Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[C-:4]#[N:5].[Na+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1>O>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]#[N:5])=[CH:10][CH:11]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(OC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
150 g of ethanol, 28 ml of water, and 31.5 g of sodium cyanide were initially charged, and 127.5 g of 4-bromomethyl-1-trifluoromethoxybenzene were added. The reaction mixture was stirred at 90° C. for 3.5 hours and then poured into 250 ml of water and extracted twice with 50 ml portions of dichloromethane. The combined organic phases were concentrated and the residue was distilled at 18 hPa. This gave 81.5 g of (4-trifluoromethoxyphenyl)acetonitrile as a colorless liquid (76.3% of theory) of b.p. 110-112° C.
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:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2>COCCO>[NH:36]1[C:37]2[C:33](=[CH:32][C:31]([NH:30][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[O:19][CH3:20])[N:6]4[N:5]=3)=[CH:39][CH:38]=2)[CH:34]=[CH:35]1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4[nH]ccc4c3)nn12
Yield: 23.1 %

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 5-Aminoindole (115 mg, 0.000870 mol) were dissolved in 2-Methoxyethanol (3.05 mL) and the 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 afford 35.70 mg of (1H-Indol-5-yl)-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a lyophilized powder. (M+H)=356.18. 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.41 (s, 1H), 8.17 (m, 2H), 8.05 (d, 1H, J=6.13 Hz), 7.54 (m, 1H), 7.29 (m, 4H), 7.22 (m, 3H), 6.41 (m, 1H), 3.85 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH3:10])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>ClCCl>[C:18]([NH:1][CH:2]([CH3:10])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(C)C(C)N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)C(C)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
To ethyl 3-amino-2-methylbutanoate (0.15 g, 1.033 mmol) in dichloromethane (3 mL) was added triethylamine (0.288 mL, 2.066 mmol) followed by the dropwise addition of benzoyl chloride (0.120 mL, 1.033 mmol) at RT. The reaction mixture was stirred at RT for 1 h, partitioned between dichloromethane (20 mL) and 1N HCL (10 mL). The dichloromethane layer was washed with 1N NaOH (10 mL), brine (10 mL), dried over sodium sulfate and concentrated to yield an oil. The oil was subjected to silica gel chromatography using an ISCO setup (12 g silica gel RediSep cartridge, hexane/EtOAc as eluent). The desired fractions are collected and concentrated to yield the title compound (0.066 g, 0.265 mmol, 25.6% yield) as an oil.
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[Si:29]([O:36]CC=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>>[Si:29]([O:36][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:9][CH2:10]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 15) and 2-(tert-butyldimethylsilyloxy)acetaldehyde following procedure described in Step 1 of Example 15. ESI-MS m/z 505 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH:23][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:20]=[CH:19][CH:18]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCC(=O)Cl
Reactant: Cc1ncoc1C(=NOCc1cccc(N)n1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1cccc(CON=C(c2ccccc2)c2ocnc2C)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (90 mg, 0.29 mmol) in dichloromethane (2 mL) were added pyridine (35 mg, 0.44 mmol) and after 15 min stirring n-hexanoyl chloride (43 mg, 0.32 mmol). After stirring at room temperature for 4 h the mixture was passed through a cartridge filled with basic alumina and 1 g silica. After rinsing with dichloromethane the final compound was eluted with heptane/ethylacetate (1/1) to afford after evaporation N-{6-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}hexanamide (95 mg, 72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[S:43][CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[S:43][CH3:44])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CSc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccc(F)cc3)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 3-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H13) according to the general procedure K. Obtained as a light yellow oil (181 mg).
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C1OCCOCCOCCOCCOCCOC1.I[CH2:39][CH2:40][CH2:41][OH:42]>C(#N)C>[OH:42][CH2:41][CH2:40][CH2:39][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Reactant: OCCCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(OCCCO)cc2)cc1
Temperature: 25 °C

Procedure:
The potassium salt of 4-hydroxy-4'-nitrostilbene from Example 4 (280 g, 1 m), acetonitrile (2 liters) and the catalyst 18-Crown-6 (1 g) were charged into a 4 liter 3 necked flask equipped with a reflux condenser, mechanical stirrer, a heating mantle, and an addition funnel, and provided with argon atmosphere. The mixture was kept gently refluxing and stirring, while 3-iodopropan-1-ol (223 g, 1.2 m) was added dropwise over a period of about 3 hours. The reaction mixture was refluxed for about 24 hours. About a liter of the solvent was then distilled off at atmospheric pressure, and the reaction mixture was allowed to cool to ambient temperature. The yellow solid was filtered, dried, and recrystallized from toluene to yield yellow crystals of compound of Formula 28. Yield 210 g (70%).
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[C:10]([CH2:35][NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=3)=[C:39]([CH3:50])[CH:38]=2)=[C:11]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[N:23][CH:24]=2)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl>C(OCC)C.CO>[Cl:8][C:9]1[C:10]([CH2:35][NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=3)=[C:39]([CH3:50])[CH:38]=2)=[C:11]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[N:23][CH:24]=2)[CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2CNc2ccc(-c3ccc(Cl)cc3)c(C)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(NCc2c(Cl)cc(C(F)(F)F)cc2-c2ccc(C(=O)NCCC(=O)O)nc2)ccc1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (1.9 mL, 5.7 mmol) was added to a THF (7.6 mL) and MeOH (3.8 mL) solution of ethyl 3-(5-(3-chloro-2-(((4′-chloro-2-methyl-[1,1′-biphenyl]-4-yl)amino)methyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (2.4 g, 3.8 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 30 min the resulting mixture concentrated and then acidified with 1M aqueous HCl. The resulting mixture was diluted with EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organics were washed with 4M NaCl, dried (Na2SO4), and concentrated. The resulting material was dissolved in diethyl ether, 1M diethyl ether solution of HCl (5.7 mL, 5.7 mmol) was added and the resulting precipitate was filtered, washed with diethyl ether, and dried in vacuo to yield the title compound.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[ClH:1].[ClH:1].[NH2:23]/[C:22](=[N:25]\[OH:26])/[C:21]1[C:15]2[S:14][C:13]([C:11]([NH:10][C@@H:4]3[CH:5]4[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]4)[CH2:3]3)=[O:12])=[CH:17][C:16]=2[CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N/C(=N\O)c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Temperature: 80 °C

Procedure:
120 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-cyano-1-benzo-thiophene-2-carboxamide hydrochloride, 45.0 mg (0.65 mmol) of hydroxylamine hydrochloride and 119.2 mg (0.86 mmol) of potassium carbonate in 1.5 ml of an 8:1 mixture of water and ethanol are heated at 80° C. for 18 h. The mixture is purified by preparative HPLC. The product fractions are combined and concentrated, acetonitrile and 1N aqueous hydrochloric acid (3:1) are added and the mixture is then again concentrated and dried under high vacuum. 58 mg (30.3% of theory) of the title compound are obtained.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])(C)C.C(C(O)=[O:21])(F)(F)F>>[CH3:15][C:14]1[CH:13]=[CH:12][CH:11]=[N+:10]([O-:21])[C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7]
Reactant: Cc1cccnc1S(=O)(=O)NC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Product: Cc1ccc[n+]([O-])c1S(N)(=O)=O
Reaction time: 6 h

Procedure:
A mixture of the N-oxide of N-(1,1-dimethylethyl)-3-methyl-2-pyridinesulfonamide (2.5 g, 8.2 mmol) and 50 mL of CF3CO2H were stirred for 6 hours. The CF3CO2H was removed under vacuun and the resulting solids were washed with butyl chloride to afford 1 g of the desired product, m.p. 233°-235° C., (M+ =188, expected, 188).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:13]4[S:18][C:17]([CH2:19][N:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[O:32]1[CH:34]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33]1>CN(C=O)C.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[C:13]4[S:18][C:17]([CH2:19][N:20]5[CH2:21][CH2:22][N:23]([CH2:33][CH:34]([OH:32])[CH2:35][O:36][C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH2:24][CH2:25]5)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1cc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)c2cn[nH]c2c1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OC(COc1ccccc1)CN1CCN(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Treatment of 4-[2-(1H-indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester with HCl in DCM/MeOH yielded 2-(1H-indazol-4-yl)-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine. A mixture of 2-(1H-indazol-4-yl)-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (150 mg) and 1,2-epoxy-3-phenoxypropane (40 mg) was suspended in 50% DMF/0.1M sodium phosphate buffer (2 mL) and shaken at 55° C. overnight. After stirring for 24 h the reaction mixture was then diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[C:7]=1[CH2:18][CH2:19][CH2:20][CH3:21])=[O:5])C.[OH-].[Na+]>CO>[CH2:18]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)[CH:14]=[CH:15][C:6]=1[C:4]([OH:5])=[O:3])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1c(C(=O)OCC)ccc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1c(C(=O)O)ccc2ccc(OC)cc12
Yield: 86.6 %

Procedure:
As in Example 112, 1-butyl-7-methoxy-2-naphthalenecarboxylic acid ethyl ester (5.4 g) in methanol (40 mL) was reacted with 2N sodium hydroxide solution (20 mL) at reflux for 2 hours to give, after the normal work up, 4.9 g of crude acid. Crystallization of the material from diethyl ether-hexane furnished 4.22 g of 1-butyl-7-methoxy-2-naphthalenecarboxylic acid, mp 123°-125° C. Anal. Calcd for C16H18O3 : C, 74.39; H, 7.02 Found: C, 74.27; H, 6.93
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14]2.Cl>C1COCC1>[OH:5][CH:4]=[C:15]1[CH2:14][C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH3:9])[CH:12]=2)[C:16]1=[O:20]
Reactant: CCOC=O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(=CO)C2=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a mixture of sodium methoxide (1.2 g, 22 mmol) in THF (20 mL) was added ethyl formate (1.6 g, 22 mmol) and 5-methoxy-1-indanone (3.24 g, 19.7 mmol) and the mixture stirred for 16 h at 23° C. The reaction mixture was added to aqueous HCl (0.1 N) and extracted with a mixture (1:1) of ethyl acetate and ether (2×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated to a residue, which was purified by chromatography (silica, 40% ethyl acetate in hexanes) to give an oil (2.6 g, 69%): 1H NMR (CDCl3) δ 7.81 (d, J=9.6 Hz, 1H), 7.47 (s, 1H), 7.00 (m, 2H), 3.94 (s, 3H), 3.9 (m, 2H); MS m/z 191 [M+H]+.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].C([Sn](=O)CCCC)CCC.[F:18][C:19]1[CH:20]=[C:21]([N:33]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:22]=[CH:23][C:24]=1[C:25]1[CH2:30][CH2:29][N:28]([C:31]#[N:32])[CH2:27][CH:26]=1.CO>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([N:33]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:22]=[CH:23][C:24]=1[C:25]1[CH2:30][CH2:29][N:28]([C:31]2[NH:32][N:3]=[N:2][N:1]=2)[CH2:27][CH:26]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C#N)CC3)c(F)c2)C(=O)O1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(c4nnn[nH]4)CC3)c(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Azidotrimethylsilane (154 mg) and dibutyltin oxide (97 mg) were added to a stirred suspension of Example 24 (240 mg) in dry toluene (10 ml), and the mixture stirred at 70° C. for 18 hours. On cooling, methanol (5 ml) was added and after stirring for 10 minutes the solvent was evaporated. The title compound was isolated by MPLC (20% MeOH/CH2Cl2. Merck 9385 silica) and crystallised on evaporating the fractions to a small volume. The title product was filtered off washed with a little cold methanol (150 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[CH:15])[CH:5]=[CH:4][C:3]1=2.C([Li])CCC.B(F)(F)F.CCOCC.CN(C)[C:33]([C:35]1[CH:46]=[CH:45][C:38]([C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])=[CH:37][CH:36]=1)=[O:34].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[O:34]=[C:33]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])=[CH:45][CH:46]=1)[C:15]#[C:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:16])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: C=CCOC(=O)c1ccc(C(=O)N(C)C)cc1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOC(=O)c1ccc(C(=O)C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
4.3 g (20 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-ethynylnaphthalene and 20 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 12.5 ml (20 mmol) of an n-butyllithium solution (1.6M in hexane) were added dropwise at −78° C. and the reaction mixture was stirred for 10 minutes. 2.7 ml of BF3—Et2O were then added at this same temperature and the reaction mixture was stirred for 30 minutes. A solution of 2.5 g (10 mmol) of allyl 4-(N,N′-dimethylcarbamoyl)benzoate in 10 ml of THF was added, while maintained at −78° C., to the solution and stirring was carried out for 1 hour. The reaction mixture was poured into an aqueous ammonium chloride solution and extraction was carried out with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (10/90). After evaporation of the solvents, 4.2 g (52%) of the expected ester were recovered in the form of an oil.
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][CH:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])C.[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[O-]CC.[Na+]>CN(C)C=O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:12]2[CH:6]([CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11])[CH2:5][C:4]([OH:21])=[C:37]([C:32]3[NH:33][S:34](=[O:35])(=[O:36])[C:29]4[CH:28]=[C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])[CH:42]=[CH:41][C:30]=4[N:31]=3)[C:38]2=[O:39])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)CC(CCC(C)C)NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)CCC1CC(O)=C(C2=Nc3ccc(NS(C)(=O)=O)cc3S(=O)(=O)N2)C(=O)N1Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
A solution of 3-(4-fluoro-benzylamino)-6-methyl-heptanoic acid ethyl ester (93 mg, 0.315 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (105 mg, 0.315 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73 mg, 0.378 mmol) in anhydrous N,N-dimethyformamide (4 mL) was treated with N-methyl morpholine (0.083 mL, 0.756 mmol). The reaction was stirred under a nitrogen environment at 50° C. for 18 h, quenched with a 6.0 M aqueous hydrochloric acid solution (50 mL), extracted with ethyl acetate (2×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was dissolved in ethanol (5 mL) and treated with sodium ethoxide (470 μL, 21% w/w, 1.26 mmol). The reaction was heated at 60° C. under a nitrogen environment for 18 h. The reaction mixture was allowed to cool to 25° C., quenched with a 1.0 M aqueous hydrochloric acid solution (50 mL), extracted with ethyl acetate (2×50 mL), washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The crude resin was purified by flash column chromatography (ISCO RediSep column, 0 to 80% ethyl acetate in hexanes) to afford the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-6-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,2-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (63.6 mg, 36%) as a white powder. 1H NMR (400 MHz, CDCl3) δ: 0.90 (6H, d, J=6.9 Hz), 1.08-1.27 (2H, m), 1.50-1.75 (3H, m), 2.60 (1H, d, J=17.3 Hz), 2.95-3.01 (1H, m), 3.06 (3H, s), 3.37-3.49 (1H, m), 3.98 (1H, d, J=14.9 Hz), 5.30 (1H, d, J=15.0 Hz), 7.03-7.08 (2H, m), 7.20-7.28 (3H, m), 7.46 (1H, bs), 7.65-7.67 (1H, m), 7.71-7.73 (1H, m). LC-MS calculated for C25H29FN4O6S2: 564.2, found 565.5 [M+H+].
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=2)[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>[OH-].[Na+].CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 55.3 %

Procedure:
In a mixture of 1N NaOH solution (4.5 ml) and methanol (10 ml), methyl 2-[4-(2-butylbenzimidazol-1-yl)methylphenyl]benzoate (1.2 g) was heated for 3 hours under reflux. The reaction mixture was concentrated, and the concentrate was dissolved in water, washed with ether, then acidified with 1N-HCl to afford crystals. The crystals were collected by filtration and recrystallized from ethyl acetate - methanol to afford colorless crystals (0.64 g, 53%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([O:38][CH3:39])=[C:14]([C:19]([CH2:22][S:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[N:25][C:26](=[O:31])C(F)(F)F)=[O:24])=[CH:20][CH:21]=2)C(OC)=O)=[CH:8]1>CO>[O:7]1[CH:11]=[CH:10][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[CH2:22][S:23](=[O:24])([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:25][C:26](=[O:31])[C:14]=3[C:13]=2[O:38][CH3:39])=[CH:8]1
Reactant: COC(=O)c1c(CS(=O)(=NC(=O)C(F)(F)F)c2ccccc2)ccc(-c2ccoc2)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1c(-c2ccoc2)ccc2c1C(=O)N=S(=O)(c1ccccc1)C2

Procedure:
Potassium carbonate (1.38 g) was added to a stirred solution of methyl 3-(furan-3-yl)-2-methoxy-6-{[S-phenyl-N-(trifluoroacetyl)sulphonimidoyl]methyl)benzoate (Intermediate 215) in methanol (20 ml) and the resultant mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness and ethyl acetate and water were added to the residue. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 20-70%. The isolated product was triturated with diethyl ether and the solid was collected by filtration to give 6-(furan-3-yl)-5-methoxy-2-oxo-2-phenyl-1H-2-λ*6*-benzo[d][1,2]thiazin-4-one (0.23 g) as a white solid.