Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:24])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:44][S:45]([C:48]1[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=1)(=[O:47])=[O:46].[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:24])/[C:13](/[C:51]1[CH:52]=[CH:53][C:48]([S:45]([CH3:44])(=[O:47])=[O:46])=[CH:49][CH:50]=1)=[CH:14]/[CH:15]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C(I)=C\C1CCCCCCC1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCCCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
A mixture of zinc dust (1.3 g, 20 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.38 g, 2 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (220 mg, 2 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclooctyl-2-iodo-acrylic acid methyl ester (3.22 g, 10 mmol) in dry tetrahydrofuran (4 mL) over 10 min. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (8 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (135 mg, 0.25 mmol) and triphenylphosphine (260 mg, 1 mmol) in dry tetrahydrofuran (10 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (2.12 g, 9 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. for 24 h The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (100 mL), and the organic compound was extracted into ethyl acetate (3×75 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-3-cyclooctyl-2-(4-(methanesulfonyl)-phenyl)-acrylic acid methyl ester (2.85 g, 90%) as a light yellow semi-solid: EI-HRMS m/e calcd for C19H26O4S (M+) 350.1552, found 350.1554.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([N:26]3[CH2:31][CH2:30][N:29](C)[CH2:28][CH2:27]3)=[N:16][N:17]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.O>CS(C)=O>[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([N:26]3[CH2:27][CH2:28][N:29]([C:2]#[N:1])[CH2:30][CH2:31]3)=[N:16][N:17]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:13][CH:12]=1
Reactant: CN1CCN(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCN(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To a stirred mixture of 1.6 g of cyanogen bromide, 2.1 g of potassium carbonate and 30 ml of dimethyl sulfoxide was added, dropwise, a solution of 4.8 g of 6-fluoro-3-(4-methyl-1-piperazinyl)-1-phenyl-1H-indazole in 30 ml of dimethylsulfoxide. The reaction mixture was stirred at ambient temperature for 2 hours and then poured into water. The resulting precipitate was recrystallized from ethanol to yield 2.3 g (48%) of 4-(6-fluoro-1-phenyl-1H-indazol-3-yl)-1-piperazine carbonitrile, m.p. 172°-174°.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:34]3[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=3)[C:9]=2[C:8]1=[O:20]
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C1c2c(-c3ccc(Cl)cc3)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 100.2 %

Procedure:
In a similar manner to Reference Example 4, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (300 mg) was reacted with 4-chlorophenylboronic acid (160 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (292 mg, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH:17]=3)[S:12][C:11]([CH3:33])([CH3:32])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=4)[CH:17]=3)[S:12][C:11]([CH3:32])([CH3:33])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(C2=CC(C)(C)Sc3ccc(CCc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 227, 940.0 mg, 2.08 mmol) in 10.0 mL THF and 5.0 mL EtOH was added NaOH (416.0 mg, 10.4 mmol, 5.2 mL of a 2M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 786.0 mg (89%) of the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.01 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.5 Hz), 7.42 (2H, m), 7.29 (2H, m), 7.22 (3H, m), 5.94 (1H, s), 2.69 (2H, q, J=7.7 Hz), 1.47 (6H, s), 1.25 (3H, t, J=7.7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[N:33]=[C:32]([NH2:34])[C:31]([N+:35]([O-])=O)=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.S1C=CC=C1.N.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[N:33]=[C:32]([NH2:34])[C:31]([NH2:35])=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: Nc1nc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: c1ccsc1
Solvent: CO
Product: Nc1ccc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)nc1N
Yield: 94 %

Procedure:
A mixture of 10 parts of N6 -[2-[4-[[1-[(4fluorophenyl)methyl]-1H-benzimidazol-2yl]amino]-1-piperidinyl]ethyl]-3-nitro-2,6-pyridinediamine, 3 parts of a solution of thiophene in methanol 4% and 400 parts of methanol, saturated with ammonia, was hydrogenated at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 9 parts (94%) of N6 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2,3,6-pyridinetriamine as a residue (intermediate 154).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[N:3]=1.[NH3:17]>>[NH2:17][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: COc1ccc2nc(Cl)c([N+](=O)[O-])cc2c1
Product: COc1ccc2nc(N)c([N+](=O)[O-])cc2c1
Temperature: 125 °C
Reaction time: 6 h

Procedure:
0.75 g of 2-chloro-6-methoxy-3-nitroquinoline (compound C3) are dissolved in 70 ml of ethanolic ammonia solution and stirred at 125° C. for 6 h in an autoclave. After cooling to room temperature, the reaction mixture is concentrated in vacuo and the residue redissolved in 30 ml of ethyl acetate and extracted two times each with 30 ml of halfsaturated aqueous potassium carbonate solution. The organic phase is dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is filtered over silica gel (dichloromethane/methanol 8:2). 0.64 g of the title compound are obtained as violet sold.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:28][C:29]1[CH:46]=[CH:45][C:32]([CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:46][CH:45]=3)=[CH:41][CH:40]=2)[C:3]=1[N:22]1[CH2:25][C:24]([F:27])([F:26])[CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(F)(F)C2)c1Br
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
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
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(F)(F)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
The Pd(Ph3P)4 (43.2 mg, 0.037 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (84 mg, 0.187 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (53.5 mg, 0.206 mmol), and sodium carbonate (139 mg, 1.31 mmol) in dioxane (2 mL) and water (0.15 mL) and stirred in a screw-capped pressure vessel for 4 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2SO4). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(4-(3,3-difluoroazetidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 60 mg (55%). 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.37 (m, 2H), 7.29 (d, J=8.1 Hz, 1H), 7.14 (t, J=8.8 Hz, 2H), 7.04-6.95 (m, 3H), 5.22 (s, 1H), 5.01-4.95 (m, 1H), 4.23 (t, J=7.0 Hz, 2H), 4.07-4.00 (m, 2H), 3.87-3.80 (m, 2H), 3.06 (t, J=7.0 Hz, 2H), 2.35 (s, 3H), 2.05 (s, 3H), 1.21 (d, J=6.2 Hz, 3H), 1.18 (d, J=6.2 Hz, 3H), 1.12 (s, 9H). UPLC (M+H)=586.4.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].N1C=CC=CC=1>CCCCCC>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Oc2ccccc2)CC1
Yield: 37.6 %

Procedure:
A reaction similar to Production example 2-1 using t-Butyl 4-aminopiperidin-1-ylcarboxylate (328 mg, 1.64 mmol), phenyl chloroformate (0.226 ml, 1.80 mmol) and pyridine (0.146 ml, 1.80 mmol); and the obtained crystals were suspended in hexane:ethyl acetate=4:1, filtered off, and the filtrate was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane:ethyl acetate=4:1 to 1:1). The purified crystals were then suspended in hexane:ethyl acetate=4:1 and filtered off. The title compound (215 mg, 0.617 mmol, 40.9%) was obtained as colorless crystals, together with the previously obtained crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[C:11]([CH:13]=2)[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[C:11]([NH:12][C:21](=[O:22])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccccc2)cc(-c2cccnc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccccc2)cc(-c2cccnc2)c1)Oc1ccccc1
Yield: 99.8 %

Procedure:
The title compound (0.289 g, 100%) was prepared by methodology of description 67 using 5-phenyl-3-(pyrid-3-yl) aniline (0.194 mg, 0.79 mmol), phenyl chloroformate (0.12 ml, 0.87 mmol) and triethylamine (0.12 ml, 0.81 mmol) in DCM (10 ml)
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:16][C:15](=[CH:17][C:18]4[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][C:19]=4[Cl:28])[CH2:14]3)[CH:10]=2)[CH:5]=[CH:4]1>CO>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:14][C:15](=[CH:17][C:18]4[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=4[Cl:28])[CH2:16]3)[CH:10]=2)[CH:5]=[CH:4]1
Reactant: COC(=O)c1ccc(C=C2CN(Cc3ccc4cc[nH]c4c3)C2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C=C2CN(Cc3ccc4cc[nH]c4c3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A 2 M aqueous solution of KOH (1.5 mL) was added to a solution of methyl 4-((1-((1H-indol-6-yl)methyl)azetidin-3-ylidene)methyl)-3-chlorobenzoate (0.3 g, 0.82 mmol) in MeOH (7 mL) and the mixture was stirred at room temperature overnight. The mixture was then evaporated under reduced pressure and water (10 mL) was added to the residue. The solution was carefully acidified to pH 5 with a 3 M aqueous solution of HCl. The precipitated solid was extracted with ethyl acetate. The EtOAc layer was washed with water (2×10 mL) and brine (1×15 mL). It was dried (Na2SO4), filtered, and concentrated in vacuo to give 4-((1-((1H-indol-6-yl)methyl)azetidin-3-ylidene)methyl)-3-chlorobenzoic acid as a white solid (0.26 g). ES+(M+H)+353.
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>C(OCC)C>[S:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][C:2]1=2
Reactant: O=C(O)c1cc2c(s1)CCC2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCc1cc2c(s1)CCC2

Procedure:
5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylic acid (commercially available: Matrix Chemicals) (0.5 g, 2.97 mmol) was suspended in dry diethyl ether (16 ml) and treated dropwise with a solution of lithium aluminium hydride (1.0 M solution in diethyl ether, 4.0 ml, 4.0 mol). The mixture was heated to reflux for 3 h and then cooled, treated dropwise with water (1.0 ml), then 1M HCl to dissolve the precipitated white solid. The product was extracted into diethyl ether (3×10 ml), dried over anhydrous magnesium sulphate and evaporated to afford 5,6-dihydro-4H-cyclopenta[b]thien-2-ylmethanol as a white solid (420 mg). This was dissolved in dichloromethane (60 ml) and treated with manganese dioxide (2.0 g). After stirring at room temperature overnight, the mixture was filtered through Kieselguhr and the solvent evaporated to afford the title compound as a yellow oil, (0.295 g, 64%).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]=[C:5]=[O:6].[N:7](=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)[OH:8]>CCOCC.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][NH:4][C:5]([O:8][N:7]=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)=[O:6]
Reactant: COCN=C=O
Reactant: CC1OCSC1=NO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COCNC(=O)ON=C1SCOC1C

Procedure:
A quantity of 5 ml of methoxymethyl isocyanate was caused to react with 5 grams of 4-oximino-5-methyl-1,3-oxathiolane dissolved in 100 ml of anhydrous ether containing 10 drops of triethylamine over a period of 48 hours at room temperature. Conventional workup and recrystallization from isopropyl ether/ethyl acetate afforded 5.5 grams of product, mp 78°-79°; structure confirmed by spectral analysis.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1)[C:25](=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)c1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of methyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (80 mg, 0.34 mmol, as prepared in the previous step) and triethylamine (118 μL, 0.850 mmol)) in 4 mL of CH2Cl2 was added acetic anhydride (320 μL, 3.40 mmol) via microsyringe and the reaction was allowed to stir overnight. At this time it was diluted with CHCl3 (50 mL), washed with satd aq NaHCO3 (2×50 mL), and dried (Na2SO4). Concentration of the solvent in vacuo and purification of the crude material using preparative TLC (4% MeOH—CHCl3) afforded 67 mg (71%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd. for C14H19N3O3, 278.1 (M+H), found 278.1.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=[C:8]([C:7]3[C:2]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:9]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(-c2cc(-c3cccnc3F)nc(N3CCOCC3)n2)cn1
Reactant: CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)Nc1ncccc1-c1cc(-c2ccc(N)nc2)nc(N2CCOCC2)n1
Temperature: 125 °C

Procedure:
To a solution of 5-[6-(2-fluoro-pyridin-3-yl)-2-morpholin-4-yl-pyrimidin-4-yl]-pyridin-2-ylamine (200 mg, 0.57 mmol) and methanesulfonamide (216 mg, 2.3 mmol) in NMP (8 mL) was added Cs2CO3 (372 mg, 1.1 mmol). The solution was heated at 125° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered and purified by reverse phase preparatory HPLC to give the title compound. LC/MS (m/z): 428.3 (MH+), Rt 1.80 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH2:15][CH3:16])[CH2:12][C:13]#[N:14].CN1CCOCC1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl.O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:15][CH3:16])[CH2:12][C:13]#[N:14])=[CH:22][CH:21]=1
Reactant: CCC(CC#N)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(CC#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 2 h

Procedure:
To a solution of the product from Step D (170 mg, 0.52 mmol) and N-methylmorpholine (105 mg, 1.04 mmol) in dichloromethane (15 mL) was added methanesulfonyl chloride (89 mg, 0.79 mmol) at room temperature. The mixture was stirred for 2 h, then diluted with water (15 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by PREP-TLC eluting with PE/EA (3/1, v/v) to give the title compound as a colorless amorphous solid. LC/MS m/z=402.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19]>C(O)=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:13])[F:14])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][C:22]([OH:24])=[O:23])=[O:19]
Reactant: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Solvent: O=CO
Solvent: O
Product: CCOC(=O)N(CC(=O)O)C(=O)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
A suspension of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(ethoxycarbonyl)glycine, 1,1-dimethylethyl ester (3.13 g, 6.39 mmol) in formic acid (120 mL) was stirred for 3 hours at room temperature under a dry nitrogen atmosphere. Dissolution occurred after an hour. The reaction mixture was diluted with water (1.5 L) and extracted with ether. The extracts were combined, washed well with water and concentrated to leave an oil. The oil was diluted with water and extracted with chloroform. The extracts were combined, dried over magnesium sulfate, filtered and concentrated. The crude solid was recrystallized from benzene:petroleum ether and dried overnight at 90° C. in vacuo to give the title compound as a white solid (2.31 g, 85%), m.p. 144°-146° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:22][C:23]1[CH:40]=[CH:39][C:26]2[S:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:22][C:23]1[CH:40]=[CH:39][C:26]2[S:27][C:28]([C:2]3[N:6]4[N:7]=[C:8]([NH:11][C:12]5[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=5)[CH:9]=[CH:10][C:5]4=[N:4][CH:3]=3)=[CH:29][C:25]=2[CH:24]=1
Reactant: CC1(C)OB(c2cc3cc(F)ccc3s2)OC1(C)C
Reactant: COc1ccc(Nc2ccc3ncc(Br)n3n2)cc1OC
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Nc2ccc3ncc(-c4cc5cc(F)ccc5s4)n3n2)cc1OC
Yield: 70.4 %

Procedure:
To a solution of 3-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazin-6-amine (118 mg, 0.338 mmol, 1.0 equiv) in acetonitrile (3.38 mL) was added 2-(5-fluorobenzo[b]thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (122 mg, 0.439 mmol, 1.3 equiv), bis(triphenylphosphine)palladium(II)dichloride (24 mg, 0.0338 mmol, 0.1 equiv), then sodium carbonate (3.38 mL, 1.0 M aqueous solution, 10 equiv). The reaction mixture was irradiated in the microwave at 150° C. for 10 min. Purification by column chromatography gave 100 mg of the brown solid, 70%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1ncc(CO)c(Cl)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CSc1ncc(C=O)c(Cl)n1
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Manganese(IV) oxide, <5 micron, activated (38.1 g, 439 mmol) was added to a solution of compound 223 (16.73 g, 87.8 mmol) in chloroform (800 mL). The reaction was stirred overnight, filtered through Celite, and the filtrate was concentrated in vacuo to yield compound 224 (13.7 g, 82.8% yield). 1H NMR (500 MHz, CDCl3) δ 10.31 (s, 1 H) 8.88 (s, 1 H) 2.65 (s, 2 H) ppm.