hz), 1.45-2.10 (m, 6H), 2.18-2.20 (s, 1H), 2.38-2.53 (m, 2H), 2.55-2.71 (m, 2H), 2.75-2.92 (m, 2H), 3.18-3.30 (m, 2H), 3.51-3.53 (s, 3H), 3.54-3.60 (d, 1H, J=12.5 Hz), 4.09-4.40 (m, 4H), 4.50-4.60 (d, 1H, J=12.7 Hz), 5.43-5.69 (m, 3H), 5.91-6.00 (m, 3H), 6.51-6.58 (d, 1H, J=7.4 Hz), 6.68-6.78 (m, 2H), 6.80-6.90 (d, 1H J=8.7 Hz), 7.05-7.12 (t, 1H, J=7.7), 7.37-7.45 (d, 1H, J=9.6), 8.15-8.38 (bs, 1H). LCMS (m/z) 599.36 [M+H] Tr=4.59 min.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:12][CH3:13])(=[O:11])[C:8]([CH3:10])=[CH2:9]>CO>[CH3:13][O:12][C:7](=[O:11])[CH:8]([CH3:10])[CH2:9][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)C(=O)OC
Reactant: NC1CCCC1
Solvent: CO
Product: COC(=O)C(C)CNC1CCCC1
Yield: 82.7 %

Procedure:
A mixture of 42.575 g (0.50 mole) of cyclopentylamine (Aldrich), 60.072 g (0.60 mole) of methyl methacrylate (Aldrich) and 250 mL of methanol was heated at reflux under an argon atmosphere for 29 hours, then ca 250 mL of solvent was distilled out at atmospheric pressure. The residue was distilled under vacuum (11 mm Hg, bp 114-116 degrees) to give 76.570 g (82%) of (rac)-3-cyclopentylamino-2-methyl-propanoic acid methyl ester.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([NH:7][C:8](/[CH:10]=[CH:11]/[C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][N:18]2[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[CH:14][CH:13]=1)=[O:9])[CH2:5][CH3:6].Cl>O.CO.O1CCCC1>[CH2:4]([NH:7][C:8](/[CH:10]=[CH:11]/[C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][N:18]2[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[CH:14][CH:13]=1)=[O:9])[CH2:5][CH3:6]
Reactant: CCCNC(=O)/C=C/c1ccc2ccn(Cc3ccc(C(=O)OC)cc3OC)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCNC(=O)/C=C/c1ccc2ccn(Cc3ccc(C(=O)O)cc3OC)c2c1
Reaction time: 20 h
Yield: 59.2 %

Procedure:
A solution of lithium hydroxide monohydrate (0.42 g) in water (5 ml) was added to a stirred solution of methyl E-4-[6-[2-(propylcarbamoyl)vinyl]-indol-1-ylmethyl]-3-methoxybenzoate (1 g) in methanol (20 ml) and tetrahydrofuran (5 ml) under an atmosphere of nitrogen. The mixture was stirred for 20 hr, diluted with water (20 ml), and acidified to pH 4 with 6M hydrochloric acid. The white precipitate which formed was isolated by filtration, washed with water, and crystallized from hot methanol (cooling the crystallizing solution to -20°) to give the title compound (0.572 g). The mother liquor, after addition of water, yielded an additional crop of the title compound (0.255 g, 84% combined yield) as a white solid; mp 210°-212°.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:8]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][O:4]1>O>[O:2]=[C:3]1[C:8]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][O:4]1
Reactant: COC(=O)c1ccc(-c2cccoc2=O)cc1
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc(-c2cccoc2=O)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 96.1 %

Procedure:
An aqueous 6 N hydrochloric acid solution (5 mL) was added to methyl 4-(2-oxo-2H-pyran-3-yl)benzoate (72 mg), followed by stirring at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, water was added, and the solid was collected by filtration. After washing with water, this solid was dried under reduced pressure to obtain 4-(2-oxo-2H-pyran-3-yl)benzoic acid (65 mg) as a pale brown solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:17][C:16]=2[F:32])[CH:11]=[CH:10][N:9]=1)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(OCC)C>[CH2:25]([O:24][C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[CH:13]=2)=[C:16]([F:32])[CH:17]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.7 %

Procedure:
[4-(4-Benzyloxycarbonylamino-2-fluorophenoxy)pyridin-2-yl]carbamic acid tert-butyl ester (510 mg) was added to a 4N hydrochloric acid-ethyl acetate (30 ml) while cooling in an ice water bath. The reaction mixture was allowed to warm to room temperature and then stirred for 16 hours. Diethyl ether (10 ml) and 5N aqueous sodium hydroxide (1 ml) were added to the reaction mixture and stirred therewith for 30 minutes. The separated organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2) and fractions containing the target compound were concentrated under reduced pressure. Diethyl ether (4 ml) and hexane (6 ml) were added to the resultant residue to produce a suspension of the precipitated solid. After filtering the solid, it was subjected to aeration drying to provide the title compound (46.6 mg, 11.7%) as pale yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[C:25]([CH3:36])=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=1.NC1C=NN(C(OC(C)(C)C)=O)C=1C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:23][C:24]2[C:25]([CH3:36])=[N:26][NH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1N
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: Cc1c(N)cnn1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1n[nH]cc1Nc1ncc(Cl)c(CCc2ccccc2C2(C(N)=O)CC2)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.120 g, 0.357 mmol), tert-butyl 4-amino-3-methyl-1H-pyrazole-1-carboxylate or tert-butyl 4-amino-5-methyl-1H-pyrazole-1-carboxylate (isomer not determined) A26 (0.141 g, 0.714 mmol) and p-toluenesulfonic acid monohydrate (0.007 g, 0.04 mmol) in 1,4-dioxane (2.0 mL) was stirred in a microwave reactor at 120° C. for 3 hours. The reaction mixture was adsorbed onto SiO2 and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-10% MeOH in DCM) to give the title compound 25 as a white solid (0.035 g, 25%). LCMS-A: rt 5.62 min; m/z 397 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@@H:7]([C@H:9]([CH2:11][O:12][S:13]([CH3:16])(=[O:15])=[O:14])[OH:10])[OH:8])(=[O:4])=[O:3].[CH2:17]=O.S(=O)(=O)(O)O>>[CH3:16][S:13]([O:12][CH2:11][C@:9]1([CH2:17][O:8][C@H:7]1[CH2:6][O:5][S:2]([CH3:1])(=[O:3])=[O:4])[OH:10])(=[O:15])=[O:14]
Reactant: C=O
Reactant: CS(=O)(=O)OC[C@H](O)[C@@H](O)COS(C)(=O)=O
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)OC[C@@H]1OC[C@]1(O)COS(C)(=O)=O
Yield: 63 %

Procedure:
L-threitol 1,4-bis(methanesulfonate) was reacted with formaldehyde and concentrated sulfuric acid as described in J. Med. Chem., 7, 14 (1964) to yield 2,3-O-methylene-L-threitol 1,4-bis-(methanesulfonate) in 63% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>CN(C=O)C>[Br:18][CH2:19][CH2:20][CH2:21][O:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[F:11]
Reactant: N#Cc1cc(F)c(O)c(F)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(OCCCBr)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 3,5-difluoro-4-hydroxybenzonitrile (2.1 g, 0.0136 mol; see step (iv) above), K2CO3 (3.76 g, 0.0272 mol) and 1,3-dibromopropane (16.48 g, 0.0816 mol) in dry DMF (50 mL) was stirred at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and partitioned between water and ethyl acetate. The organic layer was washed with water and brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure provided a residue that was purified by column chromatography over silica gel, using 2.5% ethyl acetate in petroleum ether as eluent, to yield 1.5 g (20%) of the sub-title compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](=O)[CH2:31]Br>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:31]=[C:30]([C:29]3[CH:34]=[CH:35][CH:36]=[C:27]([Cl:26])[CH:28]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3cccc(Cl)c3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 82.5 °C
Yield: 52.9 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (35 mL), 3-chlorophenacyl bromide (1.05 g, 4.48 mmol) was added. After heating the reaction mixture at 80-85° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-4-(3-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (525 mg, 53%) as a pale yellow solid: mp 156-159° C. Anal Calc'd. for C22H16N2SO2Cl2: C, 59.60, H, 3.69, N, 6.32, S, 7.23. Found: C, 59.43, H, 3.59, N, 6.15, S, 7.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:6][C:7](O)=[N:8]2.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>>[Cl:26][C:7]1[N:6]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nc(O)nc(-c3ccccc3)c2c(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2nc(Cl)nc(-c3ccccc3)c2c(OC)c1OC
Yield: 11.3 %

Procedure:
A solution of 5,6,7-trimethoxy-4-phenyl-quinazolin-2-ol (0.21 g, 0.67 mmol, 1.0 equiv) in phosphorus oxychloride (25.0 mL, 41.9 g, 273.1 mmol, 407.6 equiv) was heated to 110° C. for 1.5 h. The reaction mixture was poured on ice, the pH adjusted to 9 by addition of a 1 M solution of NaOH and the solution extracted with ethyl acetate (3×10 mL). The organic phase was dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 25.0 mg (11%) of the title compound which was used in the consecutive step without further purification. MS (ISP): 331.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][S:8]([CH3:11])(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:16][C:17]1[C:21]2[CH:22]=[C:23]([N:26]3[C:31](=[O:32])[CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]([CH3:37])[C:27]3=[O:38])[CH:24]=[CH:25][C:20]=2[S:19][N:18]=1.Cl>CS(C)=O.O1CCCC1>[CH3:37][N:28]1[C:29]([C:33]([F:34])([F:35])[F:36])=[CH:30][C:31](=[O:32])[N:26]([C:23]2[CH:24]=[CH:25][C:20]3[S:19][N:18]=[C:17]([CH2:16][N:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:6](=[O:12])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:21]=3[CH:22]=2)[C:27]1=[O:38]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CN(C(=O)OC(C)(C)C)S(C)(=O)=O)c3c2)c1=O
Yield: 78.6 %

Procedure:
tert-Butyl(methylsulfonyl)carbamate (1.52 g, 0.00780 mol) is added to a mixture of sodium hydride (60%, 0.312 g, 0.00780 mol) and tetrahydrofuran at 0° C. The mixture is allowed to come to room temperature. A solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (3.00 g, 0.00714 mol) in dimethyl sulfoxide is added dropwise. The resultant mixture is stirred overnight at room temperature, poured into dilute hydrochloric acid, and extracted with methylene chloride. The combined organic layers are washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resultant residue is chromatographed on silica gel with ether:methylene chloride to give the title compound as a white solid (3.00 g, 78.7%, mp 109-111° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:6]([N+:9]([O-])=O)=[CH:7][CH:8]=1)[NH2:5].[Sn](Cl)Cl.O.[OH-].[Na+]>CCO>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([NH2:5])[C:6]([NH2:9])=[CH:7][CH:8]=1
Reactant: Cc1c(Br)ccc([N+](=O)[O-])c1N
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(Br)ccc(N)c1N
Temperature: 70 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
To a solution of 3-bromo-2-methyl-6-nitroaniline (0.45 g, 1.95 mmol) in EtOH (6 mL) was added tin(II) chloride (1.48 g, 7.8 mmol), and the resulting solution was stirred at 70° C. for 4 hours. The mixture was cooled to room temperature and poured into water, and 1 N aq. NaOH was added to adjust to pH>7. The resulting mixture was extracted with CH2Cl2 (2×), and the combined extracts were dried over Na2SO4. The drying agent was filtered off and solvent was removed in vacuo to give the title compound as an oil (0.34 g, 88%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C@H:16]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](O)[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:15][C@@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH:29]=1
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1cncc(O[C@@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
DIAD (0.631 mL, 3.20 mmol) in DCM (5 ml) was added dropwise to a mixture of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol), pyridin-3-ol (305 mg, 3.20 mmol) and triphenylphosphine (840 mg, 3.20 mmol) in DCM (20 ml), cooled in an ice bath. The mixture was allowed to warm to room temperature, stirred for 1 hour and then concentrated. The residue was dissolved in dioxan (15 mL) and 4M HCl in dioxan (15 mL) was added. The mixture was stirred for 1 hour and concentrated. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol and pure fractions were evaporated to dryness to afford (3R)-3-(pyridin-3-yloxy)pyrrolidine (405 mg, 92%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].[CH2:7]([O:9][CH2:10][CH2:11][NH2:12])[CH3:8]>>[CH2:7]([O:9][CH2:10][CH2:11][NH:12][C:3](=[NH:4])[C:2]([Cl:6])([Cl:5])[Cl:1])[CH3:8]
Reactant: CCOCCN
Reactant: N#CC(Cl)(Cl)Cl
Product: CCOCCNC(=N)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To 15 ml (0.5 mole) trichloroacetonitrile in an ice bath, was added 8.9 g (0.10 mole) 2-ethoxyethylamine. The addition was carried out over 20 minutes and the reaction temperature rose to 35° C. After 20 minutes additional stirring at 0° C., it was stirred at room temperature overnight. The mixture was washed to give 12.0 g. Distillation yielded: (1) 9.1 g (B.P. 0.41 mm, 92°-97° C.); (2) 1.9 g (B.P. 0.41 mm, 96° C.). Total yield: 10.9 g (47%). The structure was confirmed via IR, VPC, and elemental analysis.