Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28](Br)[CH:29]=4)[CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:35]([O:39][C:40]([N:42]1[CH:47]([C:48]2[NH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56](B4OC(C)(C)C(C)(C)O4)=[CH:55][CH:54]=3)=[CH:51][N:52]=2)[CH:46]2[CH2:68][CH:43]1[CH2:44][CH2:45]2)=[O:41])([CH3:38])([CH3:37])[CH3:36].C([O-])(O)=O.[Na+].N#N>COCCOC.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:35]([O:39][C:40]([N:42]1[CH:47]([C:48]2[NH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:28]4[CH:27]=[CH:26][C:25]5[C:30](=[CH:31][CH:32]=[C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:15][CH2:14]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:34])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=6)[CH:24]=5)[CH:29]=4)=[CH:55][CH:54]=3)=[CH:51][N:52]=2)[CH:46]2[CH2:68][CH:43]1[CH2:44][CH2:45]2)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 56.3 %

Procedure:
A solution of (1-{6-[5-(6-bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.00 g, 1.9 mmol), 3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.31 g, 2.8 mmol) and aq NaHCO3 (7.6 mL of a 1M solution, 7.6 mmol) in DME (20 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (110 mg, 0.095 mmol) and then the reaction was heated to 80° C. overnight. After cooling to room temperature, the solvent was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate. The organic phase was washed with H2O and then brine then dried over sodium sulfate. After filtration the solvent was removed from the filtrate under reduced pressure. The crude material was purified by silica gel chromatography (70-100% EtOAc/Hexanes) to afford 3-{5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (835 mg, 1.07 mmol, 56% yield). LCMS-ESI+: calc'd for C46H54N7O5: 784.4 (M+H+). Found: 784.8 (M−1-H+).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:38])[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([OH:37])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:23]([O:25][C:26](=[O:38])[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH2:2][C:3]3[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=4)=[N:7][CH:8]=3)=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[CH3:24]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)Cn1ccc2cc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3CCOC)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
To a solution of 300 mg (0.91 mmol) 5-chloromethyl-4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine and 199 mg (0.91 mmol) (5-hydroxy-indol-1-yl)-acetic acid ethyl ester in 5 ml DMF was added 443 mg (136 mmol) cesium carbonate. The reaction mixture was stirred at RT for 3 h and then taken up in ether, washed with 1N HCl and water. The crude product was purified by chromatography with AcOEt/heptane 1:4 to provide 152 mg of pure {5-[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:24]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:25]([NH2:27])=[O:26])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[N:21][OH:22])[NH2:20])=[CH:15][C:14]=2[F:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:34](OCC)(OCC)OCC.B(F)(F)F.CCOCC.CCOC(C)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[CH:34][O:22][N:21]=3)=[CH:15][C:14]=2[F:23])[C@H:24]([CH2:28][CH2:29][C:30]([F:32])([F:33])[F:31])[C:25]([NH2:27])=[O:26])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H](CCC(F)(F)F)N(Cc1ccc(C(N)=NO)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: NC(=O)[C@@H](CCC(F)(F)F)N(Cc1ccc(-c2ncon2)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution of (R)-2-(4-chloro-N-(4-cyano-2-fluorobenzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide (6.5 g, 13.6 mmol) in EtOH (70 mL) was added NH2OH (50% in H2O, 2.6 mL 40.8 mmol). The resulting mixture was stirred at 80° C. under nitrogen for 1 h and then cooled to rt. The solvents were evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water and dried over Na2SO4. Evaporation of the solvent gave a white solid which was recrystallized from EtOAc and hexanes to afford the intermediate amide oxime as a white solid (6.93 g, quantitative yield). To a mixture of the intermediate (R)-2-(4-chloro-N-(2-fluoro-4-(N′-hydroxycarbamimidoyl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide (6.93 g, 13.6 mmol) and triethyl orthoformate (6.77 mL, 40.8 mmol) in dichloroethane (30 mL) was added BF3.OEt2 (0.17 mL, 1.36 mmol). The resulting mixture was stirred at 70° C. for 1 h and then cooled to room temperature. Chromatography (silica gel, biotage, 40+M column, 3% to 80% EtOAc in hexanes, 651 mL) provided the title compound as a white solid. (4.9 g, 69.3% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[CH:5]=[C:6]2[C:15]=1[CH:14]=[CH:13][C:12]1[O:11][CH2:10][CH2:9][O:8][C:7]2=1>CC(O)C>[CH:7]([O:8][C:2]1[N:3]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[CH:5]=[C:6]2[C:15]=1[CH:14]=[CH:13][C:12]1[O:11][CH2:10][CH2:9][O:8][C:7]2=1)([CH3:12])[CH3:6]
Reactant: Cc1cc(Nc2cc3c4c(ccc3c(Cl)n2)OCCO4)n[nH]1
Solvent: CC(C)O
Product: Cc1cc(Nc2cc3c4c(ccc3c(OC(C)C)n2)OCCO4)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from (8-Chloro-2,3-dihydro-1,4-dioxa-7-aza-phenanthren-6-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-propanol to give (8-Isopropoxy-2,3-dihydro-1,4-dioxa-7-aza-phenanthren-6-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 341(MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])=[C:6]([CH3:17])[CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:30].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:30].[ClH:30].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])=[C:6]([CH3:17])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCOCCO
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)ccc1NCCOCCO

Procedure:
The 2-[2-(4-nitro-2-methylphenylamino)ethoxy]ethanol (13) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[N:12]=3)=[N:9][N:10]=[C:3]12.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[F:38].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C=O)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:2]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]3[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]5)=[C:13]([O:23][CH3:24])[N:12]=4)=[N:9][N:10]=[C:3]23)=[CH:33][C:32]=1[F:38]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2ccc(Cl)c(F)c2)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A mixture of ethyl 8-chloro-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (200 mg), 4-chloro-3-fluorophenol (73.8 mg) and potassium carbonate (66.3 mg) in DMF (2 mL) was stirred at 100° C. for 2 hr. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (73.5% mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(O[CH:12]=[C:13]([C:19](=[O:21])[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)(C)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:12]=[C:13]([C:19](=[O:21])[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1ccccc1Br
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Solvent: CC(C)O
Product: CCOC(=O)C(=CNc1ccccc1Br)C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
To a solution of 2-bromoaniline (2 g, 11.63 mmol) in Isopropanol (15 mL) stirred under nitrogen at room temperature was added neat ethyl 2-(ethoxymethylene)-3-oxobutanoate (2.165 g, 11.63 mmol) in one charge. The reaction mixture was stirred at room temperature for 20 min, at which time LCMS showed only a trace amount of product. The reaction mixture was heated to 75° C. and stirred for 20 min. LCMS showed complete conversion. The mixture was cooled to room temperature and concentrated under vacuum, during which time a large amount of material precipitated out. Filtration followed by a hexanes wash afforded ethyl 2-(((2-bromophenyl)amino)methylene)-3-oxobutanoate (3.8 g, 10.96 mmol, 94% yield) that was apx. 90% pure to be used in the next step. LCMS: (M+H)+: 312.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1.C(O)(C)C>Cl>[ClH:1].[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]4[CH:21]=[N:20][CH:19]=[N:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[C:25]([F:30])[CH:24]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1cncn1
Reactant: Nc1ccc(Br)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCn1cncn1
Temperature: 80 °C
Yield: 15.8 %

Procedure:
A suspension of 4-chloro-7-(2-(1,2,4-triazol-1-yl)ethoxy)-6-methoxyquinazoline (214 mg, 0.7 mmol), 4-bromo-2-fluoroaniline (160 mg, 0.84 mmol) in isopropanolic hydrogen chloride (1 ml of a 5M solution) and isopropanol (5ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool, the precipitate was collected by filtration, washed with isopropanol and then ether and dried under vacuum at 70° C. to give 4-(4-bromo-2-fluoroanilino)-7-(2-(1,2,4-triazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (55 mg, 15%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([N+:21]([O-])=O)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2]>C1COCC1.CO.[Pd]>[NH2:21][C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:12][C:13]=2[CH:20]=1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N)ccc21

Procedure:
2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-5-nitro-benzimidazole (5.5 g, 18 mmol) in 150 mL THF and 75 mL methanol is hydrogenated in the presence of 1.0 g of 5% Pd/C at ambient temperature under normal pressure. The catalyst is filtered off, the filtrate is evaporated, not quite to dryness, diluted with 100 mL of acetonitrile and evaporated down to a residual volume of 30 mL. The crystal slurry is cooled and filtered. The crystals are washed with cold acetonitrile and ether.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:37]=2[CH:38]=[N:39][NH:40]3)O1>>[NH:40]1[C:41]2[C:37](=[C:36]([C:2]3[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]4[CH:10]=[C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]5)[S:8][C:6]=4[N:7]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[N:39]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine 32 from Example 5 was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole 7 and General Procedure A to give Formula IIa compound which was purified using flash chromatography (US 2008/0076758; WO 2006/046031, incorporated by reference herein). 400 MHz 1H NMR CDCl3: 2.67 (m, 4H, 2×CH2), 2.81 (s, 3H, CH3), 3.30 (m, 4H, 2×CH2), 3.83 (s, 2H, CH2), 3.92-3.94 (m, 4H, 2×CH2), 3.98-4.00 (m, 4H, 2×CH2), 7.17 (s, H, ArH), 7.50 (t, H, ArH, J=7.81 Hz), 7.59 (d, H, ArH, J=8.31 Hz), 8.31 (d, H, ArH, J=6.98 Hz), 10.12 (sbr, H, NH). MH+=514.10
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[O-]S([O-])(=O)=O.[Mg+2].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][C:26]3([NH:1][C:2]4[CH:6]=[C:5]([C:7]5[CH:8]=[N:9][NH:10][C:11]=5[CH3:12])[S:4][C:3]=4[C:13](=[O:14])[NH:15]3)[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Reactant: O=C1CCN(c2ccc(F)cc2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCN(c3ccc(F)cc3)CC1)N2
Temperature: 100 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene -2-carboxamide (111 mg, 0.50 mmol), N-(4-fluorophenyl)-piperidin-4-one (290 mg, 1.50 mmol), MgSO4 (120 mg, 1.00 mmol), CSA (11.6 mg, 0.05 mmol) and DMA (4 mL) was stirred at 100° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF, and the extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, EtOAc to 80:20 EtOAc/MeOH). The obtained residue was triturated with EtOAc, and the precipitates were collected by filtration to afford the title compound (102 mg, 51%) as a light yellow solid:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Br[C:6]([CH3:17])([CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8]>C(=S)=S>[F:15][C:12]1[CH:11]=[C:10]2[C:9](=[CH:14][CH:13]=1)[C:7](=[O:8])[CH:6]([CH3:17])[CH2:16]2
Reactant: CC(C)(Br)C(=O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1Cc2cc(F)ccc2C1=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a slurry of 120.2 g. (0.90 mole) of anhydrous aluminum chloride in 54 ml. of carbon disulfide is added 122.6 g. (0.50 mole) of 2-bromo-4'-fluoro-2-methylpropiophenone at 15°-20°C over one hour. The mixture is warmed to 50°C over one hour, stirred at 50°C for three hours and quenched in ice. The product is extracted into toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH:20]([F:22])[F:21])=[CH:17][CH:16]=[C:15]([F:23])[C:14]=3[Cl:24])[CH3:12])=[CH:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.CC1(C)[O:37][C@H:36]([CH2:38][N:39]2[C:43]([CH3:44])=[C:42](B3OC(C)(C)C(C)(C)O3)[C:41]([CH3:54])=[N:40]2)[CH2:35][O:34]1.C([O-])([O-])=O.[K+].[K+].O.Cl>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.O1CCOCC1>[Cl:24][C:14]1[C:15]([F:23])=[CH:16][CH:17]=[C:18]([O:19][CH:20]([F:22])[F:21])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:42]3[C:41]([CH3:54])=[N:40][N:39]([CH2:38][C@@H:36]([OH:37])[CH2:35][OH:34])[C:43]=3[CH3:44])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: Cc1nn(C[C@@H]2COC(C)(C)O2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H](c1c(OC(F)F)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(C[C@@H](O)CO)c(C)c1-c1cnc2[nH]cc([C@H](C)c3c(OC(F)F)ccc(F)c3Cl)c2c1
Temperature: 40 °C

Procedure:
A mixture of tert-butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]-ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (10.0 mg, 0.0192 mmol), 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12.9 mg, 0.0385 mmol), Pd(PPh3)4 (1.1 mg, 0.00096 mmol), K2CO3 (7.98 mg, 0.00577 mmol) and 4:1 dioxane:H2O (0.7 mL, 8 mmol) was heated in a microwave reactor at 100° C. for 45 min. 12 M of HCl in H2O (0.04 mL, 0.5 mmol) was added, and the solution was heated to 40° C. for 20 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.84 (d, J=7.3 Hz, 3H), 2.04 (s, 3H), 2.17 (s, 3H), 3.50-3.61 (m, 2H), 3.96-4.10 (m, 2H), 4.13-4.19 (m, 1H), 5.07-5.15 (m, 1H), 6.43 (br. s., 1H), 7.12 (dd, J=9.2, 4.4 Hz, 1H), 7.19 (t, J=8.7 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 7.41 (d, J=1.3 Hz, 1H), 7.96-8.04 (m, 1H). MS (ES+): m/z=509.15/511.15 (100/50) [MH+]. HPLC: tR=1.33 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2].[CH3:10][C:11]([CH3:13])=O.C(O)(=O)C.C([O-])(=O)C.[NH4+]>CN(C)C=O.[C].[Pd]>[C:1]([CH:3]([CH:11]([CH3:13])[CH3:10])[C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2]
Reactant: CC(C)=O
Reactant: N#CCC(=O)NC(N)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)C(C#N)C(=O)NC(N)=O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Cyanoacetylurea (116.1 g) was suspended in N,N-dimethylformamide (219.3 ml), and acetone (73.1 ml), acetic acid (10.8 ml) and ammonium acetate (6.93 g) were added. This suspension was subjected to catalytic hydrogenation in the presence of 10% palladium carbon (2.33 g, 50% wet product) under hydrogen pressure at 10 kg/cm2 and at 25° C. for 4 hours. The reaction mixture was heated to 70° C., and the catalyst was filtered off. Water (745 ml) was added to the filtrate to allow precipitation of crystals. The crystals were collected by filtration to give crystals of N-(2-cyano-3-methylbutanoyl)urea (yield 134.5 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:20](O)=[O:21])[C:13](=[O:28])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[O:42][NH2:43]>O>[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]([NH:43][O:42][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)=[O:21])[C:13](=[O:28])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(CCn1ccc(OCCCC2CCCCC2)cc1=O)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Solvent: O
Solvent: CN1CCOCC1
Product: CC(CCn1ccc(OCCCC2CCCCC2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
4-[4-(3-Cyclohexylpropoxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (190 mg, 0.451 mmol) and CDMT (95.6 mg, 0.539 mmol) were charged into a flask. The flask was flushed with nitrogen and 2-MeTHF (10 ml) was added, followed by NMM (64 uL, 0.581 mmol). The reaction mixture was stirred at RT for 1 hour. O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (64 mg, 0.539 mmol) was added to the reaction mixture and stirred for 16 hours at RT. Water (25 ml) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3×50 ml). The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo. Crude material was purified by chromatography on silica gel (70% heptane:30% ethyl acetate to 100% ethyl acetate) to afford a white solid (220 mg, 79%). MS (LC/MS) m/z 511.1 (M−1) 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.93 (t, J=7.02 Hz, 3H) 1.12-1.42 (m, 9H) 1.49-1.99 (m, 10H) 2.25-2.43 (m, 1H) 2.45-2.64 (m, 1H) 3.12 (d, J=5.07 Hz, 3H) 3.51-3.68 (m, 2H) 3.82-4.03 (m, 4H) 4.08-4.26 (m, 2H) 5.03-5.14 (m, 1H) 5.94 (d, J=2.54 Hz, 1H) 6.07-6.21 (m, 1H) 7.45-7.60 (m, 1H).