Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH3:22])=CC=1.CCCCCCC>C(O)C.[Pd]>[CH3:22][C:10]1[C:11]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: COc1ccc(COc2cccc(Oc3ccccc3)c2C)cc1
Agent: [Pd]
Solvent: CCCCCCC
Solvent: CCO
Product: Cc1c(O)cccc1Oc1ccccc1
Reaction time: 72 h
Yield: 32.8 %

Procedure:
1-(4-Methoxybenzyloxy)-2-methyl-3-phenoxybenzene (205 mg, 0.64 mmol) was dissolved in ethanol (5 mL) and palladium on charcoal 10% wt (60 mg) was added. The reaction mixture was agitated under an atmosphere of hydrogen (1 atm) for 72 h. The crude reaction mixture was filtered over dicalite and the solvents removed in vacuo. The crude product was taken up in DCM (4 mL) and 1N NaOH (aq) (4 mL) and the aqueous layer was separated, then acidified to pH 1 with 5N HCI (aq). The aqueous layer was extracted with DCM (10 mL) and the combined organics were concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 5:95 ethyl acetate:heptane afforded 2-methyl-3-phenoxyphenol (43 mg, 0.21 mmol, 34%).
Reaction SMILES: [NH2:1][C:2]1([C:11](OCC)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>O.C(O)C>[NH2:1][C:2]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(N)CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC1(CO)CCc2ccccc21
Yield: 85 %

Procedure:
The product of Example 93A (0.292 g, 1.423 mmol) and sodium borohydride (0.275 g, 7.113 mmol) were reacted in 1:3 v/v water/ethanol (7 mL), at reflux for 4 hours. The reaction was concentrated by rotary evaporation the partitioned between water (5 mL), ethyl ether (20 mL), 1N aqueous sodium hydroxide (0.712 mL). Solid sodium chloride was added to saturate the aqueous phase and separate the phases. The aqueous phase was extracted with ethyl ether (2×25 mL). The combined ethereal extracts were washed with brine (25 mL), dried over potassium carbonate, filtered, and concentrated by rotary evaporation to afford the title compound (0.197 g, 1.209 mmol, 85%). NMR (300 MHz, DMSO-D6) δ ppm 1.64-1.80 (m, 1 H) 1.85 (s, 2 H) 2.16-2.31 (m, 1 H) 2.63-2.91 (m, 2 H) 3.30 (d, J=5.52 Hz, 2 H) 4.74 (t, J=5.52 Hz, 1 H) 6.80-7.63 (m, 4 H). MS (DCI) m/z 164 (M+H)+, 181 (M+NH4)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:4][CH2:3]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[CH2:36][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:4][CH2:3]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a mixture of (1R)-1-(1-piperidin-4-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)ethanol hydrochloride (21.6 mg, 0.0637 mmol) and triethylamine (40.0 μL, 0.287 mmol) in methylene chloride (0.78 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (17.8 mg, 0.0765 mmol). The resulting mixture was stirred overnight at room temperature. The solvents were evaporated, and the crude residue purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6.5 mg (26%) of the desired product. LCMS calculated for C17H20F3N4OS (M+H)+: m/z=385.1. Found: 385.0.
Reaction SMILES: [H-].[Na+].[C:3]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:27][CH2:28][C:29]1[C:30]([CH2:35]Br)=[CH:31][CH:32]=[CH:33][CH:34]=1.O>C1COCC1>[Br:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][O:26][CH2:25][CH2:24][CH2:23][NH:22][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: BrCc1ccccc1COCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a suspension of NaH (909 mg/22.7 mmol) in THF (50 ml) was added 3-(tritylamino)-1-propanol, and the solution was stirred at reflux temperature for 2 hours. To the solution was added α,α′-dibromo-o-xylene, and the solution was stirred at reflux temperature for 16 hours. After cooling, the mixture was poured into water. The whole was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, 200-350 mesh/hexane:ethyl acetate=100:0-20:1) to afford a yellow oil (4.84 g/51%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][CH2:20][C:19]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:18]=2)=[CH:13][CH:12]=1.Br[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH:28]1([N:24]2[CH2:23][CH2:22][C:19]3([N:18]=[C:17]([C:14]4[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][CH:2]5[CH3:1])=[CH:16][CH:15]=4)[O:21][CH2:20]3)[CH2:26][CH2:25]2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: BrC1CCCC1
Reactant: CC1CCCN1CCCOc1ccc(C2=NC3(CCNCC3)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(C2=NC3(CCN(C4CCCC4)CC3)CO2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A solution of 2-{4-[3-(2-methyl-1-pyrrolidinyl)propoxy]phenyl}-3-oxa-1,8-diazaspiro[4.5]dec-1-ene 36 (0.11 g, 0.245 mmol) in acetonitrile (4 ml) is placed under an argon atmosphere. Bromocyclopentane (0.039 ml, 0.368 mmol, 1.5 eq), potassium carbonate (0.068 g, 0.49 mmol, 2 eq) and potassium iodide (0.08 g, 0.05 mmol, 0.2 eq) are added and the mixture is stirred at 50° C. overnight. The mixture is then filtered and the filtrate is concentrated under reduced pressure, taken up in dichloromethane, and washed twice with a saturated aqueous solution of ammonium chloride. The aqueous phases are extracted with dichloromethane and the organic extracts are collected together and dried over magnesium sulfate. Dichloromethane is removed under reduced pressure to give 0.086 g of yellow oil. This crude product is purified by chromatography over silica gel (eluent: dichloromethane/ethanol/ammonia 89:10.9:0.1) to afford 0.034 g of 8-cyclopentyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-3-oxa-1,8-diazaspiro[4.5]dec-1-ene 32.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][S:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.O>CC#N>[CH3:17][O:16][CH2:15][CH2:14][N:4]1[C:5](=[O:13])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([S:20][CH3:19])=[CH:22][CH:23]=2)[C:3]1=[O:18]
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Reactant: CSc1ccc(N)cc1
Solvent: O
Solvent: CC#N
Product: COCCN1C(=O)C(Nc2ccc(SC)cc2)=C(c2ccccc2)C1=O
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
3-Chloro-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione (0.26 mmol, 70 mg) and 4-(methylthio)aniline (0.53 mmol, 73 mg) was dissolved in dry CH3CN (2 mL) and the reaction mixture was sequentially subjected to microwave heating single node 140° C. for, 10 min, 140° C. for 10 min, and 140° C. for 20 min. 0.3 mL Water was added and the reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 49 mg (50%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.22 (bs, 1H), 7.19-7.10 (m, 3H), 7.06-7.00 (m, 2H), 6.95-6.90 (m, 2H), 6.58-6.53 (m, 2H), 3.82 (t, J=5.6 Hz, 2H), 3.63 (t, J=5.6 Hz, 2H), 3.38 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[OH-].[K+].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=[O:21]>O.[Cu]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: COc1ccccc1S
Reactant: O=C(O)Cc1ccccc1I
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Sc1ccccc1CC(=O)O

Procedure:
2-Methoxythiophenol (2.8 g, 20 mmol) was added to a solution of potassium hydroxide (4.6 g, 80 mmol) in water (50 ml) and the mixture was degassed for 15 minutes. 2-Iodophenylacetic acid (5.24 g, 20 mmol) and copper bronze (64 mg, 1 mmol) were then added to the reaction mixture, which was refluxed overnight. The solution was cooled down, filtered and the precipitate washed with water (50 ml). The filtrate was acidified with conc HCl (pH 1), extracted with dichloromethane (3×100 ml). The organics were combined, extracted with saturated brine, dried over sodium sulphate and evaporated in vacuo to give the title compound as a pale brown oil which solidified overnight. The compound was used without any further purification (5.10 g, 93%).
Reaction SMILES: [CH2:1]([C:8]1([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22](/[CH:26]=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:21]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([C:8]1([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:21]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCN1CCC(O)(Cc2ccccc2)CC1)Nc1ccnc(/C=C/c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: O=C(NCCN1CCC(O)(Cc2ccccc2)CC1)Nc1ccnc(CCc2ccccc2)c1
Reaction time: 15 h

Procedure:
A suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-[2-((E)-styryl)-pyridin-4-yl]-urea (Example 19., 47.0 mg, 0.1 mmol) and Pd—C (10%, 10 mg) in MeOH (10 mL) is stirred under hydrogen atmosphere for 15 h. The catalyst is filtered off and the reaction mixture evaporated to provide the title compound.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]#[C:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])[CH3:5].[OH-].[Na+]>CO.C1COCC1>[CH3:29][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]#[C:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:8])([CH3:5])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C#CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ccc2ccccc2c1C#CCCc1ccccc1)C(=O)O

Procedure:
20 mg 2-methyl-2-{[1-(4-phenyl-but-1-ynyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester were reacted with 60 μl of 2 M sodium hydroxide in 0.5 ml methanol and 0.5 ml THF for 48 h room temperature and for 4 h at 60° C. The organic solvents were then removed in vacuo, and the residue was treated with water, acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate, and concentrated. After chromatography on silica (ethyl acetate/heptane) 11 mg of 2-methyl-2-{[1-(4-phenyl-but-1-ynyl)-naphthalene-2-carbonyl]-amino}-propionic acid were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2]>CO.[Pd]>[NH2:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([C:1]#[N:2])[CH:12]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of methyl 2-cyano-4-nitrobenzoate (0.9 g, 4.4 mmol) in MeOH (5 mL) was added Pd/C (0.1 g). The resulting mixture was stirred at room temperature for 2 hours under hydrogen atmosphere. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to give the title product (0.77 g), which was used in the next step without further purification. LC-MS: m/z 177.2 (M+H)+
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[C:59]([O:63][C:64]1[CH:69]=[N:68][CH:67]=[C:66]([CH:70]=C)[N:65]=1)([CH3:62])([CH3:61])[CH3:60].S([O-])([O-])=O.[Na+].[Na+].O>C(O)(C)(C)C>[C:59]([O:63][C:64]1[N:65]=[C:66]([CH:70]=[O:22])[CH:67]=[N:68][CH:69]=1)([CH3:62])([CH3:61])[CH3:60]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)Oc1cncc(C=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
After adding 7.20 g of AD-mix-β to 60 ml of 50% aqueous tert-butanol, a solution of 1.00 g of 2-tert-butoxy-6-vinylpyrazine in tert-butanol (5 ml) was added and the mixture was stirred overnight at room temperature. Next, 8.40 g of sodium sulfite was added to the reaction solution, the mixture was stirred at room temperature for 1 hour, and then water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 40 ml of methanol, an aqueous solution of 2.35 g of sodium periodate (20 ml) was added while stirring on ice, and stirring was continued at room temperature for 40 minutes. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (954 mg, 96% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][NH:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 80.8 %

Procedure:
A mixture of tert-butyl 3-aminoazetidine-1-carboxylate (10.0 g, 58 mmol), ethyl 2-bromoacetate (10.7 g, 64 mmol) and potassium carbonate (24.0 g, 174 mmol) in MeCN (200 mL) was stirred at rt for 13 hrs. The reaction mixture was filtered and concentrated. The crude material was purified by silica gel column chromatography (gradient elution 0-66% EtOAc/petroleum ether) to afford tert-butyl 3-(2-ethoxy-2-oxoethylamino)azetidine-1-carboxylate (12.1 g, 81%) as a white solid. ESI-MS (EI+, m/z): 259.0 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[O-:14][Mn](=O)(=O)=O.[K+].Cl>CC#N.O>[I:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]([OH:14])=[O:5]
Reactant: COc1cc(I)c(C=O)cc1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(I)c(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a stirred solution of 2-iodo-4,5-dimethoxybenzaldehyde (1.0 g, 3.42 mmol) in CH3CN (25 mL) was added a solution of KMnO4 (0.76 g, 4.79 mmol) in water (15 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. After the reaction was complete, the pH was adjusted to <7 with 1N HCl. The mixture was extracted with DCM and the organic layers combined, washed with brine, dried over sodium sulfate, and evaporated to give 2-Iodo-4,5-dimethoxybenzoic acid (0.89 g, 85%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[CH3:17][CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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.CN(C=O)C>[CH3:17][CH:18]([C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH:5]=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:19]
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: CC(C)c1cccc(-c2cncc(NC(=O)c3ccccc3)c2)c1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 1.4 g (4.9 mmol) of N-(5-bromopyridin-3-yl)benzamide, 1.0 g (5.9 mmol) of [3-(1-methylethyl)phenyl]boronic acid and 1.4 g (9.9 mmol) of potassium carbonate were dissolved in 15 ml of 1,2-dimethoxyethane, 5 ml of water and 30 ml of DMF. The mixture was flushed with argon, 29 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 1.4 g (92% of theory)
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)=[CH:31][CH:30]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2ccncc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ccncc3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyridin-4-yl-benzaldehyde, of Preparation 24, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 8.63 (dd, 2H), 7.60 (dd, 2H), 7.47 (m, 4H), 7.24 (m, 1H), 6.96 (m, 2H), 6.78 (dd, 1H), 4.52 (s, 2H), 3.85 (s, 2H), 3.80 (s, 2H), 1.47 (s, 9H); MS 405 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][N:7]=1>C(#N)C.[Cu](Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][N:7]=1
Reactant: CC1=NNC(=O)C(C2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: Cl[Cu]Cl
Solvent: CC#N
Product: Cc1cc(C2CCN(C(=O)OCc3ccccc3)CC2)c(=O)[nH]n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
Copper(II) chloride (anhydrous; 2.02 g, 15.05 mmol) was added to a solution of benzyl 4-(6-methyl-3-oxo-2,3,4,5-tetrahydropyridazine-4-yl)piperidine-1-carboxylate (2.48 g, 7.53 mmol) in acetonitrile (26 mL). The reaction mixture was heated at 90° C. After 18 h, the mixture was cooled to ambient temperature and concentrated. The residue was diluted with dichloromethane and 1 N HCl. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) to give the title compound (1.45 g). MS 328.2 (M+1).
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:16][S:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:16][S:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:23][CH:24]=1)[N:22]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: CSc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(SC)cc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 4-methylthio-aniline were reacted and treated with phenyl oxide to obtain ethyl 6-methylthio-4-hydroxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[C:3](=[O:4])[CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>CN(C)C=O.ClCCl>[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:11]([C:9]1[CH:10]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH2:1][CH2:2][C:3]2=[O:4])=[O:13]
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC2
Reactant: COCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCNC(=O)c1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a suspension of 1-indanone-6-carboxylic acid (1.76 g) in N,N-dimethylformamide (50 mL) was added carbonyldiimidazole (3.24 g), and the mixture was stirred at room temperature for 1 hour. Thereto was added a solution of 2-methoxyethylamine (3.76 g) in dichloromethane (50 mL) under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and then dissolved in chloroform. The organic layer was washed with aqueous saturated sodium hydrogen carbonate solution, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (20 mL), and then thereto was added 1-normal hydrochloric acid (20 mL), and the mixture was stirred at room temperature for 12 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with isopropyl ether-ethyl acetate (2:1) to give N-(2-methoxyethyl)-3-oxoindan-5-carboxamide [REx(13-1)] (1.87 g) as a brown powder.