Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)=[O:19]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:3]=[CH:2]/[C:1]([NH2:5])=[O:4])=[CH:23][CH:22]=1)=[O:19]
Reactant: C=CC(N)=O
Reactant: O=C(Nc1ccc(I)cc1)Nc1cc(C(F)(F)F)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: NC(=O)/C=C/c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 2.5 h
Yield: 48.3 %

Procedure:
A mixture of acrylamide (6.2 mg, 0.087 mmol), 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(4-iodophenyl)urea (9.2 mg, 0.022 mmol), and palladium(II) acetate (1.9 mg, 0.0087 mmol) in 0.6 mL degassed DMF:triethylamine (1:1) was reacted at 90° C. After 2.5 hours, the heating was stopped and the reaction stored at rt for 3 days in the dark. Then a catalytic amount of palladium(II) acetate was added and the heating resumed at 90° C. for 7.5 hours, then the temperature lowered to 65° C. for 16 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed with dilute aqueous HCl, then aqueous NaHCO3, brine, dried with anhydrous Na2SO4 and evaporated. The resulting solid was chromatographed eluting with CHCl3/MeOH and then triturated with a CHCl3 plus 40% EtOAc/hexane mixture to give the title compound as a light tan solid (3.9 mg, 49%). 1H NMR (Acetone-d6) δ: 8.76-8.83 (m, 2H), 8.40 (d, J=2.6 Hz, 1H), 7.58-7.63 (m, 2H), 7.37-7.57 (m, 5H), 6.91 (br. s, 1H), 6.63 (d, J=15.8 Hz, 1H), 6.32 (br. s, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:48]=[CH:49][C:50]=1F)[C:35]([N:37]1[CH2:40][CH:39]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:38]1)=[O:36].[H-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[F:31][C:32]1[CH:33]=[C:34]([C:35]([N:37]2[CH2:40][CH:39]([O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)[CH2:38]2)=[O:36])[CH:48]=[CH:49][C:50]=1[O:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1
Reactant: O=C(c1ccc(F)c(F)c1)N1CC(OC2CCCCO2)C1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CC(OC4CCCCO4)C3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (150 mg, 0.348 mmol) synthesized in Example (38d) and 1-(3,4-difluorobenzoyl)-3-(tetrahydro-2H-pyran-2-yloxy)azetidine (220 mg, 0.740 mmol) synthesized in Example (42a) were dissolved in dimethyl sulfoxide (5.0 mL), and sodium hydride (60%, 70 mg, 1.75 mmol) was added, followed by stirring at 100° C. for 1.5 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, saturated brine (30 mL) was added, and extraction was carried out with ethyl acetate (30 mL). Subsequently, drying was carried out over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=65%-85%) to afford the desired compound (158 mg, yield 75%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:41])[CH2:39][CH3:40])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:29][CH2:30]1)=[O:24]
Reactant: CCC(=O)O
Reactant: NS(=O)(=O)c1cnn2c(Nc3ccc(Cl)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3ccc(Cl)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 61.7 %

Procedure:
Using 7-(2,4-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.089 mmol) obtained in step 5 and propionic acid (0.033 mL, 0.444 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.034 g, 62%) was obtained.
Reaction SMILES: [F:1][C:2]([F:38])([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:27]=2[N+:35]([O-:37])=[O:36])=[CH:21][CH:20]=1)[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].C(=O)([O-])[O-].[K+].[K+].[CH2:45](Br)[CH:46]=[CH2:47]>CN1C(=O)CCC1>[CH2:47]([N:25]([C:22]1[CH:23]=[CH:24][C:19]([C:2]([F:38])([F:1])[C:3]([F:18])([F:17])[C:4]([F:15])([F:16])[C:5]([F:13])([F:14])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8])=[CH:20][CH:21]=1)[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36])[CH:46]=[CH2:45]
Reactant: O=[N+]([O-])c1ccc(Nc2ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)c([N+](=O)[O-])c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C=CCN(c1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A mixture of N-[4-(perfluorohexyl)phenyl]-2,4-dinitrobenzenamine (3.6 g, 6.2 mmol), NMP (40 mL), potassium carbonate (3.0 g) and allyl bromide (0.65 mL) was stirred at 75° C. for 4 hr. The mixture was extracted in the normal fashion, and the product recrystallized to give N-allyl- N-[4-(perfluorohexyl)phenyl]-2,4-dinitrobenzenamine (2.9 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>C(O)C>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5]/[C:4](=[C:12]3/[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][NH:15][C:16]/3=[O:17])/[CH:3]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(S)cc1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Solvent: CCO
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Temperature: 180 °C

Procedure:
(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one (0.045 g, 0.013 mmol) was dissolved in ethanol (1.5 mL) and 4-aminothiophenol (0.017 g, 0.013 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The mixture was then concentrated and purified by LC-MS to give Example 25. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78 (t, J=7.45 Hz, 3H) 1.30-1.40 (m, 2H) 2.22-2.32 (m, 2H) 6.77 (d, J=8.34 Hz, 3H) 7.33 (d, J=8.59 Hz, 2H) 7.60 (t, J=7.33 Hz, 1H) 7.82-7.92 (m, 2H) 8.12 (d, J=8.08 Hz, 1H); ESI-MS: m/z calc'd for C21H20N4OS 376.47. found 377.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH:10]=[CH:9]2)[C:3]([OH:5])=[O:4].[CH3:23]O>S(=O)(=O)(O)O>[CH3:23][O:4][C:3](=[O:5])[CH:2]([CH3:1])[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH:10]=[CH:9]2
Reactant: CO
Reactant: CC(C(=O)O)c1ccc2nc(-c3ccc(Cl)cc3)ccc2c1
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc2nc(-c3ccc(Cl)cc3)ccc2c1
Reaction time: 2 h

Procedure:
A mixture consisting of 1.9 g of α-methyl-2-(p-chlorophenyl)-6-quinolineacetic acid, 28 ml of methanol and 28 drops of concentrated sulphuric acid is kept for 2 hours under reflux. Thereafter the reaction mixture is concentrated on a rotary evaporator. The residue is treated with ice, ehter and 50 ml of 0.5 N sodium chloride solution. After thorough shaking, the aqueous phase is separated off and the organic phase is washed with water, dried over sodium sulphate and evaporated. The residue is dissolved in 25 ml of ethyl acetate and treated with petroleum ether until it crystallises. α-Methyl-2-(p-chlorophenyl)-6-quinolineacetic acid methyl ester of melting point 114°-115°C is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.O[CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=2)=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Reactant: OC1CCc2ccccc2C1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccc3c(c2)CCCC3)o1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (318 mg), 2-hydroxytetralin (296 mg), tributylphosphine (405 mg) and tetrahydrofuran (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (400 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(5,6,7,8-tetrahydro-2-naphthoxy)propyl]oxazole was obtained as an oil from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. (358 mg, 80%).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:27]([C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:34])=[O:5])[S:12][CH:13]=2)=[CH:20][CH:21]=1)=[O:26])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(C(=O)Nc3ccccc3)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(C(=O)Nc3ccccc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
2-[(4-{2-[4-(Anilinocarbonyl)phenoxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (480 mg) obtained in Example 60-3 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (400 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13]C(=O)OCC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reaction time: 3 h

Procedure:
Under an N2 atmosphere, a solution of benzyl (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (1.85 g, 5.75 mmol) in 10 mL MeOH was added to a flask containing Pd/C (185 mg, 10% weight Pd on carbon). After evacuating the flask under vacuum and purging it twice with N2, the reaction was stirred for 3 h under an H2 atmosphere at ambient pressure. The reaction was filtered through a bed of Celite, and the solvent was evaporated under reduced pressure to obtain (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate which was used without further purification. LC/MS: m/z 187.3 (M+H)+ at 1.07 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1.ClC(Cl)(Cl)[CH:24](O)[OH:25]>C(OCC)(=O)C>[CH:24]([N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:4][C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=1[Cl:1])=[O:25]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: COc1ccc(CCNCc2ccccc2Cl)cc1OC
Solvent: CCOC(C)=O
Product: COc1ccc(CCN(C=O)Cc2ccccc2Cl)cc1OC
Temperature: 120 °C

Procedure:
N-(2-chlorobenzyl)-2-(3,4-dimethoxy-phenyl)-ethylamine (88.4 g, 0.29 mol) is mixed with chloral hydrate (52.5 g, 0.34 mol) and heated (120° C.) for 30 minutes. After cooling, ethyl acetate is added and the mixture is washed with water, dried and evaporated. Yield: 103 g.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:18][OH:19])=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: NO
Reactant: Cc1cnc(C)c(C(=O)c2ccccc2)n1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cnc(C)c(C(=NO)c2ccccc2)n1
Yield: 99 %

Procedure:
A solution of (3,6-dimethylpyrazin-2-yl)(phenyl)methanone (3.02 g, 14.2 mmol) and hydroxylamine hydrochloride (2.47 g, 35.5 mmol) in pyridine (50 mL) was stirred 7 h at 70° C. After removal of the solvent in vacuo, addition of water (100 mL) and extraction with ethyl acetate (2×100 mL), the combined organic layers were washed with water (100 mL), dried over MgSO4 and concentrated in vacuo to afford 1-(3,6-dimethylpyrazin-2-yl)-N-hydroxy-1-phenylmethanimine as an orange honey [3.39 g, yield 99%; HPLC/MS: m/z=228 (M+H); log P(HCOOH)=1.70].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][CH2:8]OS(C)(=O)=O)=[O:4].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=2)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[CH2:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CS(=O)(=O)OCCCNC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CC=C(c2ccc(Cl)cc2)CC1)C(F)(F)F
Yield: 44.9 %

Procedure:
Methanesulfonic acid 3-(2,2,2-trifluoroacetylamino)-propyl ester (4.51 g, 18.10 mmol), 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (4.20 g, 18.25 mmol) and triethylamine (5.6 mL, 40.2 mmol) in ethanol (100 mL) were refluxed for 18 hours. The mixture was concentrated, redissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate and concentrated on to silica gel. Flash chromatography using first an ethyl acetate/hexanes gradient followed by 3% methanol/ethyl acetate gave N-{3-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-propyl}-2,2,2-trifluoro-acetamide (2.82 g, 45%) as a white solid. Mp. 105-107° C.; NMR CDCl3 δ 9.58 (br s, 1H), 7.27-7.24 (m, 4H), 6.01-5.98 (m, 1H), 3.49 (g, J=5.3 Hz, 2H), 3.20-3.17 (m, 2H), 2.77 (t, J=5.7 Hz, 2H), 2.73-2.69 (m, 2H), 2.55-2.51 (m, 2H), 1.80 (p, J=3.6 Hz, 2H); 13C NMR CDCl3 δ 138.80, 134.41, 133.15, 128.52, 126.22, 120.99, 57.72, 52.80, 50.15, 40.96, 27.61, 23.23; IR (KBr) 3300, 3099, 2981, 2953, 2925, 2907, 2810, 2758, 2734, 1695, 1558, 1494, 1469, 1444, 1352, 1184, 1137, 1118, 1097,801,722,692.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:25]4[C:26](=[O:35])[O:27][C@@H:28]([CH2:29]OS(C)(=O)=O)[C@@H:24]4[CH2:23][O:22][C:21]=3[CH:36]=2)[C:13](=[O:37])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:25]4[C:26](=[O:35])[O:27][C@@H:28]([CH2:29][N:43]5[C:39](=[O:49])[C:40]6[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=6)[C:42]5=[O:44])[C@@H:24]4[CH2:23][O:22][C:21]=3[CH:36]=2)[C:13](=[O:37])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OC[C@@H]1OC(=O)N2c3ccc(N4CCN(C(=O)OCc5ccccc5)CC4=O)cc3OC[C@@H]12
Agent: [K]
Product: O=C(OCc1ccccc1)N1CCN(c2ccc3c(c2)OC[C@H]2[C@H](CN4C(=O)c5ccccc5C4=O)OC(=O)N32)C(=O)C1
Yield: 79 %

Procedure:
Using compound 4-((3R,3 aS)-3-((methylsulfonyloxy)methyl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)-3-oxopiperazin-1-carboxylic acid benzyl ester (0.916 g, 1.725 mmol), and phthalimide potassium (0.479 g, 2.558 mmol) as starting materials, preparation following the method as described in Example 1 (d) afforded white solid 0.794 g, yield: 79.1%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[N:6]=1.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](=[O:25])[CH2:23]Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:1][C:2]1[CH:3]=[CH:4][N:5]([C:7]2[N:11]([CH2:23][C:22]([C:21]3[CH:26]=[CH:27][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)=[O:25])[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[N:6]=1
Reactant: Nc1ccn(-c2nc3ccccc3[nH]2)n1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C(=O)Cn2c(-n3ccc(N)n3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 5-amino-2-(1H-benzimidazol-2-yl)pyrazole (0.10 g, 0.5 mmol), p-methoxyphenacyl bromide (0.204 g, 0.9 mmol) and dry potassium carbonate (0.173 g, 1.25 mmol) is stirred at room temperature for 16 hours. The mixture is diluted with water and the product extracted with ethyl acetate. The product is purified by chromatography on silicagel. M.p. 136-140° C., 1H-NMR (400 MHz, d6-DMSO): 8.04 (d, 2H); 7.58 (m, 2H); 7.28 (m, 3H); 7.11 (d, 2H); 6.84 (s, 2H); 6.26 (s, 2H); 5.39 (d, 1H); 3.87 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[C:23]1([CH2:29][CH2:30]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>COCCO>[C:23]1([CH2:29][CH2:30][NH:1][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=4)[C:9](=[O:22])[C:8]=3[CH:7]=[CH:6][CH:5]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NCCc1ccccc1
Solvent: COCCO
Product: O=C1c2cc([N+](=O)[O-])ccc2C(=O)c2c(NCCc3ccccc3)cccc21

Procedure:
15 g of 1,6-dinitroanthraquinone and 45 ml of β-phenylethylamine are stirred at 50° - 55° C (approx. 3 hours being required) until no further starting material is detectable. The mixture is diluted with 45 ml of ethylene glycol monomethyl ether whilst warm and the reaction product which separates out is filtered off at 50° C and rinsed with a little ethylene glycol monomethyl ether and water. 13.6 g of pure 1-β-phenylethylamino-6-nitroanthraquinone are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)C(OC)=O.[CH3:21]C1C=C(N)C2C=NNC=2C=1.IC1C=CC=CC=1>>[CH3:21][C:9]1[CH:10]=[C:2]([NH2:1])[C:3]2[CH:4]=[N:5][N:6]([C:11]3[CH:20]=[CH:19][CH:18]=[CH:13][CH:12]=3)[C:7]=2[CH:8]=1
Reactant: COC(=O)c1cccc(-n2ncc3c(N)cccc32)c1
Reactant: Cc1cc(N)c2cn[nH]c2c1
Solvent: Ic1ccccc1
Product: Cc1cc(N)c2cnn(-c3ccccc3)c2c1

Procedure:
Similarly prepared to Intermediate 9 from 6-methyl-1H-indazol-4-amine and iodobenzene.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]2([C:36](C)(C)[O:37][SiH2]C(C)(C)C)[CH2:35][CH2:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]3([CH2:36][OH:37])[CH2:33][CH2:34][CH2:35]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC2(C(C)(C)O[SiH2]C(C)(C)C)CCC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2F)C(CC2(CO)CCC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutylmethyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 115b (0.7 g, 1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.6 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][NH:10][N:11]=[C:5]2[N:4]2[CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=[C:3]12.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:10]2[CH:9]=[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3]4[N:4]([CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=4)[C:5]3=[N:11]2)=[CH:20][CH:21]=1)(=[O:27])[CH3:26]
Reactant: CN1C(=O)c2c[nH]nc2N2CC(C)(C)N=C12
Reactant: CC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Cn2cc3c(n2)N2CC(C)(C)N=C2N(C)C3=O)cc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A suspension of 7,8-dihydro-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (438 mg, 2.0 mmol), 1-(4-(bromomethyl)phenyl)ethanone (520 mg, 2.4 mmol) and K2CO3 (828 mg, 6.0 mmol) in DMF (18 mL) is stirred at room temperature over a weekend. Solvent is removed under reduced pressure. The obtained residue is purified on a basic alumina oxide column to give 634 mg of product (yield: 90%). MS (ESI) m/z 352.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:26])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: COCCN
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COCCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with 2-methoxyethylamine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=471.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[CH3:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:13][C:12]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=1[CH3:10])=[O:9]
Reactant: O=C(O)c1sccc1Br
Reactant: COc1ccc(N)c(C)c1
Product: COc1ccc(NC(=O)c2sccc2Br)c(C)c1
Yield: 75.2 %

Procedure:
Following Step 1 from General Procedure A, 3-bromothiophene-2-carboxylic acid (6.7 g, 49 mol) was reacted with 2-methyl-4-methoxyaniline (12 g, 53 mmol) to afford the desired product (13 g, 80%) as an orange solid: ESI MS m/z 331 [C12H10FNO2S+H]+.