Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([C@H:16]([CH3:29])[C@@H:17]([OH:28])[CH2:18][C@@H:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH3:21])CC1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[CH3:29][C@@H:16]([NH2:8])[C@@H:17]([OH:28])[CH2:18][C@@H:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH3:21]
Reactant: CC[C@@H](C[C@H](O)[C@@H](C)N(Cc1ccccc1)Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@@H](C[C@H](O)[C@@H](C)N)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
N,N-dibenzyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamine (1.46 g, 3.77 mmols) was dissolved in 25 ml of methanol, and 0.43 ml (7.53 mmols) of acetic acid and 0.6 g of 5% palladium on carbon (water content 50%) were added thereto. The reaction solution was stirred under a hydrogen atmosphere at 50° C. for 16 hours. Subsequently, the catalyst was removed by filtration, and the filtrate was concentrated. To the residue were added 15 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted twice with 50 ml of methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and magnesium sulfate was then removed by filtration. The filtrate was concentrated to obtain 0.61 g (2.96 mmols) of (1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamine.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[O:12]1[CH:16]=[CH:15][C:14]([C:17](OCC)=[O:18])=[CH:13]1>C(O)C>[O:12]1[CH:16]=[CH:15][C:14]([C:17]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][C:3]2=[O:11])=[O:18])=[CH:13]1
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)c1ccoc1
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2ccccc2C1C(=O)c1ccoc1
Yield: 3.1 %

Procedure:
To a stirred solution of 2.8 g (0.12 mole) of sodium in 200 ml of ethanol was added 13.3 g (0.10 mole) of 2-oxindole, followed by 16.8 g of ethyl 3-furoate. The mixture was heated under reflux for 47 hours, cooled and then the solvent was removed by evaporation in vacuo. The residue was triturated under 200 ml of ether, and the solid was collected by filtration and discarded. The filtrate was evaporated in vacuo, and the residue triturated under diisopropyl ether and recovered by filtration. The solid was suspended in 250 ml of water, which was then acidified with concentrated hydrochloric acid. This mixture was stirred to give a solid, which was recovered by filtration. This latter solid was recrystallized from acetic acid followed by acetonitrile to give 705 mg of the title compound, mp 185°-186° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:14]([CH3:22])C(=O)OC(C)(C)C)=[C:11](I)[N:12]=2)[CH:5]=[N:6][CH:7]=1.[C:23]([Cu])#[N:24]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:14][CH3:22])=[C:11]([C:23]#[N:24])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1sc(-c2cncc(F)c2)nc1I
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1sc(-c2cncc(F)c2)nc1C#N
Temperature: 120 °C

Procedure:
To a nitrogen-purged solution of tert-butyl 2-(5-fluoropyridin-3-yl)-4-iodothiazol-5-yl(methyl)carbamate (1.0 g, 2.298 mmol) in DMF (8 mL) was added CuCN (288 mg, 3.22 mmol) and the mixture was heated in a microwave at 120° C. for 80 min. The mixture was diluted with ethyl acetate (75 mL) and successively washed with an aqueous solution (15 mL) of ethylene diamine (5% v/v), and brine, dried over MgSO4 filtered, and concentrated on a rotary evaporator under vacuum to give a yellow solid, 2-(5-fluoropyridin-3-yl)-5-(methylamino)thiazole-4-carbonitrile. The solid was used in the preparation of N-(4-cyano-2-(5-fluoropyridin-3-yl)thiazol-5-yl)-N-methyl-3-(methylthio)propanamide. To a solution of crude 2-(5-fluoropyridin-3-yl)-5-(methylamino)thiazole-4-carbonitrile (200 mg, 0.83 mmol) in CH2Cl2 (2 mL) were added K2CO3 (178 mg, 1.28 mmol) and 3-(methylthio)propanoyl chloride (130 mg, 0.94 mmol) followed by dimethylaminopyridine (21 mg, 0.17 mmol). The mixture was stirred at room temperature for 36 h and diluted with ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (5 mL). The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown gummy residue. This residue was purified by silica gel chromatography (6:4 hexane/ethyl acetate) to give N-(4-cyano-2-(5-fluoropyridin-3-yl)thiazol-5-yl)-N-methyl-3-(methylthio)propanamide as a pale yellow solid (164 mg, 57% yield): mp 97-98° C.; 1H NMR (300 MHz, CDCl3) δ 8.98 (bs, 1H), 8.72 (d, J=2.7 Hz, 1H), 8.27 (dt, J=9.6, 1.8 Hz, 1H), 2.73 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.62, 2H), 2.09 (s, 3H), 2.03 (s, 3H): ESIMS m/z 337.2 (M+1).
Reaction SMILES: [C@H:1]1([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:26][CH2:25]1>>[C@H:1]1([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH:22][S:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)(=[O:32])=[O:31])[CH:19]=[CH:18][C:16]=3[N:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Reactant: Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Product: CN1CCN(S(=O)(=O)Nc2ccc3c(c2)COC(N[C@@H]2CCCc4ccccc42)=N3)CC1
Yield: 60.5 %

Procedure:
Prepared from (R)-N2-(1,2,3,4-tetrahydro-naphthalen-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 33) (100 mg, 0.341 mmol) and 4-methyl-piperazine-1-sulfonyl chloride (CAS 1688-95-5) (74 mg, 0.375 mmol) according to the procedure described for Example 27. Obtained the title compound as a light brown oil (94 mg, 61%), MS (ISP) m/e=456.3 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCc2c(ccc(Br)c2F)N1
Solvent: Cc1ccccc1
Product: Fc1c(Br)ccc2c1CCC(=S)N2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-5-fluoro-3,4-dihydroquinolin-2(1H)-one (146-5; 0.45 g, 0.00184 mol) in toluene (10 mL) was added Lawesson's reagent (0.745 g, 1.00184 mol). Reaction mass heated at 120° C. and maintained for 2 h. The reaction mixture was cooled, quenched with sodium bicarbonate solution and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the title compound. 1H NMR (400 MHz, DMSO) δ 12.364 (s, 1H), 7.543-7.503 (t, J=8.0 Hz, 1H), 6.895-6.874 (d, J=0.1-8.4 Hz, 1H) 2.968-2.930 (t, J=7.2 Hz, 2H), 2.843-2.805 J 8.0 Hz, 2H): MS (M 1): 260.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH:18][CH2:19][C:20]3[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=3)[N:8]=[C:9]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:10]=2[N:11]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH3:30][S:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[C:7]([NH:18][CH2:19][C:20]4[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=4)[N:8]=[C:9]([NH:12][CH2:13][C:14]([F:17])([F:15])[F:16])[C:10]=3[N:11]=2)[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32]
Reactant: NS(=O)(=O)c1cccc(CNc2nc(NCC(F)(F)F)c3nc(Cl)ccc3n2)c1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)c1cccc(-c2ccc3nc(NCc4cccc(S(N)(=O)=O)c4)nc(NCC(F)(F)F)c3n2)c1
Temperature: 120 °C
Yield: 49.2 %

Procedure:
3-{[6-Chloro-4-(2,2,2-trifluoro-ethylamino)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide (0.077 g) was combined with 3-methylsulfonyl-phenylboronic acid (0.067 g), palladium tetrakistriphenylphosphine (0.006 g) and potassium carbonate (0.121 g). The mixture was suspended in DME (1.6 mL) and water (0.8 mL), sealed and heated by microwave to 120° C. for 3 min. Crude product was precipitated by the addition of water. The precipitate was filtered and purified by reverse phase HPLC (5-100% ACN/H2O+0.1% TFA) to give 0.048 g (41% yield) of the title compound, which was characterized by its NMR and mass spectrum as follows: 1H NMR (d6-DMSO): d 3.34 (s, 3H), 4.40-4.46 (m, 2H), 4.73-4.82 (m, 2H), 7.35 (s, 2H), 7.52-7.7.64 (m, 2H), 7.73-7.75 (m, 1H), 7.83-7.87 (m, 2H), 8.03-8.06 (m, 2H), 8.58-8.62 (m, 1H), 8.68 (s, 1H), 8.80 (d, 1H), 9.10 (bs, 1H), 9.98 (bs, 1H); MS (m/z): 567.1 ([M+H]+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8][N:7]=1.[Se](=O)=[O:29]>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8][N:7]=1)=[O:29]
Reactant: CCOC(=O)c1cnc(Cc2cccc(O)c2)c2cc(OC)c(OC)cc12
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(C(=O)c2cccc(O)c2)c2cc(OC)c(OC)cc12
Yield: 97 %

Procedure:
To a solution of 1-(3-hydroxybenzyl)-6,7-dimethoxy-4-ethoxycarbonylisoquinoline (367 mg, 1.0 mmol) in 10 ml of ethyl acetate was added selenium dioxide (166 mg, 1.50 mmol) and the mixture was refluxed for 1.5 hr until all starting material was consumed. The mixture was filtered through a layer of silica gel and washed with ethyl acetate. After evaporation of solvents, a solid was obtained as 1-(3-hydroxybenzoyl)-6,7-dimethoxy-4-ethoxycarbonylisoquinoline (370 mg). This solid (325 mg, 0.85 mmol) was dissolved in 3 mL of DMF and the stirring solution was treated with potassium carbonate (300 mg, 2.17 mmol) followed by t-butyl-2-bromoisobutyrate (210 mg, 0.94 mmol). The resulting mixture was heated (50° C. in an oil-bath) and stirred for 25 hours. Mass spectrum and TLC indicated partial conversion to the desired product and additional potassium carbonate (330 mg, 2.17 mmol) and isobutyrate (210 mg, 0.94 mmol) were added. The mixture was heated with stirring for additional 25 hours. The reaction mixture was evaporated and the residue was partitioned with ethyl acetate (50 ml) and brine (25 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to give an oil which was purified by silica gel chromatography, using gradient mixtures of ethyl acetate and hexanes, to produce 248 mg of the isobutyrate as a yellow oil.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[C:11]([O-:14])(=[O:13])[CH3:12].[K+].CS(C)=O>O>[C:11]([O:14][CH:3]([CH:1]=[CH2:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:13])[CH3:12]
Reactant: C=CC(Cl)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CC(OC(C)=O)c1ccccc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
In a one liter 3-neck round bottom flask equipped with a condenser, mechanical stirrer and thermometer, 108 grams (0.708 mol) of vinylbenzyl chloride (60/40 m-/p-) and 808 grams (0.815 mol) of potassium acetate were added, followed by 250 mLs of DMSO. The mixture was stirred at 40° C. for 48 hours. After allowing to cool to room temperature, the mixture was diluted with water and poured into a separatory funnel. The organic layer was separated, followed by an extraction of the aqueous layer with chloroform. The combined organic layer was then washed with water, dried over magnesium sulfate and placed on the rotary evaporator to remove the chloroform. 120 grams of the vinylbenzyl acetate product was recovered, to which 10 mg of MEHQ was added as an inhibitor.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][CH2:31][OH:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH3:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31]([NH2:33])=[O:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: N
Product: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one using a procedure analogous to that described in Example 12 Step 2, followed by a procedure analogous to that described in Example 8 Step 2 using ammonia. LC-MS Method 2 tR=1.372, min, m/z=448.3; 1H NMR (CDCl3) 1.52 (d, 3H), 1.97 (m, 2H), 2.27-2.33 (m, 4H), 2.43 (m, 1H), 2.97 (m, 1H), 5.13 (s, 1H), 5.24 (s, 1H), 5.66 (m, 1H), 6.92-7.08 (m, 4H), 7.22 (m, 2H), 7.31 (m, 2H), 7.48 (m, 1H), 7.97 (m, 1H), 8.57 (m, 1H), 8.74 (m, 1H).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[Na+].[Na+].[C:8]1([S:22]([O-:25])(=[O:24])=[O:23])[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([S:18]([O-:21])(=[O:20])=[O:19])[C:12]=2[CH:11]=[CH:10][CH:9]=1>>[C:8]1([S:22]([OH:25])(=[O:24])=[O:23])[C:17]2[CH:16]=[C:15]([S:1]([OH:5])(=[O:4])=[O:3])[CH:14]=[C:13]([S:18]([OH:21])(=[O:20])=[O:19])[C:12]=2[CH:11]=[C:10]([S:1]([OH:3])(=[O:5])=[O:4])[CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: O=S(=O)([O-])c1cccc2c(S(=O)(=O)[O-])cccc12
Agent: [Na+]
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c2c1

Procedure:
To 240 ml. of 30-33% fuming sulfuric acid at 120° C. is added, portionwise, 60 g. of 1,5-naphthalenedisulfonic acid disodium salt. The mixture is heated at 180°-190° C. for 23 hours. The solution is cooled, allowed to crystallize and filtered through a course sintered glass funnel. The product is washed with concentrated sulfuric acid to give 1,3,5,7-naphthalenetetrasulfonic acid as an off-white pasty solid. Without further purification, the solid is added, portionwise, to 150 ml. of chlorosulfonic acid and the mixture is heated at 145°-150° C. for 1.5 hours. The mixture is cooled to room temperature and filtered. The product is washed, in order, with chlorosulfonic acid, methylene chloride, acetonitrile, water, acetonitrile and finally with ether. The product is air-dried and then dried further in an Abderhalden apparatus at 76° C. to provide 33.9 g. of the desired product as a colorless powder, m.p. 263°-270° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17]Cl>>[CH2:1]([NH:8][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: ClCCOCCOCCCl
Product: c1ccc(CNCCOCCOCCNCc2ccccc2)cc1

Procedure:
J. Gatto, et al. in "4,13-Diaza-18-Crown-6 (1,4,10,13-Tetraoxa-7,16-diazacyclooctadecane)," Organic Synthesis, Vol. 68, 1989, pp. 227-233, teach the preparation of the title compound by a three-step procedure that might be considered the standard preparation for these materials. First, benzylamine is reacted with 1,2-bis(2-chloroethoxy)ethane to produce 1,10-dibenzyl-4,7-dioxa-1,10-diazadecane. The product of the first step is then reacted in the presence of 1,2-bis(2-iodoethoxy)ethane, anhydrous sodium carbonate and sodium iodide in acetonitrile to give N,N'-dibenzyl-4,13-diaza-18-crown-6 in the second step. The phenyl groups of the second step product are then removed in a third, hydrogenation step over a palladium catalyst on a carbon support.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:18])[CH:14]=3)[C:9]2=[O:19])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>CN(C=O)C>[Cl:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:19])[N:8]([C:4]1[CH:3]=[C:2]([NH:1][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:7]=[N:6][CH:5]=1)[CH2:17][CH2:16]2
Reactant: Nc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Reactant: CC(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (27.3 mg, 0.1 mmol, example 15) in dry DMF (2 mL) was added at 0° C. NaH (3.0 mg, 0.12 mmol). The reaction mixture was allowed to stir at room temperature for 5 min before isobutyryl chloride (12.7 mg, 0.12 mmol) was added into the reaction mixture. The reaction mixture was stirred for additional 1 hour and then poured into ice-water and extracted with EtOAc (2×5 mL). The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (8.1 mg, 24%) as a white solid. MS: 344.1 (M+H+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[CH:19]=[C:18]([C:20]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21]2)[CH:17]=[CH:16][C:15]=1[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:52][C:53]([F:62])([F:61])[CH:54]1[CH2:59][CH2:58][CH:57](O)[CH2:56][CH2:55]1>C1COCC1>[F:13][C:14]1[CH:19]=[C:18]([C:20]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21]2)[CH:17]=[CH:16][C:15]=1[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH:57]2[CH2:58][CH2:59][CH:54]([C:53]([F:62])([F:61])[F:52])[CH2:55][CH2:56]2)=[CH:30][CH:31]=1
Reactant: O=C(O)C1(c2ccc(-c3ccc(O)cc3)c(F)c2)CC1
Reactant: OC1CCC(C(F)(F)F)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O)C1(c2ccc(-c3ccc(OC4CCC(C(F)(F)F)CC4)cc3)c(F)c2)CC1
Reaction time: 8 h
Yield: 26 %

Procedure:
Diethyl azodicarboxylate (370 μL, 2.4 mmoles) is added to a solution of 200 mg of 1-(2-fluoro-4′-hydroxy-biphenyl-4-yl)-cyclopropanecarboxylic acid (0.8 mmoles), triphenyl phosphine (623 mg, 2.4 mmoles) and 4-trifluoromethyl cyclohexanol (400 mg, 2.4 mmoles) in dry THF (3 mL) at 0° C. under nitrogen atmosphere. The resulting clear orange solution is left under stirring overnight, then quenched with water and extracted with ethyl acetate. The organic phase is washed with 10% w/v HCl solution, dried on Na2SO4 and evaporated. Purification by chromatography on silica gel by eluting with methylene chloride:methanol 98:2 v/v furnishes 1-[2-fluoro-4′-(4-trifluoromethyl-cyclohexyloxy)-biphenyl-4-yl]-cyclopropanecarboxylic acid as a white solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([OH:28])=[CH:20][CH:19]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([OH:28])=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(O)c2ccccc12
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Product: O=C(Nc1ccc(O)c2ccccc12)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-1-naphtol (Aldrich), the title compound was obtained as a grey solid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[CH:4]([C:6]1([OH:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:5].[CH2:15](Br)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[OH:12][C:6]1([CH:4]([CH3:5])[C:3]([N:2]([CH3:1])[CH3:14])=[O:13])[CH2:7][CH2:8][N:9]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:11]1
Reactant: CC(C(=O)N(C)C)C1(O)CCNCC1
Reactant: BrCCc1ccccc1
Solvent: CCO
Product: CC(C(=O)N(C)C)C1(O)CCN(CCc2ccccc2)CC1

Procedure:
2-(4-hydroxy-4-piperidyl)propionic acid N,N-dimethylamide and phenethyl bromide are reacted in a manner analogous to that described in Example 3. The resulting crude title compound is dissolved in ethanol, the calculated amount of fumaric acid is added and subsequently ether is added until the solution becomes turbid. The resulting hydrogen fumarate form of the title compound has a M.P. of 188°-189° after recrystallization from ethanol/ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C)C=O>[CH2:18]([N:11]1[CH2:12][CH2:13][C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)([O:14][CH3:15])[CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-3-methoxypyrrolidine (1.3 g, 6.1 mmol) in dry dimethyl formamide (5 mL), was added sodium hydride (60% dispersion in mineral oil, 0.27 g, 6.7 mmol). The mixture was stirred for 15 min after which a solution of benzylbromide (0.725 mL, 6.1 mmol) in dry dimethyl formamide (5 mL) was added dropwise. The mixture was stirred for 30 min, hydrochloric acid (10%, 50 ml) was added and the aqueous phase was extracted with diethylether (50 mL), the aqueous phase was made basic with Na2CO3 and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with aqueous LiCl (5%, 50 mL), dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate) gave the title compound (1.15 g, 62%). MS m/z (rel. intensity, 70 eV) 273 (10), 133 (42), 132 (23), 91 (bp), 65 (11).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:12])=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[Br:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][S:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)(=[O:22])=[O:21])=[CH:3][CH:4]=2)[CH:9]=[N:8][CH:7]=1
Reactant: Nc1ccc2c(Br)cncc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2c(Br)cncc2c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
In 1.5 ml of pyridine was dissolved 20 mg (0.09 mmol) of 7-amino-4-bromoisoquinoline (Preparation Example 20), 23 mg of 4-chlorobenzenesulfonyl chloride was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extracting with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. Then, the resulting residue was purified by silica gel thin layer chromatography, to give 13 mg of the title compound. Melting point: gradually decomposed from 229 degrees.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=[CH:25][CH:26]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3ccnc4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with quinoline-4-carboxylic acid. LC-MS (basic): tR=0.77 min; [M+H]+=488.1.