Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:21][CH3:22])=[C:11]([C:13]3[C:14](=[O:20])[CH2:15][CH2:16][C:17]=3[O:18][CH3:19])[N:12]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:31]1[CH2:36][CH2:35][CH:34]([CH:37]=[O:38])[CH2:33][CH2:32]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:21][CH3:22])=[C:11]([C:13]3[C:14](=[O:20])[CH:15]([CH:37]([OH:38])[CH:34]4[CH2:35][CH2:36][O:31][CH2:32][CH2:33]4)[CH2:16][C:17]=3[O:18][CH3:19])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=CC1CCOCC1
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC)CCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC)CC(C(O)C2CCOCC2)C1=O
Temperature: 78 °C
Reaction time: 0.67 h
Yield: 36.9 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-3-methoxy-cyclopent-2-enone (175 mg, 0.52 mmol) in anhydrous tetrahydrofuran (5 ml) at −78° C. under an atmosphere of nitrogen was added lithium diisopropylamide (1.8M in THF/heptanes/ethylbenzene; 1.1 ml, 2 mmol) dropwise over a period of 1 minute and the reaction allowed to stir at 78° C. for 40 minutes. A solution of tetrahydro-pyran-4-carbaldehyde (228 mg, 2 mmol) in anhydrous tetrahydrofuran (1 ml) was then added dropwise over a period of 30 seconds before the reaction was allowed to warm to room temperature and stirred for a further 30 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (50 ml) and the organic layer separated, dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3-methoxy-cyclopent-2-enone (86 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-])=O.CN(C)[CH:16]=[S:17].C(O)C>C1(C)C(C)=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[S:17][CH:16]=[N:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: CN(C)C=S
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc2scnc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A mixture of 10 g of 1-chloro-2,4-dinitrobenzene and 20.26 g of N,N-dimethylthioformamide is heated to 60° C. for 3 hours. The resulting solid is suspended in 25 mL of xylene and the mixture is heated to reflux for 4 hours. The mixture is allowed to cool to room temperature and 15 mL of ethanol are added. The resulting suspension is filtered, and the brown solid is washed with a minimum amount of ethanol. The solid is dissolved in 120 mL of ethanol, heated to boiling, and filtered hot to remove trace solids. After reduction of the volume to about 100 mL, the solution is allowed to stand overnight at room temperature. The resulting solid is filtered and washed with ethanol to provide 4.68 g of 5-nitrobenzothiazole as reddish-brown needles.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:26]#[C:27][C:28]4([NH:36]C(=O)OC(C)(C)C)[CH2:33][O:32]C(C)(C)[O:30][CH2:29]4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>CCO.C(C(O)=O)(F)(F)F.[Pd]>[NH2:36][C:28]([CH2:27][CH2:26][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:11]([C:1]23[CH2:2][CH:3]4[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]4)[CH2:10]2)[CH2:8]3)[CH:12]=1)([CH2:33][OH:32])[CH2:29][OH:30]
Reactant: CCCCCCCCOc1ccc(C#CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCOc1ccc(CCC(N)(CO)CO)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h
Yield: 80.3 %

Procedure:
A slurry of the product of Step B (0.04 g, 0.068 mmol) and 10% Pd/C (0.04 g) in a mixture of EtOH: CF3CO2H (10 ml: 2 drops) was stirred for 36 h under H2. The mixture was filtered through Celite bead and washed with EtOH (10 ml). The filtrates were evaporated to dryness and the residue was dissolved in MeOH:CH2Cl2 1:1 (5 ml) and 5 drops of concentrated HCl was added. The mixture was stirred for 1 h and solvents were evaporated to dryness. The residue was crystallized from CH3CN to give the titled compound (0.025 g, 81%) as colourless powder. 1H-NMR (CDCl3) 0.79 (t, 3H, J=6.57 Hz); 1.12-1.21 (m, 7H); 1.37-1.41 (m, 2H); 1.69 (s, 6H); 1.73-1.88 (m, 3H); 2.00 (b, 9H); 2.48-2.52 (m, 2H); 3.61 (d, 2H, J=11.84 Hz); 3.67 (d, 2H, J=12.2 Hz); 3.85 (tr, 2H, J=6.22 Hz); 6.69 (d, 1H, J=8.13 Hz); 6.88-7.93 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:8](=O)[CH3:9])[CH2:4][CH2:3][CH2:2]1.[BH3-]C#[N:21].[Na+]>C(Cl)Cl>[NH2:21][CH:8]([CH:7]([O:6][CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH3:9]
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)OCC1CCC1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(N)C(Cc1ccc(Cl)cc1)OCC1CCC1
Reaction time: 8 h

Procedure:
A solution of 3-cyclobutylmethoxy-4-(4-chlorophenyl)butan-2-one (247 mg, 0.925 mmol, obtained from Step C) in 0.5 mL CH2Cl2 was added to a stirred suspension of NH4OAc (715 mg, 9.25 mmol) and NaBH3CN (35 mg, 0.555 mmol) at room temperature and allowed to stir overnight. The reaction was quenched by the addition of 2.2 mL conc. HCl allowed to stir for 30 minutes. The solvents were evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous layer was washed two more times with ether. The combined organics were dried over Na2SO4. The crude product mixture obtained after filtration and removal of volatiles was purified by flash chromatography, eluting using mixtures of mixtures of CH2Cl2 and MeOH (100% CH2Cl2, to 5% MeOH in CH2Cl2) to provide the title compound as a yellow oil, homogeneous by TLC Rf0.12 (5% MeOH in CH2Cl2). 500 MHz 1H NMR (CDCl3): δ 1.16 (t, 3H); 1.67 (m, 2H); 1.85 (m, 3H); 2.01 (m, 2H); 2.48 (m, 1H); 2.74 (m, 2H); 2.90 (dd, 1H); 3.15 (d quint, 2H); 3.37 (m, 2H).
Reaction SMILES: [Na].[S:2](=[C:5]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:4])=[O:3].[CH3:13]I>CO>[CH3:13][N:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:5](=[S:2](=[O:4])=[O:3])[CH3:6])[CH2:12]1
Reactant: CC(c1cnccn1)=S(=O)=O
Reactant: CI
Agent: [Na]
Solvent: CO
Product: CC(C1=NC=CN(C)C1)=S(=O)=O

Procedure:
3.50 g of 2-(1-sulfonylethyl)pyrazine sodium salt (2300) was dissolved in 75 ml of methanol and 10 ml of methyl iodide added. The flask was then stoppered and stored in the dark at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][NH:22][C:23]([C:25]1[N:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=1)=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:31]([C:28]3[CH:27]=[CH:26][C:25]([C:23]([NH:22][CH3:21])=[O:24])=[N:30][CH:29]=3)=[O:32])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1ccc(C(=O)O)cn1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CNC(=O)c1ccc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)cn1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 6-[(methylamino)-carbonyl]-3-pyridinecarboxylic acid (CAN 170464-32-1) as starting materials; MS (EI) 465.2(M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH3:24][O:25][CH2:26][CH2:27]O>>[CH3:24][O:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1
Reactant: COCCO
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: COCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-methoxyethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CC1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 4-amino-1-methylpiperidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1-methylpiperidin-4-yl)terephthalamide. MS (Q1) 483 (M)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[NH2:17][CH2:16][CH2:15][NH:18][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCN
Reactant: CCOc1cc(Cl)nc2ccccc12
Product: CCOc1cc(NCCN)nc2ccccc12
Yield: 66.6 %

Procedure:
2-Chloro-4-ethoxyquinoline (1.119 g, 5.39 mmol) and ethylenediamine (10.8 ml, 162 mmol) were heated at 60° C. for 50 h, then evaporated to dryness. The residue was purified by flash chromotography on silica gel, eluting with 0-14% ‘10% ammonia in methanol’ in dichloromethane, to give 2-(2-aminoethylamino)-4-ethoxyquinoline (0.830 g, 67%). This material (0.820 g, 3.54 mmol) was dissolved in concentrated hydrochloric acid (25 ml) and gently refluxed for 16 h. The mixture was then cooled in an ice bath, and the precipitate filtered off and dried in vacuo to give the title compound as an off-white powder (0.861 g, 88%); δH (CD3OD) 3.2-3.35(2H, m, under methanol), 3.84 (2H, t), 6.35 (1H, s), 7.46 (1H, t), 7.7-7.9 (2H, m), 8.1 (1H, d), MS (ES+) 204 (50%, MH+) and 187 (100).
Reaction SMILES: [C-:1]1(C=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-]1C=CC=C1.[Fe+2:13].CC([C-]1C=CC=C1)=O.[CH-]1C=CC=C1.[Fe+2].C(Br)C=C.[C-:32]1([CH:37](O)[CH2:38][CH:39]=[CH2:40])[CH:36]=[CH:35][CH:34]=[CH:33]1.[CH-]1C=CC=C1.[Fe+2]>CCOCC.[Mg]>[C-:32]1([CH:37]=[CH:38][CH:39]=[CH2:40])[CH:36]=[CH:35][CH:34]=[CH:33]1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:13]
Reactant: O=C[c-]1cccc1
Reactant: C=CCC(O)[c-]1cccc1
Agent: [Fe+2]
Agent: CC(=O)[c-]1cccc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CC=C[c-]1cccc1

Procedure:
Ferrocenaldehyde or ferrocenyl methyl ketone and allyl bromide are reacted in an ether solvent and in the presence of magnesium metal as a catalyst. The liquid portion of the reaction mixture is introduced into a silica gel column, wherein the weak acidity of the silica gel is able to dehydrate the reaction intermediate 1-ferrocenyl-3-buten-1-ol product. The column is eluted with n-hexane, and after evaporating the solvent from the eluate collected, a purified ferrocenyl-1,3-butadiene product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12]C(OC(C)(C)C)=O)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>FC(F)(F)C(O)=O>[NH2:12][C:3]1[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(N)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
Methyl 3-amino-2-[(tert-butoxycarbonyl)amino]benzoate (61.8 g, 232 mmol) was added to trifluoroacetic acid (250 mL), and the mixture was stirred at room temperature for 3 hr. Trifluoroacetic acid was evaporated in vacuo, and the resulting solid was suspended in ethyl acetate (200 mL), collected by filtration and washed with ethyl acetate (50 mL). The solid was partitioned between ethyl acetate (300 mL) and saturated aqueous sodium hydrogen carbonate (400 mL), and the aqueous layer was separated and extracted with ethyl acetate (300 mL). The combined organic layer was washed with water (300 mL×2) and concentrated in vacuo to give the title compound (24.6 g, 148 mmol, 64%) as a brown solid. The filtrate described above was concentrated in vacuo, and the resulting solid was collected by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo, and the resulting solid was collected by filtration and washed with diethyl ether. The combined solid was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate (100 mL), and the aqueous layer was separated and extracted with ethyl, acetate). The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (8.29 g, 49.9 mmol, 22%) as a brown solid. Total amount: 32.9 g, 198 mmol, 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].C(O)(C(F)(F)F)=O>O>[Cl:1][C:2]1[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CN(C)C(=O)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccc(C(=O)O)c(Cl)c1

Procedure:
290 mg of dimethylamine hydrochloride was coupled to 1 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N HCl, 0.1 N NaOH and brine, dried (MgSO4) and evaporated to afford tert-butyl 2-chloro-4-(dimethylcarbamoyl)benzoate. 1.1 g of tert-butyl 2-chloro-4-(dimethylcarbamoyl)benzoate was treated with TFA (4 mL) containing trace amounts of H2O for 2 h. The reaction mixture was evaporated, and then added 0.1 N HCl. The resulting solid was filtered and washed with H2O to yield 2-chloro-4-(dimethylcarbamoyl)benzoic acid. 100 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(dimethylcarbamoyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4,N4-dimethylterephthalamide. MS (Q1) 414.1 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][CH:25]([C:40]2[N:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][N:49]([C:52](=[O:54])[CH3:53])[CH2:48][CH2:47]3)=[CH:42][N:41]=2)[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2].[CH3:57][Al](C)C.O.C(OCC)(=O)C>O1CCOCC1.CCCCCC.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(=O)([O-])[O-].[Ag+2].[Cu]Cl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([CH3:57])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][CH:25]([C:40]2[N:41]=[CH:42][C:43]([N:46]3[CH2:51][CH2:50][N:49]([C:52](=[O:54])[CH3:53])[CH2:48][CH2:47]3)=[CH:44][N:45]=2)[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C(C)=O)CC3)cn2)C[C@H]1CC
Reactant: C[Al](C)C
Agent: Cl[Cu]
Agent: [Ag+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CCOC(=O)N1c2ccc(C)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C(C)=O)CC3)cn2)C[C@H]1CC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
(2R,4S)-4-{[5-(4-Acetylpiperazin-1-yl)pyrimidin-2-yl]-[3,5-bis-(trifluoromethyl)benzyl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in 1,4-dioxane (2 ml), and thereto are added dropwise a catalytic amount of tetrakis(triphenylphosphine)palladium, silver carbonate and copper (I) chloride, and a 1M solution (362 μl) of trimethylaluminum in hexane under nitrogen flow. The mixture is stirred at 60° C. for 1 hour. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane:ethyl acetate=1:2→0:1) to give (2R,4S)-4-{[5-(4-acetylpiperazin-1-yl)pyrimidin-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (142 mg). MS (m/z): 694 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.Br[C:39]1[CH:40]=[N:41][CH:42]=[C:43]([F:45])[CH:44]=1>O1CCOCC1.CC(=O)OCC.O.[Cu]I>[F:45][C:43]1[CH:44]=[C:39]([O:1][C:2]2[CH:24]=[N:23][C:5]3[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)[C:9](=[O:10])[C:4]=3[CH:3]=2)[CH:40]=[N:41][CH:42]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(O)cnc21
Reactant: Fc1cncc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cncc(F)c3)cnc21
Temperature: 140 °C
Yield: 38.7 %

Procedure:
To a mixture of 6-hydroxy-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 2, 300 mg, 0.90 mmol), CuI (22.5 mg, 0.19 mmol), Cs2CO3 (583.5 mg, 1.79 mmol) and 2-(dimethylamino)acetic acid (46.5 mg, 0.45 mmol) in dioxane (20 mL) was added 3-bromo-5-fluoropyridine (394 mg, 2.24 mmol). The reaction was heated at 140° C. for 5 h followed by heating at 100° C. for 18 h, cooled to RT then diluted with EA (25 mL) and water (10 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (150 mg, 38.9% yield) as a white solid. LCMS: [MH+-THP] 347 and TR=1.482 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].C([O:13][C:14](=O)[CH:15]([CH3:19])[C:16]([CH3:18])=O)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:7]([C:14]([OH:13])=[C:15]([CH3:19])[C:16]([CH3:18])=[N:6]2)=[CH:8][C:9]=1[CH3:10]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: COc1cc(N)ccc1C
Product: COc1cc2nc(C)c(C)c(O)c2cc1C

Procedure:
Prepared according to procedure R using 3-methoxy-4-methylaniline (617.8 mg, 4.5 mmol), ethyl-2-methyl-acetoacetate (1.3 mL, 9.1 mmol), and PPA (1.87 g, 18.7 mmol) to give 7-methoxy-2,3,6-trimethylquinolin-4-ol.
Reaction SMILES: [C:1]1([CH:8]=[CH:7]C(O)=[CH:4][CH:3]=1)O.[B].O1CCOCC1.[CH2:16]([O:18][CH2:19][CH3:20])[CH3:17]>>[O:18]1[C:19]2[C:8](=[CH:1][CH:3]=[CH:4][CH:20]=2)[CH2:7][CH2:17][CH2:16]1
Reactant: Oc1ccc(O)cc1
Reactant: CCOCC
Agent: [B]
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 0 h

Procedure:
To a solution of hydroquinone 1 (0.01 mol) and a catalyst, preferably boron trifluotide diethyl etherate (0.016 mol) In an organic solvent, preferably dry dioxane (10 mL), is added vinyl lactone 2 (0.016 mol) in an organic solvent, preferably dry dioxane (5.0 mL) over 1-60 minutes, preferably 60 minutes, at 0-150° C., preferably 110° C., under an inert gas. The reaction mixture is stirred for 0 to 8 hours, preferably 0 hours, at the selected temperature, cooled to room temperature, and diluted with an organic solvent, preferably diethyl ether (200 mL) The reaction mixture is then washed with water (100 mL, 2×50 mL), dried over sodium sulfate (Na2SO4), and solvent is removed under reduced pressure to afford a brown oily residue. The residue is dissolved in alcohol, preferably methanol (30 mL), and the alcohol is then removed under reduced pressure. The brown oily liquid or semisolid is further purified by chromatography, preferably on silica gel, to afford pure racemic chroman derivative 3.
Reaction SMILES: C(O[K])(C)(C)C.C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[CH2:20]([N:27]1[CH:31]=[C:30]([CH:32]=O)[C:29]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(COC)OC.CO>[CH2:20]([N:27]1[CH:31]=[C:30]([CH2:32][C:16]#[N:17])[C:29]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CO
Product: N#CCc1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
To a mixture of t-butoxy potassium (11.2 g) and dimethoxyethane (50 ml) was added a solution of p-toluenesulfonylmethyl isocyanide (10.3 g) in dimethoxyethane (50 ml) at −78° C. and the mixture was stirred for 5 min. Then a solution of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (14.6 g) in dimethoxyethane (50 ml) was added. After stirring at said temperature for 1 hr, the mixture was stirred for 1 hr. while raising the temperature to room temperature. To the obtained mixture was added methanol (150 ml), and the mixture was refluxed for 1 hr. After cooling, the reaction solution was poured into saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 1-benzyl-3-benzyloxy-1H-pyrazol-4-ylacetonitrile (13.1 g, yield 86%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:3]1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1([CH3:17])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])[CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)C=C(c2ccccc2N)CC(C)(C)C1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccccc2N)CC(C)(C)C1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
In a 100 mL autoclave, 10% palladium on carbon (water content 50%, 1.2 g) was added to a solution of 2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine (4.00 g, 17.4 mmol) in ethanol (40 mL), followed by stirring at room temperature, 5 kgf/cm2 of hydrogen pressure for 5.5 hours. Then the reaction mixture was stirred at room temperature, 10 kgf/cm2 of hydrogen pressure for 3 hours, introduction of hydrogen was stopped, and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was stirred at room temperature, 10 kgf/cm2 of hydrogen pressure for 9.5 hours, introduction of hydrogen was stopped, and the reaction mixture was stirred at room temperature for 13 hours. The reaction mixture was stirred at room temperature, 10 kgf/cm2 of hydrogen pressure for 7.5 hours, and the reaction mixture was stirred at room temperature. The pressure was brought to atmospheric pressure, and the reaction mixture was filtered through Celite, and concentrated to give 3.90 g of the title compound as a brown oil.