Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:19][CH3:20].CCOC(C)=O>CN(C)C=O>[CH2:19]([N:4]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]2[C:2]([I:1])=[N:3]1)[CH3:20]
Reactant: CCI
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1nc(I)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 72 h
Yield: 51.9 %

Procedure:
To 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.766 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added cesium carbonate (300 mg, 0.919 mmol) followed by iodoethane (0.065 mL, 0.805 mmol), and the reaction mixture was stirred over the weekend (3 days) at 80° C. into a sealed vessel. The reaction was allowed to cool down to room temperature. The mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% CH2Cl2 to 90:10:1 CH2Cl2:CH3OH:NH4OH) afforded 1-ethyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (115 mg) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].Cl.[C:9]([N:12]1[C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[S:14][CH:13]1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[O:30][CH2:31][CH2:32][CH2:33][N:34](CCO)[CH:35]([CH3:37])[CH3:36])(=[O:11])[CH3:10].N1C=CC=CC=1>C(=O)([O-])O.[Na+]>[ClH:21].[C:5]([O:4][CH2:1][CH2:2][N:34]([CH2:33][CH2:32][CH2:31][O:30][C:23]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=1[CH:13]1[N:12]([C:9](=[O:11])[CH3:10])[C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[S:14]1)[CH:35]([CH3:36])[CH3:37])(=[O:7])[CH3:6]
Reactant: COc1ccc(OCCCN(CCO)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(OCCCN(CCOC(C)=O)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 171.3 %

Procedure:
Acetic anhydride (0.26 ml, 2.91 mmol) was added to a solution of 3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline hydrochloride (300 mg, 0.58 mmol) in pyridine (0.47 ml, 5.80 mmol) under ice-cooling, and then the mixture was stirred at room temperature for two hours. A saturated aqueous sodium hydrogencarbonate solution (50 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated brine (50 ml) and dehydrated with anhydrous magnesium sulfate, and ethyl acetate was evaporated under reduced pressure. The obtained oily matter was dissolved in ethyl acetate (1 ml), and then a 4 N solution (0.5 ml) of hydrogen chloride in ethyl acetate. The mixture was concentrated under reduced pressure to give 277 mg (92%) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22](=[O:34])[CH2:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:20])[C:16]([CH2:18][OH:19])=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22](=[O:34])[CH2:23][C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:20])[C:16]([CH:18]=[O:19])=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Cc1c(CO)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: Cc1c(C=O)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of N1-(3-fluoro-4-(6-(hydroxymethyl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide (12 mg, 0.026 mmol, Example 41) in 1 mL of THF was added Dess-Martin periodinane (48 mg, 0.11 mmol, Aldrich) at room temperature. The mixture was allowed to stir for 2 h and HPLC analysis indicated total consumption of the starting material. The mixture was filtered through a plug of SiO2, washed with EtOAc. The organic solvent was then removed under reduced pressure and the residue was purified on preparative HPLC to afford the title compound (10 mg, 83%). MS(ESI+) m/z 466.2 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[O:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:12]([OH:13])=[C:9]([O:10][CH3:11])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[C:7]([CH:15]=[CH:14][C:12]=1[O:13][CH2:3][C:2]#[CH:1])[CH:6]=[O:5]
Reactant: C#CCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(C=O)cc1OC
Yield: 86.4 %

Procedure:
Propargyl bromide (219 mL, 80% w/v, 1.48 mol) was added to a suspension of vanillin (150 g, 0.986 mol) and potassium carbonate (408 g, 2.96 mol) in acetone (1.50 L) and treated according to Procedure 3. 3-Methoxy-4-propargyloxybenzaldehyde (162 g, 86%) was obtained as yellow crystalline solid; mp 95° C.; δH (400 MHz, CDCl3) 2.56 (t, J=2.5 Hz, 1H, C≡CH), 3.95 (s, 3H, OCH3), 4.86 (d, J=2.5 Hz, 2H, OCH2), 7.14 (d, J5,6=6.8 Hz, 1H, H5), 7.44 (d, J2,6=1.4 Hz, 1H, H2), 7.47 (dd, J5,6=6.8, J2,6=1.4 Hz, 1H, H6), 9.87 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.0, 56.6, 77.2, 77.4, 109.4, 112.5, 126.3, 130.9, 150.0, 152.1, 190.9; HRMS (ESI) Calculated for C11H10O3 [M+H]+ 191.0703. found 191.0706; vmax 1006, 1130, 1259, 1586, 1677, 2119, 2845, 2932, 3266 cm−1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C@@:26]([CH3:41])([S:37]([CH3:40])(=[O:39])=[O:38])[C:27]([NH:29][O:30]C4CCCCO4)=[O:28])[C:20](=[O:42])[CH:19]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1>CC(O)C>[OH:30][NH:29][C:27](=[O:28])[C@:26]([CH3:41])([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:25][CH2:24][N:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:7]3[CH:8]=[N:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)=[CH:17][CH:16]=2)=[CH:19][C:20]1=[O:42]
Reactant: COc1ccc(COc2ccc(-c3ccn(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)c(=O)c3)cc2)cn1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(COc2ccc(-c3ccn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c(=O)c3)cc2)cn1

Procedure:
HCl (1.0 N in water, 2.09 mL) was added to a solution of the (2R)-4-[4-{4-[(6-methoxypyridin-3-yl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (245 mg, 0.418 mmol) in IPA (5.0 mL) for 1 hour. The reaction mixture was concentrated and the residue was triturated with IPA to afford a white suspension at 50° C. for 30 minutes. A white solid was collected by filtration. Yield 215 mg/95% LCMS MS ES− 500.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (s, 3H) 2.07-2.23 (m, 1H) 2.33-2.43 (m, 1H) 3.08 (s, 3H) 3.64-3.79 (m, 1H) 3.83 (s, 3H) 4.00-4.12 (m, 1H) 5.09 (s, 3H) 6.57-6.67 (m, 2H) 6.80-6.88 (m, 1H) 7.05-7.12 (m, 2H) 7.64-7.73 (m, 3H) 7.78 (s, 1H) 8.26 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH2:14][CH2:15][Cl:16].[N:17]1([C:23]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH:26]=[CH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[ClH:16].[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH2:14][CH2:15][N:20]1[CH2:21][CH2:22][N:17]([C:23]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH:26]=[CH:25][N:24]=2)[CH2:18][CH2:19]1
Reactant: Nc1ccc2[nH]c(=O)cc(CCCl)c2c1
Reactant: c1cc2sccc2c(N2CCNCC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2[nH]c(=O)cc(CCN3CCN(c4nccc5sccc45)CC3)c2c1
Temperature: 60 °C

Procedure:
A mixture of 0.35 g (1.35 mmol) of 6-amino-4-(2-chloroethyl)-2(1H)-quinolone hydrochloride, 0.33 g (1.5 mmol) of 4-(1-piperazinyl)thieno[3,2-c]pyridine and 0.17 g (2 mmol) of sodium bicarbonate in 10 ml of dimethylformamide is heated to 60° C. for 24 hours. After cooling to room temperature, the reaction medium is diluted in 50 ml of water and the crude product is extracted with chloroform. The organic phase is dried over sodium sulpbate and concentrated. The crude product is purified by flash chromatography on silica, eluting first with a methanol/ethyl acetate (6.5:93.5) mixture containing traces of triethylamine and then with a methanol/dichloromethane (6.5:93.5) mixture comprising traces of aqueous ammonia.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[NH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>O.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[S:17]([NH:20][C:21]([N:4]1[C:5]([CH3:8])([CH3:7])[CH2:6][C:2]([CH3:1])=[N:3]1)=[O:22])(=[O:18])=[O:19]
Reactant: CC1=NNC(C)(C)C1
Reactant: O=C=NS(=O)(=O)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=NN(C(=O)NS(=O)(=O)c2c(Cl)cccc2Cl)C(C)(C)C1

Procedure:
11.2 g of the 3,5,5-trimethyl-2-pyrazoline obtained according to example I(b) are added dropwise while stirring, cooling in cold water and under a nitrogen blanket to a solution of 25.2 g of the 2,6-dichlorobenzenesulphonylisocyanate obtained according to example I(a) in 200 ml of dry toluene. After stirring at room temperature for two hours, the precipitate is sucked off and washed successively with dry toluene and petroleum ether (40-60). The desired 1-(2,6-dichlorophenylsulphonylcarbamoyl)-3,5,5-trimethyl-2-pyrazoline is obtained in a yield of 20.07 g; melting-point 270° C. (decomposition).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41])#[N:36]>C1COCC1>[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:41])#[N:36]
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1cccc(C(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 210 mg, 0.96 mmol) in THF (20 mL) at room temperature is added 0.5 M KHMDS in toluene (4.10 mL, 2.05 mmol). After 30 min, 3-cyanobenzoyl chloride (510 mg, 3.08 mmol) is added. The mixture is stirred under N2 overnight. The reaction is quenched with aqueous ammonium chloride and the volatiles are removed in vacuo. The residue is redissolved in dichloromethane and poured into saturated aqueous sodium bicarbonate (100 mL). Extraction with dichloromethane, drying over sodium sulfate followed by concentration affords a residue which is purified on an XBridge RP18 using a 0.1% ammonium hydroxide in acetonitrile gradient. Further purification by silica gel flash chromatography (heptane-ethyl acetate, 3:2 to 2:3) affords 1-(3-cyano-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.20 (d, J=0.5 Hz, 1H), 7.22-7.26 (m, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.73-7.79 (m, 2H), 7.84 (d, 1H), 7.92-7.98 (m, 2H), 8.11 (t, J=1.5 Hz, 1H), 8.29-8.33 (m, 1H), 8.39 (dd, J=4.8, 1.5 Hz, 1H), 8.60 (dd, J=2.3, 0.8 Hz, 1H). HRMS (ESI) m/z 349.1106 [(M+H)+ Calcd for C22H13N4O: 349.1089].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nc(-c3ccccn3)cc2n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: O
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccccn3)cc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
There was suspended, in 1,4-dioxane (5 mL), 5,7-dichloro-2-pyridin-2-yl-pyrazolo[1,5-a]pyrimidine (348 mg. 1.31 mM), then morpholine (230 μL, 2.64 mM) was added to the suspension and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off from the reaction mixture, the residue obtained was diluted with water and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (312 mg, yield: 75%). 1H-NMR (300 MHz, CDCl3): δ 3.84-3.87 (m, 4H), 3.99-4.02 (m, 4H), 6.12 (s, 1H), 7.16 (s, 1H), 7.30 (ddd, 1H, J=1.2, 5.0, 7.7 Hz), 7.78 (dt, 1H, J=1.8, 7.7 Hz), 8.11 (d, 1H, J=7.7 Hz), 8.70 (m, 1H); MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:16])[CH2:13][CH2:14]Br)([O-:3])=[O:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.CN(C=O)C>O>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][N:27]1[CH2:26][CH2:25][N:24]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=2)[CH2:29][CH2:28]1)([O-:3])=[O:2]
Reactant: O=C(CCBr)Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCN(c2ccc(F)cc2)CC1)Nc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
A mixture of 14.8 gm of N-(2-nitro-4-fluorophenyl)-3-bromo-propionamide, 9.0 gm of 1 -(4-fluoro-phenyl)-piperazine, 6.46 gm of diisopropylethylamine and 150 ml DMF was kept for 48 hours at 150° C. Water (300 ml) was added at ambient temperature and the mixture was extracted with CHCl3. The CHCl3 extract was collected, washed with 20 ml water and dried over Na2SO4. The crude product obtained after removing the solvents was purified by using chromatography: solid phase (SIO2 ; 40 μm; Baker); eluent CHCI3. A sample of this purified material (12.7 gm) exhibited the following data. M+/z of 405.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([CH:18]=[CH:19][CH2:20][CH2:21][OH:22])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]3[CH:42]=[C:41]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:46])=[O:45])[C:40](B(O)O)=[CH:39][C:33]=3[C:34]=2[C:35](=[O:38])[NH:36][CH3:37])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CN(C=O)C.O.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[C:8]([C:6]1[N:7]=[C:2]([C:40]3[C:41]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:46])=[O:45])=[CH:42][C:32]4[O:31][C:30]([C:27]5[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=5)=[C:34]([C:35]([NH:36][CH3:37])=[O:38])[C:33]=4[CH:39]=3)[CH:3]=[CH:4][C:5]=1[CH:18]=[CH:19][CH2:20][CH2:21][OH:22])[NH:9]2
Reactant: OCCC=Cc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B(O)O)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C=CCCO)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Reaction time: 8 h
Yield: 54.9 %

Procedure:
A solution of 4-(6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)but-3-en-1-ol (500 mg, 1.58 mmol), (2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethyl sulfonamido)benzofuran-5-yl)boronic acid (800 mg, 1.89 mmol) and Na2CO3 (340 mg, 3.15 mmol) in dioxane/DMF/H2O (5 mL/1 mL/0.2 mL) was added Pd2(dba)3 (10 mg) and X-Phos (10 mg) under N2. It was put into a pre-heated oil-bath at 110° C. for 8 hours. The mixture was concentrated and it was extracted with EtOAc. The combined organic phase was washed with brine, and dried over Na2SO4. The crude product was purified by column (PE:EA=1:1) to give the pure product of (Z and E)-5-(6-(4-fluoro-1H-indol-2-yl)-5-(4-hydroxybut-1-en-1-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (570 mg, yield: 52%).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[NH:19][C:18]2[CH:20]=[C:21]([CH3:25])[C:22]([CH3:24])=[CH:23][C:17]=2[N:16]=1)=[N+:12]=[N-:13]>>[ClH:1].[ClH:1].[CH3:24][C:22]1[C:21]([CH3:25])=[CH:20][C:18]2[NH:19][C:15]([CH2:14][N:11]3[CH:4]=[C:3]([CH2:2][C:5]4[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=4)[N:13]=[N:12]3)=[N:16][C:17]=2[CH:23]=1
Reactant: Cc1cc2nc(CN=[N+]=[N-])[nH]c2cc1C
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: Cc1cc2nc(Cn3cc(Cc4c[nH]c(N)n4)nn3)[nH]c2cc1C
Yield: 49.7 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.047 g, 0.295 mmol) was reacted with 2-azidomethyl-5,6-dimethyl-1H-benzimidazole (0.071 g, 0.354 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(5,6 Dimethyl-1H-benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-ylmethyl]-1H-imidazol-2-ylamine dihydrochloride (0.029 g, 25%) of a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.09 (s, 1H), δ 7.45 (s, 2H), δ 6.52 (s, 1H), δ 6.08 (s, 2H), δ 3.93 (s, 2H), δ 2.35 (s, 6H) ppm; 13C (75 MHz, CD3OD) δ 142.2, 136.9, 136.6, 124.5, 124.3, 113.8, 113.4, 110.0, 100.4, 85.8, 80.6, 75.3, 74.1, 45.0, 20.9, 19.28 ppm; HRMS (ESI) calcd for C16H18N8 (M+) 323.1727, found 323.1734.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:29][CH:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([F:16])=[C:11]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([CH3:29])[CH2:35]4)[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC1CNCCN1
Reactant: CCOC(=O)Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Product: CCOC(=O)Nc1c(F)c(N2CCNC(C)C2)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1

Procedure:
In the same manner as described in Example 1 (1), ethyl 1-cyclopropyl-5-ethoxycarbonylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (m.p. 189°-190° C.) was allowed to react with 2-methylpiperazine to give ethyl 1-cyclopropyl-5-ethoxycarbonylamino-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:22].[CH3:23][C:24]1([CH3:27])[CH2:26][O:25]1>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:23][C:24]([OH:25])([CH3:27])[CH3:26])[CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:22]
Reactant: CC1(C)CO1
Reactant: Cc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Product: Cc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(C)(C)O)CC3)c2n1

Procedure:
The title compound was prepared according to the procedure described in Example 14 from 5-amino-6-chloro-2-methyl-N-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridine-8-carboxamide (Example 15, Step 2) and 2,2-dimethyloxirane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19](O)=[O:20].Cl.[CH3:23][O:24][C:25]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19]([N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:25]=2[O:24][CH3:23])[CH2:30]1)=[O:20]
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12
Reactant: COc1cc2c(c(OC)c1)CCNC2
Agent: Cl
Product: COc1cc2c(c(OC)c1)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccc(F)cc13)C2
Yield: 42.3 %

Procedure:
Reaction of 6-fluoro-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 100 (42.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.76 and 3.00 (2t, 2H), 3.48 (s, 1H), 3.52 and 4.04 (2t, 2H), 3.74-3.75 (2s, 3H), 3.87 (s, 2H), 4.32 and 4.78 (2s, 2H), 6.36-6.50 (m, 2H), 7.42-7.48 (m, 1H), 7.64-7.81 (2m, 2H), 8.03-8.39 (m, 4H); MS (ESI) m/z 462 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:33]>>[OH:12][CH:7]1[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:20]3[CH:19]=[C:18]4[C:23](=[CH:22][CH:21]=3)[N:14]([CH3:13])[C:15](=[O:33])[CH2:16][CH2:17]4)[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: OC1CCCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCCC4O)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-2 [E], Suzuki reaction of (rac)-4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-ol with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave the title compound as light red powder. MS: 309.5 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][N:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1)([O-])=O.[H][H]>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][N:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1
Reactant: [H][H]
Reactant: O=C1CN(Cc2cccc([N+](=O)[O-])c2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CN2CC(=O)NS2(=O)=O)c1

Procedure:
To a solution of the title C compound in Example 5, 5-(3-nitrobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (30 mg, 0.11 mmol) in EtOH (5 mL) is added palladium on carbon (10 mg) and the mixture is stirred under 1 atm of hydrogen for 1 h. The catalyst is removed by filtration through a plug of Celite which is washed with MeCN/water (1:1), (20 mL). The solvents are evaporated to afford 5-(3-Aminobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a brown solid: [M−1]−=240.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[CH3:23][CH:24]1[CH2:26][CH:25]1[CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.O1CCCC1>[CH3:23][CH:24]1[CH2:26][CH:25]1[CH2:27][N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: CC1CC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC1CC1CN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (300 mg, 1 mmol) produced in Example (8b), the crude product of 2-methyl-1-cyclopropanecarbaldehyde produced in Example (96a) (365 mg) and tetrahydrofuran (10 mL) were added sodium triacetoxyborohydride (424 mg, 2 mmol) and acetic acid (0.057 mL, 1 mmol) in that order, followed by stirring for 15 hours and 30 minutes at room temperature. Ethyl acetate, saturated aqueous solution of sodium hydrogencarbonate and water were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane), to give 163 mg of 1-(2-methylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil, as a mixture of cis/trans at the position of cyclopropane ring.