Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[O:16]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:24][CH:25]=3)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)nc1
Reactant: Cc1cc(-c2ccc(CN)cn2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(Oc4ccccc4)nc3)cn2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2′-methyl-[2,4′-bipyridin]-5-yl)methanamine 18-2 (20 mg, 0.10 mmol), 6-phenoxynicotinic acid 56-1 (21.5 mg, 0.10 mmol), and HATU (40 mg, 0.105 mmol) were added N,N-diisopropylethylamine (DIEA, 26 μL, 0.15 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected to reverse phase preparative HPLC separation to yield N-((2′-methyl-[2,4′-bipyridin]-5-yl)methyl)-6-phenoxynicotinamide 94 as a solid. MS m/z 397.2 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:20][CH2:21][CH2:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[C:25]([OH:27])=O.[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[NH:38][NH2:39]>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[Cl:20][CH2:21][CH2:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[C:25]([NH:39][NH:38][C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:27]
Reactant: CN(C)c1ccc(C(CCCCl)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C(CCCCl)C(=O)NNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.1 %

Procedure:
IPEA (0.555 mL), HOBt (175 mg) and EDC (249 mg) were added to a solution of 5-chloro-2-(4-dimethylaminophenyl)pentanoic acid (317 mg) and tert-butyl carbazate (103 mg) in DMF (2.5 mL), and the reaction solution was stirred at room temperature for five hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane+ethyl acetate) to obtain 106.9 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.O.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:17][N:18]1[CH:22]=[C:21]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:20]=[N:19]1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Temperature: 25 °C
Yield: 63 %

Procedure:
5-(2-Chloropyridin-4-yloxy)pyridin-2-amine (0.47 g, 2.121 mmol) was dissolved in DMF (11 ml). Water (3.67 ml) was added to the mixture, followed by 1-methyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole (0.662 g, 3.18 mmol), and cesium carbonate (2.63 g, 8.06 mmol). Argon was bubbled through the mixture for several minutes, and then palladium tetrakistriphenylphosphine (0.245 g, 0.212 mmol) was added. The flask was fitted with a condenser and argon was flushed through the system. The reaction mixture was then placed in a 90° C. oil bath under a balloon of argon and heated for 23 hours. The solution was then cooled to RT and diluted with THF (75 mL) and washed with brine (2×50 mL). The combined aqueous layers were then back extracted with THF (40 mL). The combined organic layers were dried (MgSO4), concentrated under reduced pressure and purified via silica gel chromatography (THF-ethyl acetate) to yield 5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-amine as an off-white solid (0.357 g, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.31 (d, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.27 (dd, 1H), 7.14 (d, 1H), 6.85 (s, 6.57 (dd, 1H), 6.01 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 268.1 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:20]([F:23])([F:22])[F:21])=[N:10][C:11]2[C:16]([C:17]=1O)=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O.C(C1C(C(F)(F)F)=NC2C(C=1Cl)=CC=CC=2)C1C=CC=CC=1>>[CH2:1]([C:8]1[C:9]([C:20]([F:23])([F:22])[F:21])=[N:10][C:11]2[C:16]([C:17]=1[Cl:26])=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1c(Cc2ccccc2)c(C(F)(F)F)nc2ccc(I)cc12
Agent: FC(F)(F)c1nc2ccccc2c(Cl)c1Cc1ccccc1
Product: FC(F)(F)c1nc2ccc(I)cc2c(Cl)c1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-benzyl-6-iodo-2-(trifluoromethyl)quinolin-4-ol (6.10 g, 14.2 mmol, Intermediate 71: step a) in phosphoryl trichloride (18 mL, 194 mmol) was heated at 110° C. for 3 hours, then concentrated in vacuo. After cooling down to room temperature, ice-water and DCM were added to the residue, and the mixture was basified at 4° C. by the addition of 50% aqueous NaOH and concentrated NH4OH to pH 9. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (silica gel, 2-6% EtOAc in heptanes), affording a mixture of the title compound and 3-benzyl-4-chloro-2-(trifluoromethyl)quinoline in ˜2:1 ratio.
Reaction SMILES: [CH2:1]([CH:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:18]2([C:35]3[CH:36]=[CH:37][C:32]([NH2:31])=[CH:33][CH:34]=3)[CH2:19][CH2:20][CH2:21][CH:16]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17]2)=[CH:27][CH:26]=1
Reactant: CCCCCCCCCCCCCCCC1CCCC(=O)C1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC1CCCC(c2ccc(N)cc2)(c2ccc(N)cc2)C1
Temperature: 140 °C

Procedure:
A 100 mL single necked flask fitted with a magnetic stirrer and a reflux condenser was charged with a 10.0 g (32 mmol) of 3-pentadecylcyclohexanone, 8.4 g (65 mmol) aniline hydrochloride and 12.05 g (130 mmol) of aniline. The resulting mixture was refluxed at 140° C. for 10 hours under positive pressure of nitrogen. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with aqueous sodium hydroxide solution and water and dried over sodium sulfate. Solvent was distilled off and excess aniline removed under vacuum. The desired 1,1-bis(4-aminophenyl)-3-pentadecylcyclohexan was obtained in a yield of 5.4 g (35% of theoretical). M.p. 107° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]=[C:9]([N:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][CH:28]=[CH2:29])[CH2:10][N:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C(=O)OC(C)(C)C>ClCCl>[C:31]1([CH2:30][N:26]([CH2:27][CH:28]=[CH2:29])[C:9](=[O:8])[CH2:10][NH:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C=CCN(Cc1ccccc1)C(=O)CN(Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(Cc1ccccc1)C(=O)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
TFA (3 ml) was added dropwise to a solution of 1,1-dimethylethyl {2-oxo-2-[(phenylmethyl)(2-propen-1-yl)amino]ethyl}(phenylmethyl)carbamate (D89, 1.18 g, 3 mmol) in dry dichloromethane (12 ml) at 0° C. After stirring at room temperature for 3 h the solvent was evaporated and the residue purified via SCX cartridge to give the title compound (880 mg, quant.) as a clear oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.4-7.2 (m, 10H), 5.9-5.6 (m, 1H), 5.2-5.0 (m, 2H), 4.6, 4.4 (s, 2H), 4.1-3.7 (m, 4H), 3.5 (s, 2H), 2.4 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[C:11]([CH2:13][C:14](OC)=[O:15])#[N:12].C[O-].[Na+]>CO>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[CH:4]=[C:13]([C:11]#[N:12])[C:14](=[O:15])[NH:1]2
Reactant: Nc1cccc(F)c1C=O
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc2c(F)cccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
To a solution of MeOH (60 mL) containing 2-amino-6-fluoro-benzaldehyde (1.19 g, 8.6 mmol) and methyl cyanoacetate (0.91 mL, 10.3 mmol) was added sodium methoxide (2.93 mL, 12.8 mmol, 25% in MeOH). The mixture was stirred at rt for 16 hrs. The resulting yellow precipitates were filtered, washed with MeOH and then stirred in 1N HCl (75 mL) for 2 hrs at rt. The solid was filtered, washed with water and dried in vacuo to yield 5-fluoro-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (1.2 g) as a white solid. MS [M+H]+: 189.1; tR=2.00 min. (method 1)
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([O:15]C)=[O:14])[C:5]=2[O:4][C:3]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.O1CCOCC1.[OH-].[Na+].O>CO>[CH3:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:5]=2[O:4][C:3]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cccc2c(=O)c(C)c(-c3cccnc3)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Cc1c(-c2cccnc2)oc2c(C(=O)O)cccc2c1=O
Reaction time: 1 h
Yield: 63 %

Procedure:
A mixture of 6.2 g of methyl 3-propionylsalicylate and 5.8 g of nicotinoyl chloride hydrochloride in 18 ml of anhydrous pyridine was stirred and heated at 100° C. for 2 hours under nitrogen. After that, 16 ml of triethylamine was added and heating was continued for 1 hour at the same temperature. The reaction mixture was cooled to room temperature, poured into 600 ml of water and the precipitate was collected by suction and washed with water, yielding 5.4 g of methyl 2-hydroxy-3-(2-nicotinoyl)propionylbenzoate, which was used without purification in the next step. 3.4 g of this Intermediate was heated at 100° C. for 1.5 hours after dissolution in a mixture containing 15 ml of acetic acid and 1 ml of 37% hydrochloric acid. After cooling to room temperature, the mixture was poured into 150 ml of water and extracted with ethyl acetate. The organic phase was washed with 5% aqueous sodium hydrogen carbonate solution, followed by water, dried on sodium sulfate and evaporated in vacuo, yielding 1.3 g of crude methyl 3-methyl-4-oxo-2-(3-pyridyl)-4H-1-benzopyran-8-carboxylate. 1 g of the above ester was dissolved in 9 ml of methanol and 15 ml of 1,4-dioxane and slowly added with 1.7 ml of 10N sodium hydroxide, maintaining the temperature between 20 and 25° C. After 1 hour at 50° C., the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate. The aqueous layer was acidified with in aqueous hydrochloric acid solution. The precipitate was collected by suction, yielding 0.6 g of 3-methyl-4-oxo-2-(3-pyridyl)-4H-1-benzopyran-8-carboxylic acid, which was used without purification in the next step. The title compound was prepared according to Example 86, but using the above Intermediate instead of 4-oxo-2-phenyl-4H-1- benzopyran-8-carboxylic acid and carrying out the reaction for 2 hours at room temperature. The base was purified by flash chromatography on silica gel eluting with a mixture of chloroform-methanol (98:2), followed by crystallization from acetone, yielding 0.15 g (m.p. 134.5°-137° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:24]([O:26]CC)=[O:25])[C:6](=[O:23])[N:7]2[C:12]=1[C:11]([F:13])=[C:10]([N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[C:9]([F:21])=[C:8]2[F:22])[CH3:2].[OH-].[Na+].[ClH:31]>C1COCC1>[ClH:31].[CH2:1]([C:3]1[CH:4]=[C:5]([C:24]([OH:26])=[O:25])[C:6](=[O:23])[N:7]2[C:12]=1[C:11]([F:13])=[C:10]([N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[C:9]([F:21])=[C:8]2[F:22])[CH3:2]
Reactant: CCOC(=O)c1cc(CC)c2c(F)c(N3CCN(C)CC3)c(F)c(F)n2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)c(=O)n2c(F)c(F)c(N3CCN(C)CC3)c(F)c12
Temperature: 75 °C
Reaction time: 4.5 h

Procedure:
To a solution of 199 mg (0.5 mmol) of ethyl 1-ethyl-8-(4-methylpiperazin-1-yl)-6,7,9-trifluoro-4H-quinolizin-4-one-3-carboxylate, from Step 5, in 4 mL of THF is added 4.0 mL of a 1.0N aqueous sodium hydroxide solution and the reaction mixture is heated, with stirring, at 75° C. for 4.5 hours. The reaction mixture is cooled to ambient temperature and adjusted to pH 2 with 5 mL of 1N aqueous hydrochloric acid solution. The aqueous solution is concentrated in vacuo to ~5 mL and the solid is collected by filtration and dried in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([OH:32])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:32][C:25]3[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([F:22])[CH:24]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ccnc2cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
The 7-benzyloxy-4-chloro-6-cyanoquinoline (8.82 g, 30.0 mmol) described in WO98/13350 was suspended in 1-methylpyrrolidone (30 ml), and then 3-fluoro-4-nitrophenol (5.18 g, 33.0 mmol) and N,N-diisopropylethylamine (3.88 g, 30.0 mmol) were added and the mixture was heated and stirred at 110° C. for 4 hours. After returning the reaction system to room temperature, water was added and a solid precipitated. The obtained solid was filtered out, washed with water, methanol and ethyl acetate and dried at 60° C. to obtain the title compound (4.98 g, 12.0 mmol, 40%) as colorless crystals.
Reaction SMILES: COCCOC.[CH2:7]([O:14][CH2:15][CH:16]=[CH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:18][C:19]([Cl:24])(Cl)[C:20](Cl)=[O:21]>O.C(OCC)C.[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[CH2:7]([O:14][CH2:15][CH:16]1[CH2:17][C:20](=[O:21])[C:19]1([Cl:24])[Cl:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CCOCc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: O=C1CC(COCc2ccccc2)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc dust (6.54 g, 0.1 mol) was suspended in water (30 ml) and argon bubbled through the suspension for 15 minutes before the addition of copper (II) sulphate (780 mg, 3.1 mmol). The reaction mixture was stirred at room temperature, under argon for 30 minutes. The mixture was filtered under a stream of argon and the solid washed with water (100 ml), acetone (100 ml) and dried in vacuo for 4 hours. The resultant zinc/copper couple was suspended in diethyl ether:1,2-dimethoxyethane (70 ml:10 ml) under argon and allyl benzyl ether (4.6 ml, 30 mmol) added. A solution of trichloroacetyl chloride (9 ml, 81 mmol) in diethyl ether:1,2-dimethoxyethane (58 ml:7 ml) was added dropwise over 45 minutes and the reaction mixture heated to reflux for 48 hours. The reaction mixture was filtered through Celite® and the salts washed with diethyl ether (3×70 ml). The filtrate was evaporated in vacuo and the residue redissolved in hexane (150 ml). The remaining solids were removed by filtration and the filtrate washed with a saturated aqueous solution of sodium hydrogen carbonate (2×100 ml), brine (80 ml), dried over magnesium sulphate, filtered and evaporated in vacuo. The crude material was purified by column chromatography over silica gel eluting with 10-25% hexane:diethyl ether. The title compound was obtained as a yellow oil (7.03 g, 27.3 mmol, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:83]1[CH2:88][CH2:87][O:86][CH2:85][CH2:84]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([N:83]3[CH2:88][CH2:87][O:86][CH2:85][CH2:84]3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(I)cc2)n1-c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(N3CCOCC3)cc2)n1-c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
A reaction tube charged with 5-(4-chlorophenyl)-6-(4-iodo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (100.0 mg, 0.191 mmol), Pd2(dba)3 (17.5 mg, 0.019 mmol), BINAP (23.7 mg, 0.038 mmol), and Cs2CO3 (124.2 mg, 0.381 mmol) is purged with nitrogen. Anhydrous toluene (1.0 mL) and morpholine (33.2 μL, 0.381 mmol) are added via syringe. The reaction mixture is heated at 100° C. overnight, and is partitioned between water and ethyl acetate. The organic phase is washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography to provide the title compound (64.3 mg, 70% yield) as a yellow solid product; 1H NMR (CDCl3, 400 MHz) δ 8.29 (s, 1H), 8.17 (dd, 2H), 7.50 (t, 2H), 7.35 (m, 3H), 7.28 (d, 2H), 7.12 (d, 2H), 6.77 (d, 2H), 3.86 (t, 4H), 3.21 (t, 4H); HPLC-MS calculated for C27H22ClN5O2 (M+H+) 484.1. Found 484.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C@H:9]([CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:8]([NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]1=[O:32].[I-:39].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C@H:9]([CH2:10][I:39])[C@H:8]([NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]1=[O:32]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2COS(=O)(=O)c2ccc(C)cc2)c(OC)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CI)c(OC)c1

Procedure:
To 70 ml of acetone are added 2.27 g of cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-4-(p-toluenesulfonyloxymethyl)-2-oxoazetidine and 4.95 g of sodium iodide, and the mixture is heated under reflux for 6 hours with stirring, and then concentrated in vacuo. To the residue are added methylene chloride and water to dissolve it, and the methylene chloride layer is separated and washed successively with an aqueous sodium thiosulfate solution and an aqueous sodium chloride solution. The methylene chloride layer is then dried over magnesium sulfate and the solvent is distilled off in vacuo. Ethyl acetate is added to the residue and the precipitated crystals are collected by filtration to give cis-1-(2,4-dimethoxybenzyl)-4-iodomethyl-3-phenylacetamido-2-oxoazetidine, m.p. 181°-182° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([C:14]1[S:18][C:17]([S:19]([OH:22])(=O)=[O:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:25])=O>>[CH2:7]([C:14]1[S:18][C:17]([S:19]([Cl:25])(=[O:22])=[O:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(O)c1ccc(Cc2ccccc2)s1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
Phosphorous pentachloride (2.08 g, 40 mmol) was added to a solution of 5-benzylthiophene-2-sulfonic acid in phosphorous oxychloride (6.0 g, 40 mmol) at 0° C. The reaction mixture was kept at 50° C. for 1 h, cooled to room temperature, then poured onto crushed ice (50 g) and extracted with ethyl acetate (2×30 ml). Removal of the solvent under reduced pressure gave a crude product, which was purified by column chromatography using 3% ethyl acetate in hexane to give 2-benzylthiophene-5-sulfonyl chloride (0.6 g, 39% yield).
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([NH2:17])=[O:16])=[CH:4][N:3]=1.[NH4+:18].[OH-]>>[NH2:18][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([NH2:17])=[O:16])=[CH:4][N:3]=1
Reactant: NC(=O)c1cnc(Cl)c2c1[nH]c1ccccc12
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cnc(N)c2c1[nH]c1ccccc12
Temperature: 160 °C

Procedure:
A mixture of 1-chloro-5H-pyrido[4,3-b]indole-4-carboxamide in conc. NH4OH (0.07 M) was heated in a microwave reactor at 160° C. for 1 h in a sealed tube. The reaction mixture was cooled to room temperature and partitioned between THF/EtOAc and saturated NaHCO3. After separation of the organic phase, the aqueous phase was extracted again with THF/EtOAc, and the combined organic phases were washed with brine, dried over Na2SO4 and filtered. After evaporation of the organic solvents, the residue was purified by flash chromatography (0-10% MeOH in EtOAc) to provide the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]=[O:19]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1)[OH:19]
Reactant: Fc1cccnc1
Reactant: O=Cc1ccc2ccccc2c1
Product: OC(c1ccc2ccccc2c1)c1ccncc1F

Procedure:
Using 5.2 mL of 3-fluoropyridine and 10.2 g of 2-naphthaldehyde as starting materials, 17.0 g of the title compound was obtained as a colorless powder in the same manner as described in Production example 18.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C:12]([CH3:27])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])[CH2:13][OH:14]>N1C=CC=CC=1>[C:2]([O:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]([CH3:27])([CH3:11])[CH2:13][O:14][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: CC(C)(CO)CCCCCCCC(C)(C)CO
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(CCCCCCCC(C)(C)COC(=O)c1cccnc1)COC(=O)c1cccnc1
Reaction time: 36 h
Yield: 51.9 %

Procedure:
A suspension of 53.10 grams (0.3 mole) of nicotinoyl chloride hydrochloride in 150 ml of anhydrous pyridine was added in 2 hours under stirring with a solution of 12.2 grams (0.05 mole) of 2,2,10,10-tetramethyl-1,11-undecanediol in 30 ml of anhydrous pyridine while keeping the temperature at about 70° C. The reaction was refluxed and stirred for 36 hours then, after cooling, the formed precipitate was removed by filtration. The filtrate was evaporated under vacuum and the obtained residue was treated with a mixture of 200 ml of diethyl ether and 100 ml of an 8% aqueous solution of sodium bicarbonate. The organic layer was separated and washed first with 100 of a 3% aqueous solution of sodium bicarbonate and then with 100 ml of water. After evaporating the diethyl ether in vacuo the obtained residue was dissolved in 50 ml of methylene chloride, the organic solution was twice washed with 30 ml of 1N hydrochloric acid and twice with 50 of water, dried over sodium sulphate and finally brought to dryness. The residue was crystallized from ethanol thus obtaining 11.80 grams of the title product, having m.p. 70°-71° C. Yield: 52% of theoretical.