Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][O:33][C:34](=[O:52])[C:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:40][CH:39]=1)([OH:37])[CH3:36].[Cl:53][C:54]1[CH:59]=[CH:58][C:57](O)=[CH:56][CH:55]=1>C1COCC1>[CH3:32][O:33][C:34](=[O:52])[C:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[CH:40][CH:39]=1)([O:37][C:57]1[CH:58]=[CH:59][C:54]([Cl:53])=[CH:55][CH:56]=1)[CH3:36]
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)C(C)(O)c1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(Oc1ccc(Cl)cc1)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A solution of triphenylphosphin(0.1 g, 0.38 mmol) in 5 ml of dry THF was treated at 0° C. with DEAD (0.066 g, 0.38 mmol) and stirred over 30 min. Then a solution of 4-Benzyloxyphenyl-2-hydroxypropanoic acid methyl ester (0.1 g, 0.35 mmol) and p-chlorophenol (0.048 g, 0.38 mmol) in 2 ml of THF was added to the solution and the mixture reaction was stirred at room temperature overnight. The mixture was concentrated to dryness and chromatographed in silicagel (hexanes/Ethyl acetate 3:1) to give 0.082 g of product (60%). 1H-NMR (200.15 MHz, CDCl3): δ 7.46–7.31 (m, 5H), 7.28–7.13 (m, 4H), 6.93 (d, 2H, J=8.8), 6.75 (d, 2H, J=8.8), 5.04 (s, 2H), 4.73(t, 1H, J=6.1), 3.71 s (s, 3H), 3.18 (d, 2H, J=6.4).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:7][CH2:6][NH:5][C:4]1([CH3:9])[CH3:8].C(N(CC)C(C)C)(C)C.[CH3:20][C:21]([O:24][C:25]([N:27]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:28]([C:36]1[C:41]([F:42])=[C:40](Cl)[N:39]=[C:38]([Cl:44])[N:37]=1)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])([CH3:23])[CH3:22]>CN(C=O)C>[CH3:23][C:21]([O:24][C:25]([N:27]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:28]([C:36]1[C:41]([F:42])=[C:40]([N:5]2[CH2:6][CH2:7][CH:3]([N:2]([CH3:10])[CH3:1])[C:4]2([CH3:9])[CH3:8])[N:39]=[C:38]([Cl:44])[N:37]=1)[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[O:26])([CH3:20])[CH3:22]
Reactant: CN(C)C1CCNC1(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)C1(C)C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of racemic N,N,2,2-tetramethyl-3-pyrrolidinamine (0.1466 g, 1.031 mmol) in DMF (6 mL) was added N,N-diisopropylethylamine (0.220 mL, 1.263 mmol) and tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.513 g, 1.031 mmol), and the solution was stirred overnight. The solution was partitioned between Et2O (100 mL) and water (20 mL), and the organic phase was washed with a fresh portion of water (20 mL). The combined aqueous phase was extracted with a fresh portion of Et2O (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes) to give racemic tris(1,1-dimethylethyl)2-{2-chloro-6-[3-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.4647 g, 75% yield) as a white foam. LCMS: (M+H)+: 603.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]#[N:28]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH2:26][C:27]#[N:28])[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#CCBr
Reactant: CS(=O)(=O)Nc1ccc(-c2ccnc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)N(CC#N)c1ccc(-c2ccnc(Cl)n2)cc1
Yield: 89 %

Procedure:
N-(4-(2-chloropyrimidin-4-yl)phenyl)methanesulfonamide (750 mg 2.64 mmol) and potassium carbonate (730 mg, 2 eq.) were placed in a round bottomed flask and suspended in acetone (50 mL). The mixture was stirred for several minutes before adding bromoacetonitrile (368 μL, 2 eq.). The reaction mixture was stirred at room temperature for 48 h. The crude reaction mixture was concentrated in vacuo and the residue taken up in ethyl acetate (200 mL) and washed with water (2×100 mL), brine (100 mL) and then dried (sodium sulfate). The organic phase was concentrated in vacuo to give N-(4-(2-chloropyrimidin-4-yl)phenyl)-N-(cyanomethyl)methanesulfonamide (762 mg, 89% yield) as a fawn solid. 1H NMR (300 MHz, d6-DMSO) δ 8.86 (1H, d, J=5.0 Hz); 8.28 (2H, d, J=8.7 Hz); 8.18 (1H, d, J=5.5 Hz); 7.66 (2H, d, J=8.7 Hz); 4.97 (2H, s); 3.22 (3H, s). LC-ESI-MS (method B): rt 5.9 min.; m/z 323.2/325.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[F:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:27][NH:28]2)=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([N:31]3[CH2:32][CH2:33][N:34]([CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:11]=[CH:10][CH:9]=[C:8]([C:12]5[C:20]6[C:15](=[N:16][CH:17]=[CH:18][CH:19]=6)[O:14][N:13]=5)[CH:7]=4)[CH2:35][CH2:36]3)=[N:27][NH:28]2)=[CH:24][CH:23]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCN(c2n[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 6-fluoro-3-piperazin-1-yl-1H-indazole (Table No.1, SM 4) in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=489.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:22]([OH:24])=O)[N:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH-:34])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:22](=[O:24])[C@H:12]([CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[N:13]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:14])=[CH:28][CH:27]=1
Reactant: [NH-]CCc1ccc(F)cc1
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Product: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(F)cc1

Procedure:
Nδ-Boc-Nα-benzyl-Nα-methylornithine and 2-(4-fluorophenyl)ethylamide were coupled, as per Procedure C, to afford titled compound as a glassy solid: 1H NMR (400 MHz, CDCl3) δ1.52 (s, 9H), 1.73 (m, 1H), 1.65 (m, 2H), 1.79 (m, 1H), 2.78 (t, J=7.9 Hz, 2H), 3.02 (m, 1H), 3.14 (m, 2H), 3.52 (m, 4H), 6.96 (m, 2H), 7.11 (m, 5H), and 7.28 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[C:21][CH:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[OH:23].C(=O)(O)[O-].[Na+]>C(O)(C)C.CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:11][N:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:21]=1[CH:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[OH:23]
Reactant: OC(C#Cc1ccccc1Cl)c1cccnc1
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Product: OC(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Temperature: 55 °C
Yield: 16.7 %

Procedure:
A mixture of 52 mg (0.23 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 50 mg (0.21 mmol) of 3-(2-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-ol, and 30 mg (0.36 mmol) of sodium bicarbonate in 3 mL of isopropyl alcohol was heated at 55° C. overnight with shaking. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 15 mg (0.035 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. 1H NMR (CDCl3): δ 5.80 (br s, 1). MS m/z: 431.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=O)[C:11]=2[N:10]=1.[NH2:23][C:24]1[S:25][C:26]([CH3:29])=[CH:27][N:28]=1>>[CH3:29][C:26]1[S:25][C:24]([NH:23][C:18]([C:17]2[C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:3]=4[C:2]([F:21])([F:22])[F:1])[NH:13][C:12]=3[CH:14]=[CH:15][CH:16]=2)=[O:20])=[N:28][CH:27]=1
Reactant: O=C(O)c1cccc2[nH]c(-c3cnccc3C(F)(F)F)nc12
Reactant: Cc1cnc(N)s1
Product: Cc1cnc(NC(=O)c2cccc3[nH]c(-c4cnccc4C(F)(F)F)nc23)s1

Procedure:
2-(4-(Trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylic acid 119 was coupled to 2-amino-5-methylthiazole 171 using the same general amide coupling procedure shown above to afford N-(5-methylthiazol-2-yl)-2-(4-(trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound 703). MS (ESI) calcd for C18H12F3N5OS: 403.07; found: 404 [M+H].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[F:8][C:9]([F:21])([F:20])[CH2:10][CH2:11][S:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:14])=[O:13].[H-].[Na+].Cl>CS(C)=O>[F:21][C:9]([F:8])([F:20])[CH2:10][CH2:11][S:12]([CH:15]([CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2])[C:16]([O:18][CH3:19])=[O:17])(=[O:13])=[O:14]
Reactant: C=CCCCCBr
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCCCCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a solution of 2.0 g of 6-bromo-1-hexene and 2.9 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide, 0.5 g of sodium hydride (60% in oil) was added at room temperature. The mixture was heated to 60° C., stirred for 4 hours, and then allowed to stand near room temperature. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 3.10 g of methyl 2-(3,3,3-trifluoropropylsulfonyl)-7-octenoate (hereinafter referred to as the present compound (20)).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>C(Cl)(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[C@@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCCl)CC[C@H]2c2ccc(F)cc2)cc1
Reactant: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCn3ccnc3)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=442.3 (M+H+) and [α]D20=−64.3° (c=0.2673 in chloroform), was prepared in accordance with the general method of example 82b from (2S,5S)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-imidazole.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:13](=[O:38])[C:14]4[O:37][CH:36]=[CH:35][C:15]=4[N:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:28]=[CH:27][CH:26]=[N:25]5)=[CH:20][C:19]=4[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[N:17]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([N:7]2[C:11]([C:12]3[C:13](=[O:38])[C:14]4[O:37][CH2:36][CH2:35][C:15]=4[N:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:28]=[CH:27][CH:26]=[N:25]5)=[CH:20][C:19]=4[O:29][CH2:30][C:31]([F:32])([F:33])[F:34])[N:17]=3)=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2OCC(F)(F)F)c2ccoc12
Agent: [Pd]
Solvent: CCO
Product: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2OCC(F)(F)F)c2c1OCC2
Yield: 19.9 %

Procedure:
A solution of 3-(1-phenyl-1H-pyrazol-5-yl)-1-[4-(1H-pyrazol-1-yl)-2-(2,2,2-trifluoroethoxy)phenyl]furo[3,2-c]pyridazin-4(1H)-one (35 mg) and 10% palladium on carbon (50 mg) in ethanol (5 mL) was stirred at 50° C. for 12 hr under a hydrogen atmosphere. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (7 mg).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:24]([N:23]([CH3:22])[C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: CCCCNC
Product: CCCCN(C)C(=O)C(C)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and N-methyl-n-butylamine were used to obtain N-n-Butyl-N-methyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(#N)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:30][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 4-(6fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol), K2CO3 (3.8 g, 27.5 mmol) and ethyl bromopropionate (5 g, 27.6 mmol, 1.2 eq) in acetonitrile (200 ml) was heated at reflux for 16 hours. The mixture was cooled and filtered. The solvent was removed, and the residue was purified on a flash chromatography column (60 g, SiO2, eluted with DCM). The material thus purified weighed 7.27 g (83%). The fumarate salt was prepared by treatment of the free base (2.17 g) with fumaric acid (820 mg, 1.0 eq) in ethanol. Recrystallization from ethanol yielded 2.49 g of white crystals, m.p.=135-136° C.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reaction time: 6.5 h
Yield: 97.4 %

Procedure:
To a solution of 4.5 g of 6,11-dihydro-5-(4-nitrobenzoyl)-5H-dibenz[b,e]azepine in 230 ml of glacial acetic acid is added 0.58 g of 10% palladium-on-carbon and the mixture under hydrogen (38 psi) shaken in a Parr hydrogenator for 6.5 hours. The mixture is filtered through diatomaceous earth and the filtrate concentrated to give 4.0 g of solid. The solid is extracted with 100 ml of dichloromethane and the extract washed with water, dried (Na2 SO4). The solvent is removed to give 4.0 g of yellow crystals, m.p. 168°-175° C. A sample chromatographed on a thick layer silica gel plate with hexane-ethyl acetate (8:7) as solvent gives yellow crystals, m.p. 173°-175° C. Anal. Calc'd for C21 H18N2O: C,80.2; H,5.8; N,8.9. Found: C,79.2; H,6.0; N,8.8.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:26]([O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)=[O:27]>O1CCCC1.O>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][N:12]([C:26]([O:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)=[O:27])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccco1
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3ccco3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 350 mg portion of (3R,4R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(2-furyl)pyrrolidine and 470 mg of sodium bicarbonate were suspended in 20 ml of a tetrahydrofuran-water (3:1) mixed solvent, and 320 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (mfd. by Fluka) was added in one portion thereto at room temperature. After 1Hour of stirring at room temperature, 80 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate was further added thereto at room temperature. After 2 hours of further stirring, the reaction solution was concentrated under a reduced pressure. The residue was separated by diluting it with water and diethyl ether, and then extracted with diethyl ether. The organic layer was washed with water and saturated brine in that order and dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 571 mg of 4-(methoxycarbonyl)phenyl (3R,4R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(2-furyl)pyrrolidine-1-carboxylate as a colorless oily substance.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[NH:24][N:23]=3)[C:18]([Br:30])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2].[C:31](OC(=O)C)(=[O:33])[CH3:32]>C1COCC1.O>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[N:24]([C:31](=[O:33])[CH3:32])[N:23]=3)[C:18]([Br:30])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCNC(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)n(C(C)=O)n3)n2)s1
Yield: 98.6 %

Procedure:
To N-(2-acetamidoethyl)-5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboxamide (273.8 mg, 0.56 mmol, 1.0 equiv.), acetic anhydride (114.2 mg, 1.1 mmol, 2.0 equiv.) in THF/H2O (10 ml/1 mL) was stirred at 23° C. for 2 hour. Then the mixture was extracted with THF (6×40 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated give N-(2-acetamidoethyl)-5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)thiophene-2-carboxamide (294.0 mg, 98.5%) as pale yellow solid. LC-MS (m/z)=533.1 [M+H]+;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.Br[C:25]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:33]2[C:28](=[CH:29][C:30]([CH3:35])=[C:31]([Cl:34])[CH:32]=2)[NH:27][C:26]1=[O:36]>C1COCC1>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:25]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[C:33]3[C:28](=[CH:29][C:30]([CH3:35])=[C:31]([Cl:34])[CH:32]=3)[NH:27][C:26]2=[O:36])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: Cc1cc2c(cc1Cl)C(Br)(c1ccccc1Cl)C(=O)N2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cl)C(NCCC1CCN(C(=O)OC(C)(C)C)CC1)(c1ccccc1Cl)C(=O)N2
Yield: 56.2 %

Procedure:
A solution of 1.35 g of 4-(2-aminoethyl)-1-(tert-butoxycarbonyl)piperidine and 1.75 g of triethylamine in 20 ml of THF is added dropwise at RT to a solution of 2.1 g of 3-bromo-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methylindol-2-one, obtained in step B' of Preparation 71, in 20 ml of THF and the reaction mixture is stirred for 1 hour at RT. It is concentrated under vacuum, the residue is taken up with 400 ml of AcOEt and 50 ml of THF, the resulting suspension is washed twice with a 5% solution of sodium carbonate, with water and with a saturated solution of NaCl and, after decantation, the solid in suspension is filtered off. The solid is dissolved in 400 ml of boiling THF and dried over sodium sulfate and the solvent is partially evaporated off under vacuum. The crystalline product formed is filtered off to give 1.65 g of the expected product. M.p.=245°-248° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH2:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1>>[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:30][N:29]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(Br)c1
Product: Nc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCCC2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 66 using 5-bromo-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 67.1) and (2-aminopyrimidin-5-yl)boronic acid to afford a white solid. UPLC-MS (Condition 3) tR=0.99 min, m/z=445.3 [M+H]+, m/z=443.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.84 (m, 4H) 3.18-3.26 (m, 4H) 6.77 (s, 2H) 7.34 (d, J=8.31 Hz, 2H) 7.86 (d, J=9.29 Hz, 2H) 7.95 (d, J=2.45 Hz, 1H) 8.27 (s, 2H) 8.71 (d, J=2.45 Hz, 1H) 10.12 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:8]=[CH:7]2)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].O1CCOCC1>O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH:14]=[CH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2nc(C=Cc3ccccc3)ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc2nc(C=Cc3ccccc3)ccc2c1

Procedure:
41.6 g of 6-nitro-2-styrylquinoline were added in portions to a mixture containing 69 g of reduced iron, 6.9 g of aluminum chloride, 450 ml of dioxane, and 90 ml of water with heating under reflux. After heating under reflux for a further 5 hours, the solid was filtered using a Nutsche filter in which sellaite is laid. The filtrate was condensed, 130 ml of ethyl acetate were added thereto, and the deposited crystals were filtered. 28 g (74% of the theoretical yield) of the 6 -amino-2-styrylquinoline crystals were produced.