Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4([CH2:36][O:37][CH3:38])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:39][O:40]C(=O)C)(=O)C.O[Li].O>C1COCC1.CO.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:39][OH:40])[O:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2([CH2:36][O:37][CH3:38])[CH2:34][CH2:35]2)=[CH:31][CH:32]=1
Reactant: COCC1(c2ccc(Cc3cc([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc3Cl)cc2)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCC1(c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CC1
Reaction time: 2.5 h

Procedure:
To a solution of the above crude (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(1-(methoxymethyl)cyclopropyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate BD) (25 mg) in THF:MeOH:H2O (2:3:1) (1 mL) was added LiOH.H2O (4.66 mg). After stirring for about 2.5 h, the volatiles were removed with a rotary evaporator. The residue was taken up with water (5 mL) and AcOEt (20 mL), the organic layer was separated, and the aqueous layer was extracted 3× with AcOEt. The combined organic phase was washed 1× with brine prior to drying over Na2SO4. Concentration and purification of the crude product by preparative HPLC afforded compound BE (7.5 mg). 1H NMR (CD3OD, 400 MHz) δ 7.35-7.33 (m, 2H), 7.27 (dd, J=8.0, 2.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 4.11-4.01 (m, 3H), 3.87 (d, J=9.6 Hz, 1H), 3.70-3.66 (m, 1H), 3.48 (s, 2H), 3.45-3.34 (m, 4H), 3.26 (s, 3H), 0.83-0.82 (m, 4H); MS ESI (m/z): 449 (M+H)+, 466 (M+NH4)+, 493 (M+HCO2)−.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[CH2:25](OC(OCC)OCC)C.O.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[N:17]=[C:18]4[NH:23][CH:25]=[N:22][C:19]4=[CH:20][CH:21]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CCOC(OCC)OCC
Reactant: CN(c1ccc(N)c(N)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CN(c1ccc2nc[nH]c2n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
A solution of (R)—N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine-2,5,6-triamine (35 mg, 0.11 mmol), triethoxymethane (0.58 mL, 3.45 mmol) and 4-methylbenzenesulfonic acid monohydrate (62 mg, 0.33 mmol) in methanol (3.0 mL) was stirred at 150° C. for 5 min in an Initator™ Biotage microwave reactor. The volatiles were removed and the residue is purified by chromatography to give the title product. MS (m/z): 335 (M+H)+.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[N+:20]([C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])([O-:22])=[O:21].C(N1C=CN=C1)(N1C=CN=C1)=O>O>[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([N:19]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[N+:20]([O-:22])=[O:21])[C:26]2=[O:27])[CH2:17][CH2:18]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
15 ml of a chloroform solution containing 500 mg of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine and 540 mg of 3-nitrophthalic anhydride was refluxed for 1 hour. After cooling, 756 mg of carbonyldiimidazole was added to the mixture and the resulting mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain 900 mg of N-tert-butoxycarbonyl-trans-4-(1,3-dioxo-4-nitro-2-isoindolinyl)-cyclohexylamine.
Reaction SMILES: CC([OH:4])C.[Br:5][C:6]1[CH:7]=[C:8]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1.[OH-].[K+]>CS(C)=O>[Br:5][C:6]1[CH:7]=[C:8]([C:12]2([C:18]([NH2:19])=[O:4])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1(c2cccc(Br)c2)CCOCC1
Reactant: CC(C)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: NC(=O)C1(c2cccc(Br)c2)CCOCC1
Temperature: 82 °C

Procedure:
Propan-2-ol (100 ml), tetrahydro-4-(3-bromophenyl)-2H-pyran-4-nitrile (20.0 g, 0.075 mole, 1 eq.), potassium hydroxide (13.74 g, 0.245 mole, 3.26 eq.) were added to a reaction flask set for boiling at reflux under a nitrogen atmosphere, and the reaction mixture was heated with stirring at reflux, about 82° C. for 5-6 hours under nitrogen. After reaction completion, the mixture was cooled (<30° C.) and quenched with water (100 ml). The resultant slurry was filtered and the product residue, washed with water (30 ml), and dried under vacuum at 45-50° C. to yield a white solid. Yield 19.05 g, 89.2% mp 245-247° C.; m/z 285 (m+1); 1H NMR (300 MHz, DMSO) § 7.43 (m, 5H), 7.14 (s, 1H), 3.76 (d, 2H), 3.47 (t, 2H), 2.44 (d, 2H), 1.79 (m, 2H).; IR (drifts) vmax 3363, 3174, 3062, 2973, 2935, 2879, 2828, 1685, 1631, 1588.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-])=O)[CH:21]=2)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O>CO>[NH2:27][C:22]1[CH:21]=[C:20]([C:11]([C:6]2[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([NH2:1])[CH:5]=2)([C:12]([F:13])([F:14])[F:15])[C:16]([F:17])([F:18])[F:19])[CH:25]=[CH:24][C:23]=1[OH:26]
Reactant: O=[N+]([O-])c1cc(C(c2ccc(O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1O
Solvent: CO
Product: Nc1cc(C(c2ccc(O)c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1O
Temperature: 25 °C

Procedure:
15.0 g of 2,2-bis(3-nitro-4-hydroxyphenyl)hexafluoropropane and 50.0 cc of methanol were put into a 100-cc four-neck flask equipped with a thermometer, a Dimroth condenser and a stirrer, and stirred therein, to which was added 0.23 g (dry weight) of E196R/W5%Pd (trade name, 5% palladium-carbon catalyst, manufactured by Degussa Japan Co.). This was heated and kept at 60 to 65° C., to which was dropwise added 11.8 g of an aqueous solution of 60% hydrazine monohydrate over a period of 20 minutes. If desired, the reaction system was cooled, as generating heat during the reaction. After the aqueous hydrazine solution was added, the mixture was stirred at 70° C. for 30 minutes, and then gradually cooled to room temperature. After the catalyst was removed through filtration, methanol and water were evaporated out of the reaction mixture to obtain a crude product of 2,2-bis(3-amino-4-hydroxyphenyl)hexafluoropropane. The crude yield was 12.6 g (98%). The purity in liquid chromatography was 98.3% (area %).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[C:6]([NH:10][C:11]1[C:12]([NH2:18])=[CH:13][CH:14]=[CH:15][C:16]=1[Cl:17])([CH3:9])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C.[I-].[Na+]>C1COCC1.C(#N)C>[C:6]([N:10]1[C:11]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[Cl:17])[NH:18][C:3](=[O:4])[CH2:2]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)Nc1c(N)cccc1Cl
Reactant: O=C(Br)CBr
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N1CC(=O)Nc2cccc(Cl)c21
Temperature: -78 °C

Procedure:
Bromoacetyl bromide (2.8 ml, 32 mmol) was added drop wise to a solution of N*2*-tert-butyl-3-chlorobenzene-1,2-diamine from Example 12B (4.1 g, 21 mmol) and diisopropylethylamine (11 ml, 63 mmol) in THF (75 ml) while cooling to −78° C. The mixture was allowed to warm to room temperature over 18 h and the solvent was evaporated. Chloroform was added and the mixture was washed with sodium hydrogen carbonate, dried and evaporated. To the residue were added acetonitrile (90 ml), diisopropylethylamine (5.6 ml, 32 mmol) and sodium iodide (3.2 g, 21 mmol). The mixture was heated at reflux for 18 h, cooled and evaporated. The residue was taken up in chloroform, washed with water, dried and evaporated. The residue was purified by flash chromatography on silica (eluant pet.ether:EtOAc 100:0 to 50:50) to give an orange solid; yield 1.5 g, 29%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.CC(C)(C)C(Cl)=O.[Li+].[Cl-].[CH3:23][C@H:24]1[C@@H:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][C:26](=[O:35])[NH:25]1>C(N(CC)CC)C.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([N:25]1[C@H:24]([CH3:23])[C@H:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][C:26]1=[O:35])=[O:13]
Reactant: O=C(O)CCc1ccc(F)cc1F
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A flask was charged with 29.5 g (158 mmol) of 3-(2,4-difluoro-phenyl)-propionic acid, 700 mL of THF, and 82.8 mL of triethylamine. The mixture was cooled to 0° C. and 23.4 mL of trimethyl acetyl chloride was added slowly. The mixture was stirred cold for 1 hour. Then 8.06 g (190 mmol) of LiCl and 28.1 g of (4S,5R)-4-methyl-5-phenyl-oxazolidin-2-one was added. The mixture was allowed to warm room temperature and stirred overnight. The solids were filtered off, and the solvent was removed under reduced pressure. The residue was taken up in diethyl ether and washed with sat. aq. ammonium chloride, sat. aq. sodium bicarbonate, and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography (3:1 dichloromethane/hexanes eluent) to give 54 g (99% yield) of the titled compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[CH2:28]([SH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.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].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>[CH2:28]([S:35][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Clc1ccnc2cc(Br)ccc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1ccnc2cc(SCc3ccccc3)ccc12
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
A 250-mL 3-neck round-bottom flask was charged with 7-bromo-4-chloroquinoline (BioBlocks, Inc., San Diego, Calif.; 7.000 g, 28.9 mmol), Xantphos (0.835 g, 1.443 mmol), and Pd2(dba)3 (0.661 g, 0.722 mmol), and after flushing with argon, dioxane (57.7 ml) and n,n-diisopropylethylamine (10.08 ml, 57.7 mmol) were added in sequence. The flask was fitted with a reflux condenser, and was placed in a heating bath at 80° C. for 10 minutes, after which benzyl mercaptan (3.58 ml, 30.3 mmol) was added drop wise via syringe. The reaction was stirred for 20 minutes until completion. The material was diluted with water, and washed with DCM (×3), and the combined organics were dried via phase separator (Radley's Technology) and concentrated under a vacuum. Upon dissolving the material in DCM, solids remained out of solution, and they were filtered off and washed with DCM. The corresponding filtrate was concentrated under a vacuum and purified via silica gel chromatography (120-g column) eluting with 0 to 100% ethyl acetate in heptanes to yield 7-(benzylthio)-4-chloroquinoline (7.35 g, 25.7 mmol, 89% yield) as a light yellow solid. m/z (ESI) 286.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][C:37]([F:41])([F:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:41][C:37]1([F:40])[CH2:38][CH2:39][N:34]([CH:32]2[CH2:33][N:30]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:31]2)[CH2:35][CH2:36]1
Reactant: FC1(F)CCN(C2CNC2)CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(F)(F)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.1 g, 0.26 mmol), 1-azetidin-3-yl-4,4-difluoropiperidine (0.087 g, 0.38 mmol) and 4 Å molecular sieves (0.6 g) in DCE (6 mL)was stirred for 18 h at room temperature. Sodium triacetoxyborohydride (0.109 g, 0.51 mmol) was added and the reaction mixture was stirred for 5 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 3:97) to give 492 as a yellow solid (0.097 g, 69%). LCMS (Method I): RT=2.82 min, [M+H]+ 552.3. 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.99 (m, 1 H); 7.65-7.61 (m, 1 H); 7.28-7.21 (m, 2 H); 4.30-4.23 (m, 4 H); 3.87 (s, 2 H); 3.80-3.75 (m, 7 H); 3.46-3.43 (m, 2 H); 3.25 (q, J=7.4 Hz, 2 H); 3.01-2.98 (m, 3 H); 2.37-2.33 (m, 4 H); 2.00-1.87 (m, 4 H); 1.33 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH:25]3[CH2:27][CH2:26]3)[CH3:24])=[CH:12][C:11]=2F)=O)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH:25]4[CH2:27][CH2:26]4)[CH3:24])=[CH:12][C:11]=3[O:31][N:30]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CN(CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(F)c1)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCCCCCOc1ccc2c(-c3ccc(Br)cc3)noc2c1)C1CC1
Temperature: 90 °C
Yield: 51.9 %

Procedure:
A mixture of 0.15 g of (4-bromo-phenyl)-[4-[6-(cyclopropyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-methanone, 0.17 g of hydroxylamine.hydrochloride and 0.20 g of sodium acetate in 14 ml of ethanol is heated to 90° C. for 32 hrs. and then concentrated. The residue (containing the oxime corresponding to the starting ketone) is taken up in 50 ml of methylene chloride and washed with saturated aqueous sodium hydrogen carbonate solution and sodium chloride solution. The organic phase is dried and evaporated. The residue is dissolved in 15 ml of DMA and treated with 0.22 g of potassium carbonate. The mixture is heated at 130° C. for 5 hrs. For the working-up, the reaction mixture is filtered, the filtrate is concentrated and the residue is purified by chromatography (silica gel, toluene/acetone/triethylamine 92:7:1). There is obtained 0.077 g of [6-[3-(4-bromo-phenyl)-benzo[d]isoxazol-6-yloxy]hexyl]-cyclopropyl-methyl-amine which is converted into the fumarate, MS: m/e 443 (M+H+, 1 Br).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:32][CH:31]=1)[CH2:3][C@H:4]([OH:28])[C@@H:5]([N:13](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[NH2:13][C@H:5]([C@@H:4]([OH:28])[CH2:3][C@@H:2]([NH2:1])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:34][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Solvent: CO
Product: N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 130.1 %

Procedure:
A solution of the product of Example 2-2 (3.8 g) in methanol (65 mL) in a three-necked round bottom flask equipped with a condenser was flushed with nitrogen, treated with water (5 mL), ammonium formate (2.5 g) and Pd/C (1.0 g), and stirred under nitrogen at 60° C. for 12 hours. The reaction mixture was cooled, filtered, and concentrated. A solution of the residue in dichloromethane (100 mL) was washed with saturated aqueous NaHCO3 (3×50 mL). The isolated dichlormethane layer was concentrated to afford 3.3 g of the crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:26]([O:28]C)=[O:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)=[O:12].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:26]([OH:28])=[O:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)=[O:12]
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C[C@H](NC(=O)C=Cc2c(F)cccc2F)C(=O)O)c2ccccc21
Yield: 71.6 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 24 (1.1 g), 1 mol/L of an aqueous sodium hydroxide solution (4.0 mL), and methanol (40 mL), to give the captioned compound (0.76 g, 74%) as crystals.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([Si:9]([CH2:13][CH3:14])([CH2:11][CH3:12])Cl)[CH3:8].[OH:15][C@@H:16]([C@@H:18]1[C@@H:21]([C@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[NH:20][C:19]1=[O:33])[CH3:17]>C(Cl)Cl>[CH2:7]([Si:9]([CH2:13][CH3:14])([CH2:11][CH3:12])[O:15][C@@H:16]([C@@H:18]1[C@@H:21]([C@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[NH:20][C:19]1=[O:33])[CH3:17])[CH3:8]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@H]1CCc2ccccc2C1=O
Reactant: CC[Si](Cl)(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@H]1CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.06 ml of pyridine and 0.1 ml of triethylchlorosilane were added successively at 0° C. to 100 mg (0.39 mmol) of the hydroxyethyl compound from step 1 in 3 ml of anhydrous methylene chloride and then stirred at room temperature for 3 h. The reaction mixture was diluted with 10 ml of methylene chloride and washed successively with dilute hydrochloric acid, saturated NaHCO3 solution and water. After drying over sodium sulfate and concentration in vacuo, the residue was chromatographed on silica gel (eluent: toluene/ethyl acetate=1:2). Yield: 122 mg (85%). -1H-NMR (200 MHz, CDCl3): δ=0.50-0.70 (2×m, 6H and 9H, SiCH3CH3); 1.28 (d, 3H, CH--CH3); 1.95-2.38 (m, 2H, CH--CH2 --CH2); 2.76 (dt, 1H, CH--CH2 --CH2) 3.02-3.16 (m, 3H, CH--CH2 --CH2 and H-3); 4.23 (mc, 1H, CH--CH3); 4.43 (dd, 1H, H-4); 5.8 (bs, 1H, NH); 7.22-7.38 and 7.45-7.57 (2×m, 3 H, aromatic H); 8.02 (dd, 1H, aromatic H).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[C:51]1([N:57]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59]([CH2:66][NH2:67])=[N:58]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[CH3:17][CH:16]([CH3:18])[CH2:15][C@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[C:12](=[O:14])[NH:67][CH2:66][C:59]1[C:60]2[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=2)[N:57]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:58]=1
Reactant: NCc1nn(-c2ccccc2)c2ccccc12
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)NCc1nn(-c2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.45 g, 1.8 mmol, Example 1, Step B) was dissolved in dry DMF (6 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N-methylmorpholine (0.68 mL, 6.1 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.70 g, 1.8 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; then a solution of C-(1-phenyl-1H-indazol-3-yl)-methylamine monohydrochloride (0.45 g, 1.8 mmol) in dry DMF (8 mL) was added. After additional 20 minutes stirring at 0° C., the ice-water bath was removed, and the reaction mixture was stirred and allowed to warm up to ambient temperature for 15 minutes. The reaction mixture was poured into 50 mL of EtOAc; the resulting mixture was successively washed with 3% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo affording an amber oil which was further purified by flash chromatography (80% EtOAC in hexanes). Finally, recrystallization from EtOAc-Hexanes afforded 0.39 g (48%) of the pure titled compound as a off-white solid: mp 135-136° C. APCI-MS m/z 462.0 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH2:9](B(CC)CC)[CH3:10].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O.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>[CH2:9]([C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1)[CH3:10]
Reactant: CCB(CC)CC
Reactant: Fc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(F)nc1

Procedure:
A mixture of 5-bromo-2-fluoropyridine (2-a, 5.03 g, 28.6 mmol, Lancaster Synthesis, Inc., Wyndham, N.H.), triethylborane (1M in tetrahydroftiran, 42.8 mL, 42.8 mmol), K2CO3 (15.8 g, 114.2 mmol) and Pd(PPh3)4 (1.65 g, 1.43 mmol) in N,N-dimethylformamide was heated at 85 C for 4 h. The reaction mixture was diluted with water and extracted with hexanes. The organic layer was then washed with water (×2), separated, dried (MgSO4), and concentrated in vacuo. Chromatography (50%, CH2Cl2 in hexanes) afforded the desired product (2-b); 1H NMR (500 MHz, CDCl3) δ 8.04 (d, 1H, J =1.0 Hz), 7.60 (dt, 1H, J=8.0, 2.5 Hz), 6.85 (dd, 1H, J=8.3, 2.8 Hz), 2.65 (q, 2H, J=7.8 Hz), 1.21 (t, 3H, J=7.7Hz)
Reaction SMILES: N(OC(C)(C)C)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([CH:15]=1)N.[CH3:17][S:18]SC>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([S:18][CH3:17])[CH:15]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CSc1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 504.3 %

Procedure:
t-Butyl nitrite (4 ml) was added to a mixture of 5-chloro-2-methylaniline (4 g) and dimethyl disulphide (26.3 g) in chloroform. After the reaction started t-butyl nitrite (17.7 ml) and 5-chloro-2-methylaniline (16 g) were added simultaneously. The mixture was stirred at room temperature for 2 hours and left to stand overnight. The mixture was washed with water, aqueous hydrochloric acid (2M), water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4-chloro-2-methylsulphenyltoluene (24.6 g) as a red oil, NMR (CDCl3): 2.2(s,3H), 2.4(s,3H), 6.85(s,2H), 7.0(s,1H).