Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N:12]3[CH:18]4[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]4)[CH2:14][CH2:13]3)=[N:9][C:8]=2[CH:21]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N:12]3[CH:18]4[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[N:9][C:8]=2[CH:21]=1
Reactant: O=[N+]([O-])c1ccc2oc(N3CCN4CCC3CC4)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2oc(N3CCN4CCC3CC4)nc2c1
Yield: 80.9 %

Procedure:
10% Palladium on carbon (300 mg) was added to a solution of 4-(5-nitro-benzooxazol-2-yl)-1,4diaza-bicyclo[3.2.2]nonane (288 mg, 1 mmol, prepared as in Example 21) in ethanol (5 mL) and subjected to hydrogen gas at 50 PSI at RT for a period of 16 h. The reaction mixture was diluted with ethanol (20 mL) and filtered through a pad of celite. Concentration in vacuo gave 209 mg of the title compound as a brown oil: 1H NMR (CD3OD, 400 MHz) δ 7.06 (d, 1H, J=8.3 Hz), 6.75 (d, 1H, J=1.3 Hz), 6.50 (dd, 1H, J=8.3, 1.3 Hz), 4.56 (br s, 1H), 408 (br s, 2H), 3.62-3.47 (m, 6H), 2.34-2.31 (m, 2H), 2.20-2.16 (m, 2H); MS (Cl) m/z 259.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:18])[C:15](O)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[OH:16][CH2:15][CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[CH3:18]
Reactant: CC(C(=O)O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(CO)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
A 1M solution of borane tetrahydrofuran complex (12.00 mL, 12.00 mmol) in THF, was added dropwise to a stirred suspension of 2-(1-tert-butoxycarbonylpiperazin-4-yl)propionic acid (2.58 g, 10 mmol) in tetrahydrofuran (50 mL) at 0° C., over a period of 10 mins under nitrogen. The resulting solution was stirred at 60° C. for 8 h. This was quenched with acetic acid/water (10 ml, 1:2 mixture) and evaporated to dryness. The residue was dissolved in ethyl acetate (50 ml), washed with saturated sodium bicarbonate (25 ml) and water, dried over MgSO4, filtered and evaporated to dryness to give tert-butyl 4-(1-hydroxypropan-2-yl)piperazine-1-carboxylate (0.810 g, 33.2%)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:15]1[C:19]([NH:20][CH2:21][CH2:22][O:23][CH3:24])=[N:18][O:17][N:16]=1)[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>C(OCC)(=O)C>[CH3:24][O:23][CH2:22][CH2:21][NH:20][C:19]1[C:15]([C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:13])([F:14])[F:12])[CH:6]=3)[C:25](=[O:26])[O:1][N:2]=2)=[N:16][O:17][N:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCCNc1nonc1C(=NO)Nc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: COCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 92.1 %

Procedure:
N′-Hydroxy-4-[(2-methoxyethyl)amino]-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide (1.4 g, 3.80 mmol) and 1,1′-carbonyldiimidazole (1.16 g, 7.16 mmol) were dissolved in ethyl acetate (20 mL). The reaction mixture was heated at 70° C. for 40 minutes. Additional 1,1′-carbonyldiimidazole (0.26 g, 1.16 mmol) was added. After stirring at 70° C. for another 50 minutes, the reaction was allowed to cool to room temperature. Ethyl acetate (20 mL) was added and the crude reaction was washed with 1 N HCl in water (2×20 mL). Brine was added to aid in the separation of the first wash. The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel with an eluent of ethyl acetate in hexanes gave the desired product (1.3 g, 90%). LCMS calculated for C14H13F3N5O4 (M+H)+: m/z=372.0. 1H NMR (400 MHz, DMSO-d6): δ 8.07 (s, 1H), 7.92 (m, 2H), 7.79 (t, J=8.1 Hz, 1H), 6.42 (t, J=6.0 Hz, 1H), 3.47 (t, J=5.8 Hz, 2H), 3.38 (q, J=5.0 Hz, 2H), 3.24 (s, 3H).
Reaction SMILES: C([O:8][CH2:9][C:10]([CH:15]1[CH2:18][CH2:17][CH2:16]1)([CH2:13][OH:14])[CH2:11][OH:12])C1C=CC=CC=1.N.[Na].[Cl-].[NH4+]>CCOCC>[CH:15]1([C:10]([CH2:9][OH:8])([CH2:11][OH:12])[CH2:13][OH:14])[CH2:16][CH2:17][CH2:18]1
Reactant: OCC(CO)(COCc1ccccc1)C1CCC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OCC(CO)(CO)C1CCC1
Temperature: -70 °C
Yield: 87.1 %

Procedure:
A solution of 2-benzyloxymethyl-2-cyclobutylpropane-1,3-diol (49 g, 0.2 mol) in dry ether (200 ml) was added to liquid ammonia (450 ml) stirred at -70° C. Sodium pellets (14 g, 0.6 mol) were added and the stirred mixture was allowed to warm to -33° C. over 2 hours. Ammonium chloride (35 g, 0.65 mol) was added and the ammonia was allowed to evaporate overnight. The solid residue was extracted with ether, the extracts were combined, filtered and evaporated to leave 2-cyclobutyl-2-hydroxymethylpropane-1,3-diol as an oil (27.9 g, 87%) which was purified on a silica column eluting with chloroform then increasing amounts of chloroform:methanol (up to 9:1 v/v).
Reaction SMILES: C1(N2CCN3C(CC4(C5C=CC=CC=5)CCCC4)=NC(=O)C(O)=C3C2=O)CC1.C([O:36][C:37]1[C:42](=[O:43])[N:41]=[C:40]([CH2:44][C:45]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:49][CH2:48][CH2:47][CH2:46]2)[N:39]2[CH2:56][CH2:57][N:58]([CH2:61][C:62]([CH3:65])([CH3:64])[CH3:63])[C:59](=[O:60])[C:38]=12)C1C=CC=CC=1>>[CH3:63][C:62]([CH3:65])([CH3:64])[CH2:61][N:58]1[CH2:57][CH2:56][N:39]2[C:40]([CH2:44][C:45]3([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[CH2:46][CH2:47][CH2:48][CH2:49]3)=[N:41][C:42](=[O:43])[C:37]([OH:36])=[C:38]2[C:59]1=[O:60]
Reactant: CC(C)(C)CN1CCn2c(CC3(c4ccccc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: O=C1c2c(O)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: CC(C)(C)CN1CCn2c(CC3(c4ccccc4)CCCC3)nc(=O)c(O)c2C1=O
Yield: 30.5 %

Procedure:
This compound was prepared following the same method as described for 2-cyclopropyl-9-hydroxy-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (287) from 9-benzyloxy-2-(2,2-dimethyl-propyl)-6-(1-phenyl-cyclopentyl methyl)-3,4-dihydro-2 H-pyrazino[1,2-c]pyrimidine-1,8-dione (302) (120 mg, 0.24 mmol). The product was obtained as a white solid (30 mg, 30.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[C:11]([N+:20]([O-])=O)[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.O.NN>[Ni].C(O)C>[NH2:20][C:11]1[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=1)[CH:17]=[CH:16]2
Reactant: COc1cc([N+](=O)[O-])c2nc(OCc3ccc(Cl)cc3)ccc2c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(N)c2nc(OCc3ccc(Cl)cc3)ccc2c1
Yield: 97 %

Procedure:
The foregoing nitro compound (34.48 g, 0.1 mole), 500 ml of a 1:1 mixture (v/v) of toluene and ethanol, 10 g wet Raney nickel, and 50 ml 85% hydrazine hydrate was refluxed for 6 hr. Thereafter, the condenser was placed for distillation and heated until vapors at the still-head were alkaline. A small amount of hydroquinone was added, and the hot mixture filtered. The filtrates were concentrated in vacuo, leached with a little warm ethanol, then crystallized from ethanol (charcoal). The 8-amino-2-(4-chlorobenzyloxy)-6-methoxyquinoline was obtained in 97% yield; mp 123.5°-125°.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[NH:32][N:31]=[C:30]([CH:33](O)[CH3:34])[CH:29]=3)=[O:27])[CH3:24])[N:18]=2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16].CS(Cl)(=O)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[NH:32][N:31]=[C:30]([CH:33]=[CH2:34])[CH:29]=3)=[O:27])[CH3:24])[N:18]=2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Reaction time: 8 h

Procedure:
Triethylamine (3.0 ml, 21.8 mmol) was added to a solution of N-{(S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide of Example 56 (1.74 g, 4.36 mmol) in DCM (40 ml) at 0° C. Then methanesulfonyl chloride (0.675 ml, 8.73 mmol) was added slowly at 0° C. After addition stirring was continued at RT overnight. The reaction mixture was then diluted with DCM and washed with 1 M HCl. The organic layer was dried (Na2SO4), filtered and concentrated. Crystallization in DCM afforded the title compound. 1H NMR (400 MHz, CDCl3+a drop of MeOH-d4): 1.25 (31-1, d), 4.31 (1H, distorted dd), 4.39 (1H, distorted dd), 4.55 (1H, m), 5.38 (1H, d), 5.76 (1H, d), 6.60 (1H, dd), 6.63 (1H, d), 6.79 (1H, s), 7.55 (1H, d), 7.70 (1H, distorted d), 7.73 (1H, d), 7.82 (1H, distorted dd), 7.96 (1H, d).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(OCC)(=O)C.CCCCCC>CO.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:29][CH2:30][N:46]4[CH2:45][CH2:44][C:43]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]4)[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc4c(c3)OCO4)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CO
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc4c(c3)OCO4)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(benzo[1,3]dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.22 g, 0.43 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.21 g,0.86 mmol). Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane and then 6% methanol/dichloromethane to give the title compound: Rf =0.38 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:24]=1.I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]([CH3:34])[CH3:33].CC(C)(C)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:9]1[S:8][C:7]2[CH:24]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)([CH3:34])[CH3:33]
Reactant: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Reactant: CC(C)c1ccccc1I
Agent: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(OC)ccc23)cc1
Temperature: 150 °C
Yield: 63 %

Procedure:
To a flask containing (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (800 mg, 2.35 mmol) in anhydrous DMA (3.0 mL) was added 1-iodo-2-isopropylbenzene (0.751 mL, 4.70 mmol) followed by chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos palladacycle 1st generation, 188 mg, 0.24 mmol), trimethylacetic acid (0.818 mL, 7.05 mmol) and potassium carbonate (974 mg, 7.05 mmol). The flask was sealed, purged and back-filled with nitrogen and the resulting mixture was heated to 150° C. for 2 h after which time the reaction was diluted with EtOAc, and washed with water and brine. The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a red brown residue which was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-methyl 3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (675 mg, 1.48 mmol, 63% yield). LC/MS (m/z, MH+): 459.0.
Reaction SMILES: [C-]#N.[Na+].C[NH:5][CH2:6][CH2:7]NC.BrC1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1.C(O)C1C=CC=CC=1.CCCCCCCCCCCC.[OH-].[NH4+]>[Cu]I.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:18][C:13]1[CH:12]=[C:7]([CH:16]=[C:15]([CH3:17])[CH:14]=1)[C:6]#[N:5]
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(C#N)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
An oven dried screw cap test tube was charged with NaCN (140 mg, 2.857 mmol) dried KI (79 mg, 0.476 mmol, 20 mol %) and CuI (45 mg, 0.236 mmol, 10 mol %), evacuated and backfilled with argon three times. Anhydrous toluene (1550 μl), N,N′-dimethylethylenediamine (255 μl, 2.395 mmol), 1-Bromo-3,5-dimethyl-benzene (255 μl, 1.877 mmol), and benzyl alcohol (155 μl, 1.498 mmol) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 12 h. The resulting yellow color suspension was cooled to room temperature, 2 mL of ethyl acetate, 250 μl of n-dodecane as internal standard, 1 mL of ammonium hydroxide 30% and 1 mL of water were added. The mixture was stirred at 25° C. for 10 min then the organic layer was washed with 1 mL of water and dried over MgSO4. The GC analysis showed a conversion of 91% with a yield of the title product, calculated vs internal standard, of 88%.
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[C:13]1([C:18]2[C:27]([CH:28]=[O:29])=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=[C:24]3[C:19]=2[C:20](=[O:35])[CH2:21][C:22]([CH3:34])([CH3:33])[O:23]3)[CH2:17][CH2:16][CH2:15][CH:14]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:13]1([C:18]2[C:27]([CH:28]([OH:29])[C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=3)=[C:26]([CH:30]([CH3:31])[CH3:32])[CH:25]=[C:24]3[C:19]=2[C:20](=[O:35])[CH2:21][C:22]([CH3:33])([CH3:34])[O:23]3)[CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: CC(C)c1cc2c(c(C3=CCCC3)c1C=O)C(=O)CC(C)(C)O2
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(C3=CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.75 h

Procedure:
At −78° C., 780 μl (391 μmol) of a freshly prepared 0.5 M solution of bromo[4-(trifluoromethyl)phenyl]magnesium in tetrahydrofuran are slowly added dropwise to a solution of 94 mg (301 μmol) of 5-cyclopent-1-en-1-yl-7-isopropyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 34A) in 2.3 ml of tetrahydrofuran. The mixture is then allowed to thaw slowly to −20° C. and stirred at this temperature for 45 min. 10% strength sodium bicarbonate solution is then added, the mixture is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, the solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 20:1→10:1) and then by preparative HPLC (method 1).
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@H:12]([O:21][Si](C(C)(C)C)(C)C)[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=O)=O)=CC=1.[H-].[Na+].[Cl:32][C:33]1[CH:38]=[C:37](O)[CH:36]=[CH:35][C:34]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[Cl:32][C:33]1[CH:38]=[C:37]([O:10][CH2:11][C@H:12]([OH:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:36]=[CH:35][C:34]=1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)O[Si](C)(C)C(C)(C)C)cc1
Reactant: Oc1ccc(-c2ccccc2)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 11.2 %

Procedure:
Prepared according to the method described in Example 26e) from (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-1-butyl para-toluenesulfonate (0.8 g), sodium hydride (60% dispersion in mineral oil, 0.10 g) and 2-chlorobiphenyl-4-ol (0.50 g) in dimethylformamide (15 ml). The adduct was dissolved in tetrahydrofuran (10 ml) and tetrabutylammonium fluoride (1.0 g) was added. The reaction was stirred at room temperature for 5 hours and was then poured into brine and extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give the title compound as a colourless gum (0.073 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][C:7]([Cl:12])([Cl:11])[C:8](Cl)=[O:9]>>[Cl:6][C:7]([Cl:12])([Cl:11])[C:8]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Yield: 79.2 %

Procedure:
2-(Trichloroacetyl)pyrrole was prepared from pyrrole (12.5 g, 186 mmol) and trichloroacetyl chloride (36.5 g, 200 mmol) according to the method of Bailey et al, Org. Synth., 1971, 100. In this manner the title compound (31.3 g, 80%) was obtained as a cream solid, m.p. 73-74° C. (lit. m.p. 73-75° C.). 1H n.m.r. d 9.30, broad s, 1H; 7.39, m, 1H; 7.17, m, 1H; 6.40, dt, J 3.9 and 2.4 Hz, 1H. (see also J. Org. Chem., 1972, 37, 3618; 1993, 58, 7245).
Reaction SMILES: O.NN.[F:4][C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[CH2:13][N:14]2[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([C:22]([NH2:24])=[O:23])=[N:15]2)[CH:8]=[CH:9][CH:10]=1.CN(C)C=O>[Ni].C(O)C>[NH2:19][C:17]1[C:16]([C:22]([NH2:24])=[O:23])=[N:15][N:14]([CH2:13][C:12]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=2)=[O:25])[CH:18]=1
Reactant: NC(=O)c1nn(CC(=O)Nc2cccc(F)c2)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1nn(CC(=O)Nc2cccc(F)c2)cc1N
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Hydrazine hydrate (0.4 ml, 8.26 mmol) was slowly added to a mixture of 1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-4-nitro-1H-pyrazole-3-carboxamide (580 mg, 1.89 mmol) and Raney nickel (0.25 g) in ethanol (40 ml) at 50° C., and the mixture was stirred for 1 hour. Dimethylformamide was added to the mixture to solubilize the precipitated solid. The mixture was filtered, the filtrate was evaporated and the residue triturated with a mixture of dichloromethane and diethyl ether to yield 4-amino-1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazole-3-carboxamide (430 mg, 81% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12][C:13]([CH3:15])=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6]/[C:13](/[CH3:15])=[CH:12]\[C:11]([O:17][CH3:18])=[O:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(Cl)cc(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C(/C)Nc1c(C)cc(Cl)cc1C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
To a suspended solution of 4-chloro-2,6-dimethylaniline (24.0 g) in toluene (300 mL) were added methyl acetoacetate (17.9 g) and p-toluenesulfonic acid monohydrate (293 mg) and the mixture was heated to reflux and stirred for 4 hours. The reaction mixture was concentrated. To the obtained residue was added diisopropyl ether and the insoluble matter which was precipitated was removed. The filtrate was concentrated. The obtained residue was purified by preparative medium pressure liquid chromatography W-prep 2XY (column: main column 3L, inject column L; automatic condition setting: hexane:ethyl acetate=9:1, preparative isolation mode GR) to give the title compound (24.7 g) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:6]=2[CH:18]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C@:25]([OH:29])([C:27]#[CH:28])[CH3:26])[CH:21]=1>N1CCCCC1.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.[Cu]I>[NH2:17][C:13]1[N:14]=[CH:15][N:16]=[C:11]([N:7]2[C:6]3[CH:18]=[C:2]([C:28]#[C:27][C@:25]([C:22]4[CH:21]=[C:20]([CH3:19])[O:24][N:23]=4)([OH:29])[CH3:26])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[CH3:10])[N:12]=1
Reactant: Cc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3nc(C)n(-c4ncnc(N)n4)c3c2)no1
Temperature: 95 °C
Yield: 39.4 %

Procedure:
To a solution of 4-(6-bromo-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine (160 mg, 0.52 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium(0) (60.59 mg, 0.05 mmol), copper(I) iodide (9.99 mg, 0.05 mmol) and (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (118.9 mg, 0.79 mmol). The reaction was then warmed to 95° C. for 40 minutes (75 W, microwave heating). The reaction mixture was then cooled to RT and concentrated in vacuo. Purification of the residue by flash column chromatography (4-8% MeOH gradient in DCM) gave the title compound as a pale brown solid (77 mg): 1H NMR (500 MHz, DMSO) delta 1.81 (3H, s), 2.41 (3H, s), 2.90 (3H, s), 6.37 (1H, s), 6.51 (1H, s), 7.33 (1H, dd, J=8.28, 1.50 Hz), 7.60 (1H, d, J=8.20 Hz), 8.01 (1H, br. s.), 8.06 (1H, br. s.), 8.40 (1H, s), 8.66 (1H, s); LC-MS: m/z=+376.45 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([O:30]C)=O)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH3:36]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([NH2:36])=[O:30])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: N
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(N)=O
Yield: 91 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.53 mmol) was reacted with ammonia to give the title compound as a pale solid (220 mg, 91%); NMR Spectrum 1.66 (d, 3H), 5.14 (q, 1H), 5.70 (s, 2H), 7.12-7.01 (m, 4H), 7.36 (m, 2H), 7.54 (s, 1H), 7.75 (m, 3H), 7.90 (s, 1H), 8.16 (s, 1H), 8.52 (s, 2H), 10.80 (s, 1H); Mass spectrum 457.
Reaction SMILES: [C:1]([C:4](=[CH:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])[C:5]([O:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6])(=O)[CH3:2].[NH2:22][C:23]([CH3:32])=[CH:24][C:25]([O:27][CH2:28][CH2:29][C:30]#[N:31])=[O:26].C1(C)C=CC=CC=1.C(OCC)(=O)C>C(O)(C)C>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[CH:13]1[C:4]([C:5]([O:7][CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:6])=[C:1]([CH3:2])[NH:22][C:23]([CH3:32])=[C:24]1[C:25]([O:27][CH2:28][CH2:29][C:30]#[N:31])=[O:26]
Reactant: CC(=O)C(=Cc1c(F)cccc1Cl)C(=O)OC1CCCC1
Reactant: CC(N)=CC(=O)OCCC#N
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC1=C(C(=O)OCCC#N)C(c2c(F)cccc2Cl)C(C(=O)OC2CCCC2)=C(C)N1
Yield: 56.8 %

Procedure:
280 g (0.63 mol) of cyclopentyl 2-acetyl-3-(2-chloro-6-fluorophenyl)-2-propenoate are dissolved with 97.2 g (0.63 mol) of 2-cyanoethyl 3-amino-2-butenoate in 400 ml of isopropanol and the solution is heated under reflux for about 8 hours until monitoring by thin layer chromatography (silica gel, toluene/ethyl acetate 5:1) shows complete conversion. The reaction mixture is concentrated and the residue is taken up twice more with toluene and the mixture concentrated again. Filtration twice over 2 l of silica gel each time using a toluene/ethyl acetate gradient gives 160 g of the target compound as an oil. A portion is further purified by chromatography over silica gel and crystallization from ether to give a crystalline solid of melting point 135-136° C.