Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[S:12][C:13]([C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:14][C:15]=1[NH:16]C(=O)C(F)(F)F)=[O:10].O.C(OCC)(=O)C>CO>[CH3:7][O:8][C:9]([C:11]1[S:12][C:13]([C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:14][C:15]=1[NH2:16])=[O:10]
Reactant: COC(=O)c1sc(C(=O)C2CCCC2)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C(=O)C2CCCC2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (2.275 g) was added to a solution of 5-cyclopentanecarbonyl-3-(2,2,2-trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester (1.150 g) in methanol (17 mL), and the mixture was stirred at room temperature for 2 h. Water and ethyl acetate were added. The organic phase was separated off, and the aqueous phase was re-extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The product with the molecular weight of 253.32 (C12H15NO3S) was obtained in this way; MS (ESI): 254 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:13]C(=O)C)([CH3:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[OH-].[K+].Cl.C(OCC)C>C(O)CO.C(#N)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CC(C)(C)NC(C)=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: OCCO
Solvent: CCOCC
Product: CCc1ccc(CC(C)(C)N)cc1
Temperature: 0 °C

Procedure:
16.3 g (74 mmol) of N-[2-(4-ethylphenyl)-1,1-dimethylethyl]acetamide and 8.0 g of potassium hydroxide are refluxed for 15 hours in 60 mL ethylene glycol. The reaction mixture is combined with ice water and extracted three times with diethyl ether. The combined organic phases are washed with water, dried with sodium sulfate, and freed from solvent. To prepare the hydrochloride, the crude product is dissolved in acetonitrile and ethereal hydrochloric acid and diethyl ether are added successively. The solid precipitated is suction filtered and dried. Yield: 11.0 g (69%, hydrochloride); melting point 165° C.–167° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:17])=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12](Cl)[CH:11]=1)[NH2:5].[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)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>[Cl:1][C:2]1[C:3]([F:17])=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[CH:11]=1)[NH2:5]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(Cl)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3Cl)ccn2)cn1
Temperature: 80 °C
Yield: 25.6 %

Procedure:
A solution of 3-chloro-4-(2-chloropyridin-4-yloxy)-2-fluoroaniline (10 g, 36.8 mmol) in DMF (140 mL) and water (30 mL) was treated with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.4 g, 40.5 mmol), K3PO4 (14.9 g, 73.6 mmol) and Pd(PPh3)4 (4.3 g, 3.7 mmol), sparged with N2 and heated at 80° C. for 12 h. The mixture was cooled to RT, poured into water and extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography to afford 3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (3.0 g, 26%). 1H NMR (400 MHz, DMSO-d6): δ 8.32 (d, J=6.0 Hz, 1 H), 8.24 (s, 1 H), 7.95 (s, 1 H), 7.15 (d, J=1.6 Hz, 1 H), 6.94 (d, J=8.8 Hz, 1 H), 6.80 (t, J=8.8 Hz, 1 H), 6.54-6.52 (m, 1 H), 5.51 (s, 2 H), 3.85 (s, 3H); MS (ESI): m/z 318.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]([OH:32])=O)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.[NH:33]1[CH:37]=[C:36]([CH2:38]N)[CH:35]=[N:34]1.[CH:40]([N:43](C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[NH:34]1[CH:35]=[C:36]([CH2:38][CH2:40][NH:43][C:30]([C:29]2[C:22]3[C:21]([NH:20][C@H:18]([C:7]4[N:8]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:9](=[O:11])[C:10]5=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]5[N:6]=4)[CH3:19])=[N:26][CH:25]=[N:24][C:23]=3[NH:27][CH:28]=2)=[O:32])[CH:37]=[N:33]1
Reactant: NCc1cn[nH]c1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)NCCc5cn[nH]c5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 2.6 %

Procedure:
(S)-4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (50 mg, 0.12 mmol), (1H-pyrazol-4-yl)methanamine (11 mg, 0.11 mmol) and diisopropylethylamine (163 μl, 0.94 mmol) were dissolved in DMF (2 ml) and stirred for 30 min. The reaction flask was then sealed and T3P® (50% in DMF, 270 μl, 0.46 mmol) was added dropwise and the reaction mixture stirred overnight at room temperature. The mixture was poured into ice-water and extracted with ethyl acetate. The resulting organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography using SP1® Purification System (0% to 10% DCM/MeOH) to give 1.5 mg (2% yield) of the title compound as a white solid.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:34][CH3:35])C1C=CC=CC=1>CN(C=O)C.CO.ClC(Cl)Cl.[Pd]>[ClH:1].[F:33][C:22]1[CH:23]=[C:24]([CH3:32])[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:34][CH3:35])[CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A mixture of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (700 mg, 1.4 mmol) and 10% palladium-on-charcoal (100 mg) in DMF (10 ml), methanol (10 ml) and trichloromethane (10 ml) was stirred under hydrogen at 1 atmosphere pressure for 1 hour. The catalyst was removed by filtration through diatomaceous earth and the solvent was removed by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (570 mg, 98%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2c(c1)NCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-quinolin-7-ol (200 mg, 1.34 mmol) from step 1 in anhydrous N,N-dimethyl-formamide (5 mL) was added bromomethyl-benzene (229 mg, 1.34 mmol), and potassium carbonate (556 mg, 4.02 mmol). The reaction mixture was stirred at 60° C. overnight. Added some water to the reaction mixture and extracted it with methylene chloride several times. The organic layer was combined, dried over magnesium sulfate, and filtrated. The solution was evaporated under vacuum. The crude residue was purified by MPLC (biotage) to afford 297 mg (93%) of the title compound. 1H-NMR (CDCl3) δ 7.35–7.20 (m, 5H), 6.81 (d, J=8.1 Hz, 1H), 6.05 (dd, J=7.8 Hz, 2.2 Hz, 1H), 5.98 (d, 2.5 Hz, 1H), 4.53 (bs, 1H), 4.44 (s, 2H), 3.34 (t, J=5.0 Hz, 2H), 2.73 (t, J=5.8 Hz, 2H), 1.98 (m, 2H); MS LC-MS (MH+=240.1), LC MS RT: 3.08 min.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].S(Cl)([Cl:10])=O.[CH3:12]O>>[ClH:10].[CH3:12][O:6][C:5](=[O:7])[C@H:2]([NH2:1])[CH2:3][OH:4]
Reactant: N[C@@H](CO)C(=O)O
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@H](N)CO
Product: Cl
Yield: 100 %

Procedure:
To a solution of serine (105 g, 1 mol) in methanol (1200 mL) was added thionyl chloride (87.6 mL, 142.8 g, 1.2 mol) dropwise at 0° C. After addition, the reaction mixture was heated under reflux for 12 h. Volatiles were evaporated to give (R)-2-amino-3-hydroxy-propionic acid methyl ester hydrochloride (155 g, 100%) as a solid that was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 3.71 (s, 3H), 3.79 (m, 2H), 4.08 (s, 1H), 8.51 (br s, 2H).
Reaction SMILES: C[Si](Cl)(C)C.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]1[CH2:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[CH2:12]1.[CH:19]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)=O.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:32]=[C:33]([NH:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O.C(#N)C.O>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([CH:19]([C:14]2[C:15](=[O:17])[CH2:16][CH:11]([C:7]3[S:6][CH:10]=[CH:9][CH:8]=3)[CH2:12][C:13]=2[OH:18])[NH:40][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:41])([F:42])[F:29])[CH:32]=2)=[O:39])=[CH:22][CH:23]=1)#[N:26]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Reactant: N#Cc1ccc(C=O)cc1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(c3cccs3)CC2=O)cc1
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (216 μL, 1.70 mmol) is added to a solution of 5-(thiophen-2-yl)-cyclohexane-1,3-dione (300 mg, 1.54 mmol), 4-formylbenzonitrile (202 mg, 1.54 mmol) and 1-(3-(trifluoromethyl)phenyl)urea (315 mg, 1.54 mmol) in a mixture of N,N-dimethyl-formamide (1.2 mL) and acetonitrile (2.3 mL). The mixture is stirred at room temperature over night and poured into a mixture of water and ice. The precipitate is filtered and dried under reduced pressure. Yield: 444 mg; ESI mass spectrum [M+H]+=512, Retention time HPLC: 0.75 min (V011_S01).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:35](O)=[O:36])[CH2:13][CH2:12]1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:27]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:35]([NH:11][C:17]2[CH:18]=[CH:19][C:20]([CH2:4][N:2]([CH3:1])[CH:3]3[CH2:30][CH2:29][O:28][CH2:25][CH2:24]3)=[CH:21][CH:16]=2)=[O:36])[CH2:13][CH2:12]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OC)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(2-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (190 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (139 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (104 mg) and triethylamine (476 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 3.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(2-methoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 51) (169 mg) as yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[CH2:4].Br[CH2:6]/[CH:7]=[CH:8]/[CH:9]=[CH2:10]>>[CH:9]12[CH2:10][NH:1][CH2:2][CH:3]1[CH2:4][CH2:6][CH:7]=[CH:8]2
Reactant: C=C/C=C/CBr
Reactant: C=CCN
Product: C1=CC2CNCC2CC1

Procedure:
Introduce 228 g (4.0 mol) of 1-amino-2-propene. Add dropwise with stirring 58.8 g (0.4 mol) of (E)-1-bromo-2,4-pentadiene (title compound of Example A.1.). Keep the internal temperature in a range of 20°-30° C. by means of cooling. Stir for 5 h at room temperature. Concentrate batch at 150 mbar. Add 20 g (0.5 mol) of sodium hydroxide, dissolved in 200 ml of water, extract the mixture twice using in each case 100 ml of methylene chloride, dry using sodium sulphate, add 0.1 g of 4-hydroxyanisole, concentrate and distil at 40 mbar. 10-20 ppm of 4-hydroxyanisole are added to stabilize the distillate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[SH:9][CH2:10][C:11]([OH:13])=[O:12]>[OH-].[Na+]>[C:11]([CH2:10][S:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])([OH:13])=[O:12]
Reactant: OCCCCCCCl
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CSCCCCCCO
Temperature: 50 °C

Procedure:
4.5 ml (0.04M) of 6-chloro-1-hexanol is added to a solution of 2.8 ml (0.04M) of mercaptoacetic acid in 120 ml of 1N NaOH. The solution is warmed to about 50° C. for 16 hours, then acidified and extracted repeatedly with ethyl acetate. The combined extracts are concentrated to dryness and the residue purified by recrystallization.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]12[CH2:12][CH2:11][CH2:10][C:5]3[C:4]1=[C:9]([CH:8]=[CH:7][CH:6]=3)[NH:1][C:2]2=[O:13]
Reactant: O=C1Nc2cccc3c2C1CCC3
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2a,3,4,5-Tetrahydro-1H-benz[cd]indol-2-one (3.0 g, 17 mmol) was dissolved in anhydrous N,N-dimethylformamide (120 ml), and the solution was mixed with sodium hydride (60%, 760 mg, 190 mmol) and stirred at room temperature for 1 hour. The reaction solution was mixed with 1,4-dibromobutane (6.3 ml, 52 mmol) and again stirred for 17 hours. The solvent was removed by evaporation under a reduced pressure, and ethyl acetate, water and hydrochloric acid (1 N) were added to the resulting residue. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and then the thus obtained material was separated and purified by a silica gel column chromatography to obtain 1.8 g (5.8 mmol, 33% in yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](SC)=[C:6]([CH:9]=1)[C:7]#[N:8].O[O:13][S:14]([O-:16])=O.[K+].[C:18](#N)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:14]([CH3:18])(=[O:16])=[O:13])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=S([O-])OO
Reactant: CC#N
Reactant: CSc1ccc(Cl)cc1C#N
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(Step 2) To a solution of 5-chloro-2-(methylsulfanyl)benzonitrile obtained in Step 1 (1.0 g) in acetonitrile (15 ml) was added dropwise a solution of Oxone®, (6.98 g) in water (20 ml). The resulting mixture was stirred at room temperature for 5 hr. Oxone® (1.2 g) was added, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water (25 ml), and the resulting mixture was stirred at 0° C. for 3 hr. The precipitate was collected by filtration, washed with water, and dried to give 5-chloro-2-(methylsulfonyl)benzonitrile (0.92 g) as a white solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)=[O:6]>O.CO>[C:12]1([C:9]2[O:8][C:7]([C:5]([OH:6])=[O:4])=[CH:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A solution of sodium hydroxide (200 mg) in water (5 ml) was added to a stirred solution of 5-phenyl-furan-2-carboxylic acid methyl ester (7) (384 mg, 1.90 mmoles) in methanol (20 ml) and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was diluted with water (10 ml) and acdified to pH=2 with 1 M aqueous hydrochloric acid. The precipitate was collected, washed with water and the residue was triturated with cyclohexane to afford (8) (350 mg) as a white solid. LC/MS System A; Rt=3.89 mins.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[O:14]1[CH2:17][CH:16]([NH2:18])[CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C>[N+:11]([C:6]1[CH:7]=[C:8]2[CH2:9][N:18]([CH:16]3[CH2:17][O:14][CH2:15]3)[CH2:2][CH2:3][N:4]2[N:5]=1)([O-:13])=[O:12]
Reactant: NC1COC1
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc2n(n1)CCN(C1COC1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
To a solution of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (500 mg, 1.6 mmol) in acetonitrile (20 mL) was added oxetan-3-amine (140 mg, 1.92 mmol) and diisopropylethyl amine (372 mg, 0.50 ml, 2.88 mmol) drop wise and the resulting mixture was stirred at room temperature for 24 h. The solution was concentrated and the residue dissolved in ethyl acetate (50 mL), washed with water (50 mL) and dried over magnesium sulfate. The resulting mixture was filtered and evaporated and the residue purified by flash chromatography (SF25-40 g, 50% to 100% ethyl acetate in hexanes) to give 2-nitro-5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (255 mg, 71%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].N1C=CC=CC=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1>[C:20]([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])(=[O:25])[C:21]([O:23][CH3:24])=[O:22]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
In 35 ml of toluene, 10 g (54 mmol) of pentafluorophenol and 5 ml (61 mmol) of pyridine were dissolved. To the solution, 7.2 g (59 mmol) of methyl chloroglyoxylate were added dropwise under an ice bath for the reaction. After 1 hour stirring at room temperature, the reaction mixture was filtered and concentrated. The thus obtained crude product was purified by distillation to obtain 10.1 g of pentafluorophenyl methyl oxalate. The compound had a melting point of 34 to 35° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.[C:11](N1C=CN=C1)(N1C=CN=C1)=O.[CH3:23][O:24][C:25]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26].O>O1CCCC1>[CH2:23]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([C:6]([C:3]2([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]2)=[O:7])[CH2:29][CH2:28]1)=[O:26])[CH3:11]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)C1CCNCC1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)C2(C(F)(F)F)CC2)CC1
Temperature: 27.5 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
1-(Trifluoromethyl)cyclopropanecarboxylic acid (400 g, 2.6 mol) is dissolved in 3.2 L of tetrahydrofuran and cooled to 10˜20° C. Carbonyldiimidazole (462.4 g, 1.1 eq) is added in portions. The mixture is stirred at 25-30° C. for 20 min. Then piperidine-4-carboxylic acid methyl ester (445.6 g, 1.2 eq) is added dropwise at <30° C. The mixture is stirred at 25-30° C. for 18˜20 h. 3.2 L of water are added dropwise at <30° C. and the solution is concentrated to ˜1 L of volume to remove most of tetrahydrofuran. The resulting solution is extracted with dichloromethane (2×). The combined organic layers are washed with 3 volumes of 0.5 M hydrochloric acid and concentrated. 500 mL of methyl tert-butyl ether is added and the solution is concentrated. This process is run twice. The organic layer is concentrated to provide 567 g of the title compound in 95% purity.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][C:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[C:35]([CH3:46])[NH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:36]4[C:32]([CH3:31])=[N:33][NH:34][C:35]=4[CH3:46])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2c(-c3c(C)n[nH]c3C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Yield: 25 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (140 mg, 0.267 mmol) in 1,4-dioxane (2 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (89 mg, 0.401 mmol), bis(triphenylphosphine)palladium(II) chloride (18.76 mg, 0.027 mmol) and potassium carbonate (111 mg, 0.802 mmol). Water (1 mL) was added and the mixture heated at 100° C. in a microwave for 15 min (×2). Another portion of bis(triphenylphosphine)palladium(II) chloride (18.76 mg, 0.027 mmol) was then added and the reaction mixture degassed with nitrogen for 5 min and then heated at 100° C. in a microwave for 15 min (×2). The solvent was then removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase was re-extracted with ethyl acetate (20 mL×2). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-80% ethyl acetate in cyclohexane and then further purified using MDAP (acidic conditions), to give the title compound (36 mg). LCMS (A) m/z: 539 [M+1]+, Rt 1.47 min (acidic).