Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11]2[N:12]([CH:14]=[CH:15][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29]N1C(=O)CCC1=O>O1CCCC1>[CH2:1]([C:8]1[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11]2[N:12]([C:14]([Cl:29])=[CH:15][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cc2ccccc2)nn2cccc2c1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cc2ccccc2)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
To a solution of ethyl 2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (730 mg) in tetrahydrofuran (10 ml) was added N-chlorosuccinimide (260 mg) and the mixture was stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with aqueous sodium thiosulfate, water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography eluting with a mixture of toluene and ethyl acetate (10:1) to give ethyl 2-benzyl-7-chloro-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (285 mg) as an yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:12])[CH2:11][O:10][CH2:9]2)=[C:4]([F:13])[CH:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CC(C)=O>[F:13][C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([OH:12])[CH2:9][O:10][CH2:11]1
Reactant: Nc1ccc(C2(O)COC2)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(Nc1ccc(C2(O)COC2)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a stirred solution of 3-(4-amino-2-fluorophenyl)oxetan-3-ol (0.93 g, 5.08 mmol, 1.0 eq) in acetone (10 mL) was added pyridine (0.82 mL, 10.16 mmol, 2.0 eq) and phenyl chloroformate (0.7 mL, 5.59 mmol, 1.1 eq) at 0° C. and the mixture was stirred at RT for 1 h. The solvents was evaporated and the crude product was extracted with EtOAC (25 mL), diluted with water (15 mL), washed with brine (10 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The resulting residue was washed with diethyl ether (25 mL) to get phenyl 3-fluoro-4-(3-hydroxyoxetan-3-yl)phenylcarbamate (0.892 g, 59%) as a off white solid (TLC system: 100% EtOAc, Rf: 0.55).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]([N:11]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[O:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:21][CH:22]([CH3:25])[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]([N:11]2[C:15](=[O:16])[N:14]([CH2:21][CH:22]([CH3:25])[CH3:23])[C:13](=[O:17])[O:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)N(C(=O)n1oc(=O)[nH]c1=O)c1ccc(F)cc1
Reactant: CC(C)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)on(C(=O)N(c2ccc(F)cc2)C(C)C)c1=O
Temperature: 15 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
A 50 mL round bottom flask equipped with a thermometer, a stirrer, an addition funnel, and a nitrogen inlet was charged with N-(4-fluorophenyl)-N-(1-methylethyl)-3,5-dioxo-1,2,4-oxadiazolidine-2-carboxamide (5.5 g, 0.019 m), 2-methyl-1-propanol (3 g, 0.04 mol), triphenylphosphine (6.3 g, 0.021 mol) and tetrahydrofuran (60 mL). The reaction solution was cooled to 15° C. and diethyl azodicarboxylate (4.2 g, 0.024 mol) in tetrahydrofuran (10 mL) was added dropwise over a period of 10 min. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was flash chromatographed (silica gel, 9:1 hexane-ethyl acetate) to provide the title compound as a white solid (5.6 g, 88%). The solid has a melting range of 80-81° C., and was identical to the material prepared in Example 8, Step B.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:5]([O:24][CH3:25])[CH:4]=1.COC1C=CC(C[NH:34][C:35]2[N:36]=[CH:37][S:38][CH:39]=2)=CC=1.CN1C=CN=C1.C(O)(C(F)(F)F)=O>CC#N>[F:1][CH:2]([F:26])[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:34][C:35]4[N:36]=[CH:37][S:38][CH:39]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Reactant: COc1ccc(CNc2cscn2)cc1
Agent: Cn1ccnc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(S(=O)(=O)Nc3cscn3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
A solution of 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)quinazoline-7-sulfonyl chloride (0.300 g, 0.745 mmol) and N-(4-methoxybenzyl)thiazol-4-amine (Intermediate PPPPP; 0.492 g, 2.234 mmol) in 6 mL MeCN was placed under argon and was treated with 1-methylimidazole (0.073 ml, 0.745 mmol). After stirring for 3 hours at room temperature, LC/MS showed mostly product, so the reaction mixture was concentrated. The crude residue was dissolved in TFA (2.295 ml, 29.8 mmol) and was heated to 100° C. for 2 hours. LC/MS showed mostly product, so the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18 30μ, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)-N-(thiazol-4-yl)quinazoline-7-sulfonamide (0.141 g, 0.302 mmol, 40.6% yield). 1H NMR (MeCN-d3) δ: 9.43 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.79-7.86 (m, 1H), 7.37 (d, J=5.4 Hz, 1H), 7.32 (d, J=9.9 Hz, 1H), 6.92-7.25 (m, 2H), 3.71 (s, 3H). (M+H)+=467.0.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15](Br)[CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([C:21]4[CH:22]=[CH:23][C:24]([F:25])=[C:19]([Cl:18])[CH:20]=4)[CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1cc(CC2CCCC2)cc2cccnc12
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: Fc1ccc(-c2cc(CC3CCCC3)cc3cccnc23)cc1Cl

Procedure:
6-(cyclopentylmethyl)-8-bromoquinoline and 3-chloro-4-fluorobenzene boronic acid can be combined to form 6-(cyclopentylmethyl)-8-(3-chloro-4-fluorophenyl)quinoline,
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: OCCOC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCCOC1CCCCC1)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A solution of 2-cyclohexyloxyethanol (4.56 g, 32 mmol) and triethylamine (22 mL, 160 mmol) in dichloromethane (225 mL) was stirred under nitrogen. A saturated solution of 4-bromobenzenesulfonyl chloride (9.0 g, 35 mmol) in dichloromethane was added dropwise at 0° C., and the reaction mixture was stirred overnight under nitrogen. The reaction mixture was then washed with 1N aqueous hydrochloric acid (2×200 mL) and the organic layer separated. The organic layer was washed sequentially with water (200 mL) and brine (200 mL), dried (MgSO4) and then concentrated in vacuo to give a white solid. The crude solid was dissolved in the minimum amount of dichloromethane and purified by passing through a plug of silica, which was eluted with ethyl acetate:hexane (50:50), ethyl acetate (100%) and finally methanol:ethyl acetate (10:90). The title compound was obtained as a yellow oil (4.3 g, 41%).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[C:8](SC)[CH:9]=[CH:10][CH:11]=2)[N:6]=1)([O:3][CH3:4])=[O:2].[CH3:18]SC1C=CC=CC=1N.N1C2C(=CC=CC=2)C=CC=1>>[C:1]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[C:8]([CH3:18])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc(O)c2cccc(SC)c2n1
Reactant: CSc1ccccc1N
Solvent: c1ccc2ncccc2c1
Product: COC(=O)c1cc(O)c2cccc(C)c2n1
Yield: 59 %

Procedure:
Employing the same sequence as employed in the preparation of quinoline F3 but starting with the commercially available o-toluidene (Aldrich Chemical Co.) rather than 2-methylmercaptoaniline (F1) the desired quinoline I1 was obtained (1.24 g, 59% yield over two steps).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([F:11])=[CH:4][C:3]=1[F:12].[Li]CCCC.[B:18](OC)([O:21]C)[O:19]C>C1COCC1>[CH2:9]([O:8][C:6]1[C:5]([F:11])=[CH:4][C:3]([F:12])=[C:2]([B:18]([OH:21])[OH:19])[CH:7]=1)[CH3:10]
Reactant: COB(OC)OC
Reactant: CCOc1cc(Br)c(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)c(F)cc1F
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To 97D (670 mg, 2.83 mmol) in THF (10 mL) was added n-BuLi (1.6M in hexane, 2.3 mL) at −78° C. After stirring for 15 min, trimethyl borate (0.634 mL) was introduced. The mixture was stirred from −78° C. to rt for 5 h before it was quenched by 1N HCl. It was extracted with ethyl acetate. The organic extract was washed with saturated Na2S2O3, brine and dried over MgSO4. The crude product was purified by column chromatography to give 97E (400 mg, 70% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]2([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]2)[CH:52]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:59]3[CH2:60][CH2:61][C:57]([C:53]4[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=4)([OH:62])[CH2:58]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: OC1(c2cccnc2)CCNC1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3cccnc3)C2)cc1Cl
Yield: 50 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)-isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-pyridin-3-ylpyrrolidin-3-ol dihydrochloride (9 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z: calcd for C20H18ClN3O4: 399.0986, found 399.0986.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>O1CCCC1>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[C:15]=1[O:20][CH3:21]
Reactant: BrCCCCCCBr
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(CCCCCCBr)c1OC
Yield: 32 %

Procedure:
A solution of 1.55M butyl lithium in hexane (195 mL, 0.3 mol) was added dropwise over 30 minutes to a stirred solution of 1,2-dimethoxybenzene (41.4 g, 0.3 mol) in 700 mL of anhydrous tetrahydrofuran at room temperature under argon. The reaction mixture was stirred and heated at 40° for 4 hours and then cooled to -70°. A solution of 46 mL (0.3 mol) of 1,6-dibromohexane in 250 mL of anhydrous tetrahydrofuran was added dropwise over 30 minutes. The cooling bath was removed and the reaction mixture was stirred for 1 hour and then heated at 40° for 4 hours. Most of the solvent was removed, 90 mL of 3NHCl was added and the product was extracted with hexane. The extract was washed with sodium bicarbonate solution, dried and concentrated under reduced pressure to yield an oil. Distillation gave 1-(6-bromohexyl)-2,3-dimethoxybenzene as a yellow oil (29 g, 32% yield, b.p. 125°-140°/0.15 mm).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:44])/[CH:24]=[CH:25]/[C:26]3[CH:43]=[CH:42][C:29]([O:30][CH2:31][CH2:32][N:33](C)[C:34](=O)OC(C)(C)C)=[CH:28][CH:27]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:44])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][NH:33][CH3:34])=[CH:42][CH:43]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN(CCOc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)[C@H]2c2ccc3c(c2)CCO3)cc1)C(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CNCCOc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)[C@H]2c2ccc3c(c2)CCO3)cc1
Yield: 98 %

Procedure:
A solution of Example 190 (0.33 g, 0.55 mmol) in DCM (30 mL) was treated with zinc bromide (0.63 g, 5 equiv.) for 16 hours at 30° C. A gummy solid was formed. Extraction with DCM:MeOH, washing with water, drying over Na2SO4 and recrystallization from iPrOH gave the title compound as white crystals in a 98% yield. MP: 145° C. Analysis for C31H31N3O3. 0.2H2O: Calculated: C,74.89; H,6.37; N,8.45; Found: C,74.90; H,6.70; N,8.49%. [α]D20 =-337 (c=0.4, MeOH).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[CH2:19]([SH:24])[CH2:20][CH2:21][CH2:22][SH:23].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[SH:23][CH2:22][CH2:21][CH2:20][CH2:19][S:24][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Reactant: SCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C(=O)c1ccc(SCCCCS)cc1)N1CCOCC1
Temperature: 25 °C

Procedure:
40 g (0.15 mol) of 1-(4-chlorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one and 109 g (0.89 mol) of 1,4-butanedithiol are dissolved in 300 ml of dimethylacetamide, and the solution is stirred at around 100° C. together with 41 g of potassium carbonate for 5 h. Then the solution is cooled to room temperature and poured into water. The crude product is extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate -hexane (20:80) as an eluent. Melting point 98 ° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 1.36 (t, 1H), 1.76-1.90 (m, 4H), 2.53-2.62 (m, 6H), 2.98-3.04 (m, 2H), 3.69 (t, 4H), 7.25 (d, 2H), 8.50 (d, 2H).
Reaction SMILES: [Na].CCO.[F:5][CH:6]([C:12]([O:14]CC)=O)[C:7]([O:9]CC)=O.Cl.[C:18]([NH2:21])(=[NH:20])[CH3:19]>>[OH:9][C:7]1[C:6]([F:5])=[C:12]([OH:14])[N:21]=[C:18]([CH3:19])[N:20]=1
Reactant: CCOC(=O)C(F)C(=O)OCC
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1nc(O)c(F)c(O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Part A: A mixture of sodium metal (1.55 g, 67.4 mmol) and EtOH (15.0 mL, 257 mmol) was stirred at RT until nearly all sodium had reacted. Diethyl fluoromalonate (3.54 mL, 22.4 mmol) was added followed by acetamidine hydrochloride (2.14 g, 22.7 mmol). The reaction mixture was heated at reflux for 3 h, cooled to RT and concentrated under reduced pressure. The residue was diluted with water (ca. 50 mL) and acidified (pH=2) with 6M aqueous HCl, and the mixture was stirred at RT for 1 h as a precipitate formed. The solids were collected by suction filtration and washed with water. Excess solvent was removed in vacuo to give 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.08 g, 64%) as a light gray solid. LCMS (m/z): 145 (M+H)+
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=O.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([Cl:14])=[O:10]
Reactant: O=C(O)C1CC2C=CC1C2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-norbornene-2-carboxylic acid (Aldrich, mixture of endo and exo, 1.25 g, 9.05 mmol) in dichloromethane (50 mL) was treated with oxalyl chloride (0.99 mL, 11.31 mmol) and a catalytic amount of N,N-dimethylformamide (100 μL). The reaction mixture was stirred at ambient temperature for 2 hours and then solvent and excess oxalyl chloride were removed under reduced pressure to yield the title compound which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>CCOC(C)=O.[Pd]>[NH2:13][C:6]1[CH:5]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[C:3]([O:2][CH3:1])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COCCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCOc1cc(N)c(C(=O)OC)cc1OC
Yield: 94.4 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of methyl 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate (3.19 g, 11.2 mmol) and Pd/C (10%, 0.3 g) in EtOAc (150 mL) was stirred under 1 atmosphere of hydrogen at room temperature for 6 hours, to afford methyl 2-amino-5-methoxy-4-(2-methoxyethoxyl)benzoate as a solid (2.699 g, 95%). 1H NMR (300 MHz, CDCl3) δ 7.30 (s, 1H), 6.17 (s, 1H), 5.55 (br, 2H), 4.14 (t, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79 (t. 2H), 3.44 (s, 3H); LC-MS (ESI) m/z 256 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(aa) In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 24(t)] with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzoyloxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as an almost colourless solid; MS: 580 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13](N)=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.[ClH:34].N([O-])=O.[Na+]>CC#N.O.Cl[Cu]>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13]([Cl:34])=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1
Reactant: Cl
Reactant: COC(=O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(CC1CCC1)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
To a solution of 2-[6-amino-5-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid methyl ester (14.7 g, 27.7 mmol) in a mixture of MeCN and H2O (120 mL/120 mL), concentrated HCl (25 mL) was added. The reaction mixture was cooled down to 0-5° C. and a solution of NaNO2 (2.9 g, 42.0 mmol) in water (3 mL) was added dropwise. The reaction mixture was stirred at 0-5° C. for 40 min and CuCl (I) (27 g, 272.7 mmol) was added at once. The reaction mixture was heated at 50° C. for additional 3 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water (200 mL) and brine (100 mL). The organic phase was dried over MgSO4 and evaporated to give the product (14.5 g, 95%) as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 6.98 (dd, J=6.1, 1.6 Hz, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.48 (t, J=7.7 Hz, 1H), 2.20-2.10 (m, 2H), 2.03-1.75 (m, 5H), 1.70-1.52 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.6, 153.5, 142.2, 141.0, 138.9, 129.7, 125.0 (q, 3JCF=3.6 Hz), 124.8, 124.0 (q, 1JCF=271.6 Hz), 126.6 (q, 1JCF=278.8 Hz), 121.4, 114.0, 67.3 (q, 1JCF=35.4 Hz), 52.2, 49.3, 40.8, 34.0, 28.3, 28.0, 18.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:15][CH2:16][CH2:17][NH:18][CH:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Br:29])[CH:26]=3)[O:21][CH2:20]2)[CH2:10][C@@H:9]1[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[F:38]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:15][CH2:16][CH2:17][N:18]([CH:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Br:29])[CH:26]=3)[O:21][CH2:20]2)[C:40]([NH:39][C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([Cl:31])[CH:33]=2)=[O:41])[CH2:10][C@@H:9]1[CH3:30])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1CCCNC1COc2ccc(Br)cc2C1
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1CCCN(C(=O)Nc1ccc(F)c(Cl)c1)C1COc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
To a solution of (2S,5R)-4-[3-(6-bromo-chroman-3-ylamino)-propyl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.25 mmol) in CH2Cl2 (0.5 mL) was added 3-chloro-4-fluoro-phenylisocyanate (0.043 g, 0.25 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated in vacuo and the residue was purified on reverse-phase HPLC to give 0.047 g (29%) of (2S,5R)-4-{3-[1-(6-bromo-chroman-3-yl)-3-(3-chloro-4-fluoro-phenyl)-ureido]-propyl}-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.85 (d, J=17.4 Hz, 1H), 7.62 (d, J=6.3 Hz, 1H), 7.23 (m, 2H), 7.02 (t, J=9.0 Hz, 1H), 6.71 (d, J=9.0 Hz, 1H), 6.14 (br.s, 1H), 4.55 (m, 2H), 4.26 (m, 2H), 3.92 (m, 1H), 3.60-2.70 (m, 10H), 2.05 (m, 2H), 1.46 (s, 9H), 1.37 (d, J=7.2 Hz, 3H), 1.20 (m, 3H). MS-ESI: 653.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[NH:11]1[CH2:21][CH2:20][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:12]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:21][CH2:20][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:12]2)=[S:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=S)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-chlorophenyl isothiocyanate (3.5 g, 20.7 mmol), and ethyl isonipecotate (3.19 mL, 20.7 mmol) in dichloromethane (30 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, the residue was triturated with ether and the resulting solid was filtered off and dried to afford the title compound as a white solid, 6.27 g.