Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:16])=[N:6][CH:7]=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH:2]=C.C[N+]1([O-])CC[O:21]CC1>O1CCOCC1.[Os](=O)(=O)(=O)=O>[Cl:16][C:5]1[C:4]([CH2:1][CH:2]=[O:21])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:8]=[CH:7][N:6]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1c(Cl)ncnc1-c1ccccn1
Agent: O=[Os](=O)(=O)=O
Solvent: C1COCCO1
Product: O=CCc1c(Cl)ncnc1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a stirred solution of 5-allyl-4-chloro-6-(pyridin-2-yl)pyrimidine (1 g) in dry dioxane (10 mL), N-methyl morpholine N-oxide (0.75 g) and osmium tetroxide (0.35 mL, 25% solution in water) were added. The reaction mixture was stirred at room temperature for 2 hours before being quenched by solid sodium bisulphate. The reaction mixture was filtered through celite bed and the celite bed was washed with dioxane (5 mL). The combined filtrate was taken into a 100 mL three necked round bottom flask and sodium metaperiodate (2.3 g, in 5 mL water) was added. The reaction mixture was stirred at room temperature for 3 hours and then diluted with water (30 mL). Aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of solvents under reduced pressure gave crude 2-(4-chloro-6-(pyridin-2-yl)pyrimidin-5-yl)acetaldehyde (0.7 g) which was used as was. 1H NMR (DMSO-d6): δ 4.12 (s, 2H), 7.53-7.55 (m, 1H), 7.88-8.01 (m, 2H), 8.66-8.69 (d, 1H), 8.97 (s, 1H), 9.79 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1.[N+](=[CH2:23])=[N-]>C1COCC1>[CH3:23][O:18][C:17](=[O:19])[CH:16]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:10][CH:11]=1)[CH3:20]
Reactant: CC(=CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)C=C(C)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 0.33 h

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid is dissolved in 10 ml. of THF and an ethereal solution of diazomethane is added dropwise, with stirring, until no further evolution of nitrogen is observed. After 20 minutes, the mixture is evaporated to give 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid methyl ester, m.p. 90°-92°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:8](=[O:18])[CH2:7]2)(=[O:3])[CH3:2].[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][C:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:8](=[O:18])[CH2:7]3)[O:21][CH2:20][CH2:19][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2CC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC1(c2ccc3c(c2)CC(=O)N3CC(F)(F)F)OCCO1

Procedure:
A solution of 5-acetyl-1-(2,2,2-trifluoro-ethyl)-1,3-dihydro-indol-2-one (1.04 g, 4.0 mmol), ethylene glycol (1.37 mL, 24 mmol) and p-toluenesulfonic acid (10 mg) in benzene (25 mL) was heated to reflux for 4 hours in a flask fitted with a Dean-Stark trap. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated in vacuo to an oil which solidified upon standing (1.19 g, 98%, mp 87-89° C.).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[F:12][C:13]1[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23].[OH-].[K+].Cl>CO>[C:10]([C:8]1[CH:9]=[C:4]2[C:3]([CH:19]([OH:20])[C:18]3[C:13]([F:12])=[C:14]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])[CH:15]=[CH:16][CH:17]=3)=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)#[N:11]
Reactant: N#Cc1cnc2[nH]ccc2c1
Reactant: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3ncc(C#N)cc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (13, 132 mg, 0.923 mmol), propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (22, 151 mg, 0.616 mmol) and potassium hydroxide (104 mg, 1.85 mmol) were combined in a round bottom flask with 1.2 mL of methanol. The reaction was stirred for 2 hours at room temperature. The reaction solution was neutralized with 0.1 N aqueous hydrochloric acid and extracted 3× with ethyl acetate. The organic layers were combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and dichloromethane to provide the desired compound (23, 79 mg). MS(ESI) [M−H+]31 =387.5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[N:14]([CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[N+:15]=[N-:16]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:14]([CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:15]=[N:16][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:13])[CH3:2]
Reactant: CCOC(=O)C#Cc1ccccn1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(-c2ccccn2)nnn1C[Si](C)(C)C
Yield: 21.9 %

Procedure:
To a solution of pyridin-2-yl-propynoic acid ethyl ester (1.25 g, 7.14 mmol) in benzene (22 mL) was added azidomethyl-trimethyl-silane (1.11 g, 8.56 mmol) and the reaction mixture was refluxed under nitrogen for 72 h. The mixture was then evaporated and purification by chromatography [silica, 0 to 50% ethyl acetate in heptane then HPLC (Chiralpak AD, ethanol in heptane)] afforded the title compound (477 mg, 23%) as a yellow oil. MS: m/e=305.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[S:36][CH:37]=[CH:38][CH:39]=4)[CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[CH3:40][C:5]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[S:36][CH:37]=[CH:38][CH:39]=4)[CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:18][CH:19]=1)([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:4]([OH:41])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccccc1)Oc1ccc(OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2cccc(-c3cccs3)c2)nc1CCOc1ccc(OC(C)(Cc2ccccc2)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
2-Methyl-2-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-3-phenyl-propionic acid ethyl ester (24.7 mmol) was dissolved in methanol (200 mL) and 2N NaOH (150 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously overnight. The solution was concentrated under reduced pressure, diluted with H2O (100 mL) and acidified to pH=1 with 5N HCl. The mixture was extracted with ethyl acetate (2×200 mL), dried (MgSO4), and concentrated under reduced pressure to provide an oil. The oil (8.23 g) was recrystallized from ethyl acetate (24 mL) and hexanes (56 mL) to afford 2-Methyl-2-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-3-phenyl-propionic acid as colorless needles after drying at 50° C. under vacuum for 6 h: 1H NMR (400 MHz, CDCl3) δ8.22 (t, 1H, J=1.56 Hz), 7.87 (d, 1H, J=7.82 Hz), 7.66-7.64 (m, 1H), 7.45 (d, 1H, J=7.82 Hz), 7.41-7.40 (m, 1H), 7.31-7.25 (m, 6H), 7.09 (dd, 1H, J=5.08 Hz, J=3.52 Hz), 6.84 (d, 2H, J=9.38 Hz), 6.76 (d, 2H, J=9.38 Hz), 4.17 (t, 2H, J=6.45 Hz), 3.30 (d, 1H, J=13.69 Hz), 3.15 (d, 1H, J=13.69 Hz), 3.01 (t, 2H, J=6.45 Hz), 2.40 (s, 3H), 1.35 (s, 3H); HRMS (ES+) m/z exact mass calculated for C32H30NO5S 540.1857, found 540.1857.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2].ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:47]>>[C:1]([C:3]1[C:4]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:9][NH:8][C:7]=12)(=[O:47])[NH2:2]
Reactant: N#Cc1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)OCc1ccccc1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Product: NC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)OCc1ccccc1

Procedure:
The desired product was prepared from benzyl 2-(3-cyano-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate using the procedure similar to step 2 for compound 2. MS (ESI) m/e [M+1]+ 577.9.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:19]3[CH:18]=[C:17]4[C:20]([CH3:28])([CH3:27])[C:21]5[C:26]([C:16]4=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:3][CH:2]=1.[Br:35]N1C(=O)CCC1=O>C(#N)C>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][C:4]([N:7]2[C:19]3[CH:18]=[C:17]4[C:20]([CH3:27])([CH3:28])[C:21]5[C:26]([C:16]4=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([Br:35])[CH:12]=3)=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:5][CH:6]=1
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccccc5)cc4)c3cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC1(C)c2ccccc2-c2cc3c4cc(Br)ccc4n(-c4ccc(-c5ccccc5)cc4)c3cc21
Reaction time: 18 h
Yield: 52.7 %

Procedure:
17.5 g (40.18 mmol) of 10-biphenyl-4-yl-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene are suspended in 450 ml of acetonitrile, and 7.15 g (40.18 mmol) of N-bromosuccinimide are added in portions at −20° C. at such a rate that the reaction temperature does not rise above −20° C. The mixture is stirred for a further 18 h, during which the temperature is allowed to come to RT. The reaction mixture is subsequently evaporated in a rotary evaporator, dissolved in dichloromethane and washed with water. The residue is dried, evaporated and subsequently recrystallised from toluene to a purity of 99.3%, giving 10.9 g (53%) of the product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][C:27]#[N:28]>CN(C=O)C>[C:27]([CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:16])[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)#[N:28]
Reactant: N#CCCl
Reactant: Cc1ccc(C(=O)c2ccccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2ccccc2OCC#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2'-hydroxy-4-methylbenzophenone (9 g), potassium iodide (8.46 g) and potassium carbonate (8.79 g) in DMF (200 ml) was added chloroacetonitrile (3.85 g) and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to dryness. After the addition of water, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give pale brown syrup (8.9 g, 84%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][CH2:24]O)[CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([O:12][CH2:24][CH2:23][CH2:22][C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCCCc1cccnc1
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (3.0 g; 13.9 mmol), 3-(3-Pyridyl)-1-propanol (2.90 g; 20.9 mmol), dicyclohexylcarbodiimide (4.59 g; 22.24 mmol), camphorsulfonic acid (1.08 g; 4.63 mmol), and 4-dimethylaminopyridine (0.60 g; 4.63 mmol) in dry methylene chloride (100 mL) was stirred overnight. The reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL), and the layers were separated. The organic phase was washed with water (3×100 mL), dried over magnesium sulfate, and concentrated, and the crude residue was purified on a silica gel column eluting with ethyl acetate to obtain 4.60 g (95%) of the ester as a thick oil. 1H NMR (300 MHz, CDCl3): δ 1.45 (s, 9H); 1.70-2.05 (m, 5H); 2.32 (m, 1H); 2.71 (t, 2H); 3.50 (m, 2H); 4.15 (m, 2H); 4.18 (m, 1H); 7.24 (m, 1H); 7.51 (m, 1H); 8.48 (m, 2H).
Reaction SMILES: O[NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.CO.Cl>[Zn].O>[NH2:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 70 °C

Procedure:
1-Hydroxylaminoanthraquinone 50 parts was stirred into a mixture of methyl alcohol 700 parts, water 100 parts and a 35% aqueous hydrochloric acid 60 parts. The reaction mixture was heated to 70°C and then added with zinc dust 16 parts little by little over 1 hour. After the reaction at 70°C for 3 hours, the reaction mixture was cooled to 25°C, filtered, washed with water and dried to obtain 42.5 parts of crystalline 1-aminoanthraquinone of a purity of 93%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1.[CH:25](I)([CH3:27])[CH3:26].O>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([N:9]([CH:25]([CH3:27])[CH3:26])[S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N(C(C)C)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in DMF (2.0 ml), 4′-methoxy-2′-nitro-p-toluenesulfonanilide (0.65 g (2.02 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, isopropyl iodide (1.00 g (5.88 mmol)) was added dropwise. After five hours' heating at 130° C. with stirring, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) as eluent, giving 0.21 g (28.5%) of the title compound as pale brown crystals.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH:14]([N:21]=[C:22]=S)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:22]([NH:21][C@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:13])[NH:2][C:3]=2[CH:7]=1
Reactant: CC(N=C=S)c1ccccc1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](NC1=NS(=O)(=O)c2sc(Cl)cc2N1)c1ccccc1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and L-α-methylbenzyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 195°-204° C. (ethyl acetate), 1H-NMR (DMSO-d6): δ 1.46 (d, 3H), 4.95 (m, 1H), 7.1 (s, 1H), 7.2-7.45 (m, 5H), 7.78 (br. s, 1H), 10.85 (s, 1H).
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27]C)[CH:23]=5)[C:18]4=[O:29])=[CH:13][CH:12]=3)[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:29])=[CH:15][CH:16]=3)[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)cc3)ccc2c1
Agent: Br
Product: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)cc1

Procedure:
According to Method L, 2-((R)-4-[1,3′]bipyrrolidinyl-1′-yl-phenyl)-6-methoxy-2H-isoquinolin-1-one was treated with hydrogen bromide. In this way the product was obtained with molecular weight 375.47 (C23H25N3O2); MS (ESI): 376 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:3]=1[C:14](=[O:16])[CH3:15].[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19]1>>[C:14]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]2[N:25]=[C:26]3[C:21]([CH2:20][CH2:19][C:18](=[O:17])[NH:27]3)=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1c(F)cccc1N1CCNCC1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Product: CC(=O)c1c(F)cccc1N1CCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1

Procedure:
In a manner similar to that of other examples above, 1-(2-fluoro-6-piperazin-1-yl-phenyl)-ethanone was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 441.3 (Exact Mass: 440.22).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:10][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1
Reactant: Cc1ccc(F)c(O)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
2-Fluoro-5-methylphenol (5.0 g, 40 mmol) was dissolved in chloroform (200 mL). Tetrabutylammonium tribromide (19 g, 40 mmol) was added and the reaction stirred at ambient temperature for 30 minutes. The reaction was concentrated and purified over silica gel (20% EtOAc in hexanes) to afford 4-bromo-2-fluoro-5-methylphenol (7.8 g, 38 mmol, 96% yield) as an amber oil.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Na+:5].[Na+].[C:7](=O)([OH:9])[O-:8].[OH-].[Na+]>>[OH-:2].[Na+:5].[C:7]([O-:9])(=[O:8])[C:1]([O-:3])=[O:4].[Na+:5].[Na+:5]
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])C(=O)[O-]

Procedure:
Causticisation with lime slurry then converts the sodium carbonate and bicarbonate to sodium hydroxide. The recovery of sodium hydroxide from the effluent results in soda savings of approximately 0.6 tonne/tonne of sodium oxalate. It is estimated that this will result in savings of over 5600 tonnes per annum at the Worsley Alumina refinery alone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)=[N:9][N:10]=2)[CH:7]=1.Cl.Br[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:12]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: Oc1cccc(-c2nnc3ccc(Br)cn23)c1
Reactant: BrCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2nnc(-c3cccc(OCCN4CCOCC4)c3)n2c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of Example 10 step a (250 mg, 1.21 mmol), N-(2-bromoethyl)morpholine hydrochloride (306 mg, 1.32 mmol) and K2CO3 (500 mg, 3.62 mmol) in DMF (20 mL) was heated at 50° C. for 24 h. The reaction was then allowed to cool to RT and concentrated in vacuo. The residue was purified by FCC (DCM:MeOH, 1:0 to 9:1) to afford the title compound (479 mg, 98%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.44 (1 H, dd, J 1.7, 1), 7.74-7.69 (1 H, m), 7.50 (1 H, t, J 7.9), 7.39-7.35 (2 H, m), 7.35-7.30 (1 H, m), 7.14-7.08 (1 H, m), 4.21 (2 H, t, J 5.6), 3.74 (4 H, t, J 4.6), 2.85 (2 H, t, J 5.6), 2.63-2.56 (4 H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[O-:9]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cc(Br)cs1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
4-Bromothiophene-2-carbaldehyde (1.9 g, 10 mmol) was dissolved in 40 mL of t-BuOH and 4 mL of 2-methyl-2-butene. The reaction mixture was cooled to 0° C. and NaClO2 (1.1 g, 12 mmol) dissolved in 12 mL of 1M NaH2PO4 was added. The reaction mixture was let warm to room temperature and stirred for 5 hours. The reaction mixture was concentrated to about half the volume, and poured into 20 mL 1N NaOH and 50 mL Et2O. The aqueous layer was made acidic with 6N HCl and extracted with EtOAc. This organic layer was dried over sodium sulfate and concentrated to obtain the product as a white solid, 1.75 g, 8.5 mmol, 85% yield. 1H NMR 500 MHz (DMSO-d6) 8.02 (1H, s), 7.78 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH2:5]Br.NC(N)=[S:17]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][SH:17])[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: NC(N)=S
Reactant: FC(F)(F)Oc1ccc(CBr)cc1Cl
Solvent: CCO
Product: FC(F)(F)Oc1ccc(CS)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 3-chloro-4-(trifluoromethoxy)benzylbromide (5 g) in ethanol (100 ml) was added thiourea (5 g) and the mixture heated under reflux for 2 hours. The mixture was evaporated to dryness and the residue taken up into water (100 ml). To this solution was added sodium hydroxide pellets (3 g) and the mixture heated under reflux for 1 hour. The mixture was allowed to cool to room temperature and acidified with concentrated hydrochloric acid, the mixture was extracted with ether, dried and evaporated to give the subtitle compound as a colourless waxy solid (3.5 g).
Reaction SMILES: [CH2:1]([N:4]1[C@H:18]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)=[CH:7][C@@H:6]([C:20]([OH:22])=O)[CH2:5]1)[CH2:2][CH3:3].[NH3:23]>C(O)CO>[CH2:1]([N:4]1[C@H:18]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)=[CH:7][C@H:6]([C:20]([NH2:23])=[O:22])[CH2:5]1)[CH2:2][CH3:3]
Reactant: N
Reactant: CCCN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: OCCO
Product: CCCN1C[C@@H](C(N)=O)C=C2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
By allowing 3.1 g of the methyl ester of 9,10-didehydro-6-n-propyl-8β-ergoline carboxylic acid to stand in a solution of ammonia in ethylene glycol, a mixture of the isomeric amides is obtained; chromatographic separation of the reaction product yields 1.2 g of 9,10-didehydro-6-n-propyl-8α-ergoline carboxylic acid amide. [α]D25 =+297°; c=0.5 (pyridine).