Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>>[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1noc(N)c1Br
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1noc(NS(=O)(=O)c2cccc(Cl)c2C)c1Br
Yield: 34 %

Procedure:
3-Chloro-2-methyl-N-(4-Bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3-chloro-2-methylbenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 185-187° C., yield 34%.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CO[CH:35]1[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:38]([CH3:48])([CH3:47])[CH2:37][CH2:36]1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@H:15]([C@H:35]1[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:38]([CH3:48])([CH3:47])[CH2:37][CH2:36]1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1cccc(Cl)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COC1CCC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2cccc(Cl)c2)CCC1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
A solution of (R)-4-benzyl-3-(2-(3-chlorophenyl)acetyl)oxazolidin-2-one (0.975 g, 2.96 mmol) in dry DCM (125 mL) was cooled to −78° C., and TiCl4 (3.10 mL, 3.10 mmol) was added. DIEA (0.566 mL, 3.25 mmol) was added to this stirring cold solution for 15 minutes. A solution of tert-butyl 5-methoxy-2,2-dimethylpyrrolidine-1-carboxylate (0.881 g, 3.84 mmol) in DCM (20 mL) was added to the cold mixture. The reaction was stirred for 15 minutes at −78° C. and then warmed to −10° C. (ice/acetone) and stirred for 3 hours. The reaction was quenched with NH4Cl, diluted with DCM (50 mL), water (50 mL), and the layers were separated. The aqueous layer was extracted with DCM (25 mL), dried (MgSO4) and concentrated to an oil. TLC (10% ethyl acetate/hexanes) shows desired product at Rf˜0.2. Purification by flash chromatography (5% ethyl acetate/hexanes-10% ethyl acetate/hexanes) gave (S)-tert-butyl 5-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(3-chlorophenyl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.98 g, 1.86 mmol, 62.9% yield). HPLC, 254 nm, 100% purity, retention time=3.86 minutes.
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Cl)[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]1=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](OC1C2C(=CC=CC=2)N(CCCC)C1=O)(=O)C1C=CC=CC=1.C(OCC1C2C(=CC=CC=2)N(C(=O)C2C=CC=CC=2)C=1)(=O)C1C=CC=CC=1>>[C:1]([O:9][C:10]1([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:20][CH2:21][CH2:22][CH3:34])[C:11]1=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)C(Cc2c[nH]c3ccccc23)(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Reactant: CCCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Agent: O=C(OCc1cn(C(=O)c2ccccc2)c2ccccc12)c1ccccc1
Product: CCCCN1C(=O)C(Cc2c[nH]c3ccccc23)(OC(=O)c2ccccc2)c2ccccc21

Procedure:
This compound was made in an analogous method as 3-((1H-indol-3-yl)methyl)-5-chloro-2-oxo-1-propylindolin-3-yl benzoate) using 1-butyl-2-oxoindolin-3-yl benzoate and (1-benzoyl-1H-indol-3-yl)methyl benzoate. 1H-NMR δ 8.03 (d, 2H), 7.97 (bs, NH), 7.54 (t, 1H), 7.48 (d, 1H), 7.42 (m, 2H), 7.28 (d, 1H), 7.24 (dd, 1H), 7.15 (m, 2H), 7.05 (dd, 1H), 6.94 (dd, 1H), 6.70 (m, 2H), 3.75 (d, 1H), 3.68 (m, 1H), 3.52 (d, 1H), 3.41 (m, 1H), 1.28-1.09 (m, 4H), 0.81 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[OH:16])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Br>CC(=O)CC>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH2:23][CH:25]2[O:27][CH2:26]2)=[CH:6][CH:7]=1
Reactant: BrCC1CO1
Reactant: COc1ccc(-c2ccc(Cl)nn2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(-c2ccc(Cl)nn2)c(OCC2CO2)c1

Procedure:
A stirred mixture of 3-chloro-6-(2-hydroxy-4-methoxyphenyl)pyridazine (0.1 mole), potassium carbonate (0.3 mole) and epibromohydrin (0.4 mole) in butan-2-one was heated under reflux overnight. The filtered solution was evaporated to give an oil which was purified by elution with mixtures of chloroform-methanol on a silica column to give 3-chloro-6-[2-(2,3-epoxypropoxy)-4-methoxyphenyl]pyridazine m.p. 111°-112° (ethanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:40])[F:41])=[CH:35][CH:34]=3)=[CH:21][N:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1
Yield: 85 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.0 g) synthesized in Example 162-1 and 4-trifluoromethoxyphenylboric acid (0.54 g) were dissolved in dioxane (10 mL) and 2 mol/L sodium carbonate (5 mL), tetrakis(triphenylphosphine)palladium (0.13 g) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (1.0 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH2:31]2>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH:31]2[C:7](=[O:9])[C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: O=C(O)c1csc(Br)c1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CN(C)C=O
Product: NC(=O)N1C(=O)C(C(=O)c2csc(Br)c2)c2cc(Cl)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 55. A 100 g (4.83 mmole) portion of 5-bromo-3-thiophenecarboxylic acid (prepared as described in J. Am. Chem. Soc., 76, 2445 (1954)) was combined with 848 mg (5.23 mmole) of 1,1'-carbonyldiimidazole in 5 ml of N,N-dimethylformamide and the intermediate imidazolide coupled directly with 848 mg (4.02 mmole) of 5-chloro-2-oxindole-1-carboxamide in the presence of 1.33 g (10.89 mmole) of 4-(N,N-dimethylamino)pyridine. The resulting crude green product (1.22 g, 76% yield) was recrystallized to furnish 540 mg (1.35 mmole, 34% yield) of yellow solid, m.p. 238-40° C. (acetic acid).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CN(C=O)C.[CH3:10][C:11]1[C:16]2[NH:17][C:18](=[O:20])[O:19][C:15]=2[CH:14]=[CH:13][CH:12]=1.[CH3:21][C:22](OC(C)=O)=[O:23]>O>[C:22]([C:13]1[CH:12]=[C:11]([CH3:10])[C:16]2[NH:17][C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)(=[O:23])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(C)c2[nH]c(=O)oc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
20.0 g (149.99 mmol) aluminium(III) chloride were combined with 5.0 mL DMF, with cooling. After 15 min stirring, first of all 5.0 g (33.52 mmol) 4-methylbenzo[d]oxazol-2(3H)-one and then 5.0 mL (52.90 mmol) acetanhydride were added and the mixture was stirred for 1 h at 80° C. The cooled reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:10][NH:9][CH2:8][C:7]=2[CH:29]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:37][N:38]([CH3:43])[S:39]([N:9]1[CH2:8][C:7]2[CH:29]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=2[N:15]2[C:11](=[N:12][N:13]=[C:14]2[C@H:16]2[CH2:17][CH2:18][C@H:19]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)[CH2:10]1)(=[O:41])=[O:40]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccccc3)CC2)C1
Reaction time: 72 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.062 g, 0.14 mmol) and triethylamine (0.030 ml, 0.22 mmol) in dichloromethane (2.5 ml) was added N,N-dimethylsulfamoyl chloride (0.023 ml, 0.22 mmol) at room temperature. After stirring for 72 h the reaction mixture was transferred directly onto a silica gel chromatography column. Elution with n-heptane/ethyl acetate gave the title compound (0.042 g, 58%) as white solid. MS m/e: 502 (M+H+).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27](OC)=[O:28])=[CH:20][C:14]=3[C:15]=2[C:16](=[O:19])[NH:17][CH3:18])=[CH:7][CH:6]=1.O/[N:35]=[C:36](\[NH2:43])/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CCO>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:33]=[CH:32][CH:31]=[C:26]([C:27]5[O:28][N:43]=[C:36]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[N:35]=5)[CH:25]=4)=[CH:20][C:14]=3[C:15]=2[C:16]([NH:17][CH3:18])=[O:19])=[CH:9][CH:10]=1
Reactant: N/C(=N\O)c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)OC)c3)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nc(-c5ccccc5)no4)c3)cc12
Yield: 14.3 %

Procedure:
Sodium methoxide (33 mg, 0.620 mmol) was added to a stirring slurry of methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (50 mg, 0.124 mmol) and (Z)—N′-hydroxybenzimidamide (51 mg, 0.372 mmol) in EtOH (2.5 mL) at rt. The mixture was subjected to microwave irradiation for 5 min at 160° C. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (8.7 mg, 14%). 1H NMR (400 MHz, DMSO-d6) d ppm 8.49-8.56 (1H, m), 8.44-8.49 (1H, m), 8.19-8.25 (1H, m), 8.13-8.18 (2H, m), 8.07-8.12 (1H, m), 8.00-8.07 (2H, m), 7.98 (1H, s), 7.76-7.86 (3H, m), 7.59-7.68 (3H, m), 7.41 (2H, t, J=8.91 Hz), 2.88 (3H, d, J=4.77 Hz). LC-MS retention time: 1.94 min; m/z (MH+): 490. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=17.39 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=14.58 min, purity=98%.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=O)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1C=CC=CC=1>C(N(CC)CC)C>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:18]3[N:20]=[CH:21][C:22](=[O:23])[O:24]3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(C(=O)NCC(=O)O)cc2C1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCC1Cc2ccc(C3N=CC(=O)O3)cc2C1
Temperature: 25 °C

Procedure:
Subsequently, 1.55 g (4.68 mM) of N-(2-octylindan-5-carbonyl)glycine and 25 ml of dry benzene were placed in a 50 ml-three necked flask. Under stirring at room temperature, 0.66 ml (4.74 mM) of triethylamine and 0.46 ml (4.81 mM) were successively added to the above mixture, followed by further stirring for 23 minutes at room temperature to precipitate a crystal. After the reaction, the precipitated triethylamine hydrochloride was removed by filtration and the filtrate was evaporated under reduced pressure to obtain a residue. The residue was dried under reduced pressure to obtain 2-(2-octylindan-5-yl)-5-oxazolone.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@@H:7]2[C:12]([CH3:14])([CH3:13])[O:11][C:10]([NH:15][C:16]34[CH2:23][CH:22]5[CH2:24][C:18]([C:25]([NH2:27])=[O:26])([CH2:19][CH:20]3[CH2:21]5)[CH2:17]4)=[N:9][S:8]2(=[O:29])=[O:28])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH2:6]([C@@H:7]1[C:12]([CH3:14])([CH3:13])[O:11][C:10]([NH:15][C:16]23[CH2:23][CH:22]4[CH2:24][C:18]([C:25]([NH2:27])=[O:26])([CH2:19][CH:20]2[CH2:21]4)[CH2:17]3)=[N:9][S:8]1(=[O:28])=[O:29])[C:5]1[CH:30]=[CH:31][CH:2]=[CH:3][CH:4]=1
Reactant: [H][H]
Reactant: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1Cc1ccc(Br)cc1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1Cc1ccccc1
Yield: 48.8 %

Procedure:
3a-[(R)-5-(4-bromobenzyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino]hexahydro-2,5-methanopentalene-2-carboxamide (80 mg) was dissolved in ethanol and stirred in a hydrogen atmosphere (5 bar) in the presence of palladium on charcoal (10%) for 30 min. The solution was filtered and concentrated. Purification was effected by preparative HPLC. This gave the product (33 mg) with a molecular weight of 431.5 g/mol (C22H29N3O4S), MS (ESI): (M+H+) 432.5 g/mol.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:19]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:10]([C:7]2[CH2:8][CH:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[CH2:5][CH:6]=2)=[CH:11]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), benzoyl chloride (13 μL, 0.12 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1mL) at RT.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[CH:16]1([C:19]2[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=2)[CH2:18][CH2:17]1.[F-].[Cs+].C(#N)C>O1CCOCC1.O.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[N:5]=[C:6]([C:22]2[CH:23]=[N:24][C:19]([CH:16]3[CH2:18][CH2:17]3)=[CH:20][CH:21]=2)[C:7]=1[F:8]
Reactant: OB(O)c1ccc(C2CC2)nc1
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(C3CC3)nc2)c(F)c(N)c1OC
Temperature: 85 °C
Yield: 32.2 %

Procedure:
To a tube, methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (500 mg, 2.131 mmol) (˜90% pure), (6-cyclopropylpyridin-3-yl)boronic acid (417 mg, 2.56 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78 mg, 0.107 mmol), and Cesium Fluoride (647 mg, 4.26 mmol) were charged as solids. The tube was sealed and charged with inert atmosphere. The solids were then diluted with Dioxane (5.7 ml) and Water (1.4 ml). The resulting suspension was heated to 85° C. for 18 hrs. The reaction solution was poured in to a brine solution. The aqueous phase was extracted with EtOAc (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The product was purified (flash chromatography: silica, 5-50% EtOAc in Hex 16 CV; C18 5-100% ACN in H2O 16 CV) to yield methyl 4-amino-6′-cyclopropyl-3-fluoro-5-methoxy-[2,3′-bipyridine]-6-carboxylate (0.218 g, 0.687 mmol, 32.2% yield). ESIMS for m/z 318 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 0.99 (tt, J=7.6, 2.7 Hz, 4H), 2.17 (tt, J=7.8, 5.1 Hz, 1H), 3.77 (s, 3H), 3.86 (s, 3H), 6.55 (s, 2H), 7.42 (d, J=8.9 Hz, 1H), 8.00 (ddd, J=8.2, 2.3, 1.2 Hz, 1H), 8.77 (t, J=2.0 Hz, 1H). 19F NMR (376 MHz, DMSO-d6) δ −141.19.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][CH2:59][OH:60])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH:61][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][CH2:59][OH:60])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: N[C@@H](CCO)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCO)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 65 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-1-(5-chloro-1H-benzimidazol-2-yl)-3hydroxypropylamine in tetrahydrofuran. Yield: 65%; Rf value: 0.43 (silica gel; dichloromethane/ethanol=9:1); C23H25ClN4O3 (440.93); mass spectrum: (M+H)+=441/443 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C:6]=1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][O:23][CH3:24])=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH3:10])[CH2:7][CH:6]1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][O:23][CH3:24])=[O:4]
Reactant: COCOc1ccc(OCOC)c(C2=C(C(=O)OC)C[C@@H](C)C2)c1
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc(OCOC)c(C2CC(C)CC2C(=O)OC)c1
Yield: 100 %

Procedure:
To a suspension of 10% palladium on carbon (0.5 g) in methanol (40 mL) add a solution of 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopent-1-enecarboxylic acid methyl ester 8a (2.4 g, 7.1 mmol) in methanol (10 mL). Place the mixture under hydrogen (60 psi) at 40° C. for twelve hours. Purge the reaction with nitrogen and filter through celite. Concentrate the filtrate in vacuo to yield 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylic acid methyl ester (2.47 g, 7.1 mmol, 100%) as a clear oil. 1H NMR (δ, 400 MHz, CDCl3): 6.98 (d, 1H, J=8.8 Hz), 6.85 (d, 1H, J=8.8), 6.81 (dd, 1H, J=3.2, 8.8 Hz), 5.15 (s, 2H), 5.10 (d, 1H, J=6.6 Hz), 5.07 (d, J=6.6 Hz), 3.77-3.67 (m, 1H), 3.51 (s, 3H), 3.46 (s, 3H), 3.38-3.31 (m, 1H), 3.15 (s, 3H), 2.19-2.03 (m, 2H), 1.96-1.68 (m, 3H), 1.19 (d, 3H, J=6.2 Hz). HRMS calcd. 339.1808; found (electrospray, M+1) 339.1818.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24](O)[CH2:25][CH3:26])=[C:20]([F:28])[C:19]=3[F:29])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][CH3:26])=[C:20]([F:28])[C:19]=3[F:29])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(-c3ccc(C(O)CC)c(F)c3F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=Cc1ccc(-c2ccc(-c3ccc(CCCCC)cc3)cc2)c(F)c1F

Procedure:
A solution of 3.2 g of 1-[4-(4-pentylphenyl)-phenyl]-2,3-difluoro-4(1-hydroxypropyl)-benzene and 0.3 g of p-toluenesulphonic acid in 70 ml of toluene is heated at reflux temperature for one hour, then cooled, washed with saturated sodium bicarbonate solution and dried over anhydrous magnesium sulphate. Evaporation of the solvent gives 1-[4-(4-pentylphenyl)phenyl]-2,3-difluoro-4-(1-propenyl)-benzene as a crude Z/E isomer mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](C4C=NC(Cl)=CC=4)([C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[OH:19])[CH:16]=3)[N:11]=[C:10]([O:33]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:35]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:10]4[CH:9]=[CH:8][C:17]([Cl:35])=[CH:12][N:11]=4)([OH:19])[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:16]=3)[NH:11][C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)nc3)c3cncn3C)ccc2n1
Reactant: Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1)c1ccc(Cl)cn1
Yield: 26 %

Procedure:
Following the same procedure as described in example 1F, the obtained [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanol was treated with HCl in aqueous THF to yield the title compound, 1.02 g, (2.14 mmol, 26% yield).