Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])=[C:11]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:10]3=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]([NH:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:15])=[C:11]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Reactant: NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(NC1CCCCC1)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 9.6, [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetic acid (example 9.3) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with cyclohexylamine (CAS Reg. No. 108-91-8) in the presence of DMAP to give the title compound as off-white solid. MS: m/e=468.3 [M+H+].
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:4][CH2:1][C:2]#[CH:3]
Reactant: C1=COCCC1
Reactant: C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Propargyl alcohol (13.20 g) and dihydropyran (19.81 g) are placed into a 50-ml container, and 0.2 g of anhydrous p-toluenesulfonic acid is added. The mixture is cooled in an ice bath, then stirred at room temperature for 30 minutes and neutralized with anhydrous sodium carbonate. The resulting solids are separated off. Distillation of the remaining liquid in a vacuum gives 31.3 g of propargyl tetrahydropyranyl ether (yield: 95%), b.p. 75° to 80° C./37 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[N:4][N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:6]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1cnn(-c2ccccn2)c1
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: Clc1cccc(-c2cnn(-c3ccccn3)c2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(4-bromo-1H-pyrazol-1-yl)pyridine (0.669 g, 3 mmol), 3-chlorophenylboronic acid (0.468 g, 3 mmol) and potassium carbonate (0.828 g, 6 mmol) in a mixture of ethyleneglycol dimethyl ether (20 mL) and H2O (4 mL) were degassed by argon bubbling for 15 min., then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) was added and degasing continued a further 15 min. The solution was stirred at 70° C. for 14 h, whereupon H2O (30 mL) was added, then extracted with EtOAc (3×30 mL) and the combined extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and the crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:4) to afford a white solid which was recrystallized from EtOAc/Hexane to give 2-[4(3-chlorophenyl)-1H-pyrazol-1-yl]pyridine. MP=110-111° C. 1H NMR (CD3Cl, 300 MHz) δ 8.83 (d, 1H), 8.42 (dd, 1H), 7.99 (s, 1H), 7.99 (d, 1H), 7.82 (ddd, 1H), 7.57 (t, 1H), 7.45 (dt, 1H), 7.32 (t, 1H), 7.25˜7.18 (m, 2H). MS (ESI) 255.9 (M++H).
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:13][C:6]=2[C:7]=1OS(C)(=O)=O)#[N:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[CH3:20][S:17]([C:15]1[CH:14]=[CH:13][C:6]2[C:7]([S:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[C:3]([C:1]#[N:2])[O:4][C:5]=2[CH:16]=1)(=[O:18])=[O:19]
Reactant: COc1ccc(S)cc1
Reactant: CS(=O)(=O)Oc1c(C#N)oc2cc(S(C)(=O)=O)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(Sc2c(C#N)oc3cc(S(C)(=O)=O)ccc23)cc1
Reaction time: 3 h
Yield: 38.6 %

Procedure:
A stirring solution of 14 (0.25 g) and 4-methoxybenzenethiol (0.4 g) in THF (20 mL) and DMF (5 mL) was treated with NaH (0.080 g). After 3 h, the reaction was quenched by careful addition of H2O, then diluted with 1:1 EtOAc/hexanes. The organic layer was washed with saturated aqueous NaHCO3, washed with water, washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (silica gel, 20:80 to 33:67 EtOAc/hexanes) gave 0.11 g of 6-methanesulfonyl-3-(4-methoxyphenylsulfanyl)-benzofuran-2-carbonitrile 35 as a solid; (m+H)+ 360.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[N:8]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CC)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 15 %

Procedure:
A solution of 4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (20 g), 1-bromo-3,3-dimethylbutan-2-one (8.7 mL) and cesium carbonate (21 g) in N,N-dimethylformamide (200 mL) was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (3.8 g, 15%) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>Cl.CCCCO>[CH:17]1([NH:22][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NC1CCCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(NC3CCCC3)ncn2)cc1
Temperature: 200 °C
Yield: 83 %

Procedure:
75 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 26 mg of cyclopentylamine and 90 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N4-Cyclopentyl-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]2[C:8]3[CH:15]=[CH:14][N:13](COCC[Si](C)(C)C)[C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:5][N:6]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[S:3][C:4]([C:7]2[C:8]3[CH:15]=[CH:14][NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:5][N:6]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnc(Br)s3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ncc(-c2ncnc3[nH]ccc23)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
A solution of 4-(2-bromo-1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidine (370 mg, 0.90 mmol) in DCM (5.0 mL) and TFA (1.0 mL) was stirred at room temperature for 7 hours. The mixture was then concentrated, re-dissolved in methanol (2 mL), and ethylenediamine (0.5 mL) was added. The mixture was stirred for 6 hours at room temperature. The mixture was diluted with DCM (10 mL), and the precipitate was isolated by filtration and washed with a small amount of DCM to afford desired product (182 mg, 72%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[CH:15]=1)=[O:5])C>Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH:10]=1
Reactant: CCOC(=O)c1cn2cc(F)ccc2n1
Agent: Cl
Product: O=C(O)c1cn2cc(F)ccc2n1
Yield: 99.4 %

Procedure:
A solution of the product of step (a) (1 g) in 4N HCl was refluxed for 4 hours. The solvent was evaporated to give the sub-title compound as a white solid (0.86 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:25])[C:22](=O)[CH3:23])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.Cl.[CH3:27][O:28][NH2:29]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:25])/[C:22](=[N:29]/[O:28][CH3:27])/[CH3:23])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:4][CH:3]=1
Reactant: CON
Reactant: CC(=O)C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Agent: Cl
Solvent: CO
Product: CO/N=C(\C)C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-2-oxo-propionamide (0.063 g, 169 μmol) was dissolved in methanol (1.00 mL). O-Methyl hydroxylamine hydrochloride (70.6 mg, 845 μmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate; the organic phase was dried with MgSO4 and concentrated in vacuo to deliver 67 mg (89%) of the title compound as white solid; LC-MS (UV peak area/ESI) 99.0%, 402.0825 (M+H)+.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[C:20]1(C)C=CC=C[CH:21]=1>C(O)C>[CH2:20]([O:18][C:17]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)[CH:16]=1)=[O:19])[CH3:21]
Reactant: O=C(O)c1cc(-c2ccco2)nc2ccccc12
Reactant: Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccco2)nc2ccccc12
Temperature: 25 °C

Procedure:
To 40 ml of a saturated solution of hydrochloric acid in ethanol 2 g of 2-Furan-2-yl-quinoline-4-carboxylic acid was added and the mixture was heated to reflux for 3 h. Then, after cooling to RT, 30 ml of toluene was added and the solvents were removed under reduced pressure. The obtained crude product was pure enough for the next reaction step. Yield: 2.5 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:17])=[C:14]([OH:16])[CH:15]=2)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:17])=[C:14]([O:16][S:35]([C:32]3[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[CH:15]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc(-c2cnc(N)c(O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2cnc(N)c(OS(=O)(=O)c3ccc(C)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
To a stirring solution of 4-(6-amino-5-hydroxy-pyridin-3-yl)-benzoic acid methyl ester (2.3 g, 9.3 mmol) in CH2Cl2 (180 mL) was added N,N-diisopropylethylamine (3.2 mL, 0.019 mol), 4-methyl-benzenesulfonyl chloride (2.66 g, 0.014 mol), and PS-DMAP (catalytic amount). The reaction was stirred at ambient temperature for 6 hr then filtered to remove the resin. The resin was washed with CH2Cl2 (3×20 mL), and the combined fractions were washed with 10% citric acid (100 mL), saturated NaCl (100 mL), dried (Na2SO4) and filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (silica gel, 100% CH2Cl2 to 95:5 CH2Cl2:MeOH) and the fractions containing the desired product were combined and concentrated in vacuo to yield 4-[6-Amino-5-(toluene-4-sulfonyloxy)-pyridin-3-yl]-benzoic acid methyl ester (3.3 g, 8.2 mmol, 88%). 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 3H), 3.93 (s, 3H), 4.81-4.88 (brs, 2H), 7.36-7.44 (m, 5H), 7.81 (d, 2H, J, 8.3 Hz), 8.05 (d, 2H, J, 8.4 Hz), 8.19-8.27 (brs, 1H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1>C(#N)C.[Cl-].[Zn+2].[Cl-]>[S:7]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccsc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)c2cccs2)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A mixture of p-toluenesulfonyl chloride (3 g, 15.7 mmol) and zinc chloride (3 g, 21.3 mmol) in acetonitrile (30 mL) was heated to reflux and thiophene (2.4 g, 28.5 mmol) was added dropwise. After refluxing for 4 h the mixture was cooled to rt and filtered through Celite. The filtrate was concentrated in vacuo and then 100 mL of sodium hydroxide (2 N) was added. The mixture was extracted with ethyl acetate (3×60 mL) and the combined organic layers were washed with hydrochloric acid (10%, 50 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated in vacuo and the product was purified by flash chromatography eluting with dichloromethane/hexane (2:3) to give the title compound (0.54 g, 15 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1B(O)O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:33]3[O:32][C:36]4=[CH:37][CH:38]=[CH:39][C:40]4=[CH:35][CH:34]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3-c3ccc4cccc-4o3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 2-benzofuryl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-benzofur-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [CH:1]([N:4]1[C:8]2=[N:9][C:10]3[C:15]([CH:16]=[C:7]2[C:6](N)=[N:5]1)=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[CH:11]=3)([CH3:3])[CH3:2].[BrH:20]>>[Br:20][C:6]1[C:7]2[C:8](=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[CH:11]=3)[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: COc1ccc2cc3c(N)nn(C(C)C)c3nc2c1
Reactant: Br
Product: COc1ccc2cc3c(Br)nn(C(C)C)c3nc2c1

Procedure:
3-Bromo-1-isopropyl-7-methoxy-1H-pyrazolo[3,4-b]quinoline was prepared from 1-isopropyl-7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine by preparation of the diazonium salt in hydrobromic acid followed by reaction with cuprous bromide. The product was recrystallized from ether/hexane and obtained in the form of a brown solid, m.p. 130°-131° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:7]2.Br[CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=1.O>CS(C)=O>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:7]2
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: Fc1ccc2[nH]c(-c3cccnc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Cn2c(-c3cccnc3)cc3cc(F)ccc32)cc1
Reaction time: 0.17 h

Procedure:
A flask is charged with NaH (0.284 g, 7.093 mmol) and DMSO (1.5 mL). 5-Fluoro-2-pyridin-3-yl-indole (Example 7, 0.112 g, 0.507 mmol) in DMSO (0.5 mL) is added. The flask and syringes are rinsed with DMSO (2 times 0.5 mL). After 10 min, ethyl 4-(bromomethyl)benzoate (0.192 g, 0.760 mmol) is added neat. After 10 min, water is added. The resulting precipitate is filtered through a sintered funnel and washed with water and dichloromethane to give 4-(5-fluoro-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid as an off-white solid. 1H NMR (400 MHz, MeOD) δ ppm (sodium salt) 5.49 (s, 2H), 6.77 (s, 1H), 6.92 (d, J=8.1 Hz, 2H), 6.95-7.00 (m, 1H), 7.31-7.37 (m, 2H), 7.49 (dd, J=7.7, 5.2 Hz, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.87-7.92 (m, 1H), 8.56 (dd, J=4.9, 1.5 Hz, 1H), 8.68 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 347.1212 [(M+H)+ Calcd for C21H16FN2O2: 347.1196].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:22]=[CH:21][C:15]([O:16][CH:17]([CH3:20])[CH2:18][OH:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[S:2]([O:19][CH2:18][CH:17]([O:16][C:15]1[CH:21]=[CH:22][C:12]([O:11][C:10]2[CH:23]=[CH:24][C:7]([Cl:6])=[CH:8][CH:9]=2)=[CH:13][CH:14]=1)[CH3:20])(=[O:4])(=[O:3])[CH3:1]
Reactant: CC(CO)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(COS(C)(=O)=O)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
8.1 g (0.07 mol) of methanesulphonyl chloride are run, at about 10° C., into a solution of 19.5 g (0.07 mol) of (±)-2-[4-(4-chlorophenoxy)-phenoxy]-1-propanol (CRL 40 300) prepared as indicated in Example 27, in 35 ml of pyridine. The reaction mixture is stirred for 1 hour at ambient temperature and is poured onto ice. The insoluble matter is extracted with diethyl ether and the organic phase obtained is washed with dilute hydrochloric acid and dried, to give a white pasty residue after evaporation of the solvent. The solidification of this residue is petroleum ether gives 24 g of a white powder which is insoluble in water.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])C=1CBr>CCO.O>[C:1]([O:5][C:6](=[O:25])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:22][C:23]3[C:29]([Cl:28])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:37])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CC(=O)Sc1ccc(C2CN(CCC(=O)OC(C)(C)C)CCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(SCc3c(Cl)cccc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
A mixture of 3-[2-(4-Acetylsulfanyl-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (0.31 g; 0.85 mmol) and NaOH (37 mg, 0.93 mmol) in EtOH (10 mL) and water (1 mL) was stirred for 30 min at 0° C. Subsequently, 2,6-dichlorobenzyl bromide (0.22 g; 0.93 mmol), dissolved in EtOH (2.5 mL), was added, and the mixture allowed to warm to RT. After 90 min. the mixture was partitioned between EtOAc and 5% aqueous NaHCO3. The layers were separated, and the organic layer was washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/acetone 95:5) to afford 3-{2-[4-(2,6-dichloro-benzylsulfanyl)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester (0.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([NH:18][C:19](=[O:28])[C:20]2[C:25](F)=[CH:24]C=[CH:22][C:21]=2F)=[N:16][CH:17]=1.CC1C=[N:37][CH:36]=CC=1C(Cl)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([NH:18][C:19](=[O:28])[C:20]2[CH:21]=[CH:22][N:37]=[CH:36][C:25]=2[CH3:24])=[N:16][CH:17]=1
Reactant: Cc1cnccc1C(=O)Cl
Reactant: O=C(Nc1cnc(-c2cc(C(F)(F)F)ccc2Cl)cn1)c1c(F)cccc1F
Product: Cc1cnccc1C(=O)Nc1cnc(-c2cc(C(F)(F)F)ccc2Cl)cn1

Procedure:
Compound 3 was prepared in an analogous fashion to Compound 1 except that 3-methyl-isonicotinoyl chloride was used instead of 2,6-difluoro-benzoyl chloride.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([C:10]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=2)[C:13]2[CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][CH2:16][CH2:17][C:12]=2[N:11]=1)[CH2:8][CH3:9].[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>>[CH2:7]([C:10]1[N:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:29][CH:30]=2)[C:13]2[CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:15]([C:44](=[O:47])[CH2:45][CH3:46])[CH2:16][CH2:17][C:12]=2[N:11]=1)[CH2:8][CH3:9]
Reactant: CCC(=O)Cl
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)NCC2
Agent: O=C(O)C(=O)O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(C(=O)CC)CC2
Yield: 87 %

Procedure:
The compound obtained in Example 62 (1.0 g) is treated in the same manner as in Example 64 with using propionyl chloride (0.23 g) instead of acetic anhydride to give ethyl 2-n-propyl-5-propionyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.82 g) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1cccc(S(=O)(=O)N2c3ccc(F)cc3-c3ccccc3C2C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccccc2-c2cc(F)ccc2N1S(=O)(=O)c1cccc(O)c1
Yield: 89.5 %

Procedure:
The title compound was prepared from 2-fluoro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (100 mg, 0.26 mmol), cyclohexene (528 μL, 5.2 mmol), and 1.0 M solution of boron tribromide in dichloromethane (1.6 mL) according to the procedure and in the same manner as described in Example 105, step e. The volatile components were removed in vacuo, and the crude residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-30% methyl tert-butyl ether in hexane, to afford the desired compound (86 mg, 89%) as a solid, m.p. 195-196° C.;