Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[Si:21]([O:9][CH2:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=[C:2]([Cl:1])[N:7]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(Cl)nc(CO)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)nc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of 6-chloro-2-hydroxymethyl-4-methoxypyridine (1.85 g), which was prepared by a method mentioned in Tokkaihei 10-59942 (JP1998-59942A), and imidazole (0.87 g) in N,N-dimethylformamide (30 mL) was added tert-butyldimethylchlorosilane (1.77 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=85/15) to give 2-(tert-butyldimethylsilyloxy)methyl-6-chloro-4-methoxypyridine (2.83 g). To a solution of N,N-diisopropylamine (0.54 mL) in tetrahydrofuran (20 mL) was added n-butyllithium (2.77 mol/L n-hexane solution, 1.25 mL) at −78° C., and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added a solution of 2-(tert-butyldimethylsilyloxy)methyl-6-chloro-4-methoxypyridine (1 g) in tetrahydrofuran (5 mL), and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added N,N-dimethylformamide (0.32 mL), and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was stirred at room temperature for 5 minutes. The mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/1) to give 6-(tert-butyldimethylsilyloxy)methyl-2-chloro-4-methoxy-3-formylpyridine (0.28 g). The title compound was prepared in a similar manner to that described in Reference Example 15 using 6-(tert-butyldimethylsilyloxy)methyl-2-chloro-4-methoxy-3-formylpyridine instead of 2,6-dibromo-3-formylpyridine.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][CH3:8])=[O:6].[CH3:13][N:14](C=O)C>N.C(OCC)(=O)C.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.[C-]#N.[Zn+2].[C-]#N>[C:13]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][CH3:8])=[O:6])#[N:14]
Reactant: CNC(=O)c1ccc(C)c(I)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C)c(C#N)c1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
3-Iodo-N, 4-dimethylbenzamide (772 mg), tetrakistriphenylphosphinepalladium (30 mg) and zinc cyanide (250 mg) were suspended in DMF (10 ml) under a nitrogen atmosphere, and the mixture was stirred at 120° C. for 12 hrs. The reaction mixture was diluted with 5% aqueous ammonia-ethyl acetate and the organic layer was washed with water and saturated brine. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1–0:1) for purification. The eluate was recrystallized from ethyl acetate-hexane to give the title compound (300 mg) as colorless powder crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.Cl.[N:27]1([C:33]([O:35][CH2:36][C:37]([NH:39][CH3:40])=[O:38])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:30]2[CH2:29][CH2:28][N:27]([C:33]([O:35][CH2:36][C:37]([NH:39][CH3:40])=[O:38])=[O:34])[CH2:32][CH2:31]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)COC(=O)N1CCNCC1
Reactant: OCCCc1cccc(Br)c1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)COC(=O)N1CCN(CCCc2cccc(Br)c2)CC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
A solution of 1.57 g (6.7 mmol) of 3-(3-bromophenyl)propan-1-ol, prepared in step 7.1., and 1.73 ml (10.1 mmol) of diisopropylethylamine in 38 ml of dichloromethane, cooled to 0° C., is admixed with 0.63 ml (8.14 mmol) of methanesulphonyl chloride. Stirring is continued in the cold for 0.5 hour and then at ambient temperature for 2 hours. The mixture is concentrated under reduced pressure and then the residue is suspended in 35 ml of acetonitrile. 1.34 g (5.35 mmol) of 2-(methylamino)-2-oxoethyl piperazine-1-carboxylate hydrochloride, prepared in accordance with Example 3.3., and 2.2 g (16 mmol) of potassium carbonate are added. The mixture is heated at 75° C. for 16 hours. After cooling to ambient temperature it is concentrated under reduced pressure and then the residue is taken up in water. It is extracted with ethyl acetate and dried over sodium sulphate. Following filtration, the organic phase is concentrated under reduced pressure. It is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. Crystallization from diisopropyl ether gives 0.84 g (2.10 mmol) of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.CCN(C(C)C)C(C)C.[CH3:42][N:43]([CH3:47])[C:44]([Cl:46])=[O:45]>CN1C(=O)CCC1>[CH3:42][N:43]([CH3:47])[C:44]([N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)=[O:45].[ClH:46]
Reactant: CN(C)C(=O)Cl
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (100 mg, 0.2 mmol) was stirred in 5 mL NMP. To the solution were added DIEA (0.18 mL, 1.0 mmol) and dimethylcarbamylchloride (0.055 mL, 0.6 mmol). The mixture was stirred at RT for 1 h and quenched with Me2NH. The mixture was concentrated in vacuo and subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C27H31FN6O2: 491.5. NMR (CD3OD): 8.12 (1H, s), 7.37 (1H, m), 7.34 (2H, d, J=8.4 Hz), 7.28 (1H, m), 7.17 (1H, m), 7.16-7.10 (3H, m), 5.88 (1H, s), 4.51 (2H, s), 3.82 (2H, m), 2.94 (2H, m), 2.88 (6H, s), 2.80 (1H, m), 1.86 (2H, m), 1.72 (2H, m) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[CH3:26][O:27][CH2:28][C@H:29]1[O:31][CH2:30]1>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([CH2:30][C@@H:29]([OH:31])[CH2:28][O:27][CH3:26])[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:15][C:14]([C:16]#[N:17])=[CH:13][N:12]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: COC[C@@H]1CO1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: COC[C@H](O)Cc1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)c1

Procedure:
This compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 14, step (c)) according to the procedure in Example 46 step (a) using (S)-glycidyl methyl ether as the electrophile. 1H-NMR (400 MHz, CD3OD): δ 8.10 (d, J=8.3 Hz, 1H), 7.98 (s, 1H), 7.15 (dd, J=8.3, 2.1 Hz, 1H), 7.07 (d, J=2.1 Hz, 1H), 5.73 (m, 1H), 3.91 (m, 1H), 3.36 (s, 3H), 2.80 (dd, J=13.7, 5.7 Hz, 1H), 2.69 (dd, J=13.7, 7.5 Hz, 1H), 2.31 (m, 2H), 2.07 (m, 2H), 1.58 (t, J=6.3 Hz, 2H), 1.07 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C23H28N4O3, 409.2 (M+H). found 409.1.
Reaction SMILES: CCCCCCCCCCCCCCCC([NH:18][C@@H:19]1[C:50](=[O:51])[NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46](=[O:47])[N:45]2[C@@H:41]([CH2:42][C@@H:43]([OH:55])[CH2:44]2)[C:39](=[O:40])[NH:38][C@@H:37]([C@H:56]([OH:71])[C@@H:57]([OH:70])[C:58]2[CH:59]=[CH:60][C:61]([OH:69])=[C:62]([O:64][S:65]([OH:68])(=[O:67])=[O:66])[CH:63]=2)[C:35](=[O:36])[NH:34][C@@H:33]([C@H:72]([OH:77])[CH2:73][C:74]([NH2:76])=[O:75])[C:31](=[O:32])[N:30]2[C@@H:26]([C@@H:27]([OH:79])[C@@H:28]([CH3:78])[CH2:29]2)[C:24](=[O:25])[NH:23][C@@H:22]([OH:80])[C@H:21]([OH:81])[CH2:20]1)=O.P([O-])(O)(O)=O.[K+].P([O-])([O-])(O)=O.[Na+].[Na+].C(O)(=O)C>CO>[CH3:78][C@@H:28]1[C@H:27]([OH:79])[C@H:26]2[C:24]([NH:23][C@H:22]([OH:80])[C@H:21]([OH:81])[CH2:20][C@H:19]([NH2:18])[C:50]([NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46]([N:45]3[C@H:41]([C:39]([NH:38][C@@H:37]([C@H:56]([OH:71])[C@@H:57]([OH:70])[C:58]4[CH:59]=[CH:60][C:61]([OH:69])=[C:62]([O:64][S:65]([OH:68])(=[O:67])=[O:66])[CH:63]=4)[C:35]([NH:34][C@@H:33]([C@H:72]([OH:77])[CH2:73][C:74]([NH2:76])=[O:75])[C:31](=[O:32])[N:30]2[CH2:29]1)=[O:36])=[O:40])[CH2:42][C@@H:43]([OH:55])[CH2:44]3)=[O:47])=[O:51])=[O:25]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@H](O)NC(=O)[C@@H]2[C@@H](O)[C@@H](C)CN2C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)c(OS(=O)(=O)O)c2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](O)[C@@H]1NC(=O)[C@@H](N)C[C@@H](O)[C@@H](O)NC(=O)[C@@H]2[C@@H](O)[C@@H](C)CN2C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)c(OS(=O)(=O)O)c2)NC(=O)[C@@H]2C[C@@H](O)CN2C1=O
Reaction time: 0.5 h

Procedure:
To 700 μl of the fermentation broth of Streptomyces sp. No. 6907 obtained in Example 1-3 was added 100 μl of an aqueous solution of Substance FR901379 (100 mg/ml) (10 mg as Substance FR901379; 8.35 μmol) together with 100 μl of methanol and 100 μl of buffer (0.5 M potassium dihydrogen phosphate-disodium hydrogen phosphate buffer; pH 6.0), and the reaction was carried out at 30° C. for 30 minutes. The reaction was then stopped with 4% acetic acid and following addition of 2 ml of methanol, the mixture was filtered through a membrane filter (0.45 μm) to remove the macromolecular protein and other fraction and subjected to HPLC and the acylase activity of the skeletal substance FR179642 produced was monitored and assayed at 210 nm.
Reaction SMILES: [CH3:1][C:2]1([C:32](OCC)=[O:33])[C:10]2[C:9]([NH:11][CH3:12])=[N:8][C:7]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[N:14]=3)=[N:6][C:5]=2[NH:4][C:3]1=[O:31].[CH:37]1([NH2:40])[CH2:39][CH2:38]1>CO>[CH:37]1([NH:40][C:32]([C:2]2([CH3:1])[C:10]3[C:9]([NH:11][CH3:12])=[N:8][C:7]([C:13]4[C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[N:14]=4)=[N:6][C:5]=3[NH:4][C:3]2=[O:31])=[O:33])[CH2:39][CH2:38]1
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(NC)c21
Reactant: NC1CC1
Solvent: CO
Product: CNc1nc(-c2nn(CCC(F)(F)C(F)(F)F)c3ncccc23)nc2c1C(C)(C(=O)NC1CC1)C(=O)N2
Temperature: 80 °C

Procedure:
The intermediate from Step B above (65 mg, 0.127 mmol) and cyclopropylamine (0.088 mL, 1.266 mmol) in MeOH (1 mL) were sealed in a microwave tube and heated at 80° C. for 2 days.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[CH3:2].[C:27]1(=[O:32])[CH2:31][CH2:30][CH:29]=[CH:28]1>F[B-](F)(F)F>[O:32]=[C:27]1[CH2:31][CH2:30][C@@H:29]([C:9]2[CH:8]=[C:7]([CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=2)[O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:26])[CH2:28]1
Reactant: CCOC(=O)COc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)c1
Reactant: O=C1C=CCC1
Agent: F[B-](F)(F)F
Product: CCOC(=O)COc1cc([C@@H]2CCC(=O)C2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-phenoxy]-acetic acid ethyl ester and 2-cyclopenten-1-one with Rh(R-BINAP)(nbd)]BF4 as catalyst in a manner similar to the one described for Preparation 6.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH:16]=[CH:15][C:14]([C:17]3[C:25]4[C:24]([NH:26][C@H:27]([C:29]5[N:34]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:33](=[O:41])[C:32]6=[C:42]([CH3:45])[CH:43]=[CH:44][N:31]6[N:30]=5)[CH3:28])=[N:23][CH:22]=[N:21][C:20]=4[N:19](COCC[Si](C)(C)C)[CH:18]=3)=[N:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH:16]=[CH:15][C:14]([C:17]3[C:25]4[C:24]([NH:26][C@H:27]([C:29]5[N:34]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:33](=[O:41])[C:32]6=[C:42]([CH3:45])[CH:43]=[CH:44][N:31]6[N:30]=5)[CH3:28])=[N:23][CH:22]=[N:21][C:20]=4[NH:19][CH:18]=3)=[N:13]2)(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)n2ccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)n2)c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccn(S(=O)(=O)c6cccc(O)c6)n5)c34)n(-c3ccccc3)c(=O)c12
Yield: 18.4 %

Procedure:
(S)-2-(1-((5-(1-((3-Methoxyphenyl)sulfonyl)-1H-pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (48.5 mg, 0.06 mmol) was treated with boron tribromide (1M in dichloromethane, 0.75 ml, 0.75 mmol) in dichloromethane (2 ml) and then with a solution of ammonia (7N in methanol, 5 ml, 35 mmol) according to the method described in Example 41 to give 6.7 mg (17% yield) of the title compound. Purity 98%.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([F:20])=[C:18](I)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.C([Mg]Cl)(C)C.CO[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1.[NH4+].[Cl-]>>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([F:20])=[C:18]([B:34]3[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2ncc(I)c2F)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2F)OC1(C)C
Reaction time: 1 h

Procedure:
To a solution of 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-fluoro-4-iodo-1H-pyrazole (80.0 mg, 0.188 mmol) in THF (2 mL, 20 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (0.58 mL, 0.75 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 mL, 0.94 mmol), and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was dry-loaded onto silica gel and purified via column chromatography, eluting with 2-7% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=425.28 (100) [MH+]. HPLC: tR=2.23 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:31]([NH:34][CH2:35][CH:36]=[CH2:37])[CH:32]=[CH2:33]>CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:34]([CH2:35][CH:36]=[CH2:37])[CH2:31][CH:32]=[CH2:33])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: C=CCNCC=C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCN(CC=C)CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cc1OC
Yield: 9.4 %

Procedure:
A solution of 0.24 g (0.5 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide in 1 ml of N,N-dimethylformamide and 4 ml of tetrahydrofuran was stirred with 0.49 ml (4 mmol) of diallylamine for 3 hr. The reaction was quenched with 10 ml of saturated sodium bicarbonate and 10 ml of ethyl acetate. The insoluble precipitate was collected and washed with water to give 23.7 mg of the title compound (free base); mass spectrum (electrospray, m/e): M+H 506.0. The ethyl acetate layer was washed with water. After the solvent was removed, the crude product was purified by preparative HPLC (C18 column, Gradient from 2% acetonitrile containing 0.05% trifluoroacetic acid to 100% acetonitrile containing 0.05% trifluoroacetic acid in 12 min) to yield 97.9 mg of the product as the bis-trifluoroacetate salt; mass spectrum (electrospray, m/e): M+H 506.0.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]1[C:27]2[C:28]3[C:33]([NH:34][C:26]=2[CH2:25][NH:24][CH2:23]1)=[CH:32][CH:31]=[CH:30][CH:29]=3>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:24]4[CH2:23][CH2:22][C:27]5[C:28]6[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=6)[NH:34][C:26]=5[CH2:25]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCc2c([nH]c3ccccc23)C1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and noreleagnine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=458.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(F)=C(Cl)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:23][C:18]1[CH:17]=[C:16]([N:15]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(Cl)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Fc1ccc(NCC2CCCC2)cc1Cl
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(Cl)c2)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-chloro-4-fluoro-phenyl)ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-chloro-4-fluoro-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1cc(F)ccc1F
Product: Fc1ccc(F)c(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1

Procedure:
Using 2,5-difluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 159. 1H NMR(CDCl3) δ: 7.05-6.98 (m, 1H), 6.97-6.90 (m, 1H), 6.90-6.80 (m, 1H), 6.26 (d, 1H, J=2.5 Hz), 6.14 (d, 1H, J=2.2 Hz), 4.23 (broad s, 2H), 3.59 (ABq, 2H), 3.50-3.40 (m, 1H), 3.30-3.17 (m, 2H), 3.05-2.65 (m, 6H), 2.51 (dd, 1H, J=12.7, 9.5 Hz), 1.92-1.78 (m, 2H). LRMS (ES)+: 388.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH2:33])[CH:27]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:42](O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH:33][CH3:42])[CH:27]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c(N)c2)CC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CNc1cc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3NC(=O)OC(C)(C)C)CC2)ccc1O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-amino-4-hydroxybenzyl)piperidine (20.4 mg, 0.037 mmol), 37% HCHO solution (3.0 mg, 0.037 mmol), acetic acid (0.10 mL) and methanol (1.3 mL) was added NaBH3CN (7.0 mg) in methanol (0.2 mL). The reaction mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (8 mL) and concentrated to give 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3-methylamino-4-hydroxybenzyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH:18]3[CH2:17][CH:16]2[CH:15]([NH:20][C:21]2[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=2)[CH2:14]3)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCCCC(Nc2ncnc3[nH]ccc23)C1
Solvent: CO
Solvent: ClCCl
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1CC2CC(Nc3ncnc4[nH]ccc34)C1C2
Yield: 51 %

Procedure:
A similar procedure was used as describe for the synthesis of 2-(3,5-dichlorophenylamino)-1-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino) azepan-1-yl) ethanone to afford a residue which was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (45 mg, 51%) the titled compound. 1H NMR (DMSO-d6, 400 MHz): 11.50 and 11.40 (2s, 1H), 8.18-8.10 (2s, 1H), 7.18 (bs, 1H), 7.08 (bs, 1H), 6.66 and 6.60 (2s, 2H), 6.58 and 6.50 (2s, 1H), 6.21 and 6.08 (2s, 2H), 4.62 and 4.46 (2s, 1H), 3.88-3.48 (m, 2H), 3.10-2.90 (m, 2H), 2.72-2.50 (m, 1H), 2.24-2.10 (m, 2H), 1.82-1.62 (m, 3H). LC-MS: m/z [M+1]=431.