Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>[OH-].[Na+].CC(C)=O.O>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
7.6 g 4-Aminophenylacetic acid are dissolved in 50 ml 2 N aqueous sodium hydroxide solution and 50 ml acetone. A solution of 8.8 g 4-chlorobenzoyl chloride in 10 ml acetone is added dropwise thereto at 0° C. The reaction mixture is further stirred for 3 hours at ambient temperature, then diluted with water, filtered and the filtrate acidified with dilute hydrochloric acid. The precipitate obtained is reprecipitated via its sodium salt and recrystallized from ethanol. There are obtained 4.2 g (29% of theory) 4-(4-chlorobenzamido)-phenylacetic acid; m.p. 252° C.
Reaction SMILES: CC(C)=O.[SH:5][N:6]1[NH:10][N:9]=[CH:8][N:7]1[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][Cl:21]>C(Cl)Cl>[Cl:21][CH2:20][CH2:19][S:5][N:6]1[NH:10][N:9]=[CH:8][N:7]1[CH3:11]
Reactant: ClCCBr
Reactant: CN1C=NNN1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CN1C=NNN1SCCCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an acetone (50 ml) solution containing 2-mercapto-1-methyltetrazole (4.0 g) and anhydrous potassium carbonate (20 g) was added 1-bromo-2-chloroethane (5.0 ml) under ice-cooling. The mixture was stirred for 90 minutes at room temperature, to which was added methylene chloride (50 ml). The mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure to afford 2-(chloroethylthio)-1-methyltetrazole (6.0 g) as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH3:15])[CH3:2].Cl[CH2:18][C:19]1[C:20]([CH3:35])=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:18][C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)=[CH:9][C:8]=1[O:14][CH3:15])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)cc1OC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Product: CCOC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1OC

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-2-methoxy-phenyl)-propionic acid ethyl ester was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 1N]) to give 3-{2-methoxy-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: O=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][CH:5]([C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:6]([O:8]CC)=[O:7].C([O-])(=O)C.[NH4+].C1(C2C(C(OCC)=O)=CC=C(C3C=CC=CC=3)[N:39]=2)C=CC=CC=1.C(C(CCC(=O)C1C=CC=CC=1)C(OCC)=O)(=O)C1C=CC=CC=1>C(O)(=O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:39]=1
Reactant: CCCCCCCC(=O)CCC(C(=O)OCC)C(=O)c1ccccc1Cl
Reactant: CCOC(=O)c1ccc(-c2ccccc2)nc1-c1ccccc1
Agent: CC(=O)[O-]
Agent: CCOC(=O)C(CCC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCCCCCc1ccc(C(=O)O)c(-c2ccccc2Cl)n1
Yield: 70.6 %

Procedure:
A mixture of 0.90 g of compound I, 2.73 g of ammonium acetate and 2.80 g of ferric chloride hexahydrate in 20 cc of acetic acid was heated under reflux for 8 hours. Thereafter, 0.60 g of compound J was obtained in the same manner as in the production of compound H from compound G, Yield: 70.6%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])=O)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@@H]1CO
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](N2C(=O)c3ccccc3C2=O)C[C@@H]1CO
Reaction time: 6 h
Yield: 93.5 %

Procedure:
(2R,4S)-1-(tert-Butyloxycarbonyl)-2-hydroxymethyl-4-amino-pyrrolidine 41 (1.00 g, 4.63 mmol) was dissolved in dry methanol (20 ml) and treated with N-ethoxycarbonyl phthalimide (1.09 g, 5 mmol) at room temperature. The reaction mixture was stirred for 6 h and evaporated to dryness the residue was purified by flash chromatography over silica gel using CH2Cl2 →EtOAc as the eluent. The pure fractions were collected and evaporated to give 1.5 g (94%) of pure compound as foam. 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 3.40-3.62 (m, 3H), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H) and 7.3-7.6 (m, 4H, Ph).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=O)[C:12]([O-:14])=O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[CH2:16]([NH2:19])[CH2:17][NH2:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:12](=[O:14])[NH:18][CH2:17][CH2:16][N:19]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(C(=O)C(=O)[O-])ccc21
Reactant: NCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1ncc2cc(C3=NCCNC3=O)ccc21

Procedure:
The mixture of 2-(1-methyl-1H-indazol-5-yl)-2-oxoacetate (520 mg, 2.2 mmol), ethylenediamine (0.15 mL, 2.2 mmol), and sodium sulfate in toluene (9 mL) was heated at reflux for 12 hours. The reaction was cooled, and diluted with ethyl acetate. The mixture was filtered through a pad of celite and was washed with ethyl acetate. Concentration and purification with flash column chromatography (EtOAc) gave 3-(1-methyl-1H-indazol-5-yl)-5,6-dihydropyrazin-2(1H)-one. LCMS-ESI+: calc'd for C12H13N4O: 229.3 (M+H+); Found: 229.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH:12](=[O:15])[CH2:13][CH3:14]>N1CCCCC1.C(O)(=O)CCCCCCCCCCCCCCCCC.C(O)(=O)C>[CH3:14][C:13](=[CH:10][CH2:9][CH:5]1[CH2:4][CH:3]=[C:2]([CH3:1])[C:6]1([CH3:7])[CH3:8])[CH:12]=[O:15]
Reactant: CC1=CCC(CC=O)C1(C)C
Reactant: CCC=O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(C=O)=CCC1CC=C(C)C1(C)C
Temperature: 100 °C
Yield: 94.9 %

Procedure:
A 500 mL four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel was charged with 171 g (0.98 mol) of campholenic aldehyde (purity: 88%), 3.8 g (0.045 mol) of piperidine and 13.1 g (0.046 mol) of stearic acid, and the contents in the flask were stirred while heating at 100° C. Then, 91 g (1.6 mol) of propionaldehyde was gradually dropped into the flask for 6 h, and the resultant mixture was aged for 1 h and then cooled. Thereafter, 3.2 g (0.053 mol) of acetic acid was added to the mixture to remove amines therefrom, thereby separating the mixture into two layers. The thus separated organic layer was washed with water and separated into two layers, thereby obtaining 295 g (0.93 mol) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-but-2-en-1-al (purity as measured by gas chromatography: 60.6%) (yield based on theoretical amount: 95%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[CH:6]1([N:5]([CH2:11][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][N:21]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]2=3)=[O:4])[CH3:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:7]1
Reactant: C1CCNCC1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Solvent: CC#N
Product: CN(CC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2ccccc21)C1CCCCC1

Procedure:
The title compound is prepared analogously to Example 2 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[[cyclohexyl)(methyl)amino]methyl]piperidine to give colorless crystals, mp. 146°-148° C. (acetonitrile activated charcoal).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: CO
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cnccc2n1
Temperature: 25 °C

Procedure:
To a mixture of 1,6-naphthyridine-2-carboxylic acid (1 g, 5.7 mmol) and 100 mL of methanol was added carefully ˜0.5 mL of conc. H2SO4. The mixture was kept under reflux overnight. The mixture was cooled to room temperature and solvent was evaporated. To the residue was added carefully (carbon dioxide evolution) half saturated sodium bicarbonate solution to neutralize the acid. The mixture was extracted from ethyl acetate (3 times) and the combined organic was washed with brine. After drying over anhydrous MgSO4, solvent was evaporated. The product, 1,6-naphthyridine-2-carboxylic acid methyl ester, (IIIe) was isolated as a solid (932 mg, 87% yield), which was used for the next step without further purification. A mixture of ester (IIIe) (322 mg, 1.71 mmol) and methylacetate (dry, 10 mL) was treated with NaH (60% dispersion in mineral oil, 100 mg, 2.5 mmol) and the resulting mixture was kept under reflux for 2 h, during which a cake formation was noticed. The reaction mixture was cooled to room temperature and solvent was evaporated. The residue was treated ˜20 mL of water. The mixture was neutralized with conc. HCl. A solid was obtained which was filtered, washed (water followed by hexane) and dried. Yield: 158 mg (40%). The product, ethyl 3-oxo-3-pyridino[3,4-e]pyridin-2-yl-propanoate, (Vf) was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COCCN
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Product: COCCNC(=O)Cn1cc(-c2n[nH]c3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ncc23)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and 2-Methoxyethylamine. LCMS (M+H)+=505.1/507.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CO.[CH:13](I)([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH:13]([NH:10][C:7]1[CH:8]=[CH:9][C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: Nc1ccc2c(c1)OCC2
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Nc1ccc2c(c1)OCC2

Procedure:
To a solution of 2.8 g. of 2,3-dihydro-6-benzofuranamine in 150 ml. of methanol is added 18 ml. of isopropyl iodide and 26.5 ml. of triethylamine. The solution is refluxed for 60 hours and then concentrated in vacuo. The resultant oil is extracted repeatedly with diethyl ether. The extracts are combined, filtered through Celite, and the ether removed in vacuo to give an oil of N-isopropyl-2,3-dihydro-6-benzofuranamine.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:5]([CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[C:27]([F:26])([F:36])[F:37])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[C:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:23])=[O:24])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH:2]([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(C)CNS(=O)(=O)c1ccc(C=C2CCN(S(C)(=O)=O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(Cc1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(C=C2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 110 °C
Yield: 54.9 %

Procedure:
A mixture of N-isobutyl-4-(1-methanesulfonyl-piperidin-4-ylidenemethyl)-benzenesulfonamide (375 mg, 0.97 mmol), 2-(trifluoromethyl)benzyl bromide (289 mg, 1.22 mmol) and K2CO3 (201 mg, 1.46 mmol) in DMF (5 mL) was heated at 110° C. for 6 hours. The cooled mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) and concentrating the residue from Et2O gave the title compound (290 mg, 55%). 1H NMR (400 MHz, DMSO) δ 7.83 (d, J=8.3 Hz, 2H), 7.70-7.73 (m, 3H), 7.49 (t, J=8.1 Hz, 3H), 6.51 (s, 1H), 4.46 (s, 2H), 3.22 (dt, J=30.4, 5.7 Hz, 4H), 2.96 (d, J=7.3 Hz, 2H), 2.89 (s, 3H), 2.49-2.50 (m, 4H), 1.39-1.40 (m, 1H), 0.70 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 544.9 [M+1]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([OH:10])[CH:5]=1.[CH3:11]I>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][N:7]([CH3:11])[C:6](=[O:10])[CH:5]=1
Reactant: CI
Reactant: Oc1cc(Br)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc(Br)cc1=O
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a suspension of NaH (80 mg, 2 mmol) in THF (10 mL) was added 4-bromopyridin-2-ol (80 mg, 0.46 mmol) at 0° C. The resulting mixture was stirred for 1 h. Then CH3I (355 mg, 2.5 mmol) was added to the above mixture, and the mixture was stirred overnight. The reaction was quenched with aqueous NH4Cl solution. The organic phase was concentrated to give the crude product, which was purified by column to give 4-bromo-1-methylpyridin-2(1H)-one (42.3 mg, 50%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])=[CH:4][C:3]=1[F:19].[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>O1CCOCC1.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>[CH:20]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])=[CH:4][C:3]=1[F:19])=[CH2:21]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (S)-(−)-N-[[3-[4-iodo-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (5.45 g), vinyltributyltin (5.48 g) and bis(triphenylphosphine)palladium(II) chloride (303 mg) in 1,4-dioxane (72 mL) under N2 is degassed, heated up to reflux, refluxed for seven hours, cooled to ambient temperature and stirred for 12 hours. The mixture is then diluted with ethyl acetate (40 mL) and water (50 mL) and the layers are separated. The aqueous phase is extracted with ethyl acetate (2×30 mL), and the combined organic phase is washed with saline (40 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and triturated with diethyl ether. The resultant precipitate is filtered to give the title compound, mp 165-166° C.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[NH:31]1[CH2:34][CH2:33][CH2:32]1>C(OCC)C>[N:31]1([C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:7]2)[CH2:34][CH2:33][CH2:32]1
Reactant: CS(=O)(=O)O[C@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Brc1ccc2nc(N3CCC[C@@H](N4CCC4)C3)sc2c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
One equivalent of (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 10, 0.078 g, 0.2 mmol) and two equivalents of potassium carbonate (55.3 mg, 0.40 mmol) were weighed into a 2.5 mL Biotage microwave vial equipped with a magnetic stirbar. Acetonitrile (1 mL) was added, then 6 equivalents of azetidine (68.5 mg, 1.2 mmol) was weighed into the reaction mixture. The vial was sealed with a septum cap and the reaction mixture was stirred at 80° C. for 72 hours. The reaction mixture was transferred to a 100 mL round bottom flask (methanol rinse). Volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give an oil. The oil was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF10-4 g, 100% dichloromethane to 98:2 dichloromethane/2 M NH3 in methanol). Fractions containing product were combined and concentrated under reduced pressure to give an oil that was dissolved in diethyl ether and dried (MgSO4). The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give a semi-solid that was triturated with diethyl ether/hexane to give (R)-2-(3-(azetidin-1-yl)piperidin-1-yl)-6-bromobenzo[d]thiazole as a solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.23-1.38 (m, 1H), 1.53-1.69 (m, 1H), 1.80-1.96 (m, 2H), 2.11 (pentet, J=7 Hz, 2H), 2.32-2.43 (m, 1H), 2.93-3.02 (m, 1H), 3.22-3.38 (m, 5H), 3.79 (dt, J=4, 13 Hz, 1H), 3.96 (dd, J=4, 13 Hz, 1H), 7.33 (d, J=9 Hz, 1H), 7.39 (dd, J=2, 9 Hz, 1H), 7.79 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 352 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH3:22].O>C(#N)C>[CH2:18]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:9]=[CH:10][C:2]=1[OH:1])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCBr
Reactant: O=C1CCC(c2ccc(O)c(C(=O)O)c2)CC1
Solvent: O
Solvent: CC#N
Product: CCCCCOC(=O)c1cc(C2CCC(=O)CC2)ccc1O

Procedure:
13.60 g (70 mmols) of 2-hydroxy-5-(4-oxocyclohexyl)benzoic acid was suspended in 90 ml of acetonitrile. 10.66 g (70 mmols) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) was added dropwise at 20° C. over a period of 10 minutes, followed by 11.63 g (77 mmols) pentyl bromide over a further period of 10 minutes. The suspension was then stirred under reflux for 18 hours. After cooling the reaction mixture was poured into 300 ml of water and extracted three times with 150 ml of acetic ester. The combined organic phases were washed once with 200 ml 1N HCl, three times with 150 ml of water, dried over magnesium sulphate and filtered. Removal of the solvent gave the crude product which was purified by chromatography on silica gel, eluting with cyclohexane/acetic ester to give 2-hydroxy-5-(4-oxocyclohexyl)benzoic acid pentyl ester.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH2:19]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO>[CH2:19]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCOc1ccc(N)cc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.3 g (1.173 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (for preparation see German Auslegeschrift no. 1 061 788 [published 23.07.1959]), and 0.483 g (3.52 mmol) 4-ethoxyaniline is heated for 30 min at 90° C. The cooled reaction mixture is distributed with thorough stirring between a dichloromethane/methanol mixture (18:1) and saturated aqueous sodium carbonate solution. The organic phase washed with water and brine is dried over anhydrous sodium sulfate and evaporated under vacuum. Title compound is obtained after recrystallization of the residue from acetate/methanol and acetonitrile; m.p. 223-224° C.; ESI-MS: (M+H)+=357.
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:33]([NH:32][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([Cl:31])[C:25]=2[Cl:24])=[O:34])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:18][CH2:19][S:20](=[O:23])[CH2:21][CH2:22]1)(=[O:16])=[O:15]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 44 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)aniline (117 mg, 0.35 mmol) and 2,3-dichlorophenylisocyanate (72 mg, 0.38 mmol) were coupled to form the desired urea (79 mg, 44%). 1H NMR (DMSO-d6): δ 9.34 (s, 1H), 9.27 (s, 1H), 8.28 (d, 1H), 8.05 (m, 1H), 7.32 (m, 2H), 7.21 (d, 1H), 3.75 (m, 2H), 3.65 (m, 2H), 2.89, (m, 4H).
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:13][CH:5]([CH2:6][N:7]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:8]3)[C:4]=2[CH:3]=1.N([O-])=O.[Na+].[ClH:24]>O.Cl[Cu]>[Cl:24][C:2]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:13][CH:5]([CH2:6][N:7]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:8]3)[C:4]=2[CH:3]=1
Reactant: Cl
Reactant: Nc1ccc2c(c1)C1CC2CN(C(=O)C(F)(F)F)C1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N1CC2CC(C1)c1cc(Cl)ccc12)C(F)(F)F
Temperature: 60 °C
Yield: 95 %

Procedure:
1-(4-Amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (460 mg, 1.7 mmol) was dissolved in H2O (2 mL) and concentrated HCl solution(1 mL) then cooled to 0° C. and treated with a solution of sodium nitrite (NaNO2) (275 mg) in H2O (1 mL) dropwise. To the resulting solution was added a CuCl (202 mg, prepared as described above, 2.04 mmol) in concentrated HCl solution (2 mL) over 10 minutes (gas evolution observed). The resulting solution was warmed to 60° C. for 15 minutes, then was cooled to room temperature and extracted with EtOAc (4×30 mL). After drying over Na2SO4, the solution was filtered and concentrated to an oil which was filtered through a Silica pad to remove baseline material eluting with 50% EtOAc/hexanes to give an oil (470 mg, 95%).