Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][C@@H:44]([OH:46])[CH3:45])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([N:37]4[CH2:38][CH2:39][N:40]([CH2:43][C@@H:44]([OH:46])[CH3:45])[CH2:41][CH2:42]4)=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: C[C@H](O)CN1CCN(c2ccc(N)cc2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCN(C[C@H](C)O)CC4)cc3)nn12
Yield: 55.6 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and (S)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (0.205 g, 0.000870 mol) were dissolved in 2-Methoxyethanol (1.0 mL) and The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 110.96 mg of (S)-1-(4-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-propan-2-ol as a lyophilized powder. (M+H)=459.20. 1H NMR (400 MHz, DMSO, d6) δ 9.22 (s, 1H), 8.92 (s, 1H), 7.82 (dd, 1H, J=1.44, 6.16 Hz), 7.61 (d, 2H, J=8.96 Hz), 7.43 (t, 1H, J=7.36 Hz), 6.90 (m, 4H), 4.11 (m, 2H), 3.80 (s, 3H), 3.60 (m, 3H), 3.18 (m, 3H), 3.03 (m, 3H), 1.14 (d, 3H, J=6.16 Hz).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[O:19])[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=O.[NH3:23]>CO>[CH3:20][N:15]1[C:14]2[CH:21]=[CH:22][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:23])=[O:2])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[S:18][CH2:17][C:16]1=[O:19]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=O)N3C)C(=O)O1
Reactant: N
Solvent: CO
Product: CN1C(=O)CSc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Reaction time: 3 h
Yield: 57 %

Procedure:
To a stirred suspension of the (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (Step 5, 200 mg, 0.6205 mmol) in MeOH (3 mL) is added a 2.0 M solution of ammonia in MeOH (2.0 mL). This mixture is stirred for 3 h at which time the reaction is concentrated under reduced pressure, washed with ethyl ether (6 mL) and filtered to give the title compound as a white solid (108 mg, 57%), 1H NMR (300 MHz, DMSO) δ 7.86 (s, 1H), 7.63 (d, 2H), 7.47 (dd, 1H), 7.27 (d, 1H), 5.01 (dd, 1H), 4.26 (t, 1H), 4.00 (dd, 1H), 3.52 (s, 2H), 3.32 (s, 3H); MS for C13H13N3O4SMS m/z 308.5 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@@H:2]4[NH:1][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N)no2)cc1C#N
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Product: C=CS(=O)(=O)N[C@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a stirred solution of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50 (180 mg, 0.5 mmol) in DCM (2 mL) at 0° C. was added TEA (348 μL, 2.5 mmol) and 2-chloroethanesulfonyl chloride (245 mg, 1.5 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min. Additional TEA (348 μL, 2.5 mmol) and 2-chloroethanesulfonyl chloride (245 mg, 1.5 mmol) were added and the reaction was stirred for 1 h. The solvent was removed and the product was purified by chromatography (EA/hexane) to give 144 mg (64%) of (S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide INT-14 as a white solid. LCMS-ESI (m/z) calculated for C23H22N4O4S: 450.1; found 473.1 [M+Na]+, tR=3.84 min. 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=2.1 Hz, 1H), 8.27 (dd, J=8.9, 2.2 Hz, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.64 (dd, J=16.5, 9.9 Hz, 1H), 6.32 (d, J=16.5 Hz, 1H), 5.97 (d, J=9.9 Hz, 1H), 4.94-4.85 (m, 1H), 4.83 (d, J=9.1 Hz, 1H), 4.75 (hept, J=6.1 Hz, 1H), 3.42 (ddd, J=17.4, 8.8, 3.3 Hz, 1H), 3.17-3.01 (m, 1H), 2.63 (dtd, J=13.0, 8.0, 3.4 Hz, 1H), 1.99-1.86 (m, 1H), 1.44 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.20, 168.72, 162.89, 143.74, 142.71, 137.15, 134.16, 134.00, 128.91, 127.62, 127.15, 126.54, 123.38, 116.77, 115.38, 113.70, 103.96, 72.89, 58.59, 34.71, 31.56, 21.83. (R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)ethane sulfonamide was made in an analogous fashion from (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[C:20]([C:23]([F:26])([F:25])[F:24])[C:19](=[O:27])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[N:39]=[C:40]=[O:41]>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[NH:39][C:40]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[C:20]([C:23]([F:26])([F:25])[F:24])[C:19](=[O:27])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1)=[O:41]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c(C(F)(F)F)nc23)c2ccccc12
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)Nc1ccc(Oc2ccnc3[nH]c(=O)c(C(F)(F)F)nc23)c2ccccc12

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-2-(trifluoromethyl)pyrido[2,3-b]pyrazin-3(4H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a slightly yellow solid (31 mg, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH3:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COCCOCCBr
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCCOc1ccc(C(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenyl 4-hydroxybenzoate (2.1 g, 9.8 mmol) in tetrahydrofuran (40 mL) was added a 60% suspension of sodium hydride in mineral oil (408 mg, 10.2 mmol) and the mixture was stirred at room temperature for about 30 minutes. Then 1-bromo-2-(2-methoxyethoxy)ethane (2.5 g, 13.7 mmol) was added and stirring was continued for about 5 days. The mixture was poured into saturated aqueous sodium carbonate and was extracted with ethyl acetate, the combined organic extracts were washed with saturated aqueous sodium carbonate, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (10:1) as eluent to provide the desired product. 1H NMR (500 MHz, CDCl3) δ 3.40 (s, 3H), 3.60 (m, 2H), 3.76 (m, 2H), 3.92 (t, J=8 Hz, 2H), 4.22 (t, J=8 Hz, 2H), 7.00 (d, J=8 Hz, 2H), 7.22 (m, 3H), 7.42 (d, J=8 Hz, 2H), 8.17 (d, J=8 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6](C)[CH:7]=[C:8]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[CH3:19])[C:9]#[N:10])[CH3:2].[O-][CH2:23]C.[Na+]>>[NH2:10][CH:9]1[C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][NH:6][C:5]1([C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH3:23]
Reactant: CC[O-]
Reactant: CCOC(=O)CN(C)C=C(C#N)c1c(C)cc(C)cc1C
Agent: [Na+]
Product: CCOC(=O)C1(C)NC=C(c2c(C)cc(C)cc2C)C1N

Procedure:
A solution of N-Methyl-N-[2-(2,4,6-trimethylphenyl)-2-cyanovinyl]-glycine ethyl ester (6.8 g, 24 mmol) in 0.28M ethanolic sodium ethoxide (100 mL) was heated at 70° C. for 6 h. The reaction was cooled and evaporated in vacuo. The residue was treated with water and neutralized with acetic acid and the product was extracted with ethyl acetate. After drying the solvent was removed in vacuo to afford 3-Amino-2-ethoxycarbonyl-2-methyl-4-(2,4,6-trimethylphenyl)-1H-pyrrole as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=2)[CH:23]=[N:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(Cl)CCl>CN(C=O)C>[C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[C:3]=3[N+:11]([O-:13])=[O:12])[CH:28]=2)[CH:23]=[N:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2ccc3cnn(C(=O)OC(C)(C)C)c3c2)c1[N+](=O)[O-]
Reaction time: 16 h
Yield: 58.4 %

Procedure:
To a stirring solution of 3-methyl-2-nitrobenzoic acid (1.8 g, 10.1 mmol) and 1-Boc-6-amino-indazole (2.37 g, 10.1 mmol) in DMF (20 mL) was added EDC (3.17 g, 15.2 mmol). After stirring for 16 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1 M citric acid. The layers were separated and the organic phase was washed again with 1 M citric acid, once with water, twice with satd aq NaHCO3, and once with brine. The organic phase was then dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in a minimal volume of chloroform and chromatographed over silica gel, eluting with a gradient of 40% ethyl acetate/hexanes through 70% ethyl acetate/hexanes. The product containing fractions were combined and concentrated in vacuo to give 2.34 g (58%) of off-white solid.
Reaction SMILES: [F:1][C:2]1[C:18]([C:19]#[C:20][C:21]([OH:36])([C:23]2[N:24](COCC[Si](C)(C)C)[CH:25]=[CH:26][N:27]=2)[CH3:22])=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]1[C:18]([C:19]#[C:20][C:21]([OH:36])([C:23]2[NH:27][CH:26]=[CH:25][N:24]=2)[CH3:22])=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1nccn1COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1ncc[nH]1

Procedure:
A solution of 9-fluoro-10-(3-hydroxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)but-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (200 mg, 0.39 mmol, 1.00 equiv) and TFA (1.5 mL) in dichloromethane (4.5 mL) was stirred for 5 h at room temperature. The resulting solution was diluted with 50 mL of dichloromethane. The pH value of the solution was adjusted to 9 with saturated potassium carbonate. The resulting mixture was washed with water, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (10/1) to give the titled compound as an off-white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[SH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(OCC)(=O)C>CN(C)C=O>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[S:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:5]
Reactant: O=Cc1ccccc1F
Reactant: COC(=O)CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCSc1ccccc1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
Under an argon atmosphere, 2-fluorobenzaldehyde (3 g) was dissolved in 9 ml of dimethylformamide and potassium carbonate (5.01 g) was added. Methyl 4-mercaptobutyrate (4.5 ml) was added at room temperature and-was stirred at room temperature for 14 hours. After the addition of 50 ml of ethyl acetate, the mixture was washed with 30 ml of water twice, 3 ml of a 1N hydrochloric acid, and 30 ml of water three times. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was subjected to silica gel chromatography (hexane/ethyl acetate=6/1) purification. The resulting effective fractions were concentrated to yield methyl 4-(2-formylphenylthio)butyrate (5.45 g, Yield 95%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.[CH3:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25](=[S:27])[NH2:26])[C:22]([C:28]([F:31])([F:30])[F:29])=[N:21]2)=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[S:27][CH:3]=[C:4]([NH:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)[N:26]=3)[C:22]([C:28]([F:31])([F:29])[F:30])=[N:21]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(Cn2cc(C(N)=S)c(C(F)(F)F)n2)cc1
Reactant: O=C(CCl)Nc1ccccn1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)cs3)c(C(F)(F)F)n2)cc1
Yield: 45.8 %

Procedure:
According to Scheme 3 Step 1: A solution of 2-chloro-N-(pyridin-2-yl)acetamide hydrochloride (0.48 mmol, 99 mg), 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbothioamide (0.48 mmol, 150 mg) in DCM (2.5 mL) was stirred under reflux for 5 days. The crude mixture was evaporated to dryness and was purified by flash chromatography over silica gel using DCM/EtOH/NH3 (100:0:0 to 97:2.7:0.3) as eluent to yield 2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine (0.22 mmol, 94 mg, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N+:12]([O-:24])=[C:11]([CH3:15])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccnc(C)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc[n+]([O-])c(C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A mixture of 4-(4-methoxyphenyl)-2-methylpyridine (375 mg) and metachloroperbenzoic acid (70%, 695 mg) in chloroform is stirred at room temperature for two hours. Concentration and purification over silica gel (eluent dichloromethane/methanol from 100/0 to 90/10) affords 384 mg of 4-(4-methoxyphenyl)-2-methylpyridine 1-oxide as an orange oil used without further purification.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[Na+].C(O)(=S)C.[OH-].[Na+].[N+:12]([C:15]1[CH:36]=[CH:35][C:18]([CH2:19][O:20][C:21]([O:23][CH:24]([CH:26]2[CH:29](OC(=O)C)[NH:28][C:27]2=[O:34])[CH3:25])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>O1CCOCC1.O.ClCCl>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]([O:23][CH:24]([CH:26]2[CH:29]([S:3][C:1](=[O:4])[CH3:2])[NH:28][C:27]2=[O:34])[CH3:25])=[O:22])=[CH:35][CH:36]=1)([O-:14])=[O:13]
Reactant: CC(=O)OC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC([O-])=S
Agent: CC(O)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)SC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium thioacetate, prepared by treating a solution of thioacetic acid (3.24 g) in dioxane (8 ml) and water (21.5 ml) with 1N aqueous sodium hydroxide, was added to a solution of 3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone (15.0 g) in dioxane (56 ml) at 0° to 10° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 15 minutes, diluted with ice-cooled dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was then purified by silica gel chromatography to give 3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetylthio-2-azetidinone.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].[CH2:12]([Li])[CH2:13]CC.CCCCCC.ICC.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:12]([C:10]1[N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=[CH:8][CH:9]=1)[CH3:13]
Reactant: [Li]CCCC
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1ccnn1S(=O)(=O)N(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a stirred solution of N,N-dimethyl-1H-pyrazole-1-sulfonamide (25.3 g, 144 mmol) in THF (200 mL) at −78° C. was added dropwise 1.6 M n-butyllithium in hexane (99 ml, 159 mmol). After 30 min, iodoethane (12.8 mL, 159 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min and allowed to room temperature slowly. After 1 h, the stirring became difficult by formation of white precipitate. THF (200 mL) was added dropwise to give yellow solution. The stirring was continued for 2 h. Then, the mixture was poured into saturated aqueous NaHCO3 (600 mL) and extracted with EtOAc (400 mL×2), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 30:70 hexane/EtOAc) to afford the title compound (19.8 g, 68%) as colorless liquid:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH:15]=[C:14]([C:17]#[N:18])[C:13](=[O:19])[C:12]=2[CH:20]=1)(=[O:7])[CH3:6].[N-:21]=[N+:22]=[N-:23].[Na+]>O1CCCC1>[C:5]([C:8]1[CH:20]=[C:12]2[C:11](=[CH:10][CH:9]=1)[O:16][CH:15]=[C:14]([C:17]1[NH:23][N:22]=[N:21][N:18]=1)[C:13]2=[O:19])(=[O:7])[CH3:6]
Reactant: CC(=O)c1ccc2occ(C#N)c(=O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1

Procedure:
To 40 parts by volume of tetrahydrofuran are added under cooling 4.0 parts of anhydrous aluminum chloride, 3.20 parts of 6-acetyl-4-oxo-4H-1-benzopyran-3-carbonitrile and 2.93 parts of sodium azide in the order mentioned and, under stirring, the mixture is refluxed for 30 minutes. After cooled, the reaction mixture is concentrated to dryness. To the residue are added 100 parts by volume of 1N-hydrochloric acid and 3.10 parts of sodium nitrite, and the insoluble material is recovered by filtration and recrystallized four times from dimethylformamide to obtain 0.380 part of 6-acetyl-3-(1H-tetrazol-5-yl)-chromone as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]([CH:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]([CH:15]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:24])=[CH:26][CH:27]=2)[CH2:16][CH2:17][CH3:18])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CCN
Reactant: CCCC(c1ccc(C(=O)O)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(c1ccc(C(=O)NCCC(=O)OCC)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
To a solution of 4-{1-[2-tert-butoxy-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoic acid (17.8 g, 44 mmol) in DCM (175 mL) at room temperature was added β-alanine ethyl ester hydrochloride (6.6 g, 44 mmol), HOBt (7.85 g, 52.8 mmol), EDC (9.8 g, 53 mmol) and Et3N (30 mL, 220 mmol). After being stirred for 16 hours, the mixture was diluted with DCM then washed with water then saturated NaCl (aq). The organic layer was dried over Na2SO4, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes. The two diastereomeric title compounds were separated by silica gel chromatography eluting with 40% EtOAc/hexanes. The slower-eluting diastereomer is readily resolved to provide enantiopure material by supercritical fluid chromatography on a ChiralPak IA column (3 cm×25 cm) eluting with 50 mL/min of 10% (2:1:3 MeOH:CH3CN:CHCl3) and 90% CO2 at 35° C. and 100 bar.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH3:29][O:30][C:31]1[CH:47]=[CH:46][C:34]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:40]2[CH:39]=[CH:38][C:37]([O:36][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:47][CH:46]=3)=[CH:42][CH:41]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reactant: COc1ccc(COc2ccc(B(O)O)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(OC)cc3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0454 g, 0.100 mmol), (4-((4-methoxybenzyl)oxy)phenyl)boronic acid (0.039 g, 0.150 mmol) and 2M Na2CO3 (0.125 ml, 0.249 mmol) in DMF 92 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.012 g, 9.97 μmol) was added, degassed for 5 min and placed in a oil bath pre-heated to 110 C. After 2 h, cooled and purified by pre-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0376 g, 0.064 mmol, 64.1% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.40-7.44 (m, 2H), 7.15-7.18 (m, 1H), 7.04-7.09 (m, 3H), 6.94-6.98 (m, 2H), 6.05 (br. s., 1H), 5.05-5.11 (m, 2H), 4.27 (qd, J=7.1, 10.8 Hz, 1H), 4.18 (qd, J=7.1, 10.7 Hz, 1H), 3.86 (s, 3H), 3.19 (br. s., 1H), 2.87 (br. s., 1H), 2.63 (br. s., 3H), 2.24 (br. s., 4H), 2.05 (br.s., 1H), 1.26 (t, J=7.1 Hz, 3H), 1.20 (s, 9H), 0.90 (m, 3H), 0.66 (br. s., 3H). 4H of piperidine were not resolved. LCMS (M+H)=589.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9](OC)[CH:8]=[CH:7][C:4]=1[CH:5]=O.[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N+:15]=[N-:16].CO[Na].[Cl-].[NH4+]>CO>[N:14]([C:17](=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:3]=1[O:2][CH3:1])[C:18]([O:20][CH3:21])=[O:19])=[N+:15]=[N-:16]
Reactant: COc1ccc(C=O)c(OC)c1C
Reactant: COC(=O)CN=[N+]=[N-]
Agent: CO[Na]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C(=Cc1cccc(C)c1OC)N=[N+]=[N-]
Yield: 88.5 %

Procedure:
To the mixture of 2.46 g of 2-methoxy-3-methylanisaldehyde (16 mmol) and 4.72 g of methyl azidoacetate (41 mmol) in 20 mL of MeOH is added 7.6 mL of 5.4M MeONa over 30 minute at −10 degrees. After addition the mixture was stirred for additional hour at the same temperature and then transferred in cold room (4 degrees) and stirred overnight. On the morning reaction mixture was poured in 0.5 L mixture of ice and conc. ammonium chloride solution, stirred for 10 minutes and filtered off. The solid was washed with plenty of ice cold water and then moved at ambient temperature. After air drying for 1 hr the solid was dissolved in 50 mL of DCM, dried over magnesium sulfate and passed through short silica gel plug. Evaporation of solvent produced 3.5 g of methyl 2-azido-3-(2-methoxy-3-methylphenyl)acrylate, that was used in the next step without further purification.