Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O1CCCC1>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C>[CH2:10]([N:7]1[CH:8]=[CH:9][C:4](=[O:3])[CH:5]=[CH:6]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Oc1ccncc1
Reactant: CCCCCCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCn1ccc(=O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (2.04 g) in N,N-dimethylformamide (50 ml) was added 4-hydroxypyridine (5 g) at room temperature. Octyl bromide (9.08 ml) was added thereto. The mixture was stirred for 2 hours at 50° C. The reaction mixture was added to a mixture of brine (100 ml), tetrahydrofuran (100 ml) and ethyl acetate (100 ml). The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-octyl-4-pyridone (14.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[C:13]([CH3:14])=[CH:12][S:11][CH:10]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>CN(C=O)C>[CH2:35]([NH:39][C:16](=[O:18])[C:15]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[C:13]([CH3:14])=[CH:12][S:11][CH:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:20])[CH3:19])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)CN
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1-c1cscc1C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(C(C)(C)C(=O)NCC(C)C)ccc1-c1cscc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 2-(3-methoxy-4-(4-methylthiophen-3-yl)phenyl)-2-methylpropanoic acid (example 35b) (630 mg, 2.2 mmol) in DMF (7 mL) were added HOBt (297 mg, 2.2 mmol), EDC (434 mg, 2.2 mmol) and isobutyl amine (214 μL, 2.2 mmol). The mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was dissolved in EtOAc and successively washed with water, 10% citric acid, sat. NaHCO3 and water, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (30% EtOAc-hexanes) to give 190 mg (37%) of N-isobutyl-2-(3-methoxy-4-(4-methylthiophen-3-yl)phenyl)-2-methylpropanamide. 1H NMR (400 MHz, dMSO): δ 0.73-0.75 (d, 6H), 1.48 (s, 6H), 1.69-1.72 (m, 1H), 2.00 (s, 3H), 2.49-2.50 (m, 2H), 3.71 (s, 3H), 6.91-6.94 (m, 2H), 7.08-7.10 (d, 1H), 7.18 (s, 1H), 7.24-7.25 (d, 1H), 7.34-7.35 (t, 1H).
Reaction SMILES: CC1[NH:3][CH:4]=[C:5]([C:7](F)(F)F)[N:6]=1.[CH3:11][C:12]1([CH:16]=O)[CH2:15][O:14][CH2:13]1.O=C(C)C=O.FC(F)(F)C(=O)C=O>>[CH3:7][C:5]1[N:6]=[C:16]([C:12]2([CH3:11])[CH2:15][O:14][CH2:13]2)[NH:3][CH:4]=1
Reactant: CC1(C=O)COC1
Reactant: Cc1nc(C(F)(F)F)c[nH]1
Agent: CC(=O)C=O
Agent: O=CC(=O)C(F)(F)F
Product: Cc1c[nH]c(C2(C)COC2)n1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 16.2, except 3-methyloxetane-3-carbaldehyde was used in place of acetaldehyde and 2-oxopropanal was used in place of 3,3,3-trifluoro-2-oxopropanal (compound 16.1). m/z (ES+) 153 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:4][O:3]1.I([O-])(=O)(=O)=[O:18].[Na+]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[O:1]=[S:2]1(=[O:18])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:4][O:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)[C@H]1COS(=O)N1Cc1ccccc1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)[C@H]1COS(=O)(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To an ice-cooled solution of (4S)-2-oxo-3-benzyl-4-isopropyl-1,2,3-oxathiazolidine (6.00 g, 25.07 mmol) in acetonitrile (45 mL) and water (45.0 mL) was added ruthenium chloride (5.20 mg, 0.025 mmol) followed by sodium periodate (8.04 g, 37.6 mmol). The mixture was stirred for 1 h as ice bath melted and the reaction was gradually warmed to room temperature. The mixture was extracted with ether (3×50 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4), filtered, then concentrated. The resulting oil was purified by silica gel flash column chromatography to give the title compound (1.9 g) as a colorless oil. LCMS m/z=256.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.86 (d, J=7.1 Hz, 3H), 0.90 (d, J=7.1 Hz, 3H), 1.83-1.95 (m, 1H), 3.41-3.45 (m, 1H), 4.23-4.28 (m, 2H), 4.39-4.44 (m, 2H), 7.35-7.43 (m, 5H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([CH:6]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7]1)C.CC[O:18]C(C)=O>O1CCOCC1.O.C(O)CCC>[O:15]=[C:12]1[N:11]2[CH:6]([CH2:4][CH2:3][CH2:2][CH:1]=[O:18])[CH2:7][CH2:8][CH2:9][C:10]2=[N:14][O:13]1
Reactant: CCCC(C)C1CCCc2noc(=O)n21
Reactant: CCOC(C)=O
Solvent: CCCCO
Solvent: O
Solvent: C1COCCO1
Product: O=CCCCC1CCCc2noc(=O)n21

Procedure:
Ex-28) The product of Example 27 (0.42 g; 2 mmol) and NaIO4 (0.86 g; 4 mmol) were dissolved in a mixture of 12 mL of dioxane and 8 mL of H2O. Two drops of a 2% solution of OSO4 in n-butanol was added to the mixture. The reaction mixture was stirred until tlc (100% EtOAc) indicated that the starting material was consumed. A precipitate had formed and was filtered. This solid was washed with dioxane. The filtrate was concentrated and the residue was partitioned between H2O/CH2Cl2. The organic layer was dried over MgSO4 and concentrated to afford the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH2:24]([O:26]C(C1C=CN(C2C=CC(OC)=CC=2)C=1C)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:18]=[CH:19][C:20]([O:26][CH3:24])=[CH:21][CH:22]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn(-c2ccc(OC)cc2)c1C
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccccc1
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccc(OC)cc1

Procedure:
Prepared similarly according to a reaction sequence in Example 3 steps (a), (b), and (c) for the synthesis of 2,3-dibromo-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 1-(4-Methoxy-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. The title compound, ESI MS (m/z): 469 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: Cc1cccc(OCC#N)c1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(C)cccc4OCC#N)n3)cc2CC1

Procedure:
(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-3-methyl-phenoxy)-acetonitrile was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-methyl-phenoxy]-acetonitrile in an analogous manner to Example 1221d. Title compound isolated as a white foam, (60 mg, 45%) LCMS 493.18 (M+H), HPLC purity 99%, 1H-NMR (CDCl3, 400 MHz) δ:8.04 (s, 1H), 7.32-7.28 (m, 1H), 7.11-7.08 (m, 2H), 7.03 (s, 1H), 6.96-6.93, (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 6.57 (s, 1H), 4.70 (s, 2H), 3.55 (dd, J=5.6 Hz, 2H), 3.38 (s, 3H), 2.85-2.81 (m, 2H), 2.75 (dd, J=5.6 Hz, 2H), 2.72-2.67 (m, 6H), 2.28 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14](Br)=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=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>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=2[Cl:25])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Temperature: 150 °C
Yield: 58.8 %

Procedure:
In a sealed tube, a mixture of (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (4.48 g, 14.8 mmol, prepared according to Example 1, Step 1.3), 2,4-dichloro-benzeneboronic acid (4.24 g, 22.2 mmol), Pd(PPh3)4 (855 mg, 0.74 mmol) and Na2CO3 (2.0 M solution in water, 26 mL, 52.0 mmol) in DME (50 mL) was heated at 150° C. for 17 min in a microwave oven. The reaction mixture was cooled to RT, diluted in AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→100% TBME) to yield the title compound (3.2 g, 8.7 mmol, 59%) as a white solid. MS: 368 [M−1]+; HPLC: AtRet=1.69.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:22])[C:19]#[C:20][CH3:21].C(#N)CC.NC(=N)S>>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:22][CH2:18][C:19]#[C:20][CH3:21])#[N:2]
Reactant: CC#CCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Agent: N=C(N)S
Solvent: CCC#N
Product: CC#CCN=C(NC#N)NCCSCc1[nH]cnc1C
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea (3.00 g. 0.0111 mole) and 2-butyne-1-amine (3.07 g., 0.0445 mole) in 60 ml. of propionitrile was stirred at reflux for 40 hours. TLC assay of an aliquot of the reaction mixture showed a trace of the isothiourea starting material, so the mixture was refluxed for an additional 6 hours and then stirred at room temperature for 64 hours. The solvent (along with excess amine) was removed at reduced pressure and the residual gum was placed on silica gel (100-200 mesh) and eluted with a mixture of methylene chloride (97 parts) and methanol (3 parts). The middle fractions were combined and evaporated to give 1.81 g. of yellow gum. The gum was dissolved in 20 ml. of ethyl acetate and crystallized at -15° C. The resulting pale yellow solid (1.2 g.) was dissolved in 11 ml. of hot acetonitrile and recrystallized at -15° C.; yield 1.072 g., m.p. 128°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 3.5 h

Procedure:
In methanol (10 ml) were dissolved (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (0.40 g), methyl 3-mercaptopropionate (1.42 ml) and 28% sodium methoxide-methanol (1.25 ml) and the solution was refluxed. After 2 and after 3.5 hours, (0.53 ml and 0.32 ml each of) methyl 3-mercaptopropionate were added, and after 2.5 minutes, 28% sodium methoxide-methanol (0.63 ml) was added. At 4.5 hours after the beginning of heating, the oil bath was removed and the reaction mixture was cooled, neutralized with 1N hydrochloric acid (9.6 ml) and extracted with dichloromethane (100 ml). The extract was washed with saturated aqueous sodium chloride solution (20 ml) and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane-ethyl acetate=1:3). The desired fraction was concentrated and the resulting crystals were collected and washed with isopropyl ether to give (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 43:0.22 g) as colorless needles. m.p. 176°-178° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][S:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncsc1-c1cccc(F)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncsc3-c3cccc(F)c3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([NH:13][S:14]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])(=[O:16])=[O:15])[CH:5]=1.Br[CH2:28][CH2:29]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]2[O:12][CH2:29][CH2:28][N:13]([S:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])[C:6]=2[CH:5]=1)=[O:26]
Reactant: COC(=O)c1cc(NS(=O)(=O)c2cc(Cl)ccc2OC)c(O)c(OC)c1
Reactant: BrCCBr
Product: COC(=O)c1cc(OC)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=531.1 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-methoxy-benzoic acid methyl ester (example 42, step 2) and 1,2-dibromoethane, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C@@:5]12[C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([C:33](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1>ClCCl>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:19][C:13]2[O:14][CH2:15][C:16]([F:18])([F:17])[C@:5]3([N:12]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[S:8][CH2:7][CH2:6]3)=[CH:39][CH:38]=1
Reactant: NC1=N[C@@]2(CCSc3ccc(Br)cc32)C(F)(F)CO1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=N[C@@]3(CCSc4ccc(Br)cc43)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.7 %

Procedure:
A solution of (R)-6′-bromo-5,5-difluoro-5,6-dihydro spiro[[1,3]oxazine-4,4′-thiochroman]-2-amine (intermediate B6.9) (460 mg, 1.32 mmol) and triethylamine (267 mg, 2.63 mmol) in dichloromethane (10 ml) was cooled to 0° C. and 4,4′-dimethoxytritylchloride (469 mg, 1.38 mmol) was added. The reaction mixture was left to warm to room temperature and stirred for 15 hours. For the workup, the reaction mixture was evaporated and the residue directly purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=0:100 to 60:40 as the eluent. The (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-6′-bromo-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4′-thiochroman]-2-amine (789 mg, 92% yield) was obtained as a yellow foam. MS (ISP): m/z=651.0 [M+H]+ and 353.0 [M+2+H]+.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([NH:15][C@H:16]([C:24](O)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:8]([NH:15][C@H:16]([C:24]([NH:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]
Reactant: NCc1ccco1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1ccco1
Yield: 88.6 %

Procedure:
In substantially the same manner as Working Example 2, furfurylamine (2.91 g) was condensed with Boc-L-phenylalanine (8.75 g) to give N-(Boc-L-phenylalanyl)furfurylamine (9.14 g) (yield 89%). The Boc group of the product was deprotected by using TFA, and 0.43 g of thus-deprotected compound was condensed, in substantially the same manner as Working Example 42, with monoethyl ester of (2S,3S)-N-methylaziridine-2,3-dicarboxylic acid (0.28 g) to give the above-titled compound (Compound 89; 0.23 g) as white crystals (yield 36%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>C(#N)C>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Product: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To a suspension containing 0.16 g of 1,2-difluoro-4-nitrobenzene (2) and 0.28 mL of N-diisopropyl ethylamine (DIPEA) in 4 mL acetonitrile, 0.19 of 1-(4-methoxyphenyl)piperazine (1) was added. The reaction mixture was stirred at room temperature for over night (12 h). The reaction mixture was filtered to get the yellowish solid. Then the collected solid was washed with hexane to get nitro compound 3 (0.25 g, 75%). 1H NMR (400 MHz, CDCl3, δH): 8.01 (dd, J=8.8, 2.4 Hz, 1H), 7.93 (dd, J=12.8, 2.4 Hz, 1H), 6.99-6.97 (m, 3H), 6.89-6.87 (m, 2H), 3.79 (s, 3H), 3.47 (bs, 4H), 3.26 (d, J=4.8 Hz, 4H). 13C NMR (100 MHz, CDCl3, δC): 154.4, 151.9, 121.0, 118.9, 117.3, 114.6, 112.8, 112.5, 55.6, 51.0, 49.6.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1.Cl.[CH3:21][NH2:22].[OH-].[Na+]>O>[CH3:21][NH:22][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1
Reactant: CCCN1CCC[C@H]2Cc3nc(Cl)ccc3C[C@@H]21
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCC[C@H]2Cc3nc(NC)ccc3C[C@@H]21
Temperature: 240 °C
Yield: 57.2 %

Procedure:
A mixture of (±)-trans-2-chloro-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline hydrochloride (1.00 g, 3.32 mmol) and methylamine hydrochloride (10 g) was heated to 240° C. to form a homogeneous molten semi-solid. After 30 minutes the molten semi-solid was poured into water, made basic with dilute NaOH solution, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product as a brown solid. Purification by flash chromatography (10% methanol in methylene chloride, NH4OH) provided (±)-trans-2-methylamino-6-propyl-5,5a,6,7,8,9, 9a,10-octahydropyrido[2,3-g]quinoline (Rf=0.44, 493 mg 57% yield) as an orange solid. This material was converted to the dihydrochloride salt in a manner analogous to that set forth in Example 3. Recrystallization (methanol/ethyl acetate) gave the desired dihydrochloride as a tan solid. m.p.>250° C.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:5]2[C:6]([CH:10]=[CH2:11])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Cl:1][C:2]1[N:12]=[C:5]2[C:6](/[CH:10]=[CH:11]/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CN(c1ccccc1Br)S(C)(=O)=O
Reactant: C=Cc1cccn2nc(Cl)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(c1ccccc1/C=C/c1cccn2nc(Cl)nc12)S(C)(=O)=O
Temperature: 100 °C

Procedure:
196 c) A tube was charged with 2-chloro-8-vinyl-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.5568 mmol), N-(2-bromo-phenyl)-N-methyl-methanesulfonamide (140.0 mg, 0.5300 mmol), palladium acetate (4.0 mg, 0.018 mmol) and tri-o-tolylphosphine (26.0 mg, 0.0854 mmol), triethylamine (0.35 mL, 2.5 mmol) and acetonitrile (1 mL) under an atmosphere of nitrogen. The tube was sealed and the mixture was heated at 100° C. for 18 hours then cooled to room temperature, diluted with dichloromethane (30 mL) and washed with 2N Hydrochloric acid (10 mL). The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography (silica gel column 24 g and 10%→90% ethyl acetate:hexane). N-{2-[(E)-2-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-vinyl]-phenyl}-N-methyl-methanesulfonamide was isolated as a tan foam (0.133 g, 69%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (d, J=16.1 Hz, 1H), 8.40 (d, J=6.8 Hz, 1H), 7.86 (d, J=7.1 Hz, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.46-7.30 (m, 3H), 7.20-7.05 (m, 2H), 3.36 (s, 3H), 3.19 (s, 3H). MS=363, 365 (MH)+.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([Sn](CCCC)(CCCC)CCCC)[S:7][CH:8]=1)([CH3:3])[CH3:2].Cl[C:23]1[CH:32]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:30]2[C:25](=[C:26]([CH3:45])[CH:27]=[C:28]([O:43][CH3:44])[CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([C:4]1[N:5]=[C:6]([C:23]2[CH:32]=[C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C:30]3[C:25](=[C:26]([CH3:45])[CH:27]=[C:28]([O:43][CH3:44])[CH:29]=3)[N:24]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C(C)C)cs1
Reactant: COc1ccc(COc2cc(Cl)nc3c(C)cc(OC)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-c3nc(C(C)C)cs3)nc3c(C)cc(OC)cc23)cc1
Yield: 63 %

Procedure:
Compound 219 (100 mg, 0.29 mmol), compound 221f (242 mg, 0.35 mmol), and potassium carbonate (48 mg, 0.35 mmol) in degassed anhydrous DMF were stirred under microwave radiations at 80° C. for 1 hr. Solvent was removed under reduced pressure and the crude material was purified by chromatography on silica gel (Petroleum ether/DCM) to yield compound 222f as yellow powder in 63% yield. 1H NMR (CDCl3, 400 MHz) δ 1.40 (s, 3H), 1.42 (s, 3H), 2.80 (s, 314), 3.17-3.24 (m, 1H), 3.85 (s, 3H), 3.89 (s, 3H), 5.31 (s, 2H), 6.99 (d, J=9.10 Hz, 2H), 7.00 (s, 1H), 7.21 (m, 1H), 7.31 (d, J=2.93 Hz, 1H), 7.49 (d, J=9.10 Hz, 214), 7.79 (s, 1H).