Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH2:34][CH3:35])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31](Br)[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2].[OH-:37].[K+]>CO>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH2:34][CH3:35])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([OH:37])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(Br)cnc12
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(O)cnc12
Yield: 74.4 %

Procedure:
tert-Butyl[(1R,2R)-2-({[4-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)-5-ethylthiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (0.151 g, 0.258 mmol) was dissolved in methanol (1.29 mL) and KOH (14.5 mg, 0.258 mmol) was added. The reaction was heated to 65° C. until conversion to the alcohol was complete. The reaction was then concentrated under reduced pressure. The remaining residue was mixed with dichloromethane, washed with saturated ammonium chloride (aq) twice and brine once. The organic layer was mixed with water and extracted 3× with dichloromethane. The combined organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.100 g, 0.192 mmol). LRMS (APCI) calc'd for (C24H29F2N5O4S) [M+H]+, 522.2. found 522.0.
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5](Br)=[C:4]([F:12])[C:3]=1[F:13].[CH2:14]([C:26]1[CH:27]=[C:28]([Sn](C)(C)C)[S:29][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>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.C1(C)C=CC=CC=1>[CH2:14]([C:26]1[CH:27]=[C:28]([C:2]2[C:7]3=[N:8][S:9][N:10]=[C:6]3[C:5]([C:28]3[S:29][CH:30]=[C:26]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:27]=3)=[C:4]([F:12])[C:3]=2[F:13])[S:29][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCc1csc([Sn](C)(C)C)c1
Reactant: Fc1c(F)c(Br)c2nsnc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1csc(-c2c(F)c(F)c(-c3cc(CCCCCCCCCCCC)cs3)c3nsnc23)c1
Temperature: 105 °C
Yield: 89.1 %

Procedure:
4,7-Dibromo-5,6-difluoro-benzo[1,2,5]thiadiazole (0.33 g, 1 mmol), (4-dodecyl-thiophen-2-yl)-trimethyl-stannane (1.04 g, 2.5 mmol), and Pd(PPh3)4 (20 mg) were combined in a 50-mL Schlenk flask. The system was vacuumed and backfilled with argon for three cycles before 20 mL of anhydrous toluene was added. The mixture was heated at 105° C. for 3 days. After the reaction was cooled down, the solvent was removed by rotary evaporation. The product was further purified by silica gel column with toluene/hexane (v/v, 1/4) as the eluent and recrystallization from a hexane/iso-propoanol mixture. The final product (0.60 g, 89.5% yield) was obtained as red needle crystals after drying in vacuo. 1H NMR (CDCl3, 500 MHz): δ 8.15 (d, 2H, J=1.0 Hz), δ 7.23 (d, 2H, J=1.0 Hz), δ 2.74 (t, 4H, J=7.5 Hz), δ 1.73 (m, 4H), δ 1.29 (m, 18H), δ 0.90 (t, 6H, 7.0 Hz). 13C NMR (CDCl3, 500 MHz): δ 150.8, 148.9, 143.7, 132.3, 131.2, 124.0, 111.7, 31.97, 30.60. 30.52, 29.74, 29.72, 29.70, 29.67, 29.53, 29.42, 29.39, 22.75, 14.19.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[CH:16]=[C:15]([Cl:17])[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=1>>[Cl:17][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:16]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1
Reactant: c1cn[nH]c1
Product: COc1ccc2c(Cl)cc(-n3cccn3)nc2c1
Temperature: 115 °C
Yield: 56.1 %

Procedure:
Solid pyrazole (3.2 g, 47.36 mmol) was heated to 80° C. Then 2,4-Dichloro-7-methoxyquinoline (3.6 g, 15.78 mmol) was added. The reaction mass was heated to 115° C. for 3 hr. The reaction mass was cooled to RT and was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (2.3 g, 56%) as white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH3:12])[S:8]([CH3:11])(=[O:10])=[O:9].[C:13]1(=[N:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1COCC1>[CH3:6][N:7]([CH3:12])[S:8]([CH2:11][C:13]1([NH:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:10])=[O:9]
Reactant: CC(C)(C)S(=O)N=C1CCCCC1
Reactant: CN(C)S(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)CC1(NS(=O)C(C)(C)C)CCCCC1
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
n-Butyllithium (1.3 eq, 8.07 mL of a 1.6M soln in hexanes) was added dropwise to a cooled (−78° C.) solution of N,N-dimethyl methanesulfonamide (1.35 eq, 1.65 g) in 100 mL of dry THF under anhydrous atmosphere. The mixture was stirred for 30 min at that temperature and then transferred via cannula to a solution of sulfinyl imine 1200-B (2.0 g) in 100 mL of dry THF at −78° C. After addition was completed, the reaction mixture was stirred for 1 h. The reaction was quenched at −78° C. by addition of 20 mL of aqueous saturated ammonium chloride solution. The mixture was allowed to reach room temp and then partitioned between dichloromethane (300 mL) and aqueous saturated sodium bicarbonate solution (300 mL). The aqueous layer was back extracted with dichloromethane (2×200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient:dichloromethane/hexanes; 1:1 to 30% acetone in dichloromethane/hexanes; 1:1) to afford the product 1200-C (1.36 g; 42%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.Cl.[N:24]1([C:29]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:24]1([C:29]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])=[CH:35][CH:36]=2)=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (50 mg, 0.16 mmol) and 4-(pyrrolidinylcarbonyl)phenylamine hydrochloride (43 mg, 0.19 mmol) in pyridine (3 mL) cooled in ice-bath, POCl3 (0.028 mL, 0.31 mmol) was added. The mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (15 mg). MS 491.4 and 493.4 (M+H, Cl pattern).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2Cl)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([CH2:30][NH2:31])[CH:27]=[CH:26][N:25]=1.C(=O)(O)[O-].[Na+].CC(O)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2[NH:31][CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([O:23][CH3:22])[CH:29]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CN)ccn1
Reactant: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1cc(CNc2nnc(Cl)cc2C(=O)Nc2ccc(C(C)(C)C)cc2)ccn1

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid (4-tert-butyl-phenyl)-amide (162 mg, 0.5 mmol), C-(2-Methoxy-pyridin-4-yl)-methylamine (211 mg, 1 mmol), and sodium bicarbonate (840 mg, 20 mmol) were added to IPA (2.5 mL). The reaction was ran in microwave (150° C., 15 min). Water (5 mL) was added to the reaction and the mixture was extracted with DCM (2×5 mL). The organic layer was dried over sodium sulfate and reduced. The crude was subjected to Flash chromatography (2% MeOH/DCM) for further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[N+:13]=[N-:14].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17]>C1C=CC=CC=1>[CH2:20]([O:19][C:15](=[O:18])[CH:16]=[CH:17][N:8]1[C:9]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:6]2=[CH:17][C:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])=[N:14][N:13]2[C:7]1=[O:12])[CH3:21]
Reactant: COc1ccc2c(c1)C(=[N+]=[N-])C(=O)N2
Reactant: C#CC(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)C=Cn1c(=O)n2nc(C(=O)OCC)cc2c2cc(OC)ccc21
Temperature: 25 °C

Procedure:
1.5 g (0.0079 mole) of 5-methoxy-3-diazooxindole and 0.99 g (0.01 mole of 1.3 equiv.) of 99% ethyl propiolate are refluxed in benzene (50 ml) under N2 for 24 hours. The reaction mixture is cooled down to room temperature and the precipitates that form are filtered off and washed well with ether, dried in a vacuum oven at 60° for 2 hours. Yield: 661.8 mg, m.p. 202°-204°, Rf 0.3. This crude product is taken up in 75 ml of absolute ethanol, treated with activated carbon, filtered through a celite pad and the clear filtrate is concentrated down to a volume of ~50 ml on the steam bath. After cooling, the precipitates that form are filtered off. The product is dried overnight in a vacuum oven at room temperature. Yield: 555.4 mg, m.p. 225°-227°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].[Cl:7][C:8]([O:11]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.N1C=CC=CC=1>CCOCC>[Cl:7][C:8]([O:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])=[O:11]
Reactant: COCC(C)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COCC(C)OC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml (10.2 mmol) of 1-methoxy-2-propanol (Fluka, Buchs, Switzerland) is injected slowly into an ice-cold solution of 916 mg (1.1 equivalent) of bis(trichloromethyl)carbonate (triphosgene; Fluka, Buchs, Switzerland) in 35 ml of ether using a syringe. At the same time, 1 ml (1.2 equivalents) of pyridine in 5 ml of ether is added dropwise from a dropping funnel. After the addition has ended, the mixture is left to stir at RT for a further 60 min. The reaction mixture is filtered through wadding and the solvent is carefully evaporated off (35° C. waterbath). The oily residue (title compound) is subjected to further processing without any purification. 1H-NMR (200 MHz; CDCl3)=inter alia 5.05/m (1H); 3.30/s (3H); 1.27/d (3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:12](=O)[C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([S:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:21]1([N:27]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][CH2:32]C3=O)=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:32]3[CH2:31][CH2:30][C:29]4[C:34](=[CH:35][N:27]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:28]=4)[C:12]=3[C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([S:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(SC)cc(-c2ccc(Br)cc2)oc1=O
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccc(Br)cc2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.7 %

Procedure:
A mixture of methyl 6-(4-bromophenyl)-4-(methylthio)-2-oxo-2H-pyran-3-carboxylate (353 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 6 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 317 mg (63%) of methyl 6-(4-bromophenyl)-8-(methylthio)-2-phenyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([CH:24]1[CH2:30][CH:29]2[NH:31][CH:26]([CH2:27][CH2:28]2)[CH2:25]1)[CH2:20][CH2:21][CH2:22][CH3:23]>CCCCCCC.CCOC(C)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:7][C:6](=[O:17])[N:5]([CH2:4][C@H:3]([CH3:18])[CH2:2][N:31]3[CH:26]4[CH2:27][CH2:28][CH:29]3[CH2:30][CH:24]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25]4)[C:10]=2[CH:11]=1
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCCCC1CC2CCC(C1)N2
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(OC)cc21
Yield: 43.5 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.226 g, 0.63 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (0.101 g, 0.56 mmol) were mixed according to GP16. CC (SiO2; heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF41) (0.101 g, 39%). 1H NMR (CDCl3) d 6.89 (d, J=8.8 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 4.60-4.46 (m, 2H), 4.01 (d, J=6.8 Hz, 2H), 3.77 (s, 3H), 3.15-3.02 (m, 2H), 2.32-2.26 (m, 1H), 2.20-1.79 (m; 7H), 1.68-1.51 (m, 3H), 1.42-1.16 (m, 10H), 0.89-0.85 (m, 6H); 13C NMR (CDCl3) d 168.4, 155.6, 139.8, 129.8, 117.0, 106.9, 103.8, 68.0, 60.6, 59.1, 58.1, 56.0, 45.3, 39.4, 36.6, 36.4, 32.2, 31.5, 28.4, 28.4, 28.0, 27.3, 22.8, 16.8, 14.2; HPLC-MS (ammonium acetate) [M+H]+=415.3.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1ccc(-c2cc[nH]n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Compound 17a (1 g, 6.9 mmol) obtained from the aforesaid process and 3,4-difluoro-nitrobenzene (0.74 mL) were dissolved in N,N-dimethylformamide (20 mL), and then anhydrous potassium carbonate (1.9 g) was added thereto. The mixture was reacted at 100° C. for 4 hours. After completion of the reaction, the reactant mixture was cooled to room temperature. Water was added to the mixture, resulting in a substantial amount of precipitate. Then, the precipitate was suction-filtered, and the filter cake was recrystallized with acetone to get the product 18a as a white powder (1.7 g), with a yield of 93.4%.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[O:9][CH2:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=1)=[O:4].CCO.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CCOCC>[O:22]1[CH2:23][CH2:24][N:19]([CH2:2][C:3]([C:5]2[CH:15]=[CH:14][C:8]3[O:9][CH2:10][C:11](=[O:13])[NH:12][C:7]=3[CH:6]=2)=[O:4])[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: O=C1COc2ccc(C(=O)CCl)cc2N1
Solvent: CCO
Solvent: CCOCC
Product: O=C1COc2ccc(C(=O)CN3CCOCC3)cc2N1
Temperature: 80 °C

Procedure:
To a 20 mL scintillation vial with a magnetic stirrer was added commercially available 6-(2-chloroacetyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (113 mg, 0.5 mmol) and EtOH (2.5 mL) followed by morpholine (96 mg, 1.1 mmol). The reaction was heated at 80° C. for 1 h then cooled to room temperature. The solution was diluted with Et2O (10 mL) and the resulting solid was isolated by filtration, washed with Et2O and dried in vacuo to give a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=10.91 (s, 1H), 9.31 (br. s., 1H), 7.65 (dd, J=8.3, 2.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 4.68 (s, 2H), 3.67-3.87 (m, 6H), 3.58 (t, J=4.3 Hz, 2H), 3.07 ppm (d, J=5.1 Hz, 2H). ESI-MS: m/z 277.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:17]([C:18]([NH2:20])=[O:19])[C:16]([CH3:24])(C)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:29](OCC)=[CH2:30].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.O>COCCOC.FC(F)(F)C(O[Pd]OC(=O)C(F)(F)F)=O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:25]([F:26])([F:27])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][CH:29]=[CH2:30])=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: C=COCC
Reactant: CC1(C)C=C(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)C=CC1C(N)=O
Agent: O=C(O[Pd]OC(=O)C(F)(F)F)C(F)(F)F
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: COCCOC
Solvent: O
Product: C=CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
In a solution of 0.50 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-2-meth yl benzoic acid amide synthesized in Synthetic Example 29, 0.865 g of ethyl vinyl ether and 0.022 g of 1,10-phenanthroline in 10 ml of 1,2-dimethoxyethane, 0.04 g of bis(trifluoroacetoxy)palladium (II) was added and stirred at room temperature for 19 hours. After the completion of the reaction, 30 ml of water was added in the reaction mixture, and extracted with ethyl acetate (40 ml×1), the organic phase was dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, then filtered through silica gel, and the solvent was distilled under reduced pressure to obtain 0.45 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: [Na].[CH3:2]/[C:3](/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[N:4]/[OH:5].Br[CH:14]([CH3:18])[C:15]([OH:17])=[O:16]>C(O)C>[CH3:2][C:3](=[N:4][O:5][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: CC(Br)C(=O)O
Reactant: C/C(=N/O)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: CC(=NOC(C)C(=O)O)c1ccc(Cl)cc1

Procedure:
To a solution of 1.85 g of a sodium in 150 ml of absolute ethanol 6.8 g of 4-chloroacetophenone oxime and 8.6 g of α-bromopropionic acid were added in this order with stirring. After the mixture had been stirred for 1 hour the ethanol was removed in a vacuum. The residue was mixed with water and the mixture was washed twice with ether. The aqueous solution then was acidified and extracted twice with ether. The ethereal extracts were washed 6 times with water, dried over anhydrous sodiumsulfate and concentrated by evaporation. After crystallisation of the residue from petroleum ether, the superscribed substance was obtained. After it had been washed once with water and crystallized from a mixture of benzene and petroleum ether te melting point was 88° C.-89° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a stirred solution of 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 200 mg, 0.58 mmol) in DMSO (2 ml) in sealed tube, was added pyrrolidine (0.073 ml, 0.89 mmol), K2CO3 (153 mg, 1.11 mmol) and the mixture was stirred at 90° C. for 3 h. After cooling, the crude mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined and washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (100-200 mesh silica, eluting with 10% ethyl acetate in hexane) to obtain 6-chloro-4-phenyl-2-pyrrolidin-1-yl-quinoline-3-carboxylic acid ethyl ester (150 mg, 68%) as pale yellow solid. LC-MS: 381 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[H][H].C(OCC)(=O)C>[Pd].CO>[NH2:13][C:12]1[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: CN(c1ncccc1[N+](=O)[O-])S(C)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(c1ncccc1N)S(C)(=O)=O

Procedure:
N-(3-Amino-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-methyl-N-(3-nitro-pyridin-2-yl)-methanesulfonamide (6.20 g, 26.8 mmol)(prepared as described in J. Med. Chem., 2007, 50, 3431) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, Palladium:carbon black:Water, 5.71 g, 2.68 mmol) and Hydrogen (50 psi) in 2:1 ethyl acetate:methanol (150 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as brown solid (5.15 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.85 (dd, J=3.7, 2.5 Hz, 1H), 7.10-7.08 (m, 2H), 4.24 (br s, 2H), 3.23 (s, 3H), 3.08 (s, 3H). MS=202 (MH)+. 111b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide was prepared from N-(3-amino-pyridin-2-yl)-N-methyl-methanesulfonamide (238.0 mg, 1.183 mmol) and 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.185 g, 48%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.18-8.15 (m, 1H), 8.11 (d, J=6.8 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.32-7.25 (m, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.93 (t, J=7.3 Hz, 1H), 3.31 (s, 3H), 3.07 (s, 3H). MS=353, 355 (MH)+. 111c) N-Methyl-N-(3-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 3-(4-methylpiperazin-1-yl)aniline (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.017 g, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11-8.06 (m, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.28-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.78-6.73 (m, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.32 (s, 3H), 3.29-3.24 (m, 4H), 3.09 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=518 (MH)+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]2[C:4]=1[N:5]=[C:6](OC)[N:7]2[CH2:17][CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1>O1CCOCC1.CO>[ClH:1].[CH2:13]([O:12][C:10]1[N:9]=[C:8]2[C:4]([N:5]=[CH:6][N:7]2[CH2:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)=[C:3]([NH2:2])[N:11]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2ncn(CC3CCNCC3)c2n1
Reaction time: 4.5 h

Procedure:
4N hydrogen chloride in dioxane (5.3 mL) was added to a solution of 1,1-dimethylethyl 4-{[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]methyl}-1-piperidinecarboxylate (630 mg) in methanol (16 mL). After 4.5 hours at room temperature, the reaction mixture was concentrated and dried under high vacuum.