Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1)[CH3:2].C([Li])(C)(C)C.[CH3:15][C:16]1([CH3:47])[CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]3[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=3)[CH:22]=2)[S:17]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].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>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]4[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=4)[CH:22]=3)[S:17][C:16]([CH3:15])([CH3:47])[CH:25]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)S3)cc1
Reactant: CCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)cc1
Temperature: 25 °C

Procedure:
A solution of 4-ethylbromobenzene (670.9 mg, 3.63 mmol) in 4.0 mL of THF was cooled to −78° C.; and tert-butyllithium (464.5 mg, 7.25 mmol, 4.26 mL of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (658.7 mg, 4.83 mmol) in 8.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-thio-chromen-6-ylethynyl)-benzoate (1.20 g, 2.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (111.7 mg, 0.097 mmol) in 8.0 mL THF. This solution was heated to 50° C. for 1 hour, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. The solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. Ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate was isolated by column chromatography (5% EtOAc/hexanes) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[O:10]=[CH:11][C:12]1[CH:20]=[CH:19][C:17](O)=[C:14]([O:15][CH3:16])[CH:13]=1>>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH:20]=[CH:19][C:17]=1[O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH:11]=[O:10]
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCN1CCOCC1
Product: COc1cc(C=O)ccc1OCCN1CCOCC1

Procedure:
3-Methoxy-4-(2-morpholin-4-yl-ethoxy)-benzaldehyde was prepared from N-(2-hydroxyethyl)morpholine (Aldrich) and vanillin (Aldrich) by method H above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)o2)c1

Procedure:
Carboxylic acid (145) (50 mg, 0.19 mmol) was coupled to aniline (60) (43 mg, 0.23 mmol) using Method C. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[CH3:40][C:41]1[CH:42]=[C:43]([N:48]=C=O)[CH:44]=[C:45]([CH3:47])[CH:46]=1>>[CH3:40][C:41]1[CH:42]=[C:43]([NH:48][C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])[CH:44]=[C:45]([CH3:47])[CH:46]=1
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1cc(C)cc(N=C=O)c1
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)Nc1cc(C)cc(C)c1
Yield: 2.4 %

Procedure:
The title compound was prepared from 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio} methyl)-4-oxo-4-(3-pyridyl)butanoic acid and 3,5-dimethylphenyl isocyanate as described in Example 16 in a 2.4% yield; ESMS, (M+1)+474.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a stirred solution of 43 mg (0.13 mmol) of (S)-1-[(3R,4S)-1-benzyl-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol in DMF (5 mL) was added NaH (9 mg, 0.18 mmol). The reaction mixture was stirred at RT for 30 minutes, and then at 50° C. for 20 minutes. A solution of 6-chloro-nicotinonitrile (22 mg, 0.16 mmol) in DMF (1 mL) was added dropwise and stirring was continued 3 hours at 50° C. The reaction mixture was concentrated under vacuo. Extraction with EtOAc/H2O, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 48 mg (86%) of the title compound as a colorless oil. ES-MS m/e: 436.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])=[O:20]
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: COc1cc(OC)c(-c2cccs2)cc1C=O
Product: COc1cc(OC)c(-c2cccs2)cc1/C=C/C(=O)c1ccccc1C(=O)O
Yield: 47 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-(thiophen-2-yl)-benzaldehyde (Ex-6A) and 2-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 47% yield, mp 196–198° C. 1H-NMR (DMSO-d6) δ 8.00 (s, 1H), 7.84 (d, 1H), 7.61 (m, 3H), 7.45 (m, 3H), 7.21 (d, 1H), 7.08 (t, 1H), 6.75 (s, 1H), 3.95 (s, 3H), 3.86 (s, 3H). MS m/z=394 ([M]+, 100%). Anal. calculated for C22H18O5S: C, 66.99; H, 4.60; S, 8.13. found C, 67.08; H, 4.17; S, 7.97.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH3:30][N:31]([CH3:42])[S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:41][C:38]4[CH:39]=[CH:40][C:35]([S:32](=[O:34])(=[O:33])[N:31]([CH3:30])[CH3:42])=[CH:36][CH:37]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Product: CN(C)S(=O)(=O)c1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Yield: 86 %

Procedure:
The title compound was prepared in 86% yield from compound (10) and 4-(N,N-dimethylsulfamoyl)phenylamine using the method described for Preparation 35. 1H-NMR (d6-DMSO, 500 MHz): δ 1.48 (s, 9H), 1.60 (s, 9H), 2.58 (s, 9H), 6.87 (d, J=0.63 Hz, 1H), 7.61 (d, J=9.14 Hz, 2H), 7.65 (s, 1H), 7.90 (d, J=8.83 Hz, 2H), 8.05 (d, J=0.63 Hz, 1H), 8.49 (d, J=0.63 Hz, 1H), 8.57 (d, J=0.95 Hz, 1H), 9.67 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1>CN(C)C=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]2[O:14][N:13]=[C:12]([O:1][CH:2]3[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)[C:16]=2[CH:17]=1
Reactant: CN1CCC(O)CC1
Reactant: Clc1ccc2onc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2noc3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A solution of 1.53 g (13.3 mmole) of 4-hydroxy-1-methylpiperidine in 25 ml of dimethylformamide was cooled to 5° C. in an atmosphere of nitrogen. 0.58 g (13.3 mmole) of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to the solution, and then the solution was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 5° C., and then 2.50 g (13.3 mmole) of 3,5-dichloro-1,2-benzisoxazole were added to it; the resulting mixture was then stirred at 5° C. for 30 minutes and then at room temperature for 1 hour. At the end of this time, the mixture was poured into 50 ml of ice-water and then extracted twice, each time with 50 ml of ethyl acetate. The ethyl acetate layer was separated and washed with 100 ml of a 10% w/v aqueous solution of sodium chloride; it was then dried over anhydrous magnesium sulfate, and the drying agent was removed by filtration. The solvent was removed from the filtrate by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel using ethyl acetate as the eluent to afford 2.38 g (yield 67.00%) of the title compound as a colorless powder, melting at 55°-56° C.
Reaction SMILES: S(=O)(=O)(O)O.O=[C:7]([CH3:25])[CH2:8][NH:9][C:10](=[O:24])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[O:12]>O>[CH3:25][C:7]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:11](=[O:12])[C:10](=[O:24])[NH:9][CH:8]=1
Reactant: CC(=O)CNC(=O)C(=O)Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c[nH]c(=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Conc. sulphuric acid (2.35 L) was heated to 50-55° C. and N-(2-oxopropyl)-N′-[3-(trifluoromethyl)phenyl]ethanediamide (200 g, 1 eq)) was then added portion-wise over 2 hours to give a clear brown solution. After 3.25 hours the reaction was cooled to 20° C. The reaction mixture was then added to water (6 L), keeping the temperature below 10° C. The white slurry was then stirred at 0-5° C. for a further 1 hour before filtering. The filter cake was washed with water (2 L) and the damp product recharged to the flask. Water (0.85 L) was charged and the mixture stirred for 30 minutes. The mixture was filtered and the filter cake washed with water (0.25 L). The title compound was isolated as a water-wet, off-white solid (228.0 g, water content=26.5%, corrected mass 168.0 g, 90%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46].CN(C)C=O>C(OCC)C>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:46][CH:45]=[CH2:44])[C@@:16]2([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 424 mg, 0.8 mmol), potassium carbonate (770 mg), allyl bromide (0.5 ml) and N,N-dimethylforamide (3 ml) was stirred at room temperature for 3 days. The reaction mixture was treated with 1:1 mixture diethyl ether:iso-hexane, washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (362 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([C:14]([O:16][CH3:17])=[O:15])#[C:9][C:10]([O:12][CH3:13])=[O:11]>CO>[NH:1](/[C:9](=[CH:8]\[C:14]([O:16][CH3:17])=[O:15])/[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)/C=C(\Nc1ccccc1)C(=O)OC

Procedure:
Purified aniline (15.0 g, 0.16 mole) was reacted with dimethyl acetylenedicarboxylate (19.8 ml, 0.15 mole) in 400 ml methanol according to the procedure of Heindel, et al., J. Het. Chem. 1966, 3, 222. The reaction was refluxed for 18 hours, then worked up by evaporating the solvent, dissolving the residue in ether, and washing consecutively with 0.5 N HCl, H2O, and sat. NaCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica gel in 80/20 hexane/EtOAc which yielded 29.14 g of the Michael Adduct, dimethyl anilinofumarate as a light yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:22][CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[OH:23])=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 4-fluorobenzoyl chloride (136 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization from ethyl acetate-hexane gave the title compound (182 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][OH:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[N:10]=[N:11][C:12]([Cl:18])=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O.C(OCC)(=O)C.O>[Cl:19][C:6]1[CH:5]=[C:4]([CH2:20][C:21]([OH:25])=[O:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[N:10]=[N:11][C:12]([Cl:18])=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1
Reactant: CC(C)c1cc(Sc2c(Cl)cc(CCO)cc2Cl)nnc1Cl
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(Sc2c(Cl)cc(CC(=O)O)cc2Cl)nnc1Cl
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 90.8 %

Procedure:
A solution of 2-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenyl]-ethanol (74) (100 mg, 0.26 mmol) in acetone (2.0 mL) cooled to 0° C. was treated with a 2.7M solution of Jones reagent (0.21 mL, 0.57 mmol, prepared via standard method). The reaction was stirred at 0° C. for 1.25 h. At this time, the reaction was treated with 2-propanol until the red solution turned green. This mixture was then diluted with ethyl acetate (50 mL) and water (25 mL). The organics were separated, dried with magnesium sulfate, filtered, and concentrated under vacuum to afford [3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenyl]-acetic acid (75) (92.5 mg, 89%) as an off-white foam. This material was used without further purification; LRMS-APCI for C15H13Cl3N2O2S (M+H)+ at m/z=390. Exact Mass=389.9763; Molecular weight=391.71
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:13])[NH:7]2.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([N:7]1[C:8]2[C:3](=[C:2]([Br:1])[C:11]([F:12])=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH:6]1[CH3:13])(=[O:16])[CH3:15]
Reactant: CC1CCc2c(ccc(F)c2Br)N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1c2ccc(F)c(Br)c2CCC1C

Procedure:
The 5-bromo-6-fluoro-1,2,3,4-tetrahydroquinaldine intermediate of Formula IV is reacted in step (3) with acetic anhydride to provide the novel intermediate 1-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroquinaldine of Formula V. The reaction is conducted by heating the reaction mixture, for example, using a steam bath.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:18])([CH3:17])[C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>[OH-].[Na+].C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:18])([CH3:17])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1ccc(C(C)(C)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
3.87 g of ethyl 2-(4-acetylaminophenyl)-2-methylpropionate was dissolved in a mixed solution of 16.6 ml of 2N-caustic soda solution and 30 ml of ethyl alcohol and the solution was stirred at 50° C. for 8 hours. After distilling off ethyl alcohol under reduced pressure, the aqueous layer was extracted with ether and unreacted materials were removed. After the aqueous layer was acidified with conc. hydrochloric acid, the formed crystals were collected by filtration, washed with water, and recrystallized from acetone-water to give 2.15 g of 2-(4-acetylaminophenyl)-2-methylpropionic acid (Yield: 62%). M.P. 169.7°-170.8° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1
Reactant: Cc1ccc2nc([C@H](C)N)n(-c3ccccc3)c2c1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-1-(6-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 13 (100 mg, 0.398 mmol), 6-chloro-9H-purine (65 mg, 0.418 mmol) and DIPEA (0.347 mL, 1.99 mmol) in dioxane (3 mL) was stirred in a sealed vial for 20 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% MeOH in EtOAc) and then crystallised from acetonitrile affording 118 as a white solid (35 mg, 24%). LCMS: RT 3.15 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 8.17-8.07 (2H, m), 7.88-7.78 (1H, m), 7.64-7.45 (6H, m), 7.06 (1H, d, J=8.26 Hz), 6.86 (1H, s), 5.50 (1H, br), 2.35 (3H, s), 1.54 (3H, d, J=6.82 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:27]1(=[O:34])(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1>>[O:33]=[S:27]1(=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)nc1C
Reactant: O=S1(=O)CCCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3C#N)CC2)nc1C
Yield: 82.4 %

Procedure:
Using 5-bromo-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (413 mg) described in Preparation Example 172 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (385 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][O:24][CH3:25].[Cr]([O-])([O-])(=O)=O.C(O)(=O)C(O)=O>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][O:24][CH3:25])[CH2:10]1
Reactant: OC1(c2cccc(F)c2F)CCNC1
Reactant: COCCBr
Agent: O=[Cr](=O)([O-])[O-]
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COCCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 51: Enantiomer E1 of 3-(2,3-difluorophenyl)-pyrrolidin-3-ol (0.15 g, 0.75 mmol), acetonitrile (6 mL), potassium carbonate (0.208 g, 1.5 mmol) and 1-bromo-2-methoxyethane (0.07 mL, 0.75 mmol). Flash chromate-graphy on silica gel (Ethyl acetate/methanol, 10:1). Yield: 0.07 g. [α]D=+22.5°; The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether; M.p. 149-150° C.; MS m/z (relative intensity, 70 eV) 257 (M+, 1), 212 (bp), 182 (65), 127 (22), 141 (16), 213 (12).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH2:9](B(CC)CC)[CH3:10].[O-]P([O-])([O-])=O.[K+].[K+].[K+].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].O1CCCC1>[CH2:9]([C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1)[CH3:10]
Reactant: Nc1ccnc(Cl)n1
Reactant: CCB(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nccc(N)n1
Temperature: 25 °C
Yield: 24.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 2-chloropyrimidin-4-amine (2.60 g, 20.0 mmol), triethylborane (20.0 mL, 1.0 M in THF, 20.0 mmol), Pd(dppf)Cl2 (816 mg, 1.0 mmol), K3PO4 (13.0 g, 40.0 mmol), water (2 mL), and tetrahydrofuran (50 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 14 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 229a as yellow solid (600 mg, 24%). MS-ESI: [M+H]+ 124.3