Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:18]([F:29])[CH:17]=3)[O:15][C:10]=2[C:9]([F:31])=[CH:8][C:7]=1[F:32].[N-:33]=[N+:34]=[N-:35].[Na+].O>CN(C)C=O>[N:33]([CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:18]([F:29])[CH:17]=3)[O:15][C:10]=2[C:9]([F:31])=[CH:8][C:7]=1[F:32])=[N+:34]=[N-:35]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCl)c(F)cc(F)c3o2)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCN=[N+]=[N-])c(F)cc(F)c3o2)cc1F
Temperature: 70 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
177 mg (0.38 mmol) of the resulting 5-(3-chloropropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was dissolved in 10 ml of dimethylformamide under argon atmosphere, 124 mg of sodium azide was added and the mixture was stirred at 70° C. for 18 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 179 mg (100%) of 5-(3-azidopropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:34][CH2:35][OH:36])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15](=[C:21]3[C:26](=[O:27])[N:25]([CH2:28][CH3:29])[C:24](=S)[N:23]([CH2:31][CH3:32])[C:22]3=[O:33])[CH:14]=2)=[CH:7][CH:6]=1.N1C=CC=CC=1.[O:43]1CCCC1>>[OH:1][CH2:2][CH2:3][N:4]([CH2:34][CH2:35][OH:36])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15](=[C:21]3[C:26](=[O:27])[N:25]([CH2:28][CH3:29])[C:24](=[O:43])[N:23]([CH2:31][CH3:32])[C:22]3=[O:33])[CH:14]=2)=[CH:7][CH:6]=1
Reactant: C1CCOC1
Reactant: CCN1C(=O)C(=C2C=C(C=Cc3ccc(N(CCO)CCO)cc3)CC(C)(C)C2)C(=O)N(CC)C1=S
Solvent: c1ccncc1
Product: CCN1C(=O)C(=C2C=C(C=Cc3ccc(N(CCO)CCO)cc3)CC(C)(C)C2)C(=O)N(CC)C1=O
Temperature: 20 °C

Procedure:
To 3.24 g of [3-[2-[4-[bis (2-hydroxyethyl) amino]phenyl]ethenyl] 5,5-dimethyl-2-cyclohexene-1-ylidene]-N,N'diethylthiobarbiturate and 2.93 g of hexafluorobisphenol A bischloroformate in 100 ml of THF (tetrahydrofuran) there was added dropwise in one hour 1.02 ml of pyridine, at 0° C. The reaction mixture was allowed to heat up to 20° C. After eighteen hours of stirring, the reaction product was precipitated in methanol. M.W.: 9,900, the Tg was measured to be 142°-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:17][OH:18].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:17][OH:18])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)C[C@@H](CO)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 125 °C
Yield: 82.9 %

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (0.85 g, 3.10 mmol), (S)-2-amino-4-methylpentan-1-ol (0.544 g, 4.64 mmol) and diisopropylethylamine (1.082 mL, 6.19 mmol) in DMA (Volume: 10 mL) was heated to 125° C. for 1.25 hr. After cooling to rt, ice cold water (˜60 ml) was added to the rapidly stirring reaction mixture. The reaction mixture was stirred for 15 minutes, was sonicated for 15 minutes and was stirred and additional 15 minutes. The resulting suspension was filtered and the filter cake was washed with water. Drying afforded (S)-6-bromo-4-(1-hydroxy-4-methylpentan-2-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (0.94 g, 2.57 mmol, 83% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (d, J=6.4 Hz, 3H) 0.91 (d, J=6.4 Hz, 3 H) 1.40 (m, 1 H) 1.56-1.60 (m, 1 H) 1.61-1.70 (m, 1 H) 3.39-3.48 (m, 1 H) 3.58 (m, 1 H) 4.08-4.17 (m, 1 H) 4.98 (dd, J=6.2, 4.8 Hz, 1 H) 7.04 (d, J=1.5 Hz, 1 H) 7.84 (d, J=1.8 Hz, 1 H) 8.21 (s, 1 H) 10.59 (d, J=8.6 Hz, 1 H). MS (ES+) m/z: 354.9, 356.9 (M+H); LC retention time: 2.517 min (analytical HPLC Method B).
Reaction SMILES: C(OC([N:11]1[CH2:17][C:16]2[CH:18]=[C:19]([O:25][CH3:26])[C:20]([N+:22]([O-])=O)=[CH:21][C:15]=2[NH:14][C:13](=[O:27])[CH2:12]1)=O)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:22][C:20]1[C:19]([O:25][CH3:26])=[CH:18][C:16]2[CH2:17][NH:11][CH2:12][C:13](=[O:27])[NH:14][C:15]=2[CH:21]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)NC(=O)CNC2
Reaction time: 18 h
Yield: 58.9 %

Procedure:
A solution of 7-methoxy-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (380 mg, 1.0 mmol) in ethyl acetate (50 mL) and ethanol (50 mL) was treated with 10% Pd on carbon (50 mg) and placed on a Paar shaker under an atmosphere of hydrogen gas (50 psi). After 18 hours LCMS indicated completion of reaction. The mixture was filtered and concentrated to give 8-amino-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (122 mg, 53%) as a tan solid, used without further purification; 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 6.64 (s, 1H), 6.33 (s, 1H), 4.72 (s, 2H), 3.72 (s, 3H), 3.67 (s, 2H), 3.19 (s, 2H); MS (m/e) 208 (M+1); mp 196° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([OH:12])[C:5]2[S:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH3:1][N:2]1[C:7]([C:8]([NH:23][C:24]2[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:9])=[C:6]([OH:12])[C:5]2[S:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: Nc1ncccc1O
Reactant: COC(=O)C1=C(O)c2sc3cc(C)ccc3c2S(=O)(=O)N1C
Product: Cc1ccc2c3c(sc2c1)C(O)=C(C(=O)Nc1ncccc1O)N(C)S3(=O)=O
Yield: 38 %

Procedure:
Prepared analogous to Example 1 from methyl 2,7-dimethyl-4-hydroxy-2H-[1]-benzothieno-[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-3-hydroxy-pyridine with a yield of 38% of theory.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Reactant: C1CCNC1
Product: Cc1cc(Cl)cc2c(-c3ccccc3)c(C(=O)O)c(N3CCCC3)nc12

Procedure:
The title compound was prepared in analogy to example 40 step D from 2,6-dichloro-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 40 step C) and pyrrolidine. Brown foam. MS (ESI): 367.0 (M+H)+.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([Br:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21])=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.O>[Br:19][C:17]1[C:16]([F:20])=[CH:15][C:14]([F:21])=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=1
Reactant: O=C(NC(=S)Nc1cc(Br)c(F)cc1F)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Nc1cc(Br)c(F)cc1F
Temperature: 70 °C
Reaction time: 15 h
Yield: 81.4 %

Procedure:
To a solution of 1-benzoyl-3-(5-bromo-2,4-difluoro-phenyl)-thiourea (1.70 g, 4.60 mmol) in THF (35.0 mL) was added a solution of NaOH (0.97 g, 24.25 mmol) in water (13.0 mL). The resulting reaction mixture was stirred at 70° C. for 15 h. After the completion of the reaction (TLC monitoring), THF was evaporated, added water and extracted with EtOAc (3×50 mL). The combined organics was washed with brine and concentrated to obtain the desired compound (1.0 g, 83%). MS: 267.03 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.[Br:11]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([Br:11])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(N)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)cnc(N)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred solution of 8.3 grams (0.063 mole) of 2-amino-3-cyano-4-methylpyridine in 125 mL of N,N-dimethylformamide is cooled in an ice bath, and a solution of 11.2 grams (0.063 mole) of N-bromosuccinimide in 125 mL of N,N-dimethylformamide is added dropwise during a 30 minute period, while maintaining the reaction mixture temperature at about 15°-25° C. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours. After this time, the reaction mixture is poured into 1 liter of aqueous 3N sodium hydroxide. The mixture is then diluted to a volume of about 1700 mL with distilled water. A solid precipitate is collected by filtration and dried under reduced pressure, yielding 2-amino-5-bromo-3-cyano-4-methylpyridine.
Reaction SMILES: B([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)(O)O.Br[C:17]1[C:18](=[O:26])[N:19]([CH3:25])[N:20]=[CH:21][C:22]=1[O:23][CH3:24].C(=O)([O-])[O-].[Na+].[Na+].Cl>CC#N.CO>[NH2:10][C@@H:9]([CH2:8][C:7]1[CH:14]=[CH:15][C:4]([C:17]2[C:18](=[O:26])[N:19]([CH3:25])[N:20]=[CH:21][C:22]=2[O:23][CH3:24])=[CH:5][CH:6]=1)[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: COc1cnn(C)c(=O)c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1cnn(C)c(=O)c1-c1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
4-Borono-L-phenylalanine (0.30 g, 1.0 mmol), 4-Bromo-5-methoxy-2-methyl-2H-pyridazin-3-one (0.35 g, 1.0 mmol), tetrakistriphenylphosphine palladium(0) (0.09 g), and 2.0 M aqueous sodium carbonate (3.0 mL) were refluxed in MeCN (900 mL) for 4 d. The mixture was acidified with 2.0 N HCl and treated with MeOH. The solid was filtered off and the mixture was concentrated in vacuo. The crude solid was purified using a Gilson HPLC containing a Kromasil column (10 u, 100 Å C18, column length 250×50 mm, gradient 100:0 to 10:90 H2O:MeCN) to give 2-(S)-Amino-3-[4-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-propionic acid. MS (ES+) 304.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:28])[C:22]3[CH:27]=[N:26][CH:25]=[CH:24][C:23]=3[CH:17]2[CH2:16]1)(=[O:14])=[O:13].[CH3:29]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:29][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:28])[C:22]3[CH:27]=[N:26][CH:25]=[CH:24][C:23]=3[CH:17]2[CH2:16]1)(=[O:14])=[O:13]
Reactant: CB1OB(C)OB(C)O1
Reactant: O=C1c2cnccc2C2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN12
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+]
Product: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN2C(=O)c3cnccc3C2C1
Temperature: 90 °C

Procedure:
A mixture of 2-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-1,3,4,10b-tetrahydropyrido[4′,3′:3,4]pyrrolo[1,2-a]pyrazin-6(2H)-one (250 mg), trimethylboroxin (0.190 mL), potassium carbonate (189 mg) and Pd(PPh3)4 (103 mg) was heated to 90° C. under argon for 18 hours. The reaction mixture was partitioned between EtOAc and aqueous saturated sodium bicarbonate solution. The aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with brine, dried through a hydrophobic frit and evaporated to a brown oil. This was purified by chromatography eluting with 0-5% methanol in DCM over 12 column volumes. The clean fractions were combined and evaporated to a pale yellow gum. This was purified further to remove triphenylphosphine oxide by MDAP. The clean fraction was evaporated to give the title compound as a white solid (46 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH4+].[Cl-]>C1COCC1>[CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A mechanically stirred solution of the resultant compound from Example 64 (10 g, 56.4 mmol) in dry THF (200 ml) under an atmosphere of nitrogen was treated with n-butyl-lithium in hexanes (1.05 equiv, 22.6 ml, 56.4 mmol, 2.5M) at -78° C. After stirring for an additional 20 min at -78° C., hydrocinnamoyl chloride (9.4 ml, 62 mmol, 1.1 equiv) was added and the reaction was allowed to warm to room temperature with stirring over 2 h. The clear reaction mixture was poured into 100 ml of saturated NH4Cl. The organic layer was removed and the resulting aqueous layer extracted three times with dichloromethane. The combined organic extracts were washed once with brine, dried (anhydrous sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude solid. This material was recrystallized from hot ethyl acetate/hexane at 0°-5° C. overnight. First crop yielded 12.9 g, mp 99°-100° C. Second crop afforded 3.6 g. Total yield 16.5 g (95%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][CH:16]=2)[CH2:11][CH:10]([NH:24]C(=O)OCC2C=CC=CC=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.[Pd]>[NH2:24][CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][N:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:35]
Reactant: O=C(NC1Cc2cc(-c3ccccc3)ncc2N(Cc2ccccc2)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC1Cc2cc(-c3ccccc3)ncc2N(Cc2ccccc2)C1=O
Yield: 67.3 %

Procedure:
To a solution of 3G (300 mg, 0.65 mmol) in THF (80 mL) and MeOH (80 niL) at RT was added palladium 5% wt. on activated carbon (150 mg). The reaction mixture was stirred under a hydrogen balloon for lh. The reaction was filtered and the filtrate concentrated to give the title compound as a foam (144 mg, 91%). LC/MS (method A): retention time=2.37 min, (M+H)+=330.
Reaction SMILES: [O:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)[CH3:2].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:2][O:1][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])=[CH:5][CH:4]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-methoxylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH2:15][O:16][SiH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].[Br:20]Br.C(OC(=O)C)C>ClCCl>[Br:20][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12]([CH2:15][O:16][SiH:17]([CH3:19])[CH3:18])=[N:13]2
Reactant: C[SiH](C)OCc1ccc2cccc(C(C)(C)C)c2n1
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[SiH](C)OCc1ccc2c(Br)ccc(C(C)(C)C)c2n1
Yield: 64.2 %

Procedure:
To a 500 mL flask was added 400 mL dichloromethane and 31.5 g 8-(t-butyl)dimethylsiloxyquinaldine. The mixture was vigorously stirred while 33.14 g bromine (Aldrich) dissolved in 20 mL dichloromethane was added dropwise. The reaction progress was monitored by TLC (5:95 ethylacetate:hexanes). The starting material was found to be completely consumed. Excess bromine was removed by addition of 200 mL of saturated sodium thiosulfate (Aldrich). The organic layer was separated, washed with 150 ml water, 150 ml brine and then dried over MgSO4. After filtering off the salts, the filtrate was concentrated to an oil which was purified by column chromatography, eluting with 20% dichloromethane/hexanes to give 26.04 g of 5-bromo-8-(t-butyl)dimethylsiloxyquinaldine (compound 2ii) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH3:37])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH3:37])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C

Procedure:
To 0.123 g (0.516 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.163 g (0.540 mmol) of the above prepared 3-chloromethyl-2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridine, dissolved in 4.7 ml of abs. acetonitrile, was added 0.184 g of Cs2CO3 (0.565 mmol). The reaction was stirred over night at ambient temperature. Pouring onto crashed ice/NH4Cl-solution, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2) yielded 0.243 g of pure title compound as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[C:17](=[O:31])[CH:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:38]=[C:39](B(O)O)[CH3:40]>CN(C=O)C.O>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:4]=[CH:3][C:2]([C:39]([CH3:40])=[CH2:38])=[CH:7][N:6]=4)[CH2:9][CH2:10]3)=[CH:16][C:17]2=[O:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: C=C(C)B(O)O
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ncc(Br)cn4)CC3)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)nc1
Temperature: 120 °C
Yield: 26.8 %

Procedure:
A mixture of 4-(1-(5-bromopyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (103 mg, 0.20 mmol), potassium carbonate (140 mg, 1.02 mmol, EMD) and prop-1-en-2-ylboronic acid (52.4 mg, 0.610 mmol) in DMF (1.8 mL) and Water (0.2 mL) was degassed by vacuum and purged with Argon. To the resulting mixture was added 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (16.72 mg, 0.020 mmol, Aldrich) and then heated under microwave conditions at 120° C. for 20 min. The reaction mixture was concentrated in vacuo to a brown solid. The solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in hexanes) to yield 25 mg of desired product as a light yellow solid. MS (ESI) 467 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:33])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C)C.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.O>[Cl-].[Na+].O>[CH:38]1([NH:41][C:2]2[C:3]3[C:10]([C:11]([C:13]4[C:14]([F:33])=[C:15]([NH:20][S:21]([C:24]5[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][CH3:32])=[CH:28][CH:29]=5)(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=4[F:19])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:40][CH2:39]1
Reactant: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(Cl)c34)c2F)cc1
Reactant: NC1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(NC5CC5)c34)c2F)cc1
Temperature: 80 °C
Yield: 101.7 %

Procedure:
To N-[3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide (P-1034, 50 mg, 0.10 mmol), 0.702 mL of isopropyl alcohol is added, followed by cyclopropylamine (79, 0.0357 mL, 70% aqueous solution, 0.509 mmol). The reaction is heated at 80° C. in an oil bath for 17 hours, then poured into water and brine and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (P-1040, 52 mg). MS (ESI) [M+H+]+=512.0.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([C:25]1([CH:28]([NH:31][C@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[C:29]#[N:30])[CH2:27][CH2:26]1)=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[C:25]1([C@H:28]([NH:31][C@H:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33])[C:29]#[N:30])[CH2:27][CH2:26]1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: C[C@H](NC(C#N)C1(C=O)CC1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)C1([C@@H](C#N)N[C@@H](C)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethyl orthoformate (0.2 mL, 1.20 mmol) and p-toluenesulfonate monohydrate (1 mg, 0.0053 mmol) were added to an ethanol (2.5 mL) solution of 2-(1-formylcyclopropyl)-2-{[(1S)-1-phenylethyl]amino}acetonitrile (102 mg, 0.447 mmol). The resulting mixture was stirred at room temperature for 2 hours and 30 minutes and then, at 50° C. for 4 hours. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The organic layer was washed with water and then, dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography, whereby the title compound was obtained as white crystals (40 mg, 30%, diastereomer ratio=81/19).
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Cl:17])[C:15]=1[OH:16])[C:11]#[N:12].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2](=[CH2:6])[C:3]([O:16][C:15]1[C:14]([Cl:17])=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[Cl:7])=[O:4]
Reactant: C=C(F)C(=O)Cl
Reactant: N#Cc1cc(Cl)c(O)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(F)C(=O)Oc1c(Cl)cc(C#N)cc1Cl
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
10 g (0.092 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were added dropwise, at a temperature of 5° C., with stirring and in the course of 20 minutes, to a solution of 16.7 g (0.089 mol) of 3,5-dichloro-4-hydroxybenzonitrile and 9 g (0.089 mol) of triethylamine in 200 ml of anhydrous methylene dichloride, and the reaction mixture was then stirred for a further 30 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of anhydrous methylene dichloride. After 0.005 g of hydroquinone monomethyl ether had been added, the volatile constituents in the mixture of filtrate and wash solution were removed by distillation, and the residue was recrystallized from boiling n-heptane. 18.7 g (81% of theory) of 2,6-dichloro-4-cyanophenyl α-fluoroacrylate were obtained, melting point 95° to 99° C.