Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1.[Br:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C=O)C>[Br:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:18][CH:17]=1
Reactant: CC(C)(C)CNc1ccnc(Cl)n1
Reactant: BrCc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CN(Cc1ccc(CBr)cc1)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine (2.0 g, 10.0 mmoles) and 1,4-bis-bromomethyl-benzene (4.0 g, 15.0 mmoles) are dissolved in 50 ml of DMF and NaH (0.8 g, 21.0 mmoles, 60% oil suspension) is added at 0° C. The mixture is stirred at rt for overnight. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 0.9 g of desired (4-bromomethyl-benzyl)-(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine in 24% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[CH:12][S:13][C:8]=2[CH:7]=1)=O)C.[NH3:14].[OH-].[Li+]>CO>[S:13]1[C:8]2[CH:7]=[C:6]([C:4]([NH2:14])=[O:3])[NH:10][C:9]=2[CH:11]=[CH:12]1
Reactant: CCOC(=O)c1cc2sccc2[nH]1
Reactant: N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc2sccc2[nH]1
Temperature: 100 °C
Yield: 38 %

Procedure:
Add to 4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (1.74 gm, 8.9 mmol) and 7M ammonia in methanol (100 ml) in a steel bomb a chip of lithium hydroxide (0.1 gm). Seal the bomb and heat to 100° C. for 16 hrs. Cool to room temperature, and concentrate to remove the volatiles. Purify the crude product via flash chromatography (ISCO, silica cartridge, 40 gm, elute with methanol 0-5% in methylene chloride) to provide the title compound (560 mg, 38%) as an off-white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=4[O:24][CH3:25])[N:14]=3)=[CH:9][CH:8]=2)[CH2:3]1.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:25][O:24][C:19]1[CH:18]=[C:17]([O:26][CH3:27])[CH:16]=[C:15]2[C:20]=1[C:21](=[O:23])[NH:22][C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:35](=[O:37])[CH3:36])[CH2:3]3)=[CH:8][CH:9]=1)=[N:14]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N)C4)cc3)nc2c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NC(C)=O)C4)cc3)nc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A solution of 2-(4-(3-aminopyrrolidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.41 mmol) in CH2Cl2 (10 mL) was treated with Et3N (0.114 mL, 0.82 mmol), cooled to 0° C., and acetyl chloride (0.029 mL, 0.41 mmol) was added. The mixture was stirred for 2 hours at room temperature, concentrated, and purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH. The mixture was further purified by flash chromatography on silica gel, eluting with 9:1 methylene chloride/methanol, to afford the title compound (0.130 g, 78%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 11.67 (s, 1H), 8.18 (d, J=6.8 Hz, 1H), 8.14 (d, J=6.8 Hz, 2H), 6.66 (d, J=2.3 Hz, 1H), 6.60 (d, J=9.0 Hz, 2H), 6.44 (d, J=2.3 Hz, 1H), 4.36-4.39 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.13-3.59 (m, 5H), 2.15-2.22 (m, 1H), 1.90-1.94 (m, 1H), 1.82 (s, 3H). ESI MS m/z 409 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[C:14]([CH3:21])=[C:15]([CH:19]=O)[NH:16][C:17]=1[CH3:18]>C(O)(=O)C.CCO>[Br:12][C:13]1[C:14]([CH3:21])=[C:15]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[NH:16][C:17]=1[CH3:18]
Reactant: Cc1[nH]c(C=O)c(C)c1Br
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1[nH]c(C=NNC(=O)c2ccc(O)cc2)c(C)c1Br
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.06 g, 0.0004 mol) and 4-bromo-3,5-dimethyl-pyrrole-2-carboxaldehyde (0.08 g, 0.0004 mol) in abs. EtOH (5 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give red solid 0.1 g, in 77% yield, mp: 235.4° C. 1H NMR (DMSO-d6) δ 11.46 (s, 1H), 11.21 (s, 1H), 9.99 (s, 1H), 8.26 (s, 1H), 7.76 (d, 2H), 6.82 (d, 2H), 2.15 (s, 3H), 2.03 (s, 3H). 13C NMR (DMSO-d6) δ 163.9, 162.2, 140.2, 131.6, 131.3, 126.1, 124.0, 124.3, 116.8, 13.4, 11.8. Anal. Calcd for C14H14BrN3O2 ·¼ H2O: C, 49.35; H, 4.14; N, 12.33; Br, 23.69. Found: C, 49.21; H, 3.95; N, 11.96; Br, 23.37.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)C=C.CN(C)[C:19]1[CH:24]=CC=C[CH:20]=1>C(OCC)C>[CH2:24]([C:10]1[CH:9]=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[OH:4])[CH:19]=[CH2:20]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: C=CCc1cc(-c2ccccc2)ccc1O

Procedure:
A solution of 4-allyloxy-biphenyl 65 (5.03 g, 23.9 mmol) in 20 ml of dimethylaniline was heated at 170° C. for 5 hr. The mixture was diluted with 250 ml diethyl ether and washed with 1M HCl solution. The ether phase was washed with brine, dried and concentrated to give a brown solid. The crude product was recrystallized from cyclohexane to give 2.69 g 3-allyl-biphenyl-4-ol 66. The mother liquor was concentrated and chromatographed (7% ethyl acetate/hexane) to give an additional 2.13 g of 2-allyl-4-phenyl-phenol 66.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[C:18]([C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.[OH-].[Na+]>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:18]([C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])[N:19]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2[nH]c(-c3ccc(OCc4ccccc4)cc3)nc2C(=O)Nc2nccs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: Cc1ccc(-c2[nH]c(-c3ccc(O)cc3)nc2C(=O)Nc2nccs2)cc1
Reaction time: 6 h
Yield: 56.6 %

Procedure:
2-(4-Benzyloxyphenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (5.10 g) obtained in Example 22(3) and thioanisole (6.4 ml) were dissolved in trifluoroacetic acid (100 ml) and the mixture was stirred for 6 hr. The reaction mixture was made alkaline with 2 M aqueous sodium hydroxide solution and then acidified withaqueouscitricacid. Themixturewasextractedwithethylacetate. The ethyl acetate layer was washed with saturated brine and, after drying, the solvent was evaporated. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=6:4) and recrystallized from ethyl acetate and hexane to give 2-(4-hydroxyphenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (2.33 g), melting point 286-289° C. (decomposition).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH2:12][C@H:13]1[C@@H:18]([O:19][CH3:20])[CH2:17][CH2:16][CH2:15][N:14]1[C:21]([C:23]1[N:24]=[C:25]([CH3:35])[S:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:22]>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][CH2:12][C@H:13]1[C@@H:18]([O:19][CH3:20])[CH2:17][CH2:16][CH2:15][N:14]1[C:21]([C:23]1[N:24]=[C:25]([CH3:35])[S:26][C:27]=1[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)=[O:22]
Reactant: Clc1nc2ccccc2s1
Reactant: CO[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CN
Product: CO[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CNc1nc2ccccc2s1

Procedure:
The title compound was prepared following the same general protocol as described for Example 12 using 2-chlorobenzothiazole and rac-cis-(2-(aminomethyl)-3-methoxypiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 497.0 (M+H).
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]>>[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][N:31]([CH2:15][C:14]3[CH:17]=[CH:18][C:11]([C:10]([F:20])([F:19])[F:9])=[CH:12][CH:13]=3)[C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCc1ccccc1
Product: CC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Yield: 74 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-(trifluoromethyl)benzyl bromide to react with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one, the title compound was obtained in 74% yield: mp 141-142° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 4.54 (s, 2H), 4.13-4.07 (m, 2H), 3.50-3.41 (m, 2H), 2.66 (s, 3H), 2.25 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.6, 159.6, 155.9, 155.4, 139.6, 130.2, 128.5, 126.0, 124.8, 122.1, 47.6, 42.0, 41.8, 30.5, 18.2; MS (ES+) m/z 384.1 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[C:13](=[O:27])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].CCOC(C)=O>C1COCC1>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@:14]([F:26])([CH3:25])[C@H:13]([OH:27])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(F)C(=O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a 5 L of dry three-neck round-bottomed flask fit with a mechanical stirrer, addition funnel and thermometer was charged the lactone ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl benzoate) (1a, 379 g, 1.018 mol). The solid was dissolved in anhydrous THF (1.75 L) and cooled to −30° C. under a nitrogen atmosphere. A solution of lithium tri-tert-butoxyaluminohydride (1.0 M in THF, 1.527 L) was added to the lactone solution while stirring over 1 h and maintaining the −30° C. temperature. After finishing the addition, the temperature was slowly increased and the reaction was followed by TLC (lactol Rf 0.4, 30% EtOAc in hexanes). The reaction was complete after 1 h 15 min (temperature reached −10° C.). The reaction was quenched by addition of Ethyl acetate (900 mL) via addition funnel. Sat. NH4Cl (40 mL) was added at 0° C. The cloudy mixture was decanted into a 10 L round-bottomed flask. The solid residue left behind was filtered and washed with ethyl acetate (2×200 mL). The filtrate was combined with the decanted solution and the combined solution was concentrated under reduced pressure. The oily residue was dissolved in ethyl acetate (2 L) and washed with 3 N HCl (600 mL). The aqueous layer was back-extracted with ethyl acetate (3×400 mL). The combined organic layer was washed with water (3×800 mL), sat. NaHCO3 (400 mL) and brine (400 mL). The organic solution was dried over MgSO4, filtered and concentrated under reduced pressure to afford a light brown oily residue. The residue was purified by plug column (2.2 kg of 40-63 micron silica gel, packed in a 6 L sintered glass funnel, 22 cm length of silica gel, diameter 15 cm) using suction and a step-gradient of 5%, 10%, 20%, and 30% ethyl acetate in hexanes —ca 5 L of each). The product containing fractions were combined and concentrated under reduced pressure to a colorless, very thick liquid (310.4 g).
Reaction SMILES: BrCC[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.CC1C=C(C=CC=1C)C(C1CCNCC1)=O.C(N(CC)CC)C>CN(C)C=O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: Cc1ccc(C(=O)C2CCNCC2)cc1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc2[nH]ccc2c1

Procedure:
A solution of 9.6 g of 3-(2-bromoethyl)indole, 11.5 g of 4-(3,4-dimethylbenzoyl)piperidine hydrochloride and 10.1 g of triethylamine in 300 ml of dimethylformamide is treated according to the manipulative procedure described in Example 3(b) to give an indole, which is purified on a silica gel column, eluted with a 5% methanol-benzene mixture and recrystallized from an ethanol-water mixture to give the solid, mp 172°-173° C., 3-{2-[4-(3,4-dimethylbenzoyl)piperidyl]ethyl}indole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH:13]2[CH2:15][CH2:14]2)[CH:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:33]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[OH-].[K+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH:13]2[CH2:15][CH2:14]2)[CH:10]([NH2:33])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C(C2CC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(N)C(C2CC2)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
101.5 To a stirred solution of 200 mg (3RS,4RS)-4-cyclopropyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester at 80° C. in 2 ml dioxane under an argon atmosphere were added 0.20 ml diphenylphosphoryl azide and 0.16 ml N-ethyldiisopropylamine. Stirring at 80° C. was continued for 4 hrs. Then, the hot mixture was poured onto 15 ml 1 N KOH and the product was extracted with EtOAc. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 34 mg (3RS,4SR)-3-amino-4-cyclopropyl-pyrrolidine-1-carboxylic acid tert-butyl ester as light brown gum. MS 227.3 ([M+H]+)
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[NH4+]>CO.C1COCC1.[Ni]>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2CCSCC2)nc1
Agent: [Ni]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(N2CCSCC2)nc1
Temperature: 35 °C
Reaction time: 4 h

Procedure:
To the solution of 6-thiomorpholinonicotinonitrile 8-3 (1.0 g, 4.8 mmol) in methanol (15 ml) and THF (9 ml) was added Raney-Nickel (0.7 g) and aqueous ammonium (3 mL). The reaction was stirred under hydrogen balloon at 35° C. for 4 hours. After removing the Raney-Nickel by filtering through celite pad, the filtrate was concentrated to give (6-thiomorpholinopyridin-3-yl)methanamine 8-4 as a light green solid. MS m/z 210.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])[C:5]([NH:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57])=[O:7]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: N#Cc1ccccc1Oc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3C#N)c(Cl)c2)c(O)n1
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
A solution of 3-chloro-4-(2-cyanophenoxy)benzoic acid (100 mg, 0.37 mmol) in dichloromethane (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol), N-hydroxybenzotriazole (65 mg, 0.48 mmol) and triethylamine (104 mg, 0.7 mmol), stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (56 mg, 0.37 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL). The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford 3-chloro-4-(2-cyanophenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (34 mg, 58%) as white solid. LRMS (M+H+) m/z: calcd 407.1. found 407; 1H-NMR (300 MHz, CD3OD) δ 11.47 (s, 1H), 8.53 (m, 1H), 8.14 (d, J=2.1 Hz, 1H), 7.90 (m, 2H), 7.68 (m, 1H), 7.29 (m, 2H), 6.93 (d, J=0.9 Hz, 1H), 5.86 (s, 1H), 4.29 (d, 2H, J=4.8 Hz), 2.17 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][OH:5])[CH3:2].[H-].[Na+].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>C1COCC1>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:5][CH2:4][CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(N)cccc1F
Reactant: CCC(CC)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)COc1cccc(N)c1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 2-ethylbutan-1-ol (1.02 g, 10.0 mmol) in dry THF (60 mL) was carefully added NaH (60% in mineral oil, 480 mg, 12.0 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2-amino-6-fluorobenzonitrile (1.36 g, 10.0 mmol), and the reaction solution was stirred at 0° C.—RT for 2 hrs, and then at 65° C. overnight under nitrogen. The reaction was cooled down to room temperature then quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. Filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: 20% EtOAc in hexanes) to give the title compound as colorless oil (1.29 g, 59%). 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=8 Hz, 6H), 1.55-1.43 (m, 4H), 1.73-1.65 (m, 1H), 3.90 (d, J=4 Hz, 2H), 4.10 (brs, 2H), 6.25 (d, J=8 Hz, 1H), 6.34 (d, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH2:13][C:12](=O)[NH:11][C:10]2[N:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:9]1=2.C1C[O:23][CH2:22]C1>>[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([CH2:19][CH2:22][OH:23])[CH:17]=[CH:18][C:9]1=2
Reactant: C1CCOC1
Reactant: Cc1ccc2c(n1)NC(=O)CN2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCNc2nc(CCO)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
LiAlH4 (214 mg, 5.64 mmol) was slowly added to 10 mL anhydrous THF in a round-bottom flask fitted with a stirbar and a condenser. After stirring for 10 minutes, a solution of 1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (500 mg, 2.82 mmol) in 5 mL anhydrous THF was added dropwise. Upon completion of the addition, the reaction mixture was refluxed for 16 hours. The reaction was cooled to room temperature and quenched with 1 M NaOH solution until the mixture had become a milky yellow color. The precipitate was filtered off and washed 3 times with CH2Cl2. The filtrate and washings were combined, washed with brine, dried over MgSO4. Filtered and concentrated under reduced pressure to give the desired product as light yellow oil, which solidified on standing. (420 mg, 91% yield). H NMR (400 MHz, CDCl3) δ 2.27 (s, 3H), 2.80 (s, 3H), 3.17 (t, 2H), 3.58 (m, 2H), 6.36 (d, 1H), 6.56(d, 2H). Step 5. Synthesis of tert-butyl 1,6-dimethyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate.