Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)([O-])=O.[CH3:25]O>[Pd]>[NH:15]1[CH2:14][CH2:13][CH:12]([N:11]2[C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[N:1]=[CH:25]2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c[n+]([O-])ccc2[N+](=O)[O-])CC1
Reactant: CO
Agent: [Pd]
Product: c1cc2ncn(C3CCNCC3)c2cn1

Procedure:
To a solution of tert-butyl 4-[(4-nitro-1-oxidopyridin-3-yl)amino]piperidine-1-carboxylate (4 g) in methanol (100 ml) was added 10% palladium on carbon (50 mg) and the mixture was placed under a hydrogen atmosphere (60 psi) for 48 hours. The mixture was filtered through Celite and evaporated to dryness to give the title compound as a solid, which was used without further purification. Yield 3.21 g. MS 293 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([N+:14]([O-])=O)=[CH:4][C:3]=1[N:17]1[C:22](=[O:23])[C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[N:19]([CH3:29])[C:18]1=[O:30].C(O)(=O)C.O>[Fe].C(O)C>[NH2:14][C:5]1[C:6]([C:8]#[C:9][Si:10]([CH3:13])([CH3:11])[CH3:12])=[CH:7][C:2]([F:1])=[C:3]([N:17]2[C:22](=[O:23])[C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[N:19]([CH3:29])[C:18]2=[O:30])[CH:4]=1
Reactant: Cc1c(C(F)(F)F)n(C)c(=O)n(-c2cc([N+](=O)[O-])c(C#C[Si](C)(C)C)cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1c(C(F)(F)F)n(C)c(=O)n(-c2cc(N)c(C#C[Si](C)(C)C)cc2F)c1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
A mixture consisting of 3-{2-fluoro-5-nitro-4-[2-(trimethylsilyl)-1-ethynyl]phenyl}-1,5-dimethyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (11.95 g), iron powder (15.68 g), acetic acid (14 ml), water (14 ml) and ethanol (280 ml) was heated to 80° C. and stirred for 3 hours. Then, the solvent was distilled off under reduced pressure. An aqueous sodium hydroxide solution was added thereto to make it alkaline. Then, methylene chloride was added thereto for extraction. After washing with water, it was dried over anhydrous magnesium sulfate. Then, methylene chloride was distilled off, and the resulting residue was crystallized from a mixed solvent of ethyl acetate and n-hexane (1:3 v/v) to obtain 3-{5-amino-2-fluoro-4-[2-(trimethylsilyl)-1-ethynyl]-phenyl}-1,5-dimethyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (7.70 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]4[C:13]([CH2:14][O:15][CH2:16][CH2:17]4)=[C:12]3[C:24]#[N:25])[CH:9]=2)[NH:4][N:3]=1.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.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>[F:26][C:27]1[N:32]=[CH:31][C:30]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH:11]4[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]5[C:13]([CH2:14][O:15][CH2:16][CH2:17]5)=[C:12]4[C:24]#[N:25])[CH:9]=3)[NH:4][N:3]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(Br)c3c2)C(C#N)=C2COCCN12
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: C1COCCO1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(-c4ccc(F)nc4)c3c2)C(C#N)=C2COCCN12
Temperature: 140 °C
Reaction time: 1.17 h
Yield: 49.3 %

Procedure:
To a degassed solution of 125 mg (0.315 mmol) 8-(3-bromo-1H-indazol-5-yl)-6-methyl-1,3,4,8-tetrahydropyrido[2,1-c][1,4]oxazine-7,9-dicarbonitrile (Example 12A) and 53.3 mg (0.379 mmol) (6-fluoropyridin-3-yl)boronic acid in anhydrous 1,4-dioxane (2.2 ml) were added under inert gas atmosphere 36.5 mg (0.032 mmol) tetrakis(triphenylphosphine)palladium(0) and aqueous sodium bicarbonate solution (2 M, 0.56 ml). The resulting mixture was stirred at 140° C. for 70 min under microwave conditions. After cooling to room temperature and concentration under reduced pressure, the remaining solid was dissolved in ethyl acetate (20 ml). The solution was subsequently washed with water and with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 95:5 v/v) to yield the title compound as a white solid (64 mg, 49% of th.).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[C:11]([NH2:15])=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl>C(O)(C)C.O1CCOCC1.C(Cl)Cl>[CH2:1]([N:4]1[C:10]2[C:11]([NH:15][C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=3)=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: C=CCN1CCNC(=O)c2cccc(N)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC(C)O
Product: C=CCN1CCNC(=O)c2cccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)c21
Temperature: 120 °C
Yield: 4.7 %

Procedure:
1-Allyl-9-amino-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (#) (68 mg, 0.31 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (#) (102 mg, 0.34 mmol) were combined in isopropanol (1 mL). 4 N HCl in dioxane (85 μL) was added, and the resulting mixture was heated to 120° C. in the microwave for 50 min. The resulting solution was diluted with CH2Cl2, washed with NaHCO3, dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-100% EtOAc in hexanes) to obtain 2-[2-(1-Allyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide as a white solid (7 mg, 3%). mp 186° C. (dec); LCMS: m/z=478.28 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.32 (m, 1H), 8.02 (s, 1H), 7.73 (m, 1H), 7.53 (m, 1H), 7.44 (m, 1H), 7.31 (m, 1H), 7.18 (m, 1H), 7.02 (m, 1H), 6.88 (m, 1H), 5.86 (m, 1H), 5.24 (m, 2H), 4.20 (m, 2H), 3.41 (m, 6H), 2.96 (d, J=4.5 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Product: c1cc(N2CCC(CN3CCCC3)CC2)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 9 and morpholine.
Reaction SMILES: [BrH:1].[O:2]1[CH2:13][CH:3]1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]>>[Br:1][CH2:13][CH:3]([OH:2])[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: Br
Reactant: CCOP(=O)(CC1CO1)OCC
Product: CCOP(=O)(CC(O)CBr)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
47% aqueous hydrobromic acid (82.8 g) was added dropwise to diethyl 2,3-epoxypropylphosphonate (77.6 g) under ice-cooling and with stirring over a five minute interval. After the stirring was continued for an hour under ice-cooling and for 3 hours at ambient temperature, the reaction mixture was extracted with ethyl acetate (500 ml). The ethyl acetate layer was separated, washed three times with saturated aqueous sodium bicarbonate solution (200 ml and 100 ml×2) and twice with saturated aqueous sodium chloride solution (100 ml×2), dried over magnesium sulfate and evaporated to dryness to give oily diethyl 3-bromo-2-hydroxypropylphosphonate (94.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Yield: 71 %

Procedure:
A stirred mixture of 7.8 grams (0.05 mole) of 3-fluoro-4-nitrophenol, 8.1 grams (0.05 mole) of 4-chlorophenylmethyl chloride and 6.9 grams (0.06 mole) of potassium carbonate in 80 mL of methyl ethyl ketone was heated at reflux for about 18 hours. After this time the reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 10.0 grams of 2-fluoro-4-(4-chlorophenylmethoxy)nitrobenzene, mp 86°-88° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7](C(O)=O)=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1.CCOCC>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[CH:7]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-n2cccc2)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCc1nc(-n2cccc2)cn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A suspension of 2-butyl-4-(1H-pyrrol-1yl)-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylic acid (Example 16, 50 mg) in toluene (10 mL) was heated at reflux for 1 hour. Evaporation gave a gummy solid that was redissolved in ether and evaporated again to give the title compound as a colorless powder. 1H-NMR (CDCl3) δ7.9 (d, 1H), 7.6 (m, 2H), 7.4 (d, 2H), 7.1 (d, 2H), 6.9 (d, 2H), 6.8 (s, 2H), 6.5 (s, 1H), 6.1 (s, 2H), 5.0 (s, 2H), 2.4 (t, 2H), 1.6 (m, 2H), 1.3 (m, 2H), 0.9 (t, 3H).
Reaction SMILES: [CH2:1](O)[CH3:2].Cl.[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH:15]1[CH2:24][CH2:23][CH2:22][C:21]2[N:20]=[C:19]([C:25]([OH:27])=[O:26])[CH:18]=[CH:17][C:16]1=2.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH:15]1[CH2:24][CH2:23][CH2:22][C:21]2[N:20]=[C:19]([C:25]([O:27][CH2:1][CH3:2])=[O:26])[CH:18]=[CH:17][C:16]1=2
Reactant: CCO
Reactant: O=C(O)c1ccc2c(n1)CCCC2NCCc1ccccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1O
Temperature: 25 °C

Procedure:
645 ml of anhydrous ethanol and 52 ml of a 4 N solution of hydrogen chloride in dioxane were added to 25.8 g (82.59 mmol) of 5-{[2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, and the mixture was stirred under reflux overnight. The reaction solution was then cooled to room temperature, and first ethyl acetate and then, slowly, saturated aqueous sodium bicarbonate solution were added. Subsequently, the organic phase was separated off, dried over sodium sulphate, filtered and concentrated to dryness. This gave 23.9 g (70.21 mmol, 85% of theory) of the target compound.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH2:15](Br)[CH3:16]>>[CH2:15]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)[CH3:16]
Reactant: CCBr
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Product: CCn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano [3,2-b]-indol- 4(5H)-one is alkylated with ethyl bromide to give 4.8 g of product, mp 103°-104°C, after recrystallization from methylene chloride-hexane.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:18])[C:11]=2[N:10]([CH3:38])[C:9]1=[O:39])(=O)C.O[Li].O>C1COCC1.O.C(Cl)Cl>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:15]2[C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][OH:4])[C:9](=[O:39])[N:10]([CH3:38])[C:11]=3[C:17]([CH3:18])=[C:16]2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:28])[F:29])[CH:20]=2)=[CH:32][CH:33]=1
Reactant: CC(=O)OCCCn1c(=O)c2c(c(C)c(-c3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2cccc(OC(F)(F)F)c2)n(Cc2ccc(Cl)cc2)c2c(=O)n(CCCO)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1,7-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (120 mg, 0.212 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (17.9 mg, 0.425 mmol). The reaction was stirred at RT for 30 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1,7-dimethyl-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidine-2,4 (3H,5H)-dione (15 mg, 27% yield) as a white solid. 1H NMR (CDCl3) δ: 7.49 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.13 (dd, J=16.3, 8.0 Hz, 3H), 7.04 (s, 1H), 6.71 (d, J=8.4 Hz, 2H), 5.46 (s, 2H), 4.31-4.15 (m, 2H), 3.74 (s, 3H), 3.65 (s, 1H), 3.50 (s, 2H), 2.20 (s, 3H), 1.98-1.81 (m, 2H). LCMS: MH+ 522 and TR=3.111 min.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35]C)=[O:34])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16]2([CH2:30][O:29]C(C)(C)O[CH2:26]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.CCN(C(C)C)C(C)C.C(N)(C)C>CO.C1COCC1.CC#N.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([OH:35])=[O:34])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16]2([CH2:30][O:29][CH2:26]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COc2ccccc2-3)COC(C)(C)OC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COC1)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
A catalytic amount of TsOH monohydrate was added to a suspension of methyl 14′-cyclohexyl-2,2-dimethylspiro[1,3-dioxane-5,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate (as prepared in Example 2, Step 3) in MeOH/THF 1:2 (0.03 M) and the solution was stirred at RT for 3 h. Filtration on a pad of neutral alumina with EtOAc afforded after removal of the solvent in vacuo, methyl 14-cyclohexyl-7,7-bis(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (quant). Triflic anhydride (2.8 eq) was added at 0° C. to a solution of this material in dry MeCN (0.05M), DIPEA (3.0 eq) was added and the mixture was stirred at 0° C. for 15 min, then further 3.0 eq of DIPEA were added; iPrNH2 (2 eq) was added, the mixture was transferred to a closed vessel and stirring was continued at 70° C. for 4 h. EtOAc was added, the organic phase was washed with water and brine, dried over Na2SO4 and the solvent was removed in vacuo. The residue was hydrolysed with aq. 1N KOH in dioxane (65° C., overnight); evaporation to dryness gave a residue that was purified by RP-HPLC affording the title compound (15%) and 14′-cyclohexyl-1-isopropylspiro[azetidine-3,7′-indolo[1,2-e][1,5]benzoxazocine]-111′-carboxylic acid (4%). 1H NMR (400 MHz, DMSO-d6, 330 K) δ 1.14-1.38 (m, 3H), 1.56-2.04 (m, 7H), 2.64-2.76 (m, 1H), 3.87 (d, J 15.6, 1H), 4.11 (d, J 6.1, 1H), 4.17 (d, J 12.5, 1H), 4.36 (d, J 6.1, 1H), 4.44 (d, J 12.5, 1H), 4.55 (d, J 6.3, 1H), 4.59 (d, J 6.1, 1H), 5.14 (d, J 15.4, 1H), 7.20-7.24 (m, 3H), 7.47 (bt, J 6.6, 1H), 7.66 (d, J 8.3, 1H), 7.85 (d, J 8.3, 1H), 8.38 (s, 1H); MS (ES+) m/z 418 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH3:17].[CH2:18]([O:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH2:17][C:30](=[O:31])[CH2:29][NH:28][C:26]([O:25][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:27]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(F)c(CNCC(=O)CNC(=O)OCc2ccccc2)c1
Yield: 101 %

Procedure:
According to the procedure of Preparation 4 (c), except using tert-butyl 4-fluoro-3-(methylaminomethyl)benzoate (4.00 g, 16.7 mmole), N-(benzyloxycarbonyl)glycine (3.50 g, 16.7 mmole), HOBt.H2O (2.3 g, 17 mmole), DCC (2.4 g, 11.6 mmole), and 1:1 DMF/CH2Cl2 (100 mL), the title compound (7.26 g, 100%) was prepared as a thick yellow oil following flash chromatography on silica gel (30% EtOAc/hexanes): MS (ES) m/e 431.02 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:33]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:32])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:31])[C:20]=2[N:21]2[CH2:26][CH2:25][NH:24][C@@H:23]([C:27]([F:30])([F:29])[F:28])[CH2:22]2)[N:13]=1.N>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:33][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:31])[C:20]=1[N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([C:27]([F:29])([F:30])[F:28])[CH2:22]1)=[O:32]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCN[C@@H](C(F)(F)F)C1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCN[C@H](C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of tert-Butyl (R)-2-(2,6-difluorophenyl)-4-(1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (80 mg, 0.126 mmol) in TFA (1 mL) and DCM (4 mL) was stirred at ambient temperature for 3 hours. The pH of the mixture was adjusted to about 8˜9 by addition of ammonia and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to afford 169 formic acid salt (40 mg, 73%) as white solid. 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.84 (s, 1H), 7.50-7.55 (m, 3H), 7.37 (s, 1H), 7.25-7.28 (m, 2H), 3.47 (s, 3H), 3.36-3.48 (m, 1H), 3.07-3.16 (m, 3H), 2.94-2.96 (m, 2H), 2.78-2.80 (m, 1H), 1.24 (s, 1H); MS (ESI) m/z=488.1 (M+1+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>ClCCl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:25])=[O:24])=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
To a stirred solution of morpholine (5.2 mL, 59.7 mmol) and triethylamine (11.2 mL, 79.6 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro-benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at room temperature for 4 h and then washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford 4-(4-nitro-benzenesulfonyl)-morpholine (10.0 g, 92.5%) as a white powder: MS (ESI) M+1=273.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:12]([C:13](=[O:14])[CH3:15])[C:11]([O:17][CH3:18])=[O:16])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccc(F)c(F)c1)C(C)=O

Procedure:
A mixture of 3,4-difluorobenzaldehyde (14.2 g, 0.1 mol), methyl acetoacetate (12.2 g, 0.105 mol), piperidine (0.430 g, 5 mmol), and acetic acid (0.30 g, 5 mmol) in benzene (150 mL) was stirred and refluxed with a Dean-Stark trap for 8 hours. Benzene was evaporated, the residue was dissolved in ethyl acetate (200 mL) and washed with brine (50 mL), saturated potassium bisulfate solution (50 mL), and saturated sodium bicarbonate solution in sequence. The ethyl acetate solution was dried (magnesium sulfate), solvent removed under reduced pressure and the residue was purified by column chromatography (SiO2, EtOAc/hexane, 10%-15%). The product, methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate, was obtained as a yellow oil (0.98 g, 98.3%) and was used in the next step without any further characterization.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:29](=O)/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[C:2]([OH:4])(=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:29][CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCC/C=C/C=O
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCC=CC=CCCCCC(=O)O
Yield: 42.6 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and 2-trans-octenal (2.52 g, 20 mmol) in 10% HMPA-THF (100 mL) by Wittig reaction. Kugelrohr distillation yielded the product (1.91 g, 43%) as a pale yellow oil (bp 122-125° C./0.01 torr). IR: 3500-2500, 1730 cm-1 ; 1H-NMR: 0.95 (t, 3H), 1.40 (m, 10H), 2.30 (m, 6H), 6.00 (m, 4H), 11.30 (bs, 1H). Anal. Calcd. for C14H24O2 : C, 74.95, H, 10.78%; Found: C, 75.04, H, 10.80%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCOCC1.O.O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(Cn2ccc3cc(Br)ccc32)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(Cn2ccc3cc(-c4ccccc4)ccc32)cc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 48.5 %

Procedure:
A mixture of 5-bromo-1-(4-methylbenzyl)-1H-indole (1.0 g, 3.33 mmol), benzeneboronic acid (0.621 g, 5.0 mmol), potassium carbonate (0.691 g, 5.0 mmol), and [1′1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with methylenechloride (1:1) (0.816 g, 1.0 mmol) in dioxane-water (10:1, 16.5 mL) was stirred at 70° C. for 2 day. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and brine, and then concentrated to an oil. The residue was purified by flash column chromatography using hexane/ethyl acetate (96:4) as an eluant to give the title compound as a semi-solid (0.48 g, 49%). Mass spectrum (+ESI, [M+H]+) m/z 298. 1HNMR (300 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.63 (d, 2H, J=8.4 Hz), 7.48 (d, 2H, J=11.1 Hz), 7.38-7.45 (m, 3H), 7.11 (m, 4H), 6.52 (d, 2H, J=2.8 Hz), 5.38 (s, 2H), and 2.22 ppm (s, 3H).