Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+:1].[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11](=[CH2:15])[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.C(OC(C)C)(=O)C.[H][H]>[Pd]>[K+:1].[C:2]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10][C@@H:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C

Procedure:
100 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid potassium salt (2-a, R1=Boc, R2=H, R3=CO2K) (prepared according to procedure in Example 42) is added to isopropyl acetate (1 ml). 10% Palladium on carbon (10 mg, 50% water wet, Degussa type E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×1 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-a, R1=Boc, R2=H, R3=CO2K) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-b, R1=Boc, R2=H, R3=CO2K). Spectroscopic data as in Example 42, Method 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:27]#[N:28])[CH:5]=[C:6]([CH3:26])[C:7]=1[O:8]C1N=C(NC2C=CC(C#N)=CC=2)N=C(N)C=1Br.[Cl:29][C:30]1[N:35]=[C:34]([Cl:36])[CH:33]=[C:32](Cl)[N:31]=1.CC1C=C(C=C(C)C=1O)C#N>>[Cl:29][C:30]1[N:31]=[C:32]([O:8][C:7]2[C:2]([CH3:1])=[CH:3][C:4]([C:27]#[N:28])=[CH:5][C:6]=2[CH3:26])[CH:33]=[C:34]([Cl:36])[N:35]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br
Agent: Cc1cc(C#N)cc(C)c1O
Product: Cc1cc(C#N)cc(C)c1Oc1cc(Cl)nc(Cl)n1

Procedure:
WO 2010150279 describes a process for the formation of Etravirine, comprising condensation of 2,4,6-trichloropyrimidine with 3,5-dimethyl-4-hydroxybenzonitrile to give 4-[(2,6-dichloro)-4-pyrimidinyloxy]-3,5-dimethyl benzonitrile, which is condensed with 4-aminobenzonitrile. Aminolysis of the resulting compound followed by halogenation gives Etravirine.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[Li+].CC([N-]C(C)C)C.C1C=CC(N[S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])=CC=1>C1COCC1>[F:28][C:27]([F:30])([F:29])[S:24]([O:7][C:3]1[C:2]([CH3:8])([CH3:1])[CH2:6][CH2:5][CH:4]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: CC1(C)CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCC=C1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethylcyclopentanone T1.1 (commercially available from ChemSampCo) (3.00 g, 26.75 mmol) in THF (100 mL), was slowly added LDA (14.7 mL, 2.0 M, in heptane) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour. A solution of N-phenyltriflamide (10.00 g, 28.00 mmol) was added to the mixture at −78° C., and stirring was continued at 0° C. for 2 hours and then at room temperature for 16 hours. The reaction mixture was extracted with hexane (80×2 mL). The organic layer was then washed with saturated Na2CO3 (30 mL), brine (20 mL), and dried with MgSO4. The solvent was removed, and the residue was purified by CombiFlash® silica gel chromatography (eluent was EtOAc and hexane) to give T1.2. 1H NMR (CDCl3) δ ppm 5.56 (m, 1H), 2.36 (t, J=7.1 Hz, 2H), 1.86 (t, J=7.1 Hz, 2H), 1.16 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1C(C2C=CC=CC=2[N+]([O-])=O)C(C(OCC(C)C)=O)=C(C)[NH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2[N+](=O)[O-])C(C(=O)OCC(C)C)=C(C)N1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccccc1
Yield: 71 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid isobutyl ester and 75 mmols of β-aminocrotonic acid benzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-isobutoxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 154° C (from ethanol).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([C:33]([OH:35])=O)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31].O[NH:37][C:38]([C:40]1[CH:48]=[C:47]2[C:43]([CH:44]=[CH:45][NH:46]2)=[CH:42][CH:41]=1)=[NH:39].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:33]2[O:35][N:39]=[C:38]([C:40]3[CH:48]=[C:47]4[C:43]([CH:44]=[CH:45][NH:46]4)=[CH:42][CH:41]=3)[N:37]=2)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:31])[CH3:32]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1ccc2cc[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4cc[nH]c4c3)no2)cc1Cl
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
EDCI (1.17 g) and HOBT (1.01 g) were added to a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (657 mg) in THF (5 mL) at RT. The resulting solution was stirred for 30 min. N-hydroxy-1H-indole-6-carboximidamide (D100) (1.00 g) in THF (5 mL) was added and the reaction mixture was stirred at RT for 2 hours. TBAF (3.2 g) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 90 min. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford 6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D101) (1.13 g) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.47 (6H, d), 5.51 (1H, m), 6.65 (1H, s), 7.37 (1H, t), 7.76 (1H, d), 7.93 (1H, d), 8.26 (1H, s), 8.42 (2H, d), 8.90 (1H, d). MS (ES): C18H15ClN4O2 requires 354. found 355.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)c1ccccc1CBr
Yield: 92.2 %

Procedure:
A solution of methyl-2-methylbenzoate (250 mg, 1.66 mmol), NBS (296 mg, 1.66 mmol) and dibenzoylperoxide (403 mg, 1.66 mmol) was stirred under reflux for one day. After purification by flash chromatography, 350 mg (1.53 mmol, 92%) of methyl-2-(bromomethyl)benzoate were obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([NH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[C:17]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[CH2:18]C(C)=O.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[C:8]([C:6]1[CH:7]=[C:2]2[C:18]([C:17]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:11]([C:12]([F:15])([F:14])[F:13])[NH:10][C:3]2=[N:4][CH:5]=1)#[N:9]
Reactant: N#Cc1cnc(NC(=O)C(F)(F)F)c(Br)c1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1c(C(F)(F)F)[nH]c2ncc(C#N)cc12
Temperature: 80 °C
Yield: 27.5 %

Procedure:
N-(3-Bromo-5-cyano-2-pyridinyl)-2,2,2-trifluoroacetamide (Intermediate 1, 9.53 g, 32.4 mmol), tert-butyl acetoacetate (10.59 mL, 64.8 mmol), copper(I) iodide (0.617 g, 3.24 mmol), L-proline (0.746 g, 6.48 mmol) and cesium carbonate (42.2 g, 130 mmol) were added together in DMSO (65 mL) and the resulting mixture was heated at 80° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with water and saturated ammonium chloride solution. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-30% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a brown solid (2.77 g);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[O:12]1[CH2:15][CH:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=3)[CH2:18][CH2:17]2)[CH2:13]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([N:19]3[CH2:20][CH2:21][N:16]([CH:14]4[CH2:13][O:12][CH2:15]4)[CH2:17][CH2:18]3)=[CH:27][N:26]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Clc1cc(Br)c2nccn2c1
Reactant: Nc1ccc(N2CCN(C3COC3)CC2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nccn2c1
Temperature: 100 °C
Yield: 66.1 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 8-bromo-6-chloroimidazo[1,2-a]pyridine 101a (264 mg, 1.14 mmol), 5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-amine (328 mg, 1.14 mmol), Pd2(dba)3 (102 mg, 0.11 mmol), Xantphos (63 mg, 0.11 mmol), Cs2CO3 (3.58 g, 11.0 mmol), dioxane (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. overnight. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:50 methanol/dichloromethane to afford 121a as an orange solid (290 mg, 66%). MS-ESI: [M+H]+ 385.1
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[F:33][C:34]([C:37]1[N:41]=[CH:40][NH:39][N:38]=1)([F:36])[CH3:35].CN[C@@H]1CCCC[C@@H]1NC.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[F:33][C:34]([C:37]1[N:41]=[CH:40][N:39]([C:2]2[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]3[C:10]([C:11](=[O:30])[C:12]([N:14]4[CH2:23][CH2:22][C:21]5[C:16](=[CH:17][CH:18]=[CH:19][C:20]=5[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH2:15]4)=[O:13])=[CH:9][NH:8][C:7]=23)[N:38]=1)([F:36])[CH3:35]
Reactant: CC(F)(F)c1nc[nH]n1
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cnc(-n2cnc(C(C)(F)F)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Temperature: 100 °C

Procedure:
A mixture of 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (100 mg, 0.204 mmol), 3-(1,1-difluoroethyl)-1H-1,2,4-triazole (54.2 mg, 0.407 mmol), (1R,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (5.79 mg, 0.041 mmol), K2CO3 (84 mg, 0.611 mmol) and copper (I) iodide (19.38 mg, 0.102 mmol) in dioxane (1 mL) was heated at 100° C. for 8 hours. LCMS indicated the formation of desired product. The reaction mixture was filtered and the clear solution purified by prep. HPLC to give 1-(7-(3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione as white solid (53.4 mg, 47%). LCMS: m/e 543.97 (M+H)+, 1.56 min (method 2). 1H NMR (500 MHz, MeOD) δ ppm 2.13-2.33 (m, 3H) 2.85-3.09 (m, 2H) 3.72-4.04 (m, 5H) 4.93-5.11 (m, 2H) 7.30-7.67 (m, 3H) 7.82-8.08 (m, 3H) 8.33-8.57 (m, 2H) 8.75-8.93 (m, 1H) 9.43 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:28][C:29]([C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([C:5]#[C:4][CH2:3][N:2]([CH3:1])[CH3:15])[CH:7]=2)[NH:12][CH:13]=1)=[O:30]
Reactant: O=C(Cl)Cc1cccc(F)c1F
Reactant: CN(C)CC#Cc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)CC#Cc1cnc2[nH]cc(C(=O)Cc3cccc(F)c3F)c2c1
Reaction time: 8 h

Procedure:
189 mg of crude Dimethyl-[3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-prop-2-ynyl]-amine was stirred in 5 ml of DCM with AlCl3 (4 equivalents) for 30 minutes. Two equivalents of (2,3-Difluoro-phenyl)-acetyl chloride were added and the reaction was stirred in a sealed tube overnight. The LC/MS showed the reaction to be complete and was worked-up under standard conditions. Normal phase column chromatography yielded 101 mg of 2-(2,3-Difluoro-phenyl)-1-[5-(3-dimethylamino-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-ethanone with a yield over two steps of 33%. LC/MS retention time of 1.83 minutes. M+ 354.17, M− 352.1
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1.C(OCC)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: Cc1ccc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C(N)=O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: Cc1ccc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.7 %

Procedure:
(R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzamide (230 mg, 0.47 mmol) was dissolved in pyridine (5 mL) and cooled to 0° C. Trifluoroacetic anhydride (0.67 mL, 4.72 mmol) was added dropwise. Stirred for 1 h at 0° C. after addition. The reaction was diluted with diethyl ether (100 mL) and washed with 1 N HCl (2×100 mL) and saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 33% ethyl acetate/hexanes to yield 262 mg (97%) of the desired 2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzonitrile as a clear oil.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)[C:9]([F:21])=[CH:8][C:7]=1[N+:22]([O-:24])=[O:23])=O.[NH2:27][CH:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[NH2:5][C:6]1[C:7]([N+:22]([O-:24])=[O:23])=[CH:8][C:9]([F:21])=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][NH:27][CH:28]3[CH2:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29]3)=[CH:17][CH:18]=2)[CH:11]=1
Reactant: NC1Cc2ccccc2C1
Reactant: O=Cc1ccc(Oc2cc(NC(=O)C(F)(F)F)c([N+](=O)[O-])cc2F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Nc1cc(Oc2ccc(CNC3Cc4ccccc4C3)cc2)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,2,2-trifluoro-N-{4-fluoro-5-[(4-formylphenyl)oxy]-2-nitrophenyl}acetamide (0.300 g, 0.806 mmol), 2-aminoindane (0.161 g, 1.21 mmol), and acetic acid (0.5 mL) in CH2Cl2 (3 mL) was stirred for 30 min and then Na(OAc)3BH (0.205 g, 0.967 mmol) was added slowly over 2 min. The reaction mixture stirred for 1 hour at ambient temperature and then H2O (3 mL) was added. The layers were separated and the aqueous layer extracted one additional time with CH2Cl2. The combined organics were washed 1× brine, then dried (Na2SO4), filtered and concentrated to give ({4-[(5-Amino-2-fluoro-4-nitrophenyl)oxy]phenyl}methyl)2,3-dihydro-1H-inden-2-ylamine. No further purification was necessary.
Reaction SMILES: [C:1]([C:5]1([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)=CC1C(C)C([O-])=O)(=[O:4])[CH2:2]C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:1]([C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:13]=2[CH:14]=[C:5]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[C:1]=1[OH:4])(=[O:4])[CH2:5][CH3:14]
Reactant: CCC(=O)C1(CNC(C)=O)C=C2CCCCC2=CC1C(C)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1c(O)c(CNC(C)=O)cc2c1CCCC2
Temperature: 100 °C
Yield: 106.6 %

Procedure:
1.45 g of 3-propionyl-3-acetylaminomethyl-5,6,7,8-tetrahydro-2-naphthylpropionate was dissolved in 5 ml of methylene chloride and 2.0 g of aluminum chloride was added to the solution. After a homogeneous solution was formed, methylene chloride was distilled off from the reaction system while raising temperature and solution was heated at 100° C. for 10 minutes. After allowing the solution to cool, water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water, an aqueous solution bicarbonate solution and an aqueous sodium chloride solution, dried and concentrated. The residue was chromatographed on silica gel column using a mixed solvent of methylene chloride: ethyl acetate (10:1 by volume) to obtain 640 mg of the title compound having the following physical properties.
Reaction SMILES: [CH:1](Br)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:25][CH2:24]1>O>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:32][CH2:31][CH2:30][CH2:29][N:26]2[CH2:25][CH2:24][N:23]([CH:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])[C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCN1CCN(C(c2ccc(F)cc2)c2ccccc2Cl)CC1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: O
Product: Fc1ccc(C(c2ccccc2Cl)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A mixture containing 7.4 g of benzhydryl bromide and 21.8 g of 4-[(2-chlorophenyl)-(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)piperazine is heated at 160° to 170° C. under nitrogen gas for 30 minutes, then cooled to 90° to 100° C. and poured into water. The aqueous phase is extracted with benzene, washed with water, thebenzene solution is dried over anhydrous potassium carbonate and then evaporated under reduced pressure. The residue is purified by chromatography on a Kieselgel column by using a 4:1 mixture of benzene andchloroform as eluant. The thus-obtained product is recrystallized from n-hexane to give the aimed product, m.p.: 98°-99° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>O>[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: O=Cc1ccc[nH]1
Reactant: Clc1ccncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1cccn1-c1ccncc1Cl
Temperature: 120 °C
Reaction time: 25 h
Yield: 70.4 %

Procedure:
A mixture of 2.0 g of 2-pyrrole carbaldehyde, 3.0 g of 3,4-dichloropyridine, 8.0 g of cesium carbonate and 30 ml of N-methylpyrrolidone was stirred at 120° C. for 25 hours. The reaction mixture was allowed to cool room temperature, and water was poured into the mixture. The mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 2.95 g of 1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[C:7]([CH:11]=[C:12]([CH:16]=O)[C:13]=2[O:14][CH3:15])[C:8]([OH:10])=[O:9])[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:19]O>C(O)=O>[C:16]([C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])#[N:19]
Reactant: NO
Reactant: COc1c(C=O)cc(C(=O)O)cc1C1CCC1
Agent: Cl
Solvent: O=CO
Product: COc1c(C#N)cc(C(=O)O)cc1C1CCC1
Yield: 89.4 %

Procedure:
3-cyclobutyl-5-formyl-4-methoxybenzoic acid (458 mg) was dissolved in formic acid (2.5 mL), and hydroxylamine hydrochloride (163 mg) was added to the solution, and then the mixture was refluxed for 19 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (404 mg) as a brown solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([C:24]([F:27])([F:26])[F:25])[N:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:16][C:17]1[N:18]=[C:19]([C:24]([F:27])([F:26])[F:25])[N:20]=[C:21]([N:12]2[CH2:13][CH2:14][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH:1]3[CH2:3][CH2:2]3)[C:11]2=[O:15])[CH:22]=1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: FC(F)(F)c1nc(Cl)cc(Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C1N(c2cc(Cl)nc(C(F)(F)F)n2)CCN1c1cnccc1C1CC1
Yield: 13.2 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 11 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 4,6-dichloro-2-trifluoromethylpyrimidine (120 mg, 0.541 mmol), xantphos (25 mg, 0.04428 mmol), Pd2(dba)3 (15 mg, 0.01476 mmol), cesium carbonate (225 mg, 0.6888 mmol) and 1,4-dioxane (5 mL) in a sealed tube for 5 hours. Purification by column chromatography on silica gel (1% methanol in chloroform) followed by preparative HPLC afforded 25 mg of the product (13.24% yield).