Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([CH2:21][O:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[N+:33]([O-:35])=[O:34])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH2:21][O:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[N+:33]([O-:35])=[O:34])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC[C@@H]2C[C@@H](OCc3ccccc3)CN2)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a stirred solution of methyl (2S, 4R)-4-[4-benzyloxy-1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-nitrobenzoate (681 mg, 1.4 mmol) in CH2Cl2 (2 mL) was added TFA (2 mL), and the resulting mixture was stirred for 2 hr. After the reaction mixture was concentrated, the residue was made basic by the addition of sat. NaHCO3 and extracted with CHCl3. The extract was washed with H2O, dried over MgSO4, and evaporated to give 511 mg (95%) methyl (2S, 4R)-4-[4-benzyloxy-2-pyrrolidinyl]methoxy-3-nitrobenzoate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].O>CN(C)C=O>[C:37]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:19][CH2:20]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2[nH]c(=O)cc(CCN3CCC(c4c[nH]c5ccccc45)CC3)c2c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2[nH]c(=O)cc(CCN3CCC(c4c[nH]c5ccccc45)CC3)c2c1
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a solution of 6-amino-4-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2(1H)-quinolinone (III-20) (1 g, 2.59 mmol) in dimethylformamide (8 ml) was added triethylamine (0.7 ml, 5 mmol). To the mixture was added dropwise acetyl chloride (0.2 ml, 2.75 mmol) at 0 ° C. and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into water and the separated solid was filtered off. After washing with water and drying, the solid was recrystallized from a mixture of methanol, tetrahydrofuran and water to give the desired product (III-21) (900 mg) as pale yellow crystals (yield 81.1%, mp 180°-183° C. (methanol/tetrahydrofuran/water).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Temperature: 150 °C
Yield: 81.9 %

Procedure:
29.2 g (157 mmol) of 1,1-dimethylethyl 1-piperazinecarboxylate, 37 g (157 mmol) of 2,5-dibromopyridine and 21.7 g (157 mmol) of potassium carbonate suspended in 27 ml of dimethyl sulfoxide (DMSO) are introduced into an autoclave. The mixture is then heated at 150° C. for 21 hours. The reaction mixture is allowed to cool to room temperature, it is taken up in ethyl acetate and water and the insoluble material is then separated out by filtration. The aqueous phase is separated out and extracted twice with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, eluting with a 99/1 mixture of dichloromethane and methanol. 44 g of product are thus obtained in the form of a white solid.
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].C[O-].[Na+].[CH3:8][C:9]1([CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH2:20]Cl)[C:10]1=[O:22]>CO>[CH3:8][C:9]1([CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH2:20][S:4][CH:1]([CH3:3])[CH3:2])[C:10]1=[O:22]
Reactant: CC1(C)C(=O)N(CCl)C(=O)c2ccccc21
Reactant: CC(C)S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)SCN1C(=O)c2ccccc2C(C)(C)C1=O

Procedure:
1.17 gm of isopropylmercaptan were added to a solution of 0.83 gm of sodium methylate in 50 ml of methanol. After shaking the resulting mixture, 3.3 gm of 4,4-dimethyl-2-chloromethyl-2H,4H-isoquinoline-1,3-dione were added, and the mixture was refluxed for 15 minutes. The precipitated sodium chloride was suction-filtered off, the filtrate was evaporated, and the residue was purified on a silicagel column (eluant: chloroform/cyclohexane=1:1). After evaporation of the eluate a colorless oil was obtained.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:30])([CH3:29])[O:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[CH:11][CH:10]=[C:9]([NH:21]C(=O)OC(C)(C)C)[CH:8]=2)(=[O:3])[CH3:2].Cl.O1CCOCC1>>[NH2:21][C:9]1[CH:8]=[C:7]2[C:12]([C:13]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[C:4]([C:1](=[O:3])[CH3:2])[C:5]([CH3:30])([CH3:29])[O:6]2)=[CH:11][CH:10]=1
Reactant: CC(=O)C1=C(c2ccc(F)cc2)c2ccc(NC(=O)OC(C)(C)C)cc2OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)C1=C(c2ccc(F)cc2)c2ccc(N)cc2OC1(C)C

Procedure:
The compound obtained in (3) described above (147 mg) and 4N hydrochloric acid-dioxane solution (4 mL) were treated in the same manner as Reference Example 5(5) to give the titled compound as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][C:12]([CH3:14])=[CH:13][C:6]=12.[Cl-].[NH4+]>C1COCC1.CO.[Zn]>[F:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][C:12]([CH3:14])=[CH:13][C:6]=12
Reactant: Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(Oc3ccc(N)cc3F)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.9 %

Procedure:
A mixture of 4-(2-fluoro-4-nitrophenoxy)-2-methyl-1H-pyrrolo[2,3-b]pyridine (43 mg, 0. 15 mmol), zinc dust (50 mg, 0.75 mmol) and ammonium chloride (50 mg) in THF/Methanol (½, 0.6 mL) was stirred at room temperature for 1 h, filtered and concentrated in vacuo to afford the desired product (35 mg, 90%), which was sufficiently pure to use in the subsequent reaction. 1H NMR (DMSO-d6) δ 11.71 (s, 1H), 8.04 (d, 1H, J=5.5 Hz), 7.10 (t, 1H, J=8.4 Hz), 6.64 (dd, 1H, J=10.4, 2.6 Hz), 6.51 (m, 1H), 6.35 (d, 1H, J=5.5 Hz), 5.95 (s, 1H), 5.50 (s 2H), 2.41 (s, 3H); MS(ESI+) m/z 258 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[F:8][C:9]1[CH:18]=[C:17](O)[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]>>[F:8][C:9]1[CH:18]=[C:17]([O:7][CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: OC[C@H]1CCCO1
Reactant: COC(=O)c1ccc(O)cc1F
Product: COC(=O)c1ccc(OC[C@H]2CCCO2)cc1F
Yield: 97.9 %

Procedure:
Using (2R)-tetrahydrofuran-2-ylmethanol (1.71 g, 10.0 mmol) and methyl 2-fluoro-4-hydroxybenzoate (1.24 g, 12.0 mmol) obtained in Reference Example 272 and in the same manner as in Reference Example 273, the title compound (2.49 g, yield 98%) was obtained as colorless crystals.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][N:18]([CH3:21])[C:19]#[N:20]>C1C(O)=CC=CC=1C>[ClH:1].[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:19]([N:18]([CH3:21])[CH3:17])=[NH:20])=[C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=1
Reactant: COc1ccc(N)c(-c2ccccc2)c1
Reactant: CN(C)C#N
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: COc1ccc(NC(=N)N(C)C)c(-c2ccccc2)c1

Procedure:
2-Amino-5-methoxybiphenyl hydrochloride (0.4 g) was heated with N,N-dimethylcyanamide (0.3 ml) in m-cresol (0.5 ml) at 110° C. for 8 hours to give a residue which was triturated with ether and crystallised from a 1:1 mixture of acetone and ether to give N-(5-methoxy-2-biphenylyl)-N',N'-dimethyl guanidine hydrochloride (m.p. 160° C.).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-])=O)[C:9]1=[O:21])[C:4]([NH:6][CH3:7])=[O:5].CO>[Pd]>[NH2:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][N:8]([C@H:3]([CH:2]([CH3:22])[CH3:1])[C:4]([NH:6][CH3:7])=[O:5])[C:9]2=[O:21]
Reactant: CNC(=O)[C@@H](C(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@@H](C(C)C)n1ccc2c(N)cccc2c1=O

Procedure:
(R)-3,N-Dimethyl-2-(5-nitro-1-oxo-1H-isoquinolin-2-yl)-butyramide (1.4 g, 0.0045 mol) was stirred with palladium 10% wt. on calcium carbonate (1.4 g, 0.00068 mol) in methanol (100 mL, 2 mol) under hydrogen (balloon) over 1 h at room temperature. The catalyst was filtered, the filtrate was concentrated to dryness to give a yellow solid. MS m/z 273.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]Br)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:33][CH:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH2:28][CH2:29]2)[C:15](=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Reaction time: 16 h

Procedure:
Sodium hydride (60%, 0.27 g, 6.7 mmol) is added to a solution of 4-benzyloxycarbonyl-2-oxo-piperazine (1.58 g, 6.7 mmol) in dry DMF (40 mL). After 30 minutes 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.87 g, 6.7 mmol) is added and the reaction is allowed to stir for 16 h. The solvent is removed in vacuo and the residue is dissolved in ether and washed with NH4Cl. The aqueous phase is back-extracted with ether and the combined ether fractions are washed with water and brine to provide 4-(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester which is used without further purification. 1H NMR (300 MHz, CDCl3) δ 7.36 (s, 5H), 5.16 (d, 2H), 4.16 (s, 2H), 4.13 (br, 2H), 3.73-3.69 (m, 2H), 3.44-3.30 (m, 6H), 2.68 (bt, 2H), 1.85-1.73 (m, 1H), 1.58 (bd, 2H), 1.46 (s, 9H), 1.25-1.10 (m, 2H); MS (ion spray) 432 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[S:14])[CH:5]=[C:6]([F:8])[CH:7]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[C:13]([SH:14])=[N:17][N:16]=[N:15]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cc(F)cc(CCCN=C=S)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(F)cc(CCCn2nnnc2S)c1
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)propyl isothiocyanate (0.0177 mol) in dimethylformamide (35 ml) was added water (12 ml), followed by sodium azide (0.0361 mol). The reaction was stirred one hour, then it was diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 3N aqueous hydrogen chloride, extracted into ethyl acetate, washed with water, dried over sodium sulfate and was concentrated. The residue was dissolved in ethyl ether and dicyclohexylamine (1.9 ml) was added. The resulting salt was filtered and partitioned, with stirring, between ethyl ether and 3N aqueous hydrogen chloride. The ethereal layer was washed with water, dried over sodium sulfate and concentrated. The crude product was recrystallized from pet. ether to yield 1.2 g (27%) white crystals: mp 80°-81° (pet. ether).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1.[O:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][N:16]([CH:35]4[CH2:36][CH2:37][O:32][CH2:33][CH2:34]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1
Reactant: Cn1c(OC2CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: O=C1CCOCC1
Product: Cn1c(OC2CCN(C3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
The compound was prepared from tert-butyl 4-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yloxy)piperidine-1-carboxylate following General Procedures of Boc-deprotection and reductive amination with dihydro-2H-pyran-4(3H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])O[C:8]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:7][C:6]=2[CH:16]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].Cl>[Cl-].[Na+].O.CCCCCC.C(O)CO.O.C1(C)C=CC=CC=1>[CH2:17]([N:24]1[C:10](=[O:11])[C:5]2[C:6](=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:7]=[C:8]1[CH2:12][CH:13]([CH3:15])[CH3:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)Cc1nc2cc(Cl)ccc2c(=O)o1
Reactant: NCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: OCCO
Product: CC(C)Cc1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 115 °C
Yield: 82.8 %

Procedure:
A flask, equipped with an overhead stirrer, heating mantle, condenser and Dean-Stark apparatus was charged with 1,500 mL of toluene, 412.7 g (1 eq.) of 7-chloro-2-isobutyl-benzo[d][1,3]oxazin-4-one and 281.0 g (1.5 eq.) of benzylamine and brought to reflux for 3 hours. After removal of the water, ethylene glycol (150 mL) and 14.2 g (0.2 eq.) of NaOH were added and the mixture was heated to 115° C. for 5 hours. Completion of the reaction was monitored by TLC, after which the temperature was cooled to 60° C. and the pH adjusted to about 7 with 1N HCl, followed by the addition of 1 L of brine. The top organic layer was separated and the aqueous layer extracted with methylene chloride (2×300 mL). The organic phases were combined and dried over sodium sulfate. Solvents were stripped off leaving a viscous oil to which warm hexane (500 mL) was added. The mixture was cooled in an ice bath to give white crystals, which were separated by filtration. The filter cake was washed with cold hexane (800 mL) and air dried to give the title product as a white solid (470 g). An additional 42.4 g of title product was obtained from the mother liquor (512.4 g, 90.3%).
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11].[SH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16].CC1C=CC=C(C)C=1O.[OH-].[Na+].BrCCl>O1CCCC1>[CH3:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:4]=1[O:3][CH2:2][S:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[Cl:1][CH2:2][O:3][C:4]1[C:5]([CH3:11])=[CH:6][CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: COC(=O)CCS
Agent: Cc1cccc(C)c1O
Agent: Cc1cccc(C)c1OCCl
Agent: ClCBr
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OCSCCC(=O)O
Temperature: 66 °C

Procedure:
3-([2,6-Dimethylphenoxy]methylthio)propanoic acid 29 was prepared by reaction of 2-(chloromethoxy)-1,3-dimethylbenzene with methyl 3-mercaptopropanoate followed by hydrolysis of the ester. 2-(Chloromethoxy)-1,3-dimethylbenzene: A three-necked, 500-mL flask equipped with thermometer, reflux condenser, argon inlet, and a magnetic stirring bar was charged with 6.12 g (0.05 mol) of 2,6-dimethylphenol, 100 mL dry tetrahydrofuran, and 4.0 g (0.1 mol) sodium hydroxide powder. The mixture was heated at 66° C. for 1 hour. The mixture was cooled to room temperature, and 98 mL (1.5 mol) of bromochloromethane was added. The suspension that formed was cooled to room temperature, filtered through CELITE, and the solvent was removed under reduced pressure. The oily residue was purified by vacuum distillation (1-1.5 torr, b.p., 66° C.) to afford an overall yield of 6.50 g (76%) of 2-(chloromethoxy)-1,3-dimethylbenzene. 1H NMR (400 MHz, CDCl3): 2.33 (s, 6H), 5.80 (s, 2H), 6.99-7.06 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>>[ClH:35].[ClH:35].[CH3:34][O:33][C:31]([CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]([CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH3:16])[CH2:18][CH2:19]2)=[CH:24][CH:25]=1)=[O:32]
Reactant: COC(=O)COc1ccc(N2CCC(N(C)CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Agent: Cl
Product: COC(=O)COc1ccc(N2CCC(N(C)CC3CCNCC3)CC2)cc1

Procedure:
Prepared from 4-[(1-tert-butyloxycarbonylpiperidin-4-yl)-N-methylmethylamino]-1-(4-methoxycarbonylmethyloxyphenyl)piperidine and ethereal hydrochloric acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:17]([O-:19])=[O:18])=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 23.2 g. of 3-fluorophenylacetic acid and 100 ml. of conc. sulfuric acid is added dropwise 6.5 ml. of conc. nitric acid while maintaining the temperature below 40° C. The mixture is stirred at ambient temperature for 24 hours and then poured onto one kilogram of ice. The resulting precipitate is recovered by filtering, washed with water and dried in vacuo to obtain crude 5-fluoro-2-nitrophenylacetic acid, m.p. 137°-142° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O.ClCCl.C(OCC)(=O)C>CO.[C].[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.8 %

Procedure:
6-Nitro-1-indanone (10.0 g, 56.4 mmol) was dissolved in methanol (200 mL), a 10% palladium-carbon powder (500 mg) was added, and the mixture was stirred at room temperature for 14 hr under a hydrogen atmosphere. To the reaction solution were added dichloromethane and ethyl acetate to dissolve the precipitated crystals, and the catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was washed with methanol to give the title compound (6.71 g, yield 81%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH:12]([O:15][C:16](=[O:23])[CH:17]=[C:18]([NH2:22])[O:19][CH2:20][CH3:21])([CH3:14])[CH3:13]>C(O)C>[CH:12]([O:15][C:16]([C:17]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:17]([C:16]([O:15][CH:12]([CH3:13])[CH3:14])=[O:23])[C:18]([O:19][CH2:20][CH3:21])=[N:22][C:18]=1[NH2:22])=[O:23])([CH3:14])[CH3:13]
Reactant: CCOC(N)=CC(=O)OC(C)C
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC1=NC(N)=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)C1C(=O)OC(C)C
Yield: 45 %

Procedure:
Heating a solution of 6.1 g of 3-nitrobenzaldehyde and 13.9 g of 3-amino-3-ethoxyacrylic acid isopropyl ester in 100 ml of ethanol for 8 hours yields 2-amino-6-ethoxy-4-(3-nitrophenyl)-4,5-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester of melting point 130° C (ether/petroleum ether).
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][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2].[CH3:54][N:55](C)C=O.O>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-]#N.[Zn+2].[C-]#N.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([C:54]#[N:55])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:33]=[C:34]([C:42]([F:45])([F:43])[F:44])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)N1c2ccc(C#N)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of (2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (732 mg), tetrakis(triphenylphosphine)palladium (catalytic amount), zinc cyanide (142 mg) and N,N-dimethylformamide (10 ml) is stirred at 95° C. under nitrogen flow for 8 hours. After cooling to room temperature, water and ethyl acetate are added to the reaction solution. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→2:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (572 mg). MS (m/z): 664 [M+H]+
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].Br[CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:12][O:11][CH:10]([O:13][CH3:14])[CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7]
Reactant: COC(CBr)OC
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(Cn1ccnc1C=O)OC
Temperature: 110 °C
Yield: 31.6 %

Procedure:
To a solution of the imidazole-2-carboxaldehyde (0.41 g, 4.27 mmol) in DMF (1 mL) was added 1.1 eq. of 2-bromo-1,1-dimethoxyethane (0.79 g, 4.69 mmol), potassium carbonate and a catalytic amount of potassium iodide. The reactions were heated at 110° C. for 18 hrs followed by evaporation to dryness and purified utilizing a Biotage SP4 with a gradient method of 5-50% methanol in DCM to yield the desired compound (248 mg, 1.35 mmol, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.9 (s, H), 7.85 (s, H), 7.55 (s, H), 5.82 (m, H), 4.75 (d, 2H), 3.45 (s, 6H).