Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2(CCN(C(OC(C)(C)C)=O)CC2)C2C(=CC([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=CC=2)N1.Br[C:33]1[CH:41]=[C:40]2[C:36]([C:37]([F:52])([F:51])[C:38](=[O:50])[N:39]2[CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])=[CH:35][CH:34]=1>>[F:51][C:37]1([F:52])[C:36]2[C:40](=[CH:41][C:33]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=[CH:34][CH:35]=2)[N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:38]1=[O:50]
Reactant: C[Si](C)(C)CCOCN1C(=O)C(F)(F)c2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1cc(B3OC(C)(C)C(C)(C)O3)ccc12
Product: CC1(C)OB(c2ccc3c(c2)N(COCC[Si](C)(C)C)C(=O)C3(F)F)OC1(C)C

Procedure:
Following the procedure described for intermediate 7.33 (Step 2), starting from 6-bromo-3,3-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one 7.35 (84 mg), 94 mg of crude 3,3-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one 7.36 was obtained. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH3:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Reactant: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c(=O)n1-c1ccc(F)cc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 86.3 %

Procedure:
A mixture of (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 21; 290 mg, 0.90 mmol) and iodomethane (0.15 mL, 2.3 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (magnesium sulfate), filtered, and evaporated to give (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (260 mg, 86%) as a yellow solid. ES(+)-MS (M+H) 335.
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].O1CCCC1.[O:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1.[Cl-].[NH4+]>C(OCC)C>[C:1]([C:13]1([OH:16])[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1)#[CH:2]
Reactant: C#C[Mg]Cl
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of ethynylmagnesium chloride in tetrahydrofuran (0.5 M, 12 ML, 6.0 mmol) was added with cooling in ah ice-water bath to a solution of tetrahydro-4H-pyran-4-one (0.496 g, 5.0 mmol) in diethyl ether (300 mL) dropwise over 15 min. The mixture was stirred at room temperature for 1 h. Aqueous saturated ammonium chloride solution (1.0.0 mL) was then added and mixture extracted with ether (2×20 mL). The ether layers were washed with saturated aqueous sodium chloride solution (20 mL), then combined, dried over MgSO4, filtered and concentrated to give 4-ethynyl-tetrahydro-pyran-4-ol as a colorless oil that solidified on standing. (0.60 g, 96.2% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH:19]([SH:21])[CH3:20]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:21][CH:19]([CH3:20])[CH3:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 96.6 %

Procedure:
4-Bromo-1-fluoro-2-nitrobenzene (1.0 g, 4.5 mmol) [Aldrich] and potassium carbonate (1.6 g, 11 mmol) were stirred in N,N-dimethylformamide (10 mL), and 2-propanethiol (0.42 mL, 4.5 mmol) was added. The mixture was heated to 100° C. for 16 hours. The mixture was cooled to rt, diluted with water (100 mL), and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, and evaporated to give the desired compound (1.2 g, 96%). 1H NMR (300 MHz, CDCl3): δ 8.27 (s, 1H), 7.62 (d, 1H), 7.38 (d, 1H), 3.55 (m, 1H), 1.40 (d, 6H).
Reaction SMILES: [OH:1][C:2]1([CH2:32][OH:33])[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:11]3[C:17](=[O:18])[NH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[Br:34]N1C(=O)CCC1=O>>[Br:34][C:14]1[C:12]2[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][C:2]([OH:1])([CH2:32][OH:33])[CH2:3][CH2:4]3)[N:9]=[C:10]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:21]=3)[C:11]=2[C:17](=[O:18])[NH:16][CH:15]=1
Reactant: COc1ccc(Nc2nc(N3CCC(O)(CO)CC3)nc3cc[nH]c(=O)c23)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Product: COc1ccc(Nc2nc(N3CCC(O)(CO)CC3)nc3c(Br)c[nH]c(=O)c23)cc1C(F)(F)F

Procedure:
The title compound was prepared as described in Example 183a by starting from 2-(4-hydroxy-4-(hydroxylmethyl)piperidin-1-yl)-4-(4-methoxy-3-(trifluoromethyl)phenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one and N-bromosuccinimide and continuing until the reaction yielded the title compound as pale brown solid. MS m/z: 544 and 546 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:42]=[CH:41][O:40][N:39]=2)=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O>[O:40]1[CH:41]=[CH:42][C:38]([C:35]2[CH:36]=[CH:37][C:32]([CH2:31][N:15]3[C:14](=[O:17])[N:11]4[N:12]=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[C:9]([C:18]5[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=5)[C:10]4=[N:16]3)=[CH:33][CH:34]=2)=[N:39]1
Reactant: BrCc1ccc(-c2ccon2)cc1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(Cc2ccc(-c3ccon3)cc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (0.27 g, 0.834 mmol), prepared as described in Example 244, in DMF (4 mL), potassium carbonate (0.23 g, 1.67 mmol) and 3-(4-(bromomethyl)phenyl)isoxazole (0.248 g, 1.04 mmol) were added. The resulting mixture was heated to 65° C. After 2 h, the reaction mixture was then cooled to RT and diluted with EtOAc (200 mL). The resultant solution was then washed with water and saturated aqueous NaCl. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with hexanes/EtOAc to give the title compound, 2-(4-(isoxazol-3-yl)benzyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, as a light yellow solid. HPLC RT: 2.60 min; 1H NMR (CDCl3): δ 8.64 (d, J=1.1 Hz, 1H), 8.63 (d, J=1.7 Hz, 1H), 8.45 (d, J=1.7 Hz, 1H), 8.20 (s, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.34 (m, 2H), 7.23 (m, 2H), 7.10 (m, 2H), 6.65 (d, J=2.2 Hz, 1H), 5.26 (s, 2H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[NH2:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[C:20](O)(=[O:24])[C:21](O)=[O:22]>Cl>[CH:1]1([N:7]2[C:8]3[C:9](=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)[NH:17][C:21](=[O:22])[C:20]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cc([N+](=O)[O-])ccc1NC1CCCCC1
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Yield: 22.3 %

Procedure:
A mixture of 0,9 g (3,1 mmol) N-cyclohexyl-2-amino-4-nitroaniline and 1,0 g (7, 9 mmol) oxalic acid dihydrate in 50 ml 4 N hydrochloric acid was refluxed for 5 h. After cooling to 25° C. the product was filtered off. The crude product was recrystallized (ether-water) to give 0,2 g (19%) 1-cyclo-hexyl-6-nitroquinoxaline-2,3(1H,4H)-dione. M.p. (DSC): decomp. 1H-NMR (DMSO-d6): 12.2 (1H, broad s), 8.1-7.7 (3H, m), 3.0-1.0 (11H, m).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[C:9]([CH3:15])[C:8]=1[CH3:16].Cl[C:18]1[N:23]=[C:22]([NH:24][CH3:25])[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][CH:19]=1>CN(C)C=O>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][C:18]2[N:23]=[C:22]([NH:24][CH3:25])[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][CH:19]=2)=[C:9]([CH3:15])[C:8]=1[CH3:16]
Reactant: COCOc1c(C)cc(O)c(C)c1C
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc(Oc2cc(C)c(OCOC)c(C)c2C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
To a suspension of 50 g of sodium hydride (55% by weight, washed with n-hexane) in 1000 ml of anhydrous N,N-dimethylformamide, 300 ml of a solution of 193 g of 4-methoxymethoxy-2,3,5-trimethylphenol in anhydrous N,N-dimethylformamide were added dropwise over one hour under ice cooling; the mixture was then stirred at room temperature for 2 hours. To the reaction mixture, 800 ml of a solution of 197 g of 6-chloro-2-methylamino-3-nitropyridine in anhydrous N,N-dimethylformamide were added dropwise over one hour under ice cooling, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was poured into iced water. To the resulting mixture, ethyl acetate and water were added. The insoluble product was collected by filtration and washed with water and ethanol, whereby 141 g of the title compound were obtained. Separately, the organic layer was separated from the filtrate and the water layer was extracted with ethyl acetate. The organic layer and extract were combined, followed by washing with saturated saline and drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was washed with ethanol, whereby 126 g of the title compound were obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[N:20]1([C:29](N2C=C[N+](C)=C2)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:29]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[O:30])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: C[n+]1ccn(C(=O)N2CCc3ccccc32)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCc2ccccc21

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(2,3-dihydro-indole-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to column chromatography(ethyl acetate/heptane, 1:5) (73%, crystals. HPLC-MS m/z=401.1) (M+1), Rt: 5.5 min.
Reaction SMILES: [O:1]=[C:2]1[N:11]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:21]I.Cl>CO>[CH3:19][CH:17]([CH3:18])[CH2:16][C@H:12]([N:11]1[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH3:21])[C:2]1=[O:1])[C:13]([OH:15])=[O:14]
Reactant: CC(C)C[C@@H](C(=O)O)n1c(=O)[nH]c2ccccc2c1=O
Reactant: CI
Agent: Cl
Solvent: CO
Product: CC(C)C[C@@H](C(=O)O)n1c(=O)c2ccccc2n(C)c1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of Compound 1 (0.5 g, 1.8 mmol) in 10 mL of MeOH/1N NaOH aq. solution (1:1) was added MeI (2 mL). The mixture was stirred at 80° C. in sealed tube overnight. The mixture was neutralized with concentrated HCl. Extracted by EtOAc and dried over MgSO4. Removing solvent gave the crude acid product, which used for next step without further purification. [M+H] calc'd for C15H18N2O4, 291; found, 291.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Br.Br[CH:8]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.C(N(CC)CC)C>C(#N)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:5]=[C:3]([NH:2][CH3:1])[S:4][C:8]=2[C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Reactant: CNC(N)=S
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNc1nc(-c2ccc(OC)cc2)c(-c2cccnc2)s1
Yield: 84.6 %

Procedure:
In 18 ml of acetonitrile was dissolved 242 mg of N-methylthiourea. In the solution was suspended 1.0 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide. To the suspension was added dropwise slowly 0.4 ml of triethylamine while stirring. The mixture was stirred for three hours at refluxing temperature, and the solvent was evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract was dried, then the solvent was evaporated off. The residue was recrystallized from ethyl acetate isopropyl ether to yield 650 mg (85%) of 4-(4-methoxyphenyl)-2-methylamino-5-(3-pyridyl)-1,3-thiazole, m.p. 158°-159° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.O.[C:28](OCC)(=O)C.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:24]([C:6]1[C:5]([CH2:3][OH:2])=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]([CH2:18][CH:19]=[CH2:28])=[C:8]([CH:21]([CH3:22])[CH3:23])[N:7]=1)([CH3:25])[CH3:26]
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: CCCCCC
Product: C=CCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and methyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1H NMR (300 MHz, CDCl3): δ 7.13 (m, 4 H), 5.73 (m, 1H) 4.81 (dd, J=4.8, 1.8 Hz, 2 H), 4.35 (s, 2 H), 3.43 (septet, J=6.6 Hz, 1 H), 3.21 (septet, J =6.6 Hz, 1 H), 3.07 (d, J=1.8 Hz, 2 H), 1.24 (m, 13 H). FAB-MS: calcd for (C21H26FNO) 327, found 328 (M+H). Anal. Calcd for C21H26FNO: C, 74.17; H, 7.71; N, 4.12; F, 5.59+0.7 H2O. Found: C, 74.17; H, 7.57; N, 3.94; F, 5.26. mp 69-71° C. Rf=0.35 (15% ethyl acetate/hexane).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:2].Cl.[H][H]>C(O)C.[Pt](=O)=O>[NH2:2][CH2:1][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n1CC#N
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n1CCN

Procedure:
A suspension of ethyl 1-cyanomethyl-3-phenyl-5-chloroindole-2-carboxylate (12 grams, 0.035 mole), and 0.15 grams of platinum dioxide in 200 ml absolute ethanol containing 45 ml of concentrated hydrochloric acid is shaken with hydrogen at 45 psi and 45° C, in a standard Parr apparatus. Hydrogenation is stopped after 5.5 lbs. of pressure drop is observed. After removal of catalyst by filtration the filtrate is taken to dryness under reduced pressure. The solid is stirred with water and refiltered and dried. This affords 13 grams of the hydrochloride, m.p. 196°-98° C. A sample is crystallized from ethanol, washed with acetone and dried. This material melts at 205°-206° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][CH2:25][CH2:26][NH2:27]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:27][CH2:26][CH2:25][NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[N:3]=1
Reactant: NCCNc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and N1-pyridin-2-yl-ethane-1,2-diamine in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[Li]CCCC.CCCCCC.[CH3:22][Sn:23](Cl)([CH3:25])[CH3:24]>C1COCC1>[CH3:22][Sn:23]([CH3:25])([CH3:24])[C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1csc(-c2cccs2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc(-c2cccs2)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a 3-necked flask equipped with a glass stopper, rubber septum and a nitrogen inlet was added 2,2′-bithiophene (10 g, 60.1 mmol) and anhydrous THF (100 mL). The dark (green) solution was cooled to 0° C. A 2.5 M solution of n-BuLi in hexane (26.4 mL, 66 mmol) was added via syringe. The reaction mixture was then stirred at 25° C. for 1.5 hours. The mixture was cooled to −78° C. and a 1.0 M solution of trimethylstannyl chloride in THF (66 mL, 66 mmol) was added slowly via syringe. The reaction mixture was allowed to warm to 25° C. and was stirred overnight. THF was removed in vacuo and the residue was dissolved in pentane (200 mL). The pentane layer was washed with water (3×200 mL), dried over MgSO4, and the pentane was removed in vacuo to yield a green oil. The oil was purified by vacuum distillation (118-120° C., 0.6 mmHg) to yield 12.5 g (64%) of product MS=330.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:6].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[N:8]([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:6]
Reactant: COC(=O)c1cccn1NC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1N(Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
Sodium hydride (105 mg, 2.24 mmol, 60% purity in mineral oil) was added in one portion to a stirred, ice/water-cooled solution of 1-tert-butoxycarbonylamino-1H-pyrrole-2-carboxylic acid methyl ester (448 mg, 1.86 mmol) and benzyl bromide (267 μL, 2.24 mmol) in DMF (8 mL); the mixture was stirred in the cold bath for 60 min, at which time TLC showed complete disappearance of starting material; then poured into diluted, cold ammonium chloride solution to quench, followed by extraction with EtOAc, then washed with water, and brine; the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was silica gel column purified to give the desired product (530 mg) as a clear oil. ESI (m/z): 353 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]([CH3:33])([CH3:32])[C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]([CH3:33])([CH3:32])[C:25]([OH:27])=[O:26])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C(=O)O)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
To a stirred suspension of tert-butyl 2-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-2-methylpropanoate (60 mg, 0.13 mmol) in 10 mL of dichloromethane was added drop-wise trifluoroacetic acid (4 mL) at room temperature. Then the mixture was stirred at room temperature for 16 hours. The solvent was evaporated at 40° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 40% acetonitrile/60% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 60% acetonitrile/40% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-2-methylpropanoic acid (21 mg, 40%) as a white solid. MS: (M+H)+=397; 1H NMR (300 MHz, DMSO): δ 12.93 (s, 1H), 12.52 (s, 1H), 9.13 (s, 1H), 8.55-8.54 (m, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.71 (dd, 1H, J=9.9, 1.8 Hz), 7.20 (t, 1H, J=2.1 Hz), 4.17 (s, 3H), 1.66 (s, 6H).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[Cl:26])[CH:22]([C:27](Cl)=[O:28])[CH2:21][C:20]2=[O:30].[OH-].[Na+]>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[Cl:26])[CH:22]([C:27]([N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[CH2:9][N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:28])[CH2:21][C:20]2=[O:30]
Reactant: O=C1CC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Reactant: C1CCN(CC2CCCCN2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CC(C(=O)N2CCCCC2CN2CCCCC2)c2cc(Cl)c(Cl)cc21
Yield: 52 %

Procedure:
From 1.5 g of 2-(piperidinomethyl)piperidine dihydrochloride, 2.5 g of 5,6-dichloro-3-oxoindan-1-carbonyl chloride and 45 ml of 1N aqueous sodium hydroxide solution. 1.1 g of the title compound was obtained, melting at 240°-245° C. (dec), using a procedure similar to that in Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([CH3:47])([CH3:46])[CH:44]=O)[CH2:39][CH2:38]1.N1CCCC1.C(Cl)Cl>C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:47][C:43]([N:40]4[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]4)([CH3:44])[CH3:46])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCC(O)CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.5 %

Procedure:
A mixture of (R)-3-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-oxopropanenitrile (150 mg, 0.31 mmol), 2-(4-hydroxy-1-piperidyl)-2-methyl-propanal (167 mg, 0.98 mmol), pyrrolidine (0.03 mL, 0.31 mmol) and DCM (10 mL) was stirred at room temp for 2 days and then diluted with aq. NaHCO3 (40 mL) and extracted with DCM. The organic was dried (MgSO4), filtered and concentrated to an oil. The crude material was purified at Isolera (25 g column: 30% iPrOH/DCM) to obtain the product which was isolated by lyophilization to provide 61 mg (32% yield) of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-hydroxypiperidin-1-yl)-4-methylpent-2-enenitrile as a powder. MS (pos. ion) m/z: 625 (M+1).