Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[F:15])#[N:2].[OH-:16].[K+].[Cl-].[Na+]>C(O)(C)(C)C>[CH3:14][C:10]1([CH3:13])[CH:9]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([F:15])=[C:3]([C:1]([NH2:2])=[O:16])[C:12]=2[O:11]1
Reactant: [OH-]
Reactant: CC1(C)C=Cc2ccc(F)c(C#N)c2O1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC1(C)C=Cc2ccc(F)c(C(N)=O)c2O1
Yield: 48.8 %

Procedure:
A stirred solution of 5.0 grams (0.025 mole) of 8-cyano-2,2-dimethyl-7-fluoro-2H-1-benzopyran and 5.1 grams (0.091 mole) of potassium hydroxide in 60 mL of tert.-butanol was maintained at reflux for one hour and then poured into an aqueous solution saturated with sodium chloride. The mixture was extracted with ethyl acetate, and the extract was washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 2.7 grams of 2,2-dimethyl-7-fluoro-2H-1-benzopyran-8-ylcarboxamide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:19])[CH:13]=[N:12]2.C(N(CC)CC)C.[C:27](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:28]>C(Cl)Cl>[N:19]([C:14]1[CH:13]=[N:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH3:8])[CH:10]=2)[N:15]=1)=[C:27]=[S:28]
Reactant: Cc1ccc2nc(N)cnc2c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(N=C=S)cnc2c1
Yield: 38 %

Procedure:
A mixture of 6-methylquinoxalin-2-amine 2,2,2-trifluoroacetate (546 mg, 2 mmol), triethylamine (243 mg, 2.400 mmol), and 1,1′-thiocarbonyldipyridin-2(1H)-one (557 mg, 2.40 mmol) was stirred in 5 mL DCM for 4 h. The reaction was directly eluted on a 120 g silica gel cartridge with 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min to afford 2-isothiocyanato-6-methylquinoxaline (153 mg, 0.760 mmol, 38% yield).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]O)[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:42][C:43]([F:57])([F:56])[C:44]1[CH:45]=[C:46]([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:47]=[CH:48][CH:49]=1>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]([N:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:15][CH:16]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:53]1[CH2:52][CH2:51][CH:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([C:43]([F:42])([F:56])[F:57])[CH:45]=2)[CH2:55][CH2:54]1)=[O:35]
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCO)cc1OC
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Product: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCN2CCC(c3cccc(C(F)(F)F)c3)CC2)cc1OC
Yield: 53.5 %

Procedure:
Starting with 5-[4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]-1-pentanol (0.19 g, 0.32 mmol) prepared in Example 135 and 4-[3-(trifluoromethyl)phenyl]piperidine (0.23 g, 1 mmol), the same procedure as shown in Example 136 was repeated to give the titled compound (0.13 g, yield: 53%) as a white crystal (cis:trans=3:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([CH:22]=2)[NH2:21])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([NH:21][S:38]([C:32]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=3[F:30])(=[O:40])=[O:39])[CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3ccc(F)cc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 0 °C
Reaction time: 4 h
Yield: 49.8 %

Procedure:
To a solution of 5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (12 g, 34.4 mmol) in DCM (100 mL) was added pyridine (8.2 g, 103 mmol). The mixture was cooled to 0° C. 2,4-Difluorobenzene-1-sulfonyl chloride (7.32 g, 34.4 mmol) in DCM (30 mL) was added dropwise to the mixture. The reaction was stirred at rt for 4 h. Then the reaction was washed with water (200 mL), and extracted with DCM (2×200 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:1) to afford the title compound (9.0 g, 49.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.63-10.70 (br, 1H), 8.55 (d, J=5.3 Hz, 1H), 7.71-7.82 (m, 1H), 7.50-7.57 (m, 1H), 7.41-7.48 (m, 1H), 7.34-7.40 (m, 1H), 7.24-7.32 m, 1H), 7.15-7.23 (m, 1H), 7.08 (d, J=5.3, 1H), 3.27-3.37 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (ES+): 525 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=O)[CH2:11][N:12]2C(=O)[C:20]3[C:15](=CC=CC=3)[N:14]=[CH:13]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:24][N:25](C)[CH2:26]CN.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O>[CH3:24][N:25]([CH3:26])[CH2:20][CH2:15][N:14]1[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:11][N:12]=[CH:13]1
Reactant: O=C(Cn1cnc2ccccc2c1=O)c1cccc([N+](=O)[O-])c1
Reactant: CN(C)CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)CCn1cncc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A stirred mixture of 3-[2-(3-nitrophenyl)-2-oxoethyl]-3H-quinazolin-4-one (2.00 g, 6.47 mmol), N,N-dimethyl-1,2-ethanediamine (2.28 g, 25.9 mmol), and p-toluenesulfonic acid (2.23 g, 12.9 mmol) in xylenes (150 mL) was refluxed for 48 h. After cooling to rt, water (20 mL) and sat. NaHCO3 (aq) (15 mL) were added. Layers were separated, and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (8% MeOH in CH2Cl2) to afford the desired product. 1H-NMR (CD3OD, 400 MHz): δ=2.15 (s, 6H), 2.54 (t, J=7.2 Hz, 2H), 4.22 (t, J=6.8 Hz, 2H), 7.15 (d, J=1.2 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.89 (dt, J=2.4, 7.6 Hz, 1H), 7.90 (s, 1H), 8.24-8.26 (m, 1H), 8.30 (s, 1H). MS (ES+): m/z 261.24 [MH+]. HPLC: tR=0.49 and 0.71 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]=[C:14]=[O:15]>C(#N)C>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:15]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)NCCSCc1[nH]cnc1C
Yield: 58.8 %

Procedure:
A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (5.1 g.) and methyl isocyanate (2.0 g.) in acetonitrile was heated for 18 hours in a pressure vessel at 100°. After cooling, the solid obtained was collected and recrystallised from isopropyl alcohol-acetonitrile to give N-methyl-N'-[2-((4-methyl-5-imidazolyl) methylthio)ethyl]urea (4.0 g.) m.p. 158°-159°.
Reaction SMILES: [Cl-].[C:2]([IH+:6]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].C([O-])([O-])(OCC)CC.[F:25][C:26]([F:32])([F:31])[S:27]([OH:30])(=[O:29])=[O:28].N>C(Cl)Cl>[O-:30][S:27]([C:26]([F:32])([F:31])[F:25])(=[O:29])=[O:28].[C:13]([IH+:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: CC(C)(C)[IH+](c1ccccc1)C(C)(C)C
Agent: CCOC([O-])([O-])CC
Agent: N
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Di-tert-butylphenyliodonium chloride (443 mg; 1 mmol), ethyl orthopropionate (211 mg; 1.5 mmol), and trifluoromethanesulfonic acid (165 mg; 1.1 mmol) were dissolved in anhydrous methylene chloride (10 ml), and the resultant mixture was stirred for 2 hours at room temperature. The reaction mixture was alkalinized by adding 1% aqueous ammonia (10 ml), and extracted with methylene chloride twice, followed by drying. The solvent was evaporated, and the thus-obtained solid matter was washed with ether, to thereby yield 491 mg of the target compound as white crystals (yield: 91%).
Reaction SMILES: CS(N(C1C=CC(Cl)=CC=1)[C@@H](C(O)=O)C)(=O)=O.[C:18]([NH:25][C@H:26]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:27]([NH:29][N:30]1[CH2:33][CH:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:31]1)=[O:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].BrC[C:51]([O:53][CH3:54])=[O:52]>>[C:18]([NH:25][C@H:26]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=1)[C:27]([NH:29][N:30]1[CH2:31][CH:32]([N:34]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:51]([O:53][CH3:54])=[O:52])[CH2:33]1)=[O:28])([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(NC2CCCCC2)C1
Agent: C[C@H](C(=O)O)N(c1ccc(Cl)cc1)S(C)(=O)=O
Product: COC(=O)N(C1CCCCC1)C1CN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared following the procedure described in Step A of Intermediate 135 using (2R)-2-(BOC)amino-N-[3-(cyclohexylamino)azetidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Intermediate 202 and methyl bromoacetate.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:12]=1>CC(C)=O>[C:17]([C:13]1[CH:12]=[C:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH:16]=[CH:15][N:14]=1)([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(N)ccn1
Reactant: O=C=Nc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)c1cc(NC(=O)Nc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
146 mg of phenyl isocyanate was added to a solution of 186 mg (1.2 mmol) of methyl 4-aminopicolate in 4 ml of dry acetone. The resulting mixture was agitated at room temperature overnight. Solvent was then evaporated off and the residue chromatographed in a conventional manner using silica gel (solvent:CHCl3 :acetone=4:1 volume). Fractions were collected and solvent removed by distillation. The residue was recrystallized from methanol to give the desired product having a melting point of 206°-208° C. (decompd.) in an amount of 261 mg (yiled 78.6%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[C:19]([NH2:21])=[O:20].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31](OC)=O)[CH:26]=[CH:27][C:28]=1[Cl:29].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:30][C:31]1[NH:21][C:19](=[O:20])[C:3]2[C:4]([CH2:17][CH3:18])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: CCCCCCC(CCC)n1nc(CC)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CC)c2c(=O)[nH]c(Cc3ccc(Cl)c(Cl)c3)nc21
Yield: 43.2 %

Procedure:
10 mg (0.02 mmol) of 5-amino-3-ethyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.091 mmol) of methyl 3,4-dichlorophenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 4 mg (45%) of a solid, Rf=0.67 (dichloromethane/methanol=15:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[F-].[Cs+]>C(#N)C.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 81.7 %

Procedure:
A mixture of 4-methoxyphenylboronic acid (3.70 g, 24.3 mmol), 1-chloro-4-nitrobenzene (3.84 g, 24.3 mmol) and cesium fluoride (7.40 g, 48.7 mmol) in 150 mL of 2:1 acetonitrile-water was degassed under vacuum for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (844.0 mg, 0.73 mmol) was added and the reaction refluxed for 3 h. The solvent was removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic phase was separated, dried (Na2SO4) and the solvent removed under reduced pressure. Purification of the residue on silica gel using 5% ethyl acetate hexanes as the eluent gave 4′-methoxy-4-nitro-biphenyl (4.55 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:6]2.[H-].[Na+].F[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1)=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:6]2
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(CCC(F)(F)F)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(CCC(F)(F)F)cc2c1
Yield: 71 %

Procedure:
6-(Methyloxy)-2-phenyl-3-(3,3,3-trifluoropropyl)-1-naphthalenol (125) (0.35 g, 1.00 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.32 g (71%) of the title compound (126) as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 2.10-2.25 (m, 2H), 2.80-2.90 (m, 2H), 3.94 (s, 3H), 6.67 (d, J=8.8 Hz, 2H), 7.07-7.14 (m, 3H), 7.18 (d, J=2.4 Hz, 1H), 7.22-7.30 (m, 3H), 7.60-7.64 (m, 3H), 7.70 (d, J=9.2 Hz, 1H), 9.80 (s, 1H). LCMS (ESI): m/z 451 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])=[CH2:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:26])[C:21]([O:23]CC)=[O:22])[CH2:16][CH2:15]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])=[CH2:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:26])[C:21]([OH:23])=[O:22])[CH2:16][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)c1ccc(N2CCN(C(=O)C(=O)OCC)CC2)c(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(N2CCN(C(=O)C(=O)O)CC2)c(C(C)(C)C)c1
Yield: 109.2 %

Procedure:
To a stirred solution of ethyl {4-[2-tert-butyl-4-(1-methylethenyl)phenyl]piperazin-1-yl}(oxo)acetate (Example 166, 0.057 g, 0.158 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 2 h the reaction mixture was acidified with 1 M HCl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide {4-[2-tert-butyl-4-(1-methylethenyl)phenyl]piperazin-1-yl}(oxo)acetic acid (0.057 g, quant.) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH2:44]([S:46](Cl)(=[O:48])=[O:47])[CH3:45]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][N:19]([S:46]([CH2:44][CH3:45])(=[O:48])=[O:47])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reactant: CCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCS(=O)(=O)N1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)c3ccc(OC)c(C(F)(F)F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.90 mmol) in acetone (0.5 mL) was added potassium carbonate (finely milled) (19 mg, 0.13 mmol), ethanesulfonyl chloride (13 μL, 0.13 mmol) and acetone (0.5 mL). The suspension was stirred for 18 h at ambient temperature. It was diluted with ethyl acetatec (10 mL) and washed with an aqueous solution of Na2CO3 (1 M, 10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=30:70 to 0:100) afforded the title compound (44 mg, 76%) as an off-white foam. MS m/e: 650.2 [M]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=1.[CH3:21][O:22][C:23]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:24]=1[CH:25]=[O:26]>O.C1(C)C=CC=CC=1.C(OCC)C>[CH3:21][O:22][C:23]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:24]=1[CH:25]([C:19]1[C:18]([Br:20])=[CH:17][N:16]=[CH:15][C:14]=1[Br:13])[OH:26]
Reactant: Brc1cncc(Br)c1
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(O)c2c(Br)cncc2Br)c(OC)c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
57.0 ml (88.9 mmol) of n-butyllithium (1.56 M hexane solution) was dropwise added to a diethyl ether (110 ml) solution of 12.5 ml (89.2 mmol) of diisopropylamine at 0° C., followed by stirring for 60 minutes. The solution was cooled to −78° C., a toluene (80 ml) solution of 20 g (85 mmol) of 3,5-dibromopyridine was added thereto, followed by stirring for 5 minutes, and then a toluene 50 ml solution of 21.0 g (100 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde was added thereto, followed by stirring for 2 hours. 50 ml of water was added to the mixture to terminate the reaction, the aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 11.8 g (yield 31%) of (2,3,4-trimethoxy-6-methylphenyl)(3,5-dibromo-4-pyridyl)methanol (yellow oily substance).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:36]=[C:24]1[CH2:25][C:26]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=2)=[N:7][C:8]2[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:11]([C:19]([F:22])([F:20])[F:21])=[CH:10][C:9]=2[NH:23]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3cc(N4CCCC4)c(C(F)(F)F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M36) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (65 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[CH2:15](Br)[CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(NC(C)=O)c([N+](=O)[O-])c1

Procedure:
2.94 G. of 1-acetamido-4-hydroxy-2-nitrobenzene, 4.0 g. n-butyl bromide, and 4.2 g. of anhydrous potassium carbonate in 100 ml. of acetone are refluxed overnight with stirring. The mixture is evaporated, diluted with water and extracted with ether to afford 1-acetamido-4-n-butoxy-2-nitrobenzene. This latter compound is treated in accordance with the second paragraph of Example XXXI to afford 1-amino-4-n-butoxy-2-nitrobenzene. This latter compound is treated in accordance with the first paragraph of Example VI to afford 4-n-butoxy-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene. This latter compound is treated in accordance with the iron reduction technique set forth in the third paragraph of Example XIX to afford 2-amino-4-n-butoxy-1-(3-methoxycarbonyl-2-thioureido)benzene. This latter compound is treated in accordance with the first paragraph of Example XVII to afford 4-n-butoxy-1-(3-methoxycarbonyl-2-thioureido)-2-succinamidobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[C:24]([S:35][CH3:36])=[N:25][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27]=1[NH2:28])=O)C.O>O=S(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C:21](=[O:20])[C:23]3[C:24]([S:35][CH3:36])=[N:25][N:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:27]=3[N:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CCOC(=O)c1c(SC)nn(-c2ccccc2)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: CSc1nn(-c2ccccc2)c2nc(-c3ccc(Br)cc3)n(-c3ccc(Cl)cc3)c(=O)c12
Temperature: 150 °C

Procedure:
A mixture of 4-bromo-N-(4-chloro-phenyl)-benzamide (1.14 g, 3.67 mmol) in SOCl2 (4.5 mL) is heated to 80° C. for 2 h before SOCl2 is removed in vacuo. The resulted imidoyl chloride intermediate is dissolved in anhydrous dichloroethane (18 mL) and transferred into a sealed tube. After adding 5-amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.12 g, 4.04 mmol) and TiCl4 (0.80 mL, 7.3 mmol), the reaction tube is sealed and heated at 150° C. overnight. After cooling down to room temperature the reaction mixture is poured into water (200 mL) and extracted with chloroform (3×100 mL). The organic layers are combined, washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography to provide 6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as a white solid product; HPLC-MS calculated for C24H16BrClN4OS (M+H+) 523.0, found 523.0.