Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.C(O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:12]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]2)=[O:13])[CH:16]=1
Reactant: CCOC(=O)C1CCN(C(=O)Oc2cccnc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(C(=O)Oc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.5 %

Procedure:
4-Ethyl 1-pyridin-3-yl piperidine-1,4-dicarboxylate (0.732 g) was dissolved in THF (15 ml) and ethanol (8.0 ml), and under ice cooling, an aqueous 1 M sodium hydroxide solution (3.9 ml) was dropwise added thereto. This was stirred at room temperature for 2 hours, and neutralized with 1 M hydrochloric acid (0.5 ml). The reaction liquid was concentrated under reduced pressure, methanol was added to the residue, and the precipitated salt was removed through suction filtration. The filtrate was concentrated to obtain 1-[(pyridin-3-yloxy)carbonyl]piperidine-4-carboxylic acid (0.727 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[N:13]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH2:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>CC#N>[Cl:12][C:4]1[N:3]=[C:2]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:13]=[CH:14][CH:15]=[CH:16]3)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: NCc1ccc2ncccc2c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a mixture of 2,6-dichloro-3-nitropyridin-4-amine (624 mg, 3 mmol) and quinolin-6-ylmethanamine (316 mg, 2 mmol) in CH3CN (10 mL) was added Et3N (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. After cooled to room temperature, the mixture was concentrated to afford the title compound (658 mg). MS (m/z): 330 (M+1)+.
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[OH:6][C:7]1[CH:17]=[CH:16][C:10]([CH:11]([OH:15])[C:12]([OH:14])=[O:13])=[CH:9][C:8]=1[CH3:18].[OH-].[Na+].Cl>O>[C:3]([CH2:2][O:6][C:7]1[CH:17]=[CH:16][C:10]([CH:11]([OH:15])[C:12]([OH:14])=[O:13])=[CH:9][C:8]=1[CH3:18])([OH:5])=[O:4]
Reactant: Cc1cc(C(O)C(=O)O)ccc1O
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(O)C(=O)O)ccc1OCC(=O)O
Temperature: 80 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
4.7 g (0.05 mol) of chloroacetic acid is added to a solution of 9.11 g (0.05 mol) of 4-hydroxy-3-methylmandelic acid and 6.0 g (0.15 mol) of sodium hydroxide in 25 ml of water, and the mixture is then stirred at 80° C. for 3 hours. The reaction mixture is acidified with concentrated hydrochloric acid, cooled with ice/water, and the precipitated product is filtered, washed with water and dried in a high vacuum, giving 5.65 g (62%) of 4-carboxymethoxy-3-methylmandelic acid, melting point 95°-100° C.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[NH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10]O.O>C1(C)C=CC=CC=1>[OH:4][CH2:1][CH2:2][N:8]1[CH2:7][CH2:6][N:5]=[C:9]1[CH3:10]
Reactant: CC(=O)O
Reactant: NCCNCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=NCCN1CCO

Procedure:
Sixty parts (1 mole) of acetic acid was added little by little to 104 parts (1 mole) of N-(beta-aminoethyl) ethanolamine and 16 parts of toluene. After generation of the heat of neutralization reaction ceased, the mixture was heated under reflux at 150° to 160° C. until 36 parts (2 moles) of water distilled. Finally, the solvent was removed under reduced pressure to give 128 parts of N-hydroxyethyl-2-methylimidazoline (amine value about 440). Then, 380 parts (1 mole) of bisphenol A diglycidyl ether having an epoxy equivalent of about 190, 85 parts (0.1mole) of polycaprolactone diol having a hydroxyl equivalent of about 425 and 1.28 parts of the N-hydroxyethyl-2-methylimidazoline obtained above were mixed under heat, and reacted at 140° C. until the epoxy value of the product decreased to 3.8 (mg equivalent/1 g of solids; the same unit applies hereinafter), and then 114 parts (0.5 mole) of bisphenol A was added, and the mixture was reacted at 130° C. until the epoxy value of the product decreased to 1.35. Then, the reaction mixture was diluted with 219 parts of ethylene glycol monobutyl ether and cooled. An 80% aqueous solution of a diethylene-triamine/ ethylene carbonate adduct (mole ratio 1:2) prepared in advance (139.5 parts; 0.4 mole) was added, and the misture was reacted at 90° C. until the amine value of the product decreased to 2 or below (mg of KOH/g of resin solids; the same unit applies hereinafter). The reaction mixture was further reacted with 38.4 parts (0.3 mole) of the above N-hydroxyethyl -2-methylimidazoline until there was no rise in viscosity. As a result, an epoxy resin derivative in accordance with this invention was obtained.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][N:21]=3)[N:17]=[C:16]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=3)[N:17]=[C:16]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH:15]=2)=[O:13])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)c(Cl)c3)cc2C(=O)N[C@H]2CC[C@@H](C(C)(C)C)CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@@H](NC(=O)c2cc(-c3ccc(Cl)c(Cl)c3)nn2Cc2ccc(C(=O)O)cn2)CC1

Procedure:
To a solution of the intermediate from step G (isomer B) (0.14 g, 0.24 mmol) in 10 ml of 1:1 THF/MeOH was added 5 N NaOH (1 mL). After stirring the reaction at room temperature for 2 hours, it was concentrated in vacuo. The residue was acidified with 1N HCl (10 ml) and the resulting mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4 filtered and concentrated in vacuo. This material was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19](O)=[O:20])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH2:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>CN(C=O)C>[C:25]1([CH:24]=[CH:23][CH2:22][NH:31][C:19]([C:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]=2[CH3:18])=[O:20])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCC=Cc1ccccc1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C([N+](=O)[O-])=C(C)N1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCC=Cc2ccccc2)C(c2cccc(Cl)c2)C([N+](=O)[O-])=C(C)N1

Procedure:
93 mg (0.30 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-5-nitro-1,4-dihydropyridine-3-carboxylic acid, 100 mg (0.75 mmol) of cinnamylamine, 138 mg (0.54 mmol) of 2-chloro-1-methylpyridinium iodide and 0.15 ml (1.08 mmol) of triethylamine were stirred in 5 ml of DMF at room temperature for 2 days. DMF was evaporated under reduced pressure. Ethyl acetate was added to the reaction mixture. After washing with 1 N hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate. After the concentration under reduced pressure, the residue was purified by the silica gel chromatography (hexane/ethyl cetate=4/1) to obtain the title compound.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:10][C:11]1([CH3:34])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:34])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a suspension of cyclopropanesulfonamide (610 mg, 5.0 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (200 mg, 5.0 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A31. A solution of 4,4-dimethyl-2-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (350 mg, 1.0 mmol) and 1,1′-carbonyldiimidazole (320 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B31. Solution B31 was added to Solution A31 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (140 mg, 30%) as a white solid: MS (ESI) M+1=453.3.
Reaction SMILES: [S:1]1(=[O:8])(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]Cl)[CH:15]=1.[H-].[Na+]>>[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6][S:1]2(=[O:8])=[O:7])[CH:13]=[N:12][CH:11]=1
Reactant: ClCc1cncc(Br)c1
Reactant: O=S1(=O)CCCCN1
Agent: [H-]
Agent: [Na+]
Product: O=S1(=O)CCCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-12 [B] and to the procedure described for the preparation of intermediate A-3 [C], [1,2]thiazinane 1,1-dioxide was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in the presence of NaH to give 2-(5-bromo-pyridin-3-ylmethyl)-[1,2]thiazinane 1,1-dioxide, which was subsequently reacted 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) to give the title compound as an off-white solid. MS: 386.2 (M+H+).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][N:35]=[C:36]=[O:37])[CH:29]=1.CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:5][CH2:6][N:7]([C:36](=[O:37])[NH:35][CH2:34][C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:9]1)#[N:3]
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Reactant: O=C=NCc1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)NCc2cccnc2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and 3-pyridyl-methyl isocyanate in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[N:12]1([C:18]([CH2:20][C:21]([NH2:23])=[S:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([C:18]([CH2:20][C:21]2[S:22][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:23]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC(=S)CC(=O)N1CCCCC1
Reactant: O=C1c2ccccc2CC1Br
Product: O=C(Cc1nc2c(s1)Cc1ccccc1-2)N1CCCCC1

Procedure:
2-Bromo-1-indanone, (piperidinocarbonyl)thioacetamide
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.[OH-].[Na+].CO>C1COCC1>[CH3:32][C:29]([CH3:30])([CH3:31])[C:28](=[O:33])[CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]([C:13]2[CH:12]=[CH:11][C:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=3[CH:14]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:21][C:22]=1[CH3:34]
Reactant: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)oc2c1
Yield: 95.5 %

Procedure:
6-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid ethyl ester (980 mg, 2.11 mmol) and NaOH (2 N, 10.0 mL) and MeOH (5.0 mL) and THF (5.0 mL) are reacted analogous to Example 2 to give the title compound (880 mg, 96%). MS (ES) m/e: 435.3 (M−1).
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[CH:10][CH:9]=1)[NH2:6].[H][H]>CO.[Pd]>[ClH:1].[CH3:2][NH:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[NH2:6]
Reactant: [H][H]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC(=O)[C@@H](N)Cc1ccc(O)cc1
Reaction time: 4 h
Yield: 104.6 %

Procedure:
To a solution of O-benzyl-L-tyrosine N-methylamide HCl (1.13 g) in methanol (50 ml) was added 10% Pd/C and the mixture was stirred in an atmosphere of hydrogen at room temperature and atmospheric pressure for 4 h. The catalyst was then filtered and the solvent was removed in vacuo to yield L-tyrosine N-methylamide HCl as a foam (0.85 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[S:23][C:24]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH2:18][N:17]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:16][CH:15]2[CH2:14]1)=[O:12]
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Reactant: Fc1ccc2nc(Cl)sc2c1
Product: COc1ccc(C(=O)N2CC3CN(c4nc5ccc(F)cc5s4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 38 and 2-chloro-6-fluoro-benzothiazole. MS (ESI) mass calcd. for C22H22FN3O3S, 427.5; m/z found, 428.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:18])[C:15]([CH3:17])=[CH2:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5].[ClH:19].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)C>[CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:18])[C:15]([Cl:19])([CH3:17])[CH3:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5]
Reactant: Cl
Reactant: C=C(C)C(C)Oc1cc(OCC#CCC)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC#CCOc1cc(OC(C)C(C)(C)Cl)ncn1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution containing 0.3 g of 4-(2-pentynyloxy)-6-(1,2-dimethyl-2-propenyloxy)pyrimidine in 3 ml of tetrahydrofuran was added dropwise 3.66 ml of a 1 mol/l solution of hydrogen chloride in diethyl ether, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into a saturated aqueous sodium hydrogencarbonate solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium chloride, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.07 g of 4-(2-pentynyloxy)-6-(2-chloro-1,2-dimethylpropyloxy)pyrimidine (the present compound (41)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([O:29]C)=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].[Li+].[OH-].CO.O.Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([OH:29])=[O:28])[S:26][C:19]=23)=[CH:31][CH:32]=1)=[O:11]
Reactant: COC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Temperature: 50 °C

Procedure:
To a stirred suspension of methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-phenoxy]thieno[3,2-b]pyridine-2-carboxylate (50 mg, 0.11 mmol) in MeOH (3 ml), was added 0.4M LiOH/MeOH solution (10 ml, 4.0 mmol). The mixture was heated at 50° C. for 7 hours, and poured into 100 ml of water. 1M HCl was added until pH=4. The resulting precipitates were filtered, washed with water and dried in vacuo to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid as light grey solid. Yield: 40 mg, 83%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCCCO3)c2n1
Temperature: 25 °C
Yield: 85 %

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.20 g) was heated with anhydrous potassium carbonate (0.315 g) in dry DMF (5 mL) at 60° C. for 1 hour and cooled to room temperature. 2-(Bromomethyl) tetrahydro-2H-pyran (73 uL) was added and the reaction mixture heated at 50° C., overnight. The reaction mixture was quenched into water (50 mL) and extracted into ethyl acetate (25 mL, 3 times). The combined organic layers were separated and passed through a hydrophobic frit to dry, then stripped to dryness and the pale yellow gum (145 mg), which turned to a white solid when triturated with methanol, was purified by MDAP to give the title compound (6 mg) (˜85% pure).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[N:4]=[CH:3]1.C(O)(C(F)(F)F)=O.[Br:28][C:29]1C(Cl)=[C:31]([N+:36]([O-:38])=[O:37])[C:32]([NH2:35])=[N:33][CH:34]=1>C(Cl)Cl>[Br:28][C:29]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=3)[CH2:13][CH2:12]2)=[C:31]([N+:36]([O-:38])=[O:37])[C:32]([NH2:35])=[N:33][CH:34]=1
Reactant: Cn1cnc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)c1
Reaction time: 1 h
Yield: 51.1 %

Procedure:
tert-Butyl 4-((1-methyl-1H-imidazol-4-yl)methyl)piperazine-1-carboxylate (0.130 g, 0.46 mmol, 1.1 eq) was dissolved in DCM (1.45 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (1.45 mL). Stirring was continued at this temperature for 1 h. The solvents were removed in vacuo, the resulting crude material was azeotroped with toluene and dried. The resulting 1-((1-methyl-1H-imidazol-4-yl)methyl)piperazine (supposedly 0.083 g, 0.46 mmol, 1 eq) was suspended in iPrOH (1.4 mL) and DIPEA (0.35 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.100 g, 0.42 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.085 g, 47%); 1H-NMR (500 MHz, DMSO-d6): δ 2.50-2.58 (br s, 4H, piperazine N(CH2)2), 3.03 (m, 4H, piperazine N(CH2)2), 3.39 (s, 2H, NCH2), 3.60 (s, 3H, imidazole Me), 6.95 (s) and 6.97 (s), (3H, NH2 and 6-H), 7.46 (s, 1H), 8.14 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=1.25 min—396/398 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2cncn2)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
4Fluoronitrobenzene (2 g, 0.014 mol), 1,2,4-triazole (1 g, 0.014 mol), potassium carbonate (1.96 g, 0.014 mol) were dissolved in DMSO (50 ml) and stirred at 90° C. for 24 h under dry conditions. The yellow suspension was poured into water (150 ml), extracted (EtOAc), dried (Na2SO4) and evaporated under reduced pressure to afford an orange solid which was purified by flash column chromatography on silica eluting with n-pentane/ethyl acetate (50-100%) to afford a white solid (2.57 g 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.CN(C)C=O.[Br:25]N1C(=O)CCC1=O>O>[Br:25][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2ccccc2cc1-c1ccccc1F
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(-c2ccccc2F)cc2ccccc2c1Br
Temperature: 60 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
13.4 g of 2-methoxy-3-(2-fluorophenyl)naphthalene and 100 mL of N,N-dimethylformamide were placed in a flask. Then, 40 mL of a N,N-dimethylformamide solution of 11.3 g of N-bromosuccinimide was added. The reaction solution was stirred at 60° C. for 8 hours. After cooling to room temperature, 500 mL of water was added. Then, an organic substance was extracted with toluene. The toluene solution was sequentially washed with sodium thiosulfate and saturated saline. After drying with magnesium sulfate, the organic phase was concentrated. Residues were purified by silica gel column chromatography, whereby 15.8 g (yield: 95%) of 1-bromo-2-methoxy-3-(2-fluorophenyl)naphthalene was obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:14])[CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:14][S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(N)cccc2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCc2c(cccc2NS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 2-acetyl-5-amino-1,2,3,4-tetrahydroisoquinoline (6.6 g) in a mixture of dry pyridine (3 g) and dichloromethane (450 ml) at approximately 5° C. was added dropwise, over 15 minutes, benzenesulphonyl chloride (6.2 g). The orange solution was stirred overnight at room temperature and was then washed several times with water, dried and the solvent was then evaporated to give a dark orange oil. Crystallisation from 2-propanol gave 2-acetyl-5-phenylsulphonamido-1,2,3,4-tetrahydroisoquinoline as a pale pink solid (9.5 g) m.p. 131°-132° C.