Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[S:18][C:17]([N:19]([CH3:30])[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[N:16][N:15]=1.CC(O)=[O:33].CC(OC(C)=O)=O>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:3]([C:14]2[S:18][C:17]([N:19]([CH3:30])[CH:20]3[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:26])([CH3:27])[CH2:25]3)=[N:16][N:15]=2)=[C:4]([OH:33])[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: CC(=O)O
Reactant: CN(c1nnc(-c2ccc(-c3cnn(C)c3)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CN(c1nnc(-c2c(O)cc(-c3cnn(C)c3)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Example 25) (125 mg, 0.281 mmol) in 1:1 AcOH:Ac2O (2.8 mL) was added Phl(OAc)2 (127 mg, 0.393 mmol) followed by Pd(OAc)2 (6 mg, 0.028 mmol). The reaction mixture was warmed to 80° C. and stirred for 48 hours. The reaction mixture was cooled to room temperature, then diluted with MeOH (10 mL) and loaded onto a 2 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the crude product as a brown glass-like solid. The crude material was taken up in MeOH (3 mL), passed through a syringe filter, and purified by mass-directed preparative HPLC under basic conditions (5 mM NH4OH) to give the crude product as a brown glass-like solid. The crude solid was re-dissolved in MeOH (3 mL) and re-purified by UV-directed preparative HPLC under acidic conditions (0.1% TFA), collecting at 348 nm. The combined fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH) and the cartridge washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as an off-white glass-like solid (6 mg, 5% yield). LC-MS: Rt 0.52 mins; MS m/z 461.3/463.2 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (s, 1H), 7.95 (s, 1H), 7.32 (s, 1H), 7.15 (d, J=1.52 Hz, 1H), 4.35 (br. s., 1H), 3.87 (s, 3H), 3.01 (s, 3H), 1.65 (d, J=9.60 Hz, 2H), 1.48 (br. s., 2H), 1.22 (br. s., 6H), 1.11 (br. s., 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[CH2:7]2.[N:15]1([C:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[S:23][N:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1CCCCC1>[CH:27]1[CH:28]=[CH:29][C:24]2[S:23][N:22]=[C:21]([N:15]3[CH2:16][CH2:17][N:18]([CH2:2][CH2:3][C:4]4[CH:5]=[C:6]5[CH2:7][C:8](=[O:14])[NH:9][C:10]5=[CH:11][C:12]=4[Cl:13])[CH2:19][CH2:20]3)[C:25]=2[CH:26]=1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1CCCCC1
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 87.4 %

Procedure:
Refluxed the reaction mixture of 5-(2-chloroethyl)-6-chloro oxindole (100 gm), 3-(1-piperazinyl)-1,2-benzisothiazole (104.7 gm), sodium carbonate (92.2 gm), sodium iodide (6.4 gm), tetra butyl ammonium bromide (28 gm) and cyclohexane (1000 mL) till the reaction was completed. The reaction mass was cooled to a temperature of 30° C. and the solid was filtered. To the wet compound was added water (1000 mL) and continued stirring for 45 minutes. The solid was filtered and washed with water (100 mL). To the water wet compound was added acetone (500 mL) and there was stirring for 2 hours at room temperature. The compound was filtered and washed with acetone (200 mL) and dried at a temperature of 70-75° C. to afford the Crude Ziprasidone base (156.9 g)
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.O.[C:23](OCC)(=[O:25])C>O1CCCC1>[CH3:14][C:10]1[N:9]=[C:8]([O:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([CH:23]=[O:25])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(OCc2ccc(Br)cc2)n1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(OCc2ccc(C=O)cc2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 2-(4-bromo-benzyloxy)-6-methyl-pyridine (7.30 g, 26.2 mmol) described in Manufacturing Example 3-1-1 in anhydrous tetrahydrofuran (200 mL) was added dropwise n-butyl lithium (2.67 M n-hexane solution, 11.8 mL, 31.4 mmol) on a dry ice-ethanol bath (−78° C.), which was stirred for 30 minutes at −78° C. N,N-dimethylfornamide (4.04 mL, 52.4 mmol) was added to this mixture at −78° C., and stirred for 5 minutes. Water and ethyl acetate were added to the reaction mixture, which was stirred for 10 minutes at room temperature, and the organic layer was then s separated. This organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (4.19 g, 70%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[OH:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O-])([O-])=O.[Cs+].[Cs+].C1(Br)CCCC1.C1(O)C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[O:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(-c2ccc(O)c(OC3CCCC3)c2)c1
Agent: BrC1CCCC1
Agent: [Cs+]
Solvent: Oc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc([N+](=O)[O-])c2)cc1OC1CCCC1
Yield: 53.9 %

Procedure:
2-Cyclopentyloxy-4-(3-nitrophenyl)phenol (600 mg, 2.45 mmol) was dissolved in DMF (40 ml) and treated with Cs2CO3 (730 mg, 2.24 mmol) and cyclopentyl bromide (0.32 ml, 2.94 mmol). After stirring overnight at RT some of the phenol remained (SiO2 :t.l.c, CH2Cl2). Cs2CO3 (870 mg, 2.67 mmol) and cyclopentyl bromide (0.32 ml, 2.94 mmol) were added. After stirring at RT for 3 h the phenol had been consumed. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in Et2O (50 ml), filtered, and concentrated in vacuo to give a yellow solid which was recrystallised from dichloromethane/hexane to afford the title compound (378 mg) as yellow needles. δH (CDCl3 ; 80 mHz) 1.5-2.1 (8H, br m, (CH2)4), 3.87 (3H, s, OMe), 4.84 (1H, br m, OCHCH2), 6.91 (1H, d, J 9.1 Hz, ArH ortho to OMe), 7.0-7.2 (2H, m, ArH meta to OMe), 7.54 (1H, d, J 7.5 Hz, ArH meta to NO2), 7.80 (1H, ca. dt, J ca 7.5, 1.5 Hz, ArH para to NO2), 8.09 (1H, ca. dt, J ca.8, 1.5 Hz, ArH para to aryl), 8.33 (1H, ca. t, J ca 2 Hz, ArH ortho to NO2 and aryl); m/z 313 (M+, 7%), 246 (17), 245 (M+ -cyclopentyl, 100), 230 (41), 202 (8), and 139 (9).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[NH:30][C:29]3=[O:36])[C:9]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[O:10])=[CH:4][CH:3]=1.[CH:37](=O)[CH3:38].C([BH3-])#N.[Na+].Cl>CO.[Ti](Cl)(Cl)(Cl)Cl>[CH2:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[NH:30][C:29]3=[O:36])[C:9]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:22])[CH3:23])=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[O:10])=[CH:6][CH:7]=1)[CH3:38]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)NC(=O)C(Oc2ccc3c(c2)C(=O)NC3=O)c2ccc(N)cc2)cc1
Reactant: CC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCNc1ccc(C(Oc2ccc3c(c2)C(=O)NC3=O)C(=O)NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 30 h

Procedure:
A solution of 6 g of 2-(4-aminophenyl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)-N-(4-tert-butylphenylsulfonyl)acetamide and 0.5 g of titanium tetrachloride in 100 ml of methanol is treated with 1 ml of freshly distilled acetaldehyde. 4 g of sodium cyanoborohydride are then added and the mixture is stirred for 30 hours. Half-concentrated hydrochloric acid is added, the mixture is worked up in the customary manner and 2-(4-ethylaminophenyl)-2-(1,3-dihydro-1,3-dioxo-isoindol-5-yloxy)-N-(4-tert-butylphenylsulfonyl)-acetamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N+:23]([O-])=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5]>CCOC(C)=O.[Pd]>[NH2:23][C:19]1[C:20]([F:22])=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C(CNC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)NCC(=O)O)c(Cl)cc1F
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 67.3 %

Procedure:
To a solution of benzyl 2-(2-chloro-4-fluoro-5-nitrobenzamido)acetate (190 mg) in EtOAc (10 mL) was added Pd/C (200 mg) and stirred under the atmosphere of H2 gas at 60° C. for 20 min. Work-up of the reaction mixture as described in example 1 gave the product as an off-white solid (86 mg, 67%), mp 225-227° C. (decomposed). 1H NMR (400 MHz, DMSO-d6): δ 8.52 (1H, br s), 7.19 (1H, d, J=10.8 Hz), 6.89 (1H, d, J=9.2 Hz), 5.48 (2H, br s), 3.86 (2H, d, J=3.6 Hz); LC-MS (negative ion mode): m/z 245, 247 (M−H)−.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[CH3:32][N:33]1[CH:37]=[N:36][N:35]=[C:34]1[CH:38]([NH2:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:40][CH:38]([C:34]1[N:33]([CH3:32])[CH:37]=[N:36][N:35]=1)[CH3:39])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(N)c1nncn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1)c1nncn1C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 17 mg, 0.039 mmol), (R/S)-1-(4-methyl-4H-1,2,4-triazol-3-yl)ethanamine (7.46 mg, 0.059 mmol), 4-methylmorpholine (15.95 mg, 0.158 mmol), and HATU (19.48 mg, 0.051 mmol) were dissolved in DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.2 min) to provide 2-hydroxy-N-(1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.014 mmol, 34.6% yield) as a racemic mixture of diastereomers. LCMS=540.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.90 (1 H, s), 8.16 (2 H, d, J=8.36 Hz), 7.52-7.77 (7 H, m), 5.36 (1 H, q), 5.21 (1 H, s), 3.62 (3 H, s), 1.69 (3 H, d, J=7.04 Hz); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:20]([C:10]2[N:11]=[C:12]3[N:18]([CH3:19])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])=[CH:26][CH:25]=1
Reactant: CN1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1CCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Reaction time: 3 h
Yield: 76.7 %

Procedure:
A mixture of 6-(benzyloxy)-1-methyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.393 g, 1.30 mmol) and 4-fluorobenzylamine (0.163 g, 1.30 mmol) in acetonitrile (15 ml) was treated at 25° C. with triethylamine (0.42 ml, 2.5 mmol) followed by benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.662 g, 1.49 mmol). After 3 h, the reaction mixture was diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residual solid from ethyl acetate gave 0.407 g (76% yield) of the title amide as white cubes; mp 189-191° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.02 (3H, s, NCH3), 3.70 (2H, t, J=9 Hz, CH2), 4.15 (2H, t, J=9 Hz, CH2), 4.50 (2H, d, J=5.6 Hz, NCH2), 5.11 (2H, s, OCH2), 7.0 (2H, m, aromatics), 7.24 (2H, m, aromatics), 7.3-7.45 (SH, m, aromatics), 7.71 (1H, broad t, NH). Anal. Calcd for C22H21FN4O3: C, 64.69; H, 5.18; N, 13.71. Found: C, 64.41; H, 5.10; N, 13.72.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(C)=O)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 82 g of 1-(4-methoxyphenyl)-2-propanone, 500 ml of acetic acid and 500 ml of aqueous hydrobromic acid is boiled under reflux for 2 hours and then evaporated in vacuo. The oily residue is extracted four times with 700 ml of hexane/ether (5:2) each time, the extract is evaporated and the residue is chromatographed over silica gel using hexane/ethyl acetate (3:1). 1-(4-Hydroxyphenyl)-2-propanone is thus obtained with a melting point of 40-41°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].O.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]>[Cu]I>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccccc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1F

Procedure:
A mixture of 2-fluoroaniline (5.0 g), potassium carbonate (2.5 g) and copper(I)iodide (414 mg) in 2-fluoronitrobenzene (16.9 ml) was heated to 180° under nitrogen for 18 h. The cooled mixture was poured into water (300 ml) and extracted with ethyl acetate (2×250 ml) then the combined extracts were washed with saturated brine and evaporated. The residual brown oil was azeotroped with ethanol/water then toluene. The residue was chromatographed with hexane-DE (100:0 to 95:5) to give the title compound (3.25 g) as a bright orange solid, m.p.58°-9°.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[C:9]([N+:28]([O-:30])=[O:29])=[CH:8][N:7]=1.O.[OH-].[Li+]>CO.O>[C:24]([O:23][C:21]([NH:20][CH:17]1[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:10]2[C:9]([N+:28]([O-:30])=[O:29])=[CH:8][N:7]=[C:6]([NH:5][CH2:4][C:3]([OH:31])=[O:2])[N:11]=2)[CH2:15][CH2:16]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)CNc1ncc([N+](=O)[O-])c(NCC2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCC(=O)O)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 124 %

Procedure:
To a suspension of {4-[(4-tert-butoxycarbonylamino-cyclohexylmethyl)-amino]-5-nitro-pyrimidin-2-ylamino}-acetic acid methyl ester (845 mg, 1.9 mmol) in a mixture of MeOH (90 mL) and water (30 mL) was added lithium hydroxide monohydrate (404 mg, 9.6 mmol). The heterogeneous mixture was stirred at room temperature for 1 h. The mixture was concentrated and the resulting residue was acidified to pH 5 using 1M HCl. The product was extracted using ethyl acetate (×3). The combined organic phase was dried over Na2SO4 and concentrated to yield 1.0 g of the crude {4-[(4-tert-butoxycarbonylamino-cyclohexylmethyl)-amino]-5-nitro-pyrimidin-2-ylamino}-acetic acid as a white solid. This product was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].[Cl:6][C:7]1[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH:24](OC)OC)[CH:18]=2)=[N:9][N:10]([CH3:16])[C:11]=1[O:12][CH:13]([F:15])[F:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH:24]3[S:5][CH2:1][CH2:2][CH2:3][S:4]3)[CH:18]=2)=[N:9][N:10]([CH3:16])[C:11]=1[O:12][CH:13]([F:14])[F:15]
Reactant: COC(OC)c1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Reactant: SCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Cl)c(C3SCCCS3)c2)c(Cl)c1OC(F)F
Temperature: 65 °C

Procedure:
0.5 g (4.6 mmol) of 1,3-propanedithiol was added to a solution of 1.7 g (4.6 mmol) of 4-chloro-3-[4-chloro-3-(dimethoxymethyl)phenyl]-5-difluoromethoxy-1-methyl-1H-pyrazole in 50 ml of toluene. The mixture was heated to 60-70° C. and then a spatula-tipful of p-toluenesulfonic acid was added. The reaction mixture was stirred at reflux temperature for 3 hours and then cooled and diluted with 50 ml of toluene. The organic phase was washed with 10% strength by weight sodium hydrogen carbonate solution and water and then dried over magnesium sulfate and concentrated. The crude product thus obtained was purified by chromatography on silica gel (eluent: hexane/ethyl acetate=4:1). Yield: 1.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1.N1C=CC=CC=1.S(Cl)([Cl:28])(=O)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:28])[S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccnc2c1C(=O)CC(c1sccc1Cl)C2
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccnc2c1C(=O)CC(c1sc(Cl)cc1Cl)C2
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a solution of 7-(3-chlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.74 g) in ethyl acetate (10 ml) were added pyridine (0.21 g) and sulfuryl chloride (1.1 g) at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction solution was added ethyl acetate, and the mixture was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give 7-(3,5-dichlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.56 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>ClCCl>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:4]2[CH2:3][C:2]([CH3:20])([CH3:1])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[NH:5]2)[CH:14]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3ccccc3F)c1)N2
Yield: 47.1 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (135 mg, 0.5 mmol) in dichloromethane (3 mL) was added pyridine (60 mg, 0.75 mmol) in dichloromethane (2 mL) and 2-fluoro-benzenesulfonyl chloride (108 mg, 0.56 mmol) under nitrogen. The resultant mixture was stirred for 4 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether:ethyl acetate=15:1) to afford 100 mg of 2-fluoro-N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide yellow solid (Yield: 47%). MS (ESI+APCI) M+1=425.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH3:9])[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:13])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:8]([Cl:13])[CH3:9])[CH:3]=1
Reactant: CC(O)c1cncc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1cncc(Br)c1

Procedure:
To a solution of 1-(5-bromo-pyridine-3-yl)-ethanol (201 mg, 1 mmol) in DCM (10 mL) was added dropwise thionyl chloride (200 uL). The resulting reaction mixture was heated to reflux for 3 hours before the solvent was removed in vacuo to give a crude product as a white solid. It was used directly in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2].O>C1(C)C=CC=CC=1.O1CCCC1>[CH:27]([C:6]1[C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:9]([CH2:10][OH:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[N:5]=1)([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
21 ml (80.5 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 9.2 g (23 mmol) of the compound from Example 3 in 100 ml of dry tetrahydrofuran at -10° C. to -5° C. and the mixture is stirred for 5 h at room temperature. After cooling to 0° C., 100 ml of water are cautiously added dropwise and the mixture is extracted three times using 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The residue is chromatographed on a column (200 g of silica gel 70-230 mesh, φ4.5 cm, using ethyl acetate/petroleum ether 3:7).