Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:10])[CH:4]=[C:5]([CH2:8][CH3:9])[CH2:6][CH3:7]>O1CCOCC1.[Pd]>[CH2:6]([CH:5]([CH2:8][CH3:9])[CH2:4][C:3]([OH:10])=[O:2])[CH3:7]
Reactant: CCC(=CC(=O)OC)CC
Agent: [Pd]
Solvent: C1COCCO1
Product: CCC(CC)CC(=O)O
Reaction time: 4 h
Yield: 65.5 %

Procedure:
3-ethyl-pent-2-enoic acid methyl ester (150 mg, 1.056 mmol) was dissolved in dioxane (1 ml), and palladium 10% on activated carbon (30 mg) was added; the slurry was hydrogenated under pressure (40 p.s.i.) for 4 h. The carbon was filtered off and the filter was washed with dioxane (1 ml); 1N NaOH (2 ml) was added to the mixture which was left overnight at room temperature; after addition of 1N hydrochloric acid (3 ml), the product was extracted with ethyl acetate. The organic solution was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure, obtaining 90 mg of 3-ethyl pentanoic acid as colourless oil. Yield 65.5%.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.[N-]=C=O>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:15][NH:14][C:12](=[O:13])[CH2:11][C@H:8]2[CH2:9][CH2:10][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:7]2)=[O:25])=[CH:19][CH:18]=1
Reactant: NNC(=O)C[C@H]1CCN(C(=O)C2CC2)C1
Reactant: O=C=Nc1ccc(Br)cc1
Agent: [N-]=C=O
Solvent: ClCCl
Product: O=C(C[C@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
In a round bottom flask under nitrogen, a solution of 2-[(3R)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (2.16 mmol) in dichloromethane (5 mL) was cooled to 0° C. and 1-bromo-4-isocyanatobenzene (2.16 mmol) was added. Once the isocyanate dissolved, the cooling bath was removed and the reaction was allowed to warm to room temperature and was stirred for 3 h. The reaction was filtered to collect the white precipitate, washed with 10 mL cold dichloromethane, air dried for 1 h and then dried in a vacuum oven (60° C.) overnight to provide the title compound (88% yield). MS(ES)+ m/e 409.1, 411.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.Br[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C(OCC)(=O)C>C1COCC1>[O:3]1[CH2:8][CH2:7][CH:6]([O:9][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:5][CH2:4]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(COC2CCOCC2)cc1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil; 490 mg, 12.2 mmol) in THF (10 mL) was added a solution of tetrahydro-2H-pyran-4-ol (1.20 g, 12.2 mmol) in THF (2 mL) at rt. The reaction mixture was stirred at it for several minutes and then heated to reflux for 15 min. After cooling to rt, 4-(bromomethyl)benzonitrile (2.00 g, 10.2 mmol) was added, and the reaction mixture was stirred at it over night. Ethyl acetate was added and the mixture was washed with water. The organic layer was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 7:3) to afford the title compound (1.57 g, 71%): 1H NMR (400 MHz, CDCl3) δ 7.53 (d, 2H), 7.45 (d, 2H), 4.61 (s, 2H), 4.00-3.92 (m, 2H), 3.65-3.58 (m, 1H), 3.49-3.41 (m, 2H), 1.99-1.92 (m, 2H), 1.72-1.62 (m, 2H); ES-MS m/z 218, HPLC RT (Method D) 1.86 min.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]>C1COCC1>[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C1CCCN1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCN1C(=O)Oc1ccccc1
Temperature: -60 °C
Yield: 100.1 %

Procedure:
To a solution of 7.36 g (184 mmol) of NaH (60%) in 200 ml of THF was added 15.68 g (184 mmol) of 2-oxopyrrolidine with stirring under ice-cooling, and further the mixture was stirred at room temperature for 1 hr. until H2 gas ceased to evolve. The reaction solution was added to a solution of 29.7 g (190 mmol) of phenyl chloroformate in 100 ml of THF cooled at -60° C. and then stirred at room temperature for 4 hr. The reaction solution was poured into ice water, and then extracted with ethyl acetate. After drying, the solvent was removed by evaporation. When the crystalline residue was recrystallized from CH2CL2 - ether, 37.8 g of the objective compound (II) melting at 120.0°-121.5° C. was obtained as crystals. Yield:84.0%
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:13]=1[I:14])[C:8](Cl)=[O:9])(=[O:3])[CH3:2].Cl.[CH2:22]([O:24][C:25](=[O:35])[C@H:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH2:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:35])[C@H:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:27][C:8](=[O:9])[C:7]1[C:6]([I:20])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:13]([I:14])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:11]=1[I:19])[CH3:23]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)Cl)c1I
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Product: CCOC(=O)CC[C@H](NC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I)C(=O)OCC

Procedure:
Following the procedure of example 13, 155 g (65%) of product is synthesized from 192 g (0.3 Mol) 3,5-diacetamido-2,4,6-triiodobenzoyl chloride and 108 g (0.45 Mol) L-glutamic acid diethyl ester hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([CH:12]=O)=[CH:7]2.C([O-])(=O)C.[NH4+].[N+:19]([CH3:22])([O-:21])=[O:20]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](/[CH:12]=[CH:22]/[N+:19]([O-:21])=[O:20])=[CH:7]2
Reactant: C[N+](=O)[O-]
Reactant: Cn1c(C=O)cc2cccc(F)c21
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cn1c(/C=C/[N+](=O)[O-])cc2cccc(F)c21

Procedure:
To a solution of 7-fluoro-1-methyl-1H-indole-2-carboxaldehyde (1.80 g) in nitromethane (20 ml) was added ammonium acetate (780 mg) and the mixture was heated at reflux for 1 h. The solvent was removed in vacuo and the residue was suspended in ethyl acetate (300 ml). This suspension was washed with 8% aqueous sodium bicarbonate solution (2×300 ml), dried, and the solvent was removed in vacuo to leave the title compound (1.26 g) as a solid, m.p. 153°-155.5°.
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[CH:4][C:5]([Cl:9])=[C:6]([F:8])[CH:7]=1.[Cu][C:12]#[N:13].CC(CC(O)CO)C.C1(C)C(C)=CC=CC=1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:10][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([F:8])=[CH:7][C:2]=1[C:12]#[N:13]
Reactant: Fc1cc(Br)c(Cl)cc1Cl
Reactant: N#C[Cu]
Agent: CC(C)CC(O)CO
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: N#Cc1cc(F)c(Cl)cc1Cl

Procedure:
97.6 g (0.4 mol) of 5-bromo-2,4-dichlorofluorobenzene, 35.8 g (0.4 mol) of copper(I)cyanide, 10.0 g (0.014 mol) of trimethyl(ethoxypolyoxypropyl)ammonium chloride, 5.0 g (0.015 mol) of tetrabutylphosphonium bromide and 5.0 g (0.01 mol) of polyethylene glycol dimethyl ether 500 were introduced together with 20.0 g (0.19 mol) of xylene into a 250 ml 3-neck flask fitted with a reflux condenser and blade stirrer and azeotropically dried at up to 150° C. under reduced pressure. Amount of 2,4-dichloro-5-fluorobenzonitrile formed: after 5 hours: 19 GC area-%. after 26 hours: 75 GC area-%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][CH3:10])[CH2:5][N:4]1[C:11]([C:13]1[N:14]=[C:15]([CH3:25])[S:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)=[O:12].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[C:36](O)=[O:37])[CH:29]=[CH:28][CH:27]=1>>[F:24][C:20]1[CH:19]=[C:18]([C:17]2[S:16][C:15]([CH3:25])=[N:14][C:13]=2[C:11]([N:4]2[CH2:5][CH:6]([O:9][CH3:10])[CH2:7][CH2:8][CH:3]2[CH2:2][NH:1][C:36]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:35]=2[N:26]=[CH:27][CH:28]=[CH:29]3)=[O:37])=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: COC1CCC(CN)N(C(=O)c2nc(C)sc2-c2cccc(F)c2)C1
Product: COC1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2nc(C)sc2-c2cccc(F)c2)C1

Procedure:
The title compound was prepared according to general procedure A using (2-(aminomethyl)-5-methoxypiperidin-1-yl)(5-(3-fluorophenyl)-2-methylthiazol-4-yl)methanone and quinoline-8-carboxylic acid. (ESI) 519 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:17]([CH:18]=[N:19][C:20]=2[C:23]([OH:25])=O)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:40]1[CH:41]=CC2N(O)N=[N:46][C:44]=2[CH:45]=1.C(Cl)CCl.CCN(C(C)C)C(C)C.N1CCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:10][C:11](=[O:12])[N:13]1[CH2:22][C:21]2[N:17]([CH:18]=[N:19][C:20]=2[C:23]([N:46]2[CH2:41][CH2:40][CH2:45][CH2:44]2)=[O:25])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1Cc2ccccc2-n2cnc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1Cc2ccccc2-n2cnc(C(=O)N3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
To a solution of (R)-5-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid (60 mg, 0.11 mmol) in dry DCM (15 mL), was added HOBT (19 mg, 0.14 mmol), EDC (27 mg, 0.14 mmol) and DIPEA (0.08 mL; 0.46 mmol) and the reaction mixture was stirred for 10 min. Pyrrolidine (0.02 mL, 0.24 mmol) was added and the reaction was stirred at r.t. overnight under nitrogen atmosphere. After the completion of the reaction, as confirmed by TLC, the crude product was extracted with DCM (15 mL) and washed with 10% HCl solution (10 mL) and saturated sodium bicarbonate solution (10 mL). The organic layer was separated washed with water, dried over Na2SO4 and concentrated in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 3:7 to 9:1 EtOAc:Pet.Ether) to afford (R)-[3-oxo-3-[3-(pyrrolidine-1-carbonyl)-4H,6H-2,5,10b-triaza-benzo[e]azulen-5-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (55 mg, 83%) as a solid.
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH2:2]1.[C:13](N)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:4]12([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][CH2:1][CH2:2][CH2:3]1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:13](=[O:20])[O:5]2
Reactant: O=C1CCCCc2ccccc21
Reactant: NC(=O)c1ccccc1
Product: O=C1OC2(CCCCc3ccccc32)c2ccccc21

Procedure:
Using a procedure similar to that described in Example 1a except adding 1-benzosuberone to the solution of dilithiated benzamide, the title compound was obtained as a white crystalline solid (46%), mp 150°-151° C. Analysis for C18H16O2 : Calculated: C, 81.79; H, 6.10. Found: C, 81.97; H, 6.08.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CS(C)=O.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cccc(Oc2ccnc(Cl)c2)c1
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a mixture of 3-aminophenol (3.7 g, 34.09 mmol) in DMSO (50 mL) was added Cs2CO3 (30.7 g, 94.46 mmol). The mixture stirred for 10 minutes and then 2,4-dichloropyridine (5.0 g, 33.79 mmol) was added. The mixture was stirred at 120° C. for 1.5 h. The mixture was cooled and diluted with water. The aqueous solution was extracted with EtOAc (3×100 mL). The organic extracts were combined, dried over MgSO4 and concentrated to afford a dark oil. The oil was purified via column chromatography, eluting with 30-40% EtOAc/hexanes, to afford 4-(3-Aminophenoxy)-2-chloropyridine (6.63 g, 89%) as a brown solid.
Reaction SMILES: Br[C:2]1[O:3][C:4]([Br:23])=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][NH:31][CH3:32].C1COCC1>>[Br:23][C:4]1[O:3][C:2]([N:31]([CH3:32])[CH3:30])=[N:6][C:5]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]
Reactant: CCC(CC)c1cc(C)nn2c(-c3nc(Br)oc3Br)c(C)nc12
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3nc(N(C)C)oc3Br)c(C)nc12
Temperature: 130 °C
Yield: 87 %

Procedure:
67 mg of 3-(2,5-Dibromo-oxazol-4-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.15 mmol), 146 mg of cesium carbonate (0.45 mmol) and 3.0 ml of dimethylamine 2.0M in THF (6 mmol) are placed into a 4 ml of reaction vial and the vial is capped with a Teflon cap. The reaction vial is heated at 130° C. overnight. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOE t=3:1) to give 53 mg of the title compound (87%); mass spectrum (m/e): 406; 1H-NMR (CDCl3): 6.72 (s, 1H), 3.37 (m, 1H), 3.15 (s, 6H), 2.58 (s, 3H), 2.53 (s, 3H), 1.85 (m, 4H), 0.90 (t, 6H, J=7.2 Hz).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29](O)=[O:30])[CH2:7][CH2:6]1)(=[O:4])=[O:3].S(Cl)(Cl)=O.[CH3:36][N:37]([CH:39]=O)[CH3:38]>>[CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][O:25][CH:26]([CH3:28])[CH3:27])=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([NH:5][C:11]2[CH:12]=[CH:13][C:14]([CH2:39][N:37]([CH3:36])[CH:38]3[CH2:24][CH2:23][O:22][CH2:19][CH2:18]3)=[CH:15][CH:10]=2)=[O:30])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)OCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)OCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
In DMF (6.5 ml) was dissolved 1-methylsulfonyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (296 mg). To the solution was added thionyl chloride (0.12 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added THF (15.0 ml). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (234 mg) was added THF (10.0 ml), and then was added triethylamine (0.69 ml). To the obtained mixture was added dropwise at 0° C. the previously prepared acid chloride suspension, and the mixture was stirred at room temperature for 3 hour. To the mixture was added ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25 g, ethyl acetate→ethyl acetate:ethanol:triethylamine=100:10:1) and recrystallized from ethanol to give 1-methylsulfonyl N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 15) (248 mg, 58%) as white crystals.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[CH:3][CH:2]=1>CCOC(C)=O.[Pd]>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reaction time: 4 h
Yield: 93 %

Procedure:
1-Benzyl 4-tert-butyl 2-(biphenyl-4-ylmethyl)succinate (500 mg, 1.161 mmol) was dissolved in 10 mL of EtOAc and hydrogenated with 10% Pd/C at room temperature. After 4 hours of the hydrogenation, the mixture was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 2 to 5% MeOH/DCM) and gave the title compound: 296 mg (yield: 93%). LCMS (condition G): 339.1 (M−1); retention time=0.70 min.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[O:35][C:36]([CH:39]2[O:43][CH2:42][CH2:41][O:40]2)=[CH:37][CH:38]=1)CCC>O1CCOCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:34]5[O:35][C:36]([CH:39]6[O:43][CH2:42][CH2:41][O:40]6)=[CH:37][CH:38]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Brc1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Solvent: C1COCCO1
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5ccc(-c6ccc(C7OCCO7)o6)cc45)ccc32)cc1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(6-bromoquinazolin-4-yl)-amine (4.3 g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (J. Chem. Soc., Chem Commun., (1988), 560) (10 g) and 1,4-bis(diphenylphosphino) palladium (II) chloride (1 g) in dioxane. The solvent was removed in vacuo and the residue chromatographed on silica. Subsequent trituration gave the title compound δH [2H6]-DMSO 10.13 (1H, s), 8.85 (1H, s), 8.54 (1H, s), 8.20 (3H, m), 7.80 (3H, m), 7.30 (5H, m), 7.13 (1H, d), 6.79 (1H, d), 6.04 (1H, s), 5.71 (2H, s), 4.15 (4H,m).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19].N(CC)(CC)CC.FC(C(O)=O)(F)F.C(O)(C(F)(F)F)=O>C(O)(C)C.CCN(CC)CC>[CH3:24][C:23]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[NH:14][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1-c1ccncn1
Reactant: Cc1ccc(C(=O)O)cc1N
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)O)cc1Nc1ncccc1-c1ccncn1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
4-(2-Chloro-pyridin-3-yl)-pyrimidine (10.4 g, 54 mmol), 3-amino-4-methylbenzoic acid (19.4 g, 128 mmol), 17 g Et3N-TFA salt (The liquid Et3N-TFA reagent was generated by adding 2.5 mL TFA dropwise to a 0° C. solution of 3 mL Et3N in isopropanol, then concentrating by rotary evaporator followed by 30 minutes under high vacuum.), and 15 mL DMSO were mixed together in a sealed tube under argon. The mixture was stirred at 95° C. for 65 h. After cooling to RT, the residue was sonicated in 100 mL methanol to break up the solids, then filtered to obtain product as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[OH:37]>CCOCC>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[O:37][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: COC(C1=CN(C)CS1)c1ccccc1CCl
Reactant: Oc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(C1=CN(C)CS1)c1ccccc1COc1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To 0.25 g (1 mmol) of 5-(2-chloromethyl-α-methoxybenzyl)-3-methylthiazole, 2 ml of N,N-dimethylformamide, 0.28 g (2 mmol) of potassium carbonate and 0.33 g (2 mmol) of 2,5-dichlorophenol were added and stirred at 80° C. for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) and recrystallized from ether/n-hexane to give 5-[2-(2,5-dichlorophenoxymethyl)-α-methoxybenzyl]-3-methylthiazole (0.28 g, 74.0%) as colorless crystals. mp. 78.5-79.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[CH:30]=[CH:29][O:28][CH:27]=2)[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=2)=[CH:3][C:4]=1[C:26]1[CH:30]=[CH:29][O:28][CH:27]=1)#[N:25]
Reactant: OB(O)c1cccc(F)c1
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(Cl)cc1-c1ccoc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1ccoc1
Reaction time: 0.08 h
Yield: 70.1 %

Procedure:
100 mg (0.22 mmol) of 4-((6-chloro-4-(furan-3-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 2.4 mL of 1,4-dioxane, and 33.6 mg (0.24 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 8.3 mg (3 mol %) of Pd(PPh3)4, 76.2 mg (0.72 mmol) of Na2CO3, and 2.4 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 80 mg (70% yield) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@H:7](O)[CH3:8])=[CH:3][CH:2]=1.[Li]CCCC.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>C1COCC1.O>[N:26]([C@H:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH3:8])=[N+:27]=[N-:28]
Reactant: C[C@@H](O)c1ccncc1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccccc1S(=O)(=O)Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](N=[N+]=[N-])c1ccncc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(R)-1-Pyridin-4-yl-ethanol (0.160 g) was dissolved in THF (10 mL) and cooled to 0° C. nBuLi (2.5 M in hexanes, 0.52 mL) was added slowly and the reaction was stirred at 0° C. for 5 min. Toluenesulfonyl chloride (0.250 g) was added and the stirring was continued for 30 min. NaN3 (0.30 g) was added, the reaction was warmed to RT and stirred overnight. The mixture was added to H2O and the layers were separated. The aqueous layer was extracted with Et2O and the combined organic phases were dried over Na2SO4, filtered and evaporated in vacuo to yield a yellow oil. This crude material was purified by silica gel chromatography (30 g, 33 to 75% Et2O/hexanes w/1% Et3N) to afford (S)-4-(1-azido-ethyl)-pyridine as a clear oil.