Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>ClCCl>[CH:1]1([NH:5][S:22]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)(=[O:23])=[O:24])[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NC2CCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a stirred solution of cyclobutylamine (4.3 g, 59.7 mmol) and triethylamine (11.2 mL, 79.6 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro-benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at room temperature for 4 h and then washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford N-cyclobutyl-4-nitro-benzenesulfonamide (9.4 g, 92.5%) as a white powder: MS (ESI) M+1=257.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:14])=[N:5][C:6](Cl)=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#[N:2].[NH2:15][CH:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][OH:18].C(NC(C)C)(C)C.ClCl>>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:7]=[C:6]([NH:15][CH:16]([CH2:17][OH:18])[CH:19]([CH3:21])[CH3:20])[N:5]=1
Reactant: CC(C)C(N)CO
Reactant: N#Cc1c(C(F)(F)F)cc(Cl)nc1Cl
Agent: ClCl
Solvent: CC(C)NC(C)C
Product: CC(C)C(CO)Nc1cc(C(F)(F)F)c(C#N)c(Cl)n1

Procedure:
Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine (0.641 g, 6 mmol) (Compound 14) was added by pipette at a dropwise rate over 3 minutes to 2-amino-3-methyl-butan-1-ol (1.5 g, 6 mmol) (Compound 15). Di-isopropylamine (0.9 g, 7 mmol) was added after 10 minutes and the resultant mixture was heated in a sealed tube at 70° C. for 30 minutes to selectively displace the chlorine at position 6 before quenching in ice-cold water and extracted with dichloromethane. Organic extracts were washed twice with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with diethylether and the resultant solid was used in the next step without further purification. 2-Chloro-6-[[1-(hydroxymethyl)-2-methyl-propyl]amino]-4-(trifluoromethyl) pyridine-3-carbonitrile (Compound 13) was isolated in 50% yield.
Reaction SMILES: [CH2:1]([C:5]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](S(C)=O)[N:15]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH:2]([CH3:4])[CH3:3].[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:28][C:16]2[N:15]=[C:14]([C:13]3[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[N:6][N:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=34)[CH:19]=[CH:18][N:17]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)Cc1nn2ccccc2c1-c1ccnc(S(C)=O)n1
Reactant: NC1CCCC1
Product: CC(C)Cc1nn2ccccc2c1-c1ccnc(NC2CCCC2)n1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 2-isobutyl-3-[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (930 mg, 2.98 mmol) in cyclopentylamine (5 mL) was heated at 130° C. for 4 h. The mixture was cooled to room temperature and concentrated in vacuo and the residue was purified by flash chromatography on silica gel (2:1 to 1:1 hexane-ethyl acetate) to give N-cyclopentyl-4-(2-isobutylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (890 mg, 89%) as a White solid. 1H NMR (CDCl3) δ 8.44 (d, 1H), 8.28–8.25 (m, 2H), 7.26 (m, 1H), 6.85–6.76 (m, 2H), 5.08 (m, 1H), 4.40 (m, 1H), 3.00 (d, 2H), 2.26–2.05 (m, 3H), 1.83–1.51 (m, 6H), 1.00 (d, 6H); MS m/z 336 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[Br:21]Br>CN(C=O)C.C(OCC)(=O)C>[Br:21][C:3]1[CH:4]=[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=S(=O)(Nc1ccc(O)c2ccccc12)c1cccs1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cc(Br)c(O)c2ccccc12)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
305.7 mg N-(4-hydroxynaphthalen-1-yl)thiophene-2-sulfonamide (3) was dissolved in 1 ml DMF, to which at 0° C. was added 320 mg Br2 in 1 ml dichloromethylene solution. After stirred at r.t. for 1 h, 558 μl TEA was added at 0° C. The reaction was stirred at r.t. overnight and diluted with ethyl acetate to 50 ml. The organic phase was washed with water and brine. Dried over Na2SO4, the organic phase was filtered and concentrated. The crude product was purified via flash chromatography (Hex/EtOAc gradient) affording an orange-red solid 140 mg (36.4%), m.p.: 128-130° C.
Reaction SMILES: [C:1]([C:4]1[NH:8][CH:7]=[C:6]([C:9](=[O:14])C(Cl)(Cl)Cl)[CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:9]([C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[NH:8][CH:7]=1)=[O:14])[CH3:22]
Reactant: CCO
Reactant: CC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1c[nH]c(C(C)=O)c1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 1-(5-Acetyl-1H-pyrrol-3-yl)-2,2,2-trichloro-ethanone (0.980 g, 3.85 mmol) in ethanol (10 mL), potassium carbonate (0.224 g, 1.62 mmol) was added and the mixture refluxed for 1 h. The mixture was cooled at room temperature and filtred through a celite pad washing with ethanol (50 mL). Organic solvent was evaporated to dryness and the residue dissolved in ethylacetate (15 mL) and washed with water (2×10 mL) and brine (5 mL), dried over sodium sulfate, filtered, and concentered in vacuo to give 0.567 g (81%) of the title compound as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.[CH:29]1[CH:34]=[C:33]2[CH:35]([OH:39])[O:36][C:37](=O)[C:32]2=[CH:31][CH:30]=1.C[O-].[Na+]>CO>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[CH:37][C:32]1[CH:31]=[CH:30][CH:29]=[CH:34][C:33]=1[C:35]([OH:39])=[O:36]
Reactant: O=C1OC(O)c2ccccc21
Reactant: ClCc1ccccc1Cl
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: O=C(O)c1ccccc1C=Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To 78 g (297 mmol) of triphenylphosphine in 150 ml of methanol were added dropwise with stirring 48.3 g (300 mmol) of 2-chlorobenzyl chloride, and the reaction mixture was heated under reflux for 2 hours. After the reaction mixture had been cooled down to 0° C., 46.4 g (309 mmol) of o-phthalaldehydic acid were added with stirring in the course of about 1 min. Thereafter 135 g (750 mmol) of a 30% strength solution of sodium methylate in methanol were added at 0°-10° C. with stirring in the course of 45 min and stirred in at 0°-10° C. for 3 hours, and the reaction mixture was worked up in a conventional manner to give 72 g (94%) of (E/Z)-2-[2-(2-chlorophenyl)ethenylbenzoic acid in a ratio of ~11:89 in the form of colorless crystals having a melting point of 144°-148° C.
Reaction SMILES: [Na].[C:2](#[N:6])[CH2:3][C:4]#[N:5].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23](=O)[CH3:24])[CH:13]=[CH:14][CH:15]=1)[CH3:8]>C(O)C>[C:21]1([C:22]2[C:3]([C:4]#[N:5])=[C:2]([NH2:6])[N:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:7][CH3:8])[CH:11]=3)[CH:17]=2)[CH:20]=[CH:19][CH:18]=[CH:23][CH:24]=1
Reactant: N#CCC#N
Reactant: CCOc1cccc(Nc2ccccc2C(C)=O)c1
Agent: [Na]
Solvent: CCO
Product: CCOc1cccc(-n2cc(-c3ccccc3)c(C#N)c2N)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.4 g of sodium is dissolved in 70 ml of ethanol and subsequently first 1.24 g of malononitrile and then 4.0 g of 2'-(3-ethoxyphenylamino)acetophenone are added at RT and the mixture is stirred at 50° C. for 2 h. The mixture is then cooled and concentrated in an RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4 and concentrated, 4-phenyl-1-(3-ethoxyphenyl)-2-amino-3-cyanopyrrole being obtained. The oily product is employed in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:14][C@H:13]([OH:15])[CH2:12][C@H:11]2[C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[Si:25]([O:15][C@H:13]1[CH2:14][N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]#[N:9])=[CH:5][N:4]=2)[C@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1c1ncc(C#N)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1c1ncc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a solution of methyl (2S,4R)-1-(3-chloro-5-cyanopyridin-2-yl)-4-hydroxypyrrolidine-2-carboxylate (0.270 g; 0.96 mmol) and imidazole (0.098 g; 1.44 mmol) in DMF (3 mL) was added tert-butyl dimethylsilylchloride (0.159 g; 1.05 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. Further imidazole (0.049 g; 0.72 mmol) and tert-butyldimethylsilyl chloride (0.080 g; 0.53 mmol) was added and the reaction stirred at ambient temperature for 3 hours. The reaction mixture was diluted with EtOAc and washed sequentially with water and brine. The organic phase was poured through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (6:1) to afford the title product (0.311 g, 82%). 1H NMR (CDCl3, 400 MHz) δ 8.16 (1H, d, J=2 Hz), 7.57 (1H, d, J=2 Hz), 4.79 (1H, t, J=8 Hz), 4.46-4.44 (1H, m), 4.17-4.13 (1H, dd, J=11.2, 4.8 Hz), 3.77-3.74 (1H, m), 3.63 (3H, s), 2.15 (1H, m), 1.96 (1H, m), 0.79 (9H, s), 0.14-0.02 (6H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]=[CH:12][N:13]([C:52]=2[N:53]=[C:54]([NH:56][C:57](=[O:66])[CH2:58][O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[N:55]=1)[C@@H:14]1[O:51][C@H:25]([CH2:26][O:27]C(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]2[N:11]=[CH:12][N:13]([C:52]=2[N:53]=[C:54]([NH:56][C:57](=[O:66])[CH2:58][O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[N:55]=1)[C@@H:14]1[O:51][C@H:25]([CH2:26][OH:27])[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(OCc5ccccc5)nc(NC(=O)COc5ccccc5)nc43)C[C@@H]2O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cnc3c(OCc4ccccc4)nc(NC(=O)COc4ccccc4)nc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.07 h
Yield: 85 %

Procedure:
A solution of 3% TCA (67.8 mL, 19.9 mmol) in CH2Cl2 is added to a solution of 8 (4.51 g, 4.97 mmol) dissolved in CH2Cl2 (100 mL) and stirred at room temperature for 4 minutes. Et3N (2.77 mL, 19.9 mmol) is added to the solution, and the solvent is removed under reduced pressure. The resulting solid is purified by column chromatography (silica, 90:10 CH2Cl2: EtOAc) to afford 9 as an off-white foam (2.56, 85.0%). 1H NMR (DMSO-d6) δ 10.69 (1H, s, N2H, exchanges with D2O), 8.47 (1H, s, H-8), 7.54 (2H, dd, J=8.4, J=1.6, PAc Ar), 7.42-7.34 (3H, m, Bn Ar), 7.31-7.26 (2H, m, Bn Ar), 6.97-6.92 (3H, m, PAc Ar), 6.33 (1H, t, J=6.8, H-1′), 5.63 (2H, s, CH2-Ph), 5.04 (2H, s, Pac-CH2), 4.94 (1H, t, J=5.4, 5′-OH, exchanges with D2O), 4.60 (1H, ddd, J=5.6, J=2.8, J=2.8, H-3′), 3.84 (1H, ddd, J=4.8, J=4.8, J=2.8, H-4′), 3.57 (1H, ddd, J=11.6, J=5.6, J=5.6, H-5′), 3.51 (1H, J=11.2, J=5.2, J=4.8, H-5′), 2.82 (1H, ddd, J=13.2, J=6.0, J=2.0, H-2′), 2.28 (1H, ddd, J=13.2, J=6.0, J=3.2, H-2′), 0.875 (9H, s, Si—C(CH3)3), 0.094 (3H, s, Si—CH3), 0.088 (3H, s, Si—CH3). Anal. (C31H39N5O6Si) C, H, N.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@H:13]([OH:30])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@@H:13]1[O:30][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[CH2:19]3)[CH2:14]1)([CH3:6])([CH3:7])[CH3:8]
Reactant: O=C(Cl)Cl
Reactant: CCCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC(C)(C)C)OC3=O)cc(F)c21
Reaction time: 0.5 h

Procedure:
Phosgene (20% solution in toluene, 0.770 ml, 7.86 mmol) is added to (R)-[3-(7-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-ylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.400 g, 1.05 mmol) and triethylamine (0.726 ml, 5.24 mmol) in dichloromethane (5 ml) at 0° C. and stirred for 30 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a dark yellow solid. HPLC r.t. 5.28 min; MS for C20H26FN3O5 m/z 408.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:21]([O:20][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH3:17])[C:13]=1[O:18][CH3:19])[CH2:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1)[CH:22]=[CH2:23]
Reactant: C=CCBr
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Product: C=CCOc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC

Procedure:
The title compound was prepared from 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine (20.0 g, 72.4 mmol) and allyl bromide by the procedure of Example 1A. Recrystallization from 95% ethanol gave title compound as white crystals (14.9 g); mp 160°-162°. Anal. Calcd for C16H20N4O3 : C, 60.74; H, 6.37; N, 17.71. Found: C, 60.94; H, 6.45; N, 17.62.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].C([CH:12]1[O:14][CH2:13]1)Cl>[OH-].[Na+]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH:13]1[CH2:12][O:14]1)[CH3:2]
Reactant: CCc1cccc(O)c1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cccc(OC2CO2)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 3-ethyl phenol (1.50 g, 12.28 mmol) in NaOH (1N) was added epichlorohydrin (2.07 g, 22.47 mmol). The reaction mixture was stirred at room temperature for 4 days. Excess epichlorohydrin was removed by concentration in vacuo and the two-phase mixture treated with NaOH (1N) (10 ml) after addition of THF (10 ml). The reaction mixture was heated to 55° C. for 15 minutes and then stirred at room temperature for 30 minutes. The THF was removed by concentration in vacuo and the product extracted with ethyl acetate (2×50 ml), concentrated in vacuo and purified by flash column chromatography on silica (150:10:1 dichloromethane:methanol:ammonia) to give the product as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[S:30](N)([NH2:33])(=[O:32])=[O:31].CCN(C(C)C)C(C)C>O1CCOCC1>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][S:30]([NH2:33])(=[O:32])=[O:31])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: NS(N)(=O)=O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(N)(=O)=O)no2)cc1C#N
Temperature: 110 °C
Yield: 41.9 %

Procedure:
Prepared using General Procedure 5: To a stirring solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile HCl 3 (50 mg, 0.12 mmol) in dioxane (3 mL) were added sulfamide (58 mg, 0.61 mmol) and DIEA (47.2 μL, 0.37 mmol) and the mixture was heated to 110° C. for 14 h. The solvent was evaporated and the residue was purified by preparative HPLC to provide 22.8 mg (42%) of (R)-N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamide 26. LCMS-ESI (m/z) calculated for C22H23N5O4S: 453.5; found 454.1 [M+H]+, tR=3.47 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.97 (dd, J=7.7, 1.2 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 4.78 (ddd, J=13.4, 11.7, 5.7 Hz, 2H), 4.59 (d, J=19.8 Hz, 2H), 4.55 (d, J=8.2 Hz, 1H), 3.19 (dt, J=18.0, 5.6 Hz, 1H), 3.02 (dt, J=18.2, 7.2 Hz, 1H), 2.23-2.03 (m, 2H), 1.92 (dt, J=12.4, 6.3 Hz, 2H), 1.48 (d, J=6.1 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=[O:21])=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH:11]=[CH:12][CH:13]=[O:21]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCc1ccc(OC)c(OC)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1ccc(C=CC=O)cc1OC
Temperature: 95 °C
Yield: 79 %

Procedure:
A solution of 3,4-dimethoxyphenylpropane (1 g) in 40 mL of dry dioxane was placed in 100 ml round bottom flask. To this was added a catalytic amount of para-toluenesulphonic acid (0.04 to 0.1 g and 4.5 g of DDQ and finally started refluxing the mixture at 50 to 140° C. for 7 to 16 hrs. The mixture was cooled and the precipitated DDQH2 was filtered and further washed with chloroform. The filtrate and washings were combined and evaporated under reduced pressure. The product was taken in ether (50 ml) and the ether layer was washed with aqueous NaOH (15%, 2×10 ml). The combined aqueous layers are further extracted with ether (3×10 ml). The ether layers were combined and washed with saturated sodium chloride (3×10 ml), dried over anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude yellow liquid which was loaded on silica gel column and the column was eluted with hexane (40-50 ml) and then with an increasing amount of hexane/ethyl acetate (9:1 to 1:9). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 3,4-dimethoxycinnamaldehyde in 79% yield as a yellow solid; mp 74-77° C. ; 1H NMR δ 9.67 (1H, d, H-3′), 7.43 (1H, d, H-1′), 7.15 (1H, d, H-5), 7.08 (1H, s, H-3), 6.91 (1H, d, H-3), 6.61 (1H, dd, H-2′), 3.94 (s, 3H, 3-OCH3), 3.93 (s, 3H, 4-OCH3). The remaining physical and spectral data was found similar as reported.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[N:5]2.CN(C=O)C.O=P(Cl)(Cl)[Cl:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:20])[CH:6]=[N:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc2cc(Br)ccc2[nH]1
Solvent: CN(C)C=O
Product: Clc1cnc2cc(Br)ccc2n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
6-bromoquinoxalin-2(1H)-one (9.0 g, 40 mmol) was dissolved in POCl3 (50 mL) and DMF (2 mL) was added at RT. The mixture was heated at 50° C. for 2 hours. After completion of the reaction it was cooled to RT and was poured slowly into ice cold water. The mixture was stirred for 30 minutes and then filtered to afford crude product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:23])[N:9]([C@@H:11]([CH2:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[CH2:12]O)[CH2:10][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:23])[N:9]([C@@H:11]([CH2:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[CH2:12][N:47]3[C:43](=[O:53])[C:44]4[C:45](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:46]3=[O:48])[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1c2cnc(Cl)cc2CN1[C@H](CO)Cc1cc(F)cc(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cc(F)cc(F)c1)N1Cc2cc(Cl)ncc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of 6-chloro-2-[(1S)-1-(3,5-difluorobenzyl)-2-hydroxyethyl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (0.340 g, 1.00 mmol), triphenylphosphine (0.263 g, 1.00 mmol) and phthalimide (0.148 g, 1.00 mmol) in tetrahydrofuran (10 mL) at 25° C. was added diethyl azodicarboxylate (0.514 mL, 1.30 mmol). The reaction was stirred at room temperature overnight. After concentration, the residue was purified by combi-flash chromatography eluting with EtOAc/hexane (10-60%). The purification gave 0.360 g (76.7% yield) of the desired product as light green solid. LC/MS found: 468.0 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[OH-].[Na+].C1(C)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(OCCC#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(OCCCN)cc1
Reaction time: 3 h
Yield: 78.2 %

Procedure:
Under an argon atmosphere, 3-(4-methoxyphenoxy)propionitrile (5.0 g) was dissolved in tetrahydrofuran (20 mL), and borane-tetrahydrofuran complex (1.02 mol/L, 30.0 mL) was added dropwise at 80° C. for 10 minutes. After stirring for 3 hours at the same temperature, the reaction liquor was returned to room temperature. In an ice-cold bath, a 4 N aqueous sodium hydroxide solution (30 mL) was added for 10 minutes. After 10 minutes, the mixture was stirred at room temperature for 5 minutes, and then stirred at 80° C. for 12 hours. The mixture was returned to room temperature, and toluene (100 mL) was added, and the mixture was stirred for 1 hour, and then insoluble material was removed using Celite. An organic layer was isolated, and washed with water (100 mL×2 times) and saturated brine (100 mL), and then dried over anhydrous sodium sulfate (80 g). The resultant was filtered, and then the filtrate was concentrated under reduced pressure to obtain a white solid (4.0 g, 79.0%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:30]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:30]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[F:24])[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccncc4F)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 3-fluoro-pyridine-4-boronic acid following a procedure analogous to that described for Example 3. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=398 [M+H]+.