Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(N3CCOCC3)cc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cc(N3CCOCC3)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:20](B(O)O)[CH:21]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:20]([C:2]2[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=2)[CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COCCOCOc1ccc(C(C)(C)C)cc1B(O)O
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COCCOCOc1ccc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)nn1
Temperature: 80 °C
Yield: 87.7 %

Procedure:
A mixture of 3-chloro-6-trifluoromethylpyridazine [purchased from Combi-Blocks] (250 mg, 1.37 mmol), (5-(tert-butyl)-2-((2-methoxyethoxy)methoxy)phenyl)boronic acid [Intermediate 7] (463.8 mg, 1.64 mmol) and potassium carbonate (284.5 mg, 2.06 mmol) in dimethoxyethane (7.5 mL) and water (2.5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (79.1 mg, 0.068 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 22 hours. The cooled reaction mixture was partitioned between ethyl acetate (50 mL) and 10% aqueous sodium carbonate solution (50 mL), the organic phase separated, washed with water (50 mL) and saturated brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a brown syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 30% ethyl acetate in hexanes to give 3-(5-(tert-butyl)-2-((2-methoxyethoxy)methoxy)phenyl)-6-(trifluoromethyl)pyridazine (0.462 g, 88% yield) as a colorless syrup.
Reaction SMILES: [F:1][C:2]([F:17])([S:13](F)(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>CCOCC>[CH2:18]([N:20]([CH2:21][CH3:22])[S:13]([C:2]([F:17])([F:1])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])(=[O:15])=[O:14])[CH3:19]
Reactant: CCNCC
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCOCC
Product: CCN(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Under a blanket of nitrogen, a mixture of 55 g (0.180 moles) of perfluorobutane sulfonyl fluoride and 70.7 g (0.970 moles) of diethylamine was heated at reflux for nine hours. The reaction mixture was dissolved in 600 ml of ether and percolated through a column of 60 g of acidic alumina. The ether was stripped and the product was distilled at 56°-58° C. at 2.0 mm. Yield 41.6 g (65%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[OH:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:21][CH2:22]2)[CH:31]=[CH:32][C:33]=1[OH:34]
Reactant: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: OB(O)c1ccc(O)c(Cl)c1
Product: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(-c4ccc(O)c(Cl)c4)cc23)CC1
Yield: 58.5 %

Procedure:
Following general procedure D, (6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (25 mg, 0.060 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (21 mg, 0.120 mmol) to afford the desired product (16.3 mg, 59%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.74 (s, 1H), 8.28 (s, 1H), 8.05-7.98 (m, 2H), 7.70 (d, J=2.3 Hz, 1H), 7.53 (dd, J=8.4, 2.3 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.53 (d, J=12.7 Hz, 2H), 3.21 (t, J=11.5 Hz, 2H), 2.60-2.51 (m, 1H), 2.43 (d, J=6.8 Hz, 2H), 2.35 (s, 6H), 2.00-1.84 (m, 3H), 1.65-1.53 (m, 2H), 1.34-1.28 (m, 2H), 1.28-1.17 (m, 2H); ESI MS m/z 464 [C27H30ClN3O2+H]+; HPLC>99% (AUC), tR=10.38 min.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.CO.[OH-].[Na+].Cl>O>[NH:36]1[C:32]([C:29]2[CH:28]=[CH:27][C:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:21][CH:22]=3)=[CH:31][CH:30]=2)=[N:33][N:34]=[N:35]1
Reactant: COC(=O)CCCCCCCCCCCCCCCOc1ccc(-c2ccc(-c3nnn[nH]3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCCCCCCCCCOc1ccc(-c2ccc(-c3nnn[nH]3)cc2)cc1
Yield: 96.1 %

Procedure:
A mixture of 16-(4′-(5-tetrazolyl)biphenyl-4-yloxy)hexadecanoic acid methyl ester (2.87 g, 5.66 mmol), MeOH (30 ml), and a solution of NaOH (1.51 g, 37.8 mmol) in water (2.0 ml) was stirred at 70° C. After 4 d water (100 ml) and 1N HCl (50 ml) were added, and the product was filtered, washed with water, coevaporated with MeCN/PhMe, and dried under reduced pressure. 2.68 g (96%) of 16-(4′-(5-tetrazolyl)biphenyl-4-yloxy)hexadecanoic acid was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].S(Cl)(Cl)=O.[CH2:19]([O:21][C:22]([C:24]1[C:29](=[O:30])[N:28]2[CH:31]=[CH:32][CH:33]=[C:34]([SH:35])[C:27]2=[N:26][CH:25]=1)=[O:23])[CH3:20]>CN(C=O)C.C1C=CC=CC=1>[CH2:19]([O:21][C:22]([C:24]1[C:29](=[O:30])[N:28]2[CH:31]=[CH:32][CH:33]=[C:34]([S:35][C:10](=[O:12])[C:9]3[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14][CH:13]=3)[C:27]2=[N:26][CH:25]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Reactant: CCOC(=O)c1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(C(=O)Sc2cccn3c(=O)c(C(=O)OCC)cnc23)cc1
Yield: 105.5 %

Procedure:
To a mixture of 1.47 g (2.4 mmol) of 4-ethoxycarbonylbenzoic acid, 3 drops of DMF and 10 ml of benzene is added 0.52 g (4.4 mmol) of thionyl chloride, and the resultant mixture is refluxed for 3 hours under stirring and concentrated in vacuo to dryness. The residue is dissolved in acetone and mixed with 1.4 g of solid potassium carbonate and then 0.5 g (2 mmol) of 3ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1, and the resultant mixture is vigorously stirred at room temperature for 20 minutes. The reaction mixture is concentrated in vacuo to dryness, and the residue is distributed in chloroformwater. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate to give 0.9 g of the titled compound Ie-56.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][C:15]#[CH:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33](O)=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][C:15]#[CH:16])=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]
Reactant: C#CCC(N)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: C#CCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 47 from 1-(2-piperidino-phenyl)-3-butyn-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=O)=O.[CH:38]1[C:50]2[CH:49]([CH2:51][O:52][C:53]([NH:55][C@@H:56]([CH2:64][SH:65])[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:54])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:24]([O:23][C@H:8]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][S:65][CH2:64][C@@H:56]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[NH:55][C:53](=[O:54])[O:52][CH2:51][CH:49]1[C:50]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=2[C:43]2[C:48]1=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)OCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2,3-bis(dodecyloxy)propyl trifluoromethanesulfonate (1 eq) in ethanol (0.15 M) was added (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-mercaptopropanoate (8, 1.5 eq) and potassium carbonate (1 eq). The reaction mixture was stirred at 60° C. for 30 minutes. The salt from the reaction was filtered off and the filtrate was concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% EtOAc/Hex to give the product.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:47][CH2:46][NH:45][C:44](=[O:48])[C:43]3[S:49][C:50](I)=[CH:51][C:42]2=3)=[CH:37][CH:36]=1.[NH:53]1[CH2:58][CH2:57][O:56][C@H:55]([CH2:59][OH:60])[CH2:54]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:47][CH2:46][NH:45][C:44](=[O:48])[C:43]3[S:49][C:50]([N:53]4[CH2:58][CH2:57][O:56][CH:55]([CH2:59][OH:60])[CH2:54]4)=[CH:51][C:42]2=3)=[CH:37][CH:36]=1
Reactant: OC[C@@H]1CNCCO1
Reactant: O=C1NCCC(c2ccc(Cl)cc2)c2cc(I)sc21
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NCCC(c2ccc(Cl)cc2)c2cc(N3CCOC(CO)C3)sc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 15.7 %

Procedure:
RuPhospalladium(II)phenethylaminechloride (2.83 mg, 0.00388 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (1.81 mg, 0.00388 mmol), 4-(4-chlorophenyl)-2-iodo-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one (31.3 mg, 0.0776 mmol), (2S)-morpholin-2-ylmethanol (16.0 mg, 0.137 mmol), and tetrahydrofuran (0.63 mL) were combined in a rbf equipped with a stirbar. The flask was sealed with a septum then evacuated and refilled with argon three times. To this solution was added a solution of lithium bis(trimethylsilyl)amide) in tetrahydrofuran (1.0 M, 0.31 mL, 0.31 mmol). The sealed r×n was vigorously stirred @ 40° C. for 19 hr. The reaction was cooled to rt, quenched into saline, extracted into EA, washed with saline, dried over Na2SO4, filtered, and concentrated in vacuo. The crude oil was purified using column chromatography on silica gel (24 g ISCO column, gradient 100% DCM to 100% EA over 50 minutes; after unreacted starting material and dehalogenated starting material eluted, the eluant was switched to 5% MeOH in EA) to give the title compound (4.8 mg, 16%) as a mixture of diastereomers. LCMS: (FA) ES+ 393, 395. 1H NMR (400 MHz, DMSO) δ 7.78 (t, J=4.6 Hz, 1H), 7.38-7.35 (m, 2H), 7.15-7.11 (m, 2H), 5.59 (s, 1H), 4.80-4.75 (m, 1H), 4.34-4.31 (m, 1H), 3.91-3.79 (m, 1H), 3.61-3.35 (m, 6H), 3.24 (d, J=11.9 Hz, 1H), 3.11-3.07 (m, 2H), 2.81-2.69 (m, 1H), 2.22-2.14 (m, 1H), 2.02-1.88 (m, 1H).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[C:11]([C:15]1[CH:16]=[C:17]([C:26]2[N:27]=[C:28]3[N:32]([CH:33]=2)[CH2:31][CH2:30][S:29]3)[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:11]([C:15]1[CH:16]=[C:17]([C:26]2[N:27]=[C:28]3[N:32]([C:33]=2[CH:3]=[O:4])[CH2:31][CH2:30][S:29]3)[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(-c2nc3n(c2C=O)CCS3)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
To a solution of 1.5 ml of dimethylformamide in 10 ml of chloroform was added 1.1 g of phosphorus oxychloride under ice-cooling and the mixture was allowed to stand for one hour. To the reaction mixture was added 1.5 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole and the mixture was refluxed for 4 hours. To the reaction mixture was added 20 ml of an aqueous 10% potassium carbonate solution and the mixture was stirred for 15 minutes. The chloroform layer was dried and concentrated. The crystals thus obtained were recrystallized from ethanol to provide 1.0 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-formyl-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)[C:5]([O:7]C)=[O:6].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:21])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1cc(Cl)c(Oc2ccc(O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75.8 %

Procedure:
To a stirred solution of methyl 3,5-dichloro-4-(4′-methoxyphenoxy)benzoate (1.5 g, 4.5 mmol) in CH2Cl2 (50 mL) at −78° C. was added BBr3 (11.4 mL, 11.4 mmol, 1 M solution in CH2Cl2). The reaction mixture was stirred at room temperature for 14 h, poured into ice water (100 mL) and stirred for 1 h. The reaction mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was recrystallized from CH2Cl2 filtered and dried under reduced pressure to afford 3,5-dichloro-4-(4′-hydroxyphenoxy)benzoic acid as a brown solid (1.02 g, 75%): mp 163-165° C.; 1H NMR (300 MHz, DMSO-d6): δ 9.02 (bs, 1 H), 8.0 (s, 2 H), 6.67 (m, 4 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (2:3); Rf=0.3.
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:10]=1)(=O)=O.[NH3:19].C1COCC1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[N:10]=[C:5]([NH2:19])[N:6]=[N:7][CH:8]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: N
Reactant: COc1cccc(-c2cnnc(S(C)(=O)=O)n2)c1
Solvent: C1CCOC1
Product: COc1cccc(-c2cnnc(N)n2)c1
Yield: 45 %

Procedure:
5-(3-Methoxyphenyl)-1,2,4-triazin-3-amine (0.31 g, 45%) was prepared from 3-(methylsulfonyl)-5-(3-methoxyphenyl)-1,2,4-triazine (0.90 g, 3.39 mmol) and 0.5 M ammonia in THF (50 mL, 25.0 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Cl:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]1[N:15]=[C:16]([N:20]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[CH:27]3)[CH2:21][CH2:22][CH3:23])[S:17][C:18]=1[CH3:19]>CN(C)C=O>[Cl:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]1[N:15]=[C:16]([N:20]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH3:3])[CH:28]=[CH:27]3)[CH2:21][CH2:22][CH3:23])[S:17][C:18]=1[CH3:19]
Reactant: CI
Reactant: CCCN(c1ccc2[nH]ccc2c1)c1nc(-c2ccc(OC)cc2Cl)c(C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(c1ccc2c(ccn2C)c1)c1nc(-c2ccc(OC)cc2Cl)c(C)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.045 g of 55% sodium hydride in oil and then 0.12 ml of methyl iodide are added, at 4° C., to 0.39 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(indol-5-yl)-N-propylamino]thiazole obtained above (EXAMPLE 7) in solution in 5 ml of dimethylformamide. After stirring for 5 hours at room temperature, the reaction mixture is poured into ice-cold water. The mixture is extracted with ethyl acetate and the organic phase is washed a number of times with water, dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel eluted with a 9/1 (v/v) cyclohexane/ethyl acetate mixture. The expected product is isolated in the form of a white solid; M.p.=146° C. 1H NMR (CDCl3): 0.92 (m, 3H), 1.58-1.73 (m, 2H), 2.01 (s, 3H), 3.81-4.0 (m, 8H), 6.51 (d, J=2.8, 1H), 6.85 (dd, J=2.2, 8.4, 1H), 6.99 (d, J=2.0, 1H), 7.09-7.20 (m, 2H), 7.35-7.40 (m, 2H), 7.62 (s, 1H).
Reaction SMILES: ClC1C=C2C(C=CN=C2)=CC=1F.C(OC(=O)N[C@H]1CC[C@@H](O)CC1)(C)(C)C.[C:28]([O:32][C:33](=[O:53])[NH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([O:41][C:42]2[C:43]([Cl:52])=[C:44]3[C:49](=[CH:50][CH:51]=2)[CH:48]=[N:47][CH:46]=[CH:45]3)[CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:53])[NH:34][C@H:35]1[CH2:36][CH2:37][C@@H:38]([O:41][C:42]2[CH:51]=[C:50]3[C:49](=[CH:44][C:43]=2[Cl:52])[CH:48]=[N:47][CH:46]=[CH:45]3)[CH2:39][CH2:40]1)([CH3:29])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccc3cnccc3c2Cl)CC1
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: Fc1cc2ccncc2cc1Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2cc3ccncc3cc2Cl)CC1

Procedure:
Starting with 7-chloro-6-fluoro-isoquinoline (6) and cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester, the title compound was prepared by the protocol described for trans-[4-(5-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (10). Rt=1.07 min (Method #4). Detected mass: 377.2/379.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.B>C1COCC1>[CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(F)ccc1NCC(=O)NCc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1NCCNCc1ccccc1
Yield: 93.6 %

Procedure:
To a solution of N-benzyl-2-(4-fluoro-2-methyl-phenylamino)-acetamide (17 g) in THF (500 mL) was added a solution of borane tetrahydrofuran complex (499.4 mL, 1M in THF). The solution was heated to reflux for 4 h, was concentrated and redissolved in a mixture of 2M HCl and TBME. The inorganic phase was extracted with TBME, the organic phases washed with 2M HCl. The pH of the combined inorganic phases was adjusted to pH 11 by the addition of concentrated NaOH, and the solution was extracted with TBME. The combined organic phases were dried (Na2SO4), filtered and evaporated to yield N-benzyl-N′-(4-fluoro-2-methyl-phenyl)-ethane-1,2-diamine (15.1 g) as a crude product, MS: 259.3 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1([CH3:34])[CH2:32][C:31](=[O:33])[O:30][C:28]1=[O:29].C(C1C=C(NC(C2C=CC(N3CCN(C(=O)CC(C)(C)C(O)=O)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:31](=[O:33])[CH2:32][C:27]([CH3:34])([CH3:26])[C:28]([OH:30])=[O:29])[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Reactant: CC1(C)CC(=O)OC1=O
Agent: CC(C)(CC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cn2)CC1)C(=O)O
Product: CC(C)(CC(=O)N1CCC(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1)C(=O)O

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-2,2-dimethyl-4-oxo-butyric acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 2,2-dimethylsuccinic anhydride in a method similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-2,2-dimethyl-4-oxo-butyric acid above. LCMS calcd for C28H36N2O4 (m/e) 464, obsd 465 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O>[C:10]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCCC(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCNC(=O)c1ccccc1
Reaction time: 6 h
Yield: 74.7 %

Procedure:
6.4 g of gamma-aminobutyric acid and 4.5 g of sodium hydroxide were dissolved in 100 mL of purified water, and 7.9 g of benzoyl chloride was dropwise added thereto under ice-cooling. After stirring the mixture for 6 hours, hydrochloric acid was added to adjust the pH to 2 or less. The precipitated crude product was filtered, and then recrystallized with ethanol solution to give 8.7 g of the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:3])[NH2:2].O1CCOCC1.C(=O)(O)[O-].[Na+].[C:27](=O)([O:33]C(C)(C)C)[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>O>[C:29]([O:28][C:27]([N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1](=[O:3])[NH2:2])[CH2:11][CH2:12]1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: NC(=O)c1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
1-(2-Carbamoylphenyl)piperazine (300 mg, 1.5 mmol) was dissolved in water (2 ml) and 1,4-dioxane (2 ml) The resulting solution was mixed with sodium bicarbonate (250 mg, 2.9 mmol) and di-t-butyl carbonate (480 mg, 2.2 mmol), and then stirred at a room temperature for 4 hours. The reaction solution was mixed with water (20 ml), and the reaction product was extracted with chloroform (80 ml) and washed with water and saturated brine. Then the solvent was evaporated under a reduced pressure to obtain colorless crystals. Thereafter, the crystals were washed with hexane and then dried to obtain 430 mg of the title compound (1.4 mmol, 96% in yield).