Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7]1)(=[O:31])[CH3:30]
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1

Procedure:
The title compound was prepared using essentially the method of Example 73, starting from 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (0.59 g, 1.35 mmol) and acetyl chloride. Purification by chromatography, eluting with a gradient increasing in polarity from 0 to 2.5% MeOH in dichloromethane gave the desired product (142 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH3:28][CH:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:31]([CH:29]([CH3:30])[CH3:28])(=[O:33])=[O:32])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Product: Cc1ccc(Sc2ccc(OS(=O)(=O)C(C)C)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 5 (80.0 mg, 0.195 mmol) was reacted with the propane-2-sulfonyl chloride (27.8 mg, 0.195 mmol) for 18 h following the procedure from Example 58 giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (20 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.90 (d, J=8.46 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 7.76 (d, J=8.82 Hz, 1H) 7.43-7.49 (m, 1H) 7.35-7.42 (m, 2H) 7.24-7.29 (m, 2H) 7.12-7.19 (m, 2H) 6.33 (d, J=6.99 Hz, 1H) 2.75 (s, 3H) 3.66 (m, 1) 2.39 (s, 3H) 1.40 (d, J=6.99 Hz, 6H); MS (DCI NH3+) m/z 480 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(OC(=O)C)C>CS(C)=O>[N:14]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(C(F)(F)F)c(N2CCCCC2)c1
Temperature: 55 °C
Reaction time: 43 h
Yield: 87.3 %

Procedure:
To a solution of 3-fluoro-4-(trifluoromethyl)benzonitrile (300 mg, 1.59 mmol) in DMSO (5.0 mL) was added piperidine (675 mg, 7.93 mmol), and the mixture was stirred for 43 hours at 55° C. After the mixture was cooled to room temperature, ethylacetate was added and washed with water then brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane:ethylacetate=10:1) to afford 3-piperidin-1-yl-4-(trifluoromethyl)benzonitrile (353 mg, 88% yield).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:42])[C:14]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][C:31]=4[CH3:41])=[O:27])=[CH:15][N:16]3[CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:11][C:10]=2[F:43])[CH2:3]1.[C:44]([NH2:48])(=[O:47])[CH:45]=[CH2:46].Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C.CS(C)=O>[NH2:48][C:44](=[O:47])[CH2:45][CH2:46][N:7]1[CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:42])[C:14]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:38])[F:39])=[CH:32][C:31]=4[CH3:41])=[O:27])=[CH:15][N:16]3[CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:11][C:10]=2[F:43])[CH2:3][CH:2]1[CH3:1]
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Reactant: C=CC(N)=O
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1c(N2CC(C)N(CCC(N)=O)C(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Temperature: 70 °C

Procedure:
A few drops of acetonitrile are added at room temperature to 55 mg of the compound of Example 52, 18 mg of acrylamide and 35 mg of lithium perchlorate, so that a stirrable suspension results. The mixture is heated to 70° C. over night and left to cool. After the addition of DMSO the whole mixture is separated by preparative HPLC (Method 5). After concentrating the suitable fractions and drying under high vacuum 30 mg (40% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13]([OH:21])=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])[S:5][C:6]=1[Cl:7].[O:22]1[C:26]2[CH:27]=[CH:28][C:29](B(O)O)=[CH:30][C:25]=2[CH2:24][CH2:23]1>>[Cl:7][C:6]1[S:5][C:4]([S:8]([NH:11][C:12]2[C:13]([OH:21])=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])=[CH:3][C:2]=1[C:29]1[CH:28]=[CH:27][C:26]2[O:22][CH2:23][CH2:24][C:25]=2[CH:30]=1
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2cc(Br)c(Cl)s2)c1O
Reactant: OB(O)c1ccc2c(c1)CCO2
Product: O=C(O)c1cccc(NS(=O)(=O)c2cc(-c3ccc4c(c3)CCO4)c(Cl)s2)c1O
Yield: 46 %

Procedure:
The product was prepared from 3-{[(4-bromo-5-chlorothiophen-2-yl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 22) (20.6 mg, 0.050 mmol) and 2,3-dihydrobenzofuran-5-boronic acid (9 mg, 0.055 mmol) according to the General Procedure 12, described in Example 135. The title compound was obtained in 46% yield (10.6 mg). 1H NMR (500 MHz, MeOH-d4) δ ppm 3.23 (t, J=8.70 Hz, 2 H) 4.58 (t, J=8.70 Hz, 2 H) 6.76 (d, J=8.24 Hz, 1 H) 6.90 (t, J=7.95 Hz, 1 H) 7.14-7.17 (ddt, J=8.24, 1.97, 0.71 Hz, 1 H) 7.25 (dt, J=1.97, 1.30 Hz, 1 H) 7.31 (s, 1 H) 7.66 (dd, J=7.95, 1.65 Hz, 1 H) 7.74 (dd, J=7.95, 1.65 Hz, 1 H). MS (ESI+) m/z 452 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]=[O:13]>CO.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:12][OH:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: C=O
Solvent: CO
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1CCO
Temperature: 900 °C
Reaction time: 2.5 h
Yield: 54.7 %

Procedure:
Triton B (4 ml, 35% in MeOH) was added to a mixture of 4-chloro-2-nitrotoluene (50 g, 291 mmol) and paraformaldehyde (3.8 g, 120 mmol) in DMSO (40 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å) and stirred for 2.5 h at 900° C. It was neutralized with a few drops of conc. HCl, diluted with H2O (100 ml) and extracted using EtOAc (5×150 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The oily residue was purified by sublimation in a high vacuum (p=0.1 torr, oil bath temperature 1100° C.). 2-(4-chloro-2-nitrophenyl)ethanol (13.23 g, 55%) was obtained in the form of yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:3]=1.[C:14]([Cl:20])(=O)[CH2:15][C:16]([Cl:18])=O>C(#N)C.[OH-].[Na+]>[Cl:18][C:16]1[CH:15]=[C:14]([Cl:20])[N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)[CH:3]=[C:2]2[N:1]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Cc1ccc(-c2cc(N)[nH]n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ccc(-c2cc3nc(Cl)cc(Cl)n3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
There was dissolved, in acetonitrile (40 mL), 5-amino-3-(4-methyl-phenyl)-pyrazole (2.00 g, 11.5 mM) in an argon gas atmosphere, malonyl chloride (1.34 mL, 13.8 mM) was added to the resulting solution with ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction liquid, there was added malonyl chloride (134 μL, 1.38 mM) followed by the further stirring of the mixture for 30 minutes. This reaction liquid was diluted with a 1M aqueous sodium hydroxide solution, washed with methylene chloride, and hydrochloric acid was added to the aqueous phase to make the same acidic (pH 2), followed by the extraction with ethyl acetate. The resulting extracts were combined and then concentrated, and the resulting solid was washed with diethyl ether. After the addition of phosphoryl chloride (5 mL) to the resulting solid with ice-cooling, the resulting suspension was stirred for 3 hours, while refluxing the same with heating. The phosphoryl chloride was distilled off from the reaction liquid, ethanol was added to the residue thus obtained with ice-cooling and then the mixture was stirred for 15 minutes. The reaction liquid was concentrated and then the resulting residue was purified by the silica gel column chromatography (ethyl acetate/hexane=1:10) to thus give the title compound (153 mg, overall yield of these two steps: 4%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].[CH3:17][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:17])=[O:11])=[CH:13][CH:14]=1)=[O:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(NC(=O)C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
step b To a solution of 120 (4.29 g, 18.40 mmol) in MeOH (50 mL) and toluene (75 mL) was added dropwise trimethylsilyldiazomethane (15.64 mL, 31.3 mmol) until the yellow color persisted. The resulting solution was stirred for 30 min then the reaction was quenched with several drops of HOAc until the yellow color disappeared. The solvents were evaporated to afford methyl 4-(2,2,2-trifluoro-acetylamino)-benzoate (122) which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][N:28]4[CH2:27][CH2:26][O:25][CH2:30][CH2:29]4)=[CH:38][CH:37]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Product: O=c1c2cnc(Nc3ccc(CN4CCOCC4)cc3)nc2n2ccnc2n1-c1ccccc1Cl

Procedure:
A mixture of Example 1E (0.060 g, 0.167 mmol) and 4-(morpholinomethyl)aniline (0.051 g, 0.267 mmol) was heated in a capped vial at 90° C. for 1 hour. The crude material was purified by HPLC (see protocol in Example 1F). The TFA salt was treated with saturated aqueous NaHCO3 and extracted into ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with methanol/ethyl acetate (5:95 to 10:90) to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 2.56-2.39 (m, 4H), 3.54 (s, 2H), 3.73-3.67 (m, 4H), 7.05 (d, J=1.9 Hz, 1H), 7.43-7.36 (m, 2H), 7.61-7.52 (m, 3H), 7.70-7.67 (m, 1H), 7.80-7.73 (m, 2H), 7.86 (s, 1H), 9.15 (s, 1H). MS (ESI+) m/z 488.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([C:20]([OH:22])=[O:21])=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N12CCCN=C1CCCC[CH2:30]2.IC>C1COCC1>[CH3:30][O:21][C:20]([C:11]1[CH:10]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)=[O:22]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COCCOCOc1c(-c2ccccc2)cc(C(=O)O)cc1-c1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: COCCOCOc1c(-c2ccccc2)cc(C(=O)OC)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
At 0° C., to a stirred solution of 2′-(2-methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carboxylic acid (1.72 g, 4.55 mmol) in THF (4.55 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene. After 0.5 h, to the reaction was added iodomethane and the reaction was stirred for 16 h, eventually warming to ambient temperature. The reaction was filtered and the filtrate concentrated. The crude product was dissolved in EtOAc, washed sequentially with sat. aq. NaHCO3 (3×), with 1 N HCl (3×), brine (3×), dried (K2CO3) and concentrated. Purification on Biotage KP-Sil eluting with 20% acetone/hexane gave 1.641 g (92%) of the title compound as a yellow oil. 1H NMR (DMSO-d6) δ 2.77-2.80 (m, 2H), 2.88-2.91 (m, 2H), 3.01 (s, 3H), 3.87 (s, 3H), 4.40 (s, 2H), 7.40-7.53 (m, 6H), 7.60-7.62 (m, 4H), 7.90 (s, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.Cl[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12]>[OH-].[Na+].O1CCOCC1>[CH2:14]([O:13][C:11]([N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][CH:4]1[C:7]([OH:9])=[O:8])=[O:12])[CH:15]=[CH2:16]
Reactant: O=C(O)[C@@H]1CC(O)CN1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCOC(=O)N1CC(O)CC1C(=O)O

Procedure:
To a solution of 4-hydroxyproline (0.25M) in 4N sodium hydroxide (78ml), at 0°-5° C., was added allyl chloroformate (0.31M) in dioxan (156 ml) and 4N sodium hydroxide (78 ml). The dioxan solution and sodium hydroxide were added simultaneously, in batches, allowing the temperature to return to below 5° C. after each addition. The mixture was stirred for a further hour, washed with ethyl acetate, acidified (conc. HCl) and extracted into ethyl acetate. The organic phase was washed with brine, dried and evaporated to give 1-allyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid as a viscous syrup. This (0.1M) was treated with 4-methoxybenzyl chloride (0.19M) and triethylamine (0.2M) in DMF (200 ml), under argon, at 70° C. for 10 hours. Ethyl acetate was added and the mixture was washed with water and brine and evaporated to give a gum. This was subjected to medium pressure chromatography (gradient elution with ether to ether/1% methanol) to give 4-methoxybenzyl 1-allyloxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl>[C:6]([O:5][C:1]([NH:2][NH:3][C:16](=[O:18])[CH3:17])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl carbazate (1.0 g, 7.6 mmol) and pyridine (3.1 ml) in methylene chloride (5 ml) was slowly added acetic acid anhydride (1.5 ml) and the mixture was stirred overnight. The mixture was added to methylene chloride (50 ml) and washed with water (2×10 ml) and brine (10 ml) and dried (MgSO4), filtered and concentrated in vacuo to give 0.95 g of N'-acetylhydrazinecarboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:14][CH3:15])[S:9][C:10]=1[C:11](Cl)=[O:12])=[O:5])[CH3:2].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].Cl>ClCCl>[C:16]([NH:20][C:11]([C:10]1[S:9][C:8]([S:14][CH3:15])=[N:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1nc(SC)sc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1nc(SC)sc1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 100.2 %

Procedure:
3.50 g (13.2 mmol) of 4-ethoxycarbonyl-2-methylthiothiazole-5-carboxylic acid chloride was dissolved in 20 ml of dichloromethane and dripped, at 0° C., into a solution of 3.20 g (44 mmol) of tert-butylamine in 50 ml of dichloromethane. The mixture was allowed to warm up to room temperature and was then stirred for 14 hours. 100 ml of 10% strength hydrochloric acid was added and the organic phase was separated, washed with 50 ml of water and dried over sodium sulfate. The solvent was removed under reduced pressure, leaving 4.00 g (100%) of product as a yellow crystalline slurry.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7][CH:6]=[C:5]2[C:17]([CH3:20])([CH3:19])[CH3:18].C([Li])CCC.CN(C)[CH:28]=[O:29]>CCOCC>[C:17]([C:5]1[C:4]2[CH:3]=[C:2]([CH:28]=[O:29])[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:9]=2[C:8]([CH3:16])([CH3:15])[CH2:7][CH:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOc1cc2c(cc1Br)C(C(C)(C)C)=CCC2(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOc1cc2c(cc1C=O)C(C(C)(C)C)=CCC2(C)C
Temperature: -40 °C

Procedure:
To a solution of 6-bromo-4-tert-butyl-7-ethoxy-1,1-dimethyl-1,2-dihydronaphthalene (Compound A-6, 600 mg, 1.78 mmol) in ether (10 mL) at −78° C. was added n-butyllithium (2.3 mL 1.6 M in hexane, 3.9 mmol). After stirring at −78° C. for 25 nm, N,N-dimethylformamide (2 mL) was added and the reaction mixture was allowed to warm to −40° C. over 10 min. The reaction mixture was quenched with water and extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 3% to 10% ethyl acetate in hexane) afforded the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4].[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[CH2:11]([O:13][P:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4])([O:15][CH2:16][CH3:17])=[O:18])[CH3:12]
Reactant: C=C(CBr)c1ccccc1
Reactant: CCOP(OCC)OCC
Product: C=C(CP(=O)(OCC)OCC)c1ccccc1
Temperature: 25 °C

Procedure:
α-(Bromomethyl)styrene was treated with an equimolar ratio of triethylphosphite at reflux for 1 h. After the mixture was cooled to room temperature, the by-product, ethyl bromide, was removed under reduced pressure, and the product α-(diethoxyphosphorylmethyl)styrene was obtained in quantitative yield as a yellowish syrup: 1H NMR (CDCl3) δ 1.20 (6H, t, 2×OCH2CH3, J 7.5 Hz), 3.05 (2H, d, CH2P(O), J 22.5 Hz), 4.00 (4H, m, 2×OCH2CH3), 5.35 (1H, d, olefinic proton, J 6.0 Hz), 5.50 (1H, d, olefinic proton, J 6 Hz), 7.25-7.55 (5H, m, aromatic protons).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=O.Cl.[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][NH2:25])[CH:20]=[CH:19][C:18]=12.N1C=CC=CC=1>C(O)C>[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][N:25]=[C:2]([C:4]3[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH3:12])[CH:5]=3)[CH3:1])[CH:20]=[CH:19][C:18]=12
Reactant: COc1cc(C(C)=O)ccc1F
Reactant: NOCc1ccc2nonc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cc(C(C)=NOCc2ccc3nonc3c2)ccc1F
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of 4-fluoro-3-methoxyacetophenone (0.056 g, 0.332 mmol), (benzo[c][1,2,5]oxadiazol-5-yl)methoxyamine hydrochloride (0.072 g, 0.359 mmol) and pyridine (0.10 ml, 1.24 mmol) in ethanol (5 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a pale yellow oil which was diluted with dichloromethane/water. The resultant mixture was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to a white solid. The crude product was purified by column chromatography (SiO2), eluting with 9:1 petrol/ethyl acetate, to give a 4′-fluoro-3′-methoxyacetophenone-O-[(benzo[c][1,2,5]oxadiazol-5-yl)methyl]oxime (CP9-129) as a white solid (0.078 g, 74%), m.p. 65°.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:32][C:33]([CH3:36])=[N:34][N:35]=2)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)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.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[O:32][C:33]([CH3:36])=[N:34][N:35]=5)[CH:28]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nnc(-c2cccc(I)c2)o1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nnc(C)o4)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 73.1 %

Procedure:
To a solution of the compound from Example 3 (El) (0.125 g, 0.4 mmol) and 1-iodo-3-(5-methyl-[1,3,4]oxadiazol-2-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 2:1 ethyl acetate/hexanes, followed by recrystallization from ethyl acetate/hexanes, provided the title compound as a white solid (0.11 g, 61%), m.p. 117-119° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].[NH3:27]>C(COC)OC.C(OCC)(=O)C>[NH2:27][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19]
Reactant: N
Reactant: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(C#CC3(O)CCCC3)nc21
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Temperature: 70 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
1-{2-[6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl)-1-ethynyl}-1-cyclopentanol (732 g) was dissolved in 16 liters of dimethoxyethane, 8 liters of a concentrated aqueous ammonia were added and the mixture was stirred at 70° C. for 5 hours using a sealed tube reactor. After the reaction solution was cooled in room temperature, it was diluted with 20 liters of ethyl acetate and washed with water twice (8 liters and 4 liters). The organic layer was concentrated to about 15 liters and the resulting residue was diluted with 15 liters of hexane, filtered and washed with hexane twice. Then it was dried at 50° C. for 2.5 hours to give 620 g of the product. The yield was 89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(S(N)(=O)=O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Methyl 2-methoxy-5-sulfamoylbenzoate (4.91 g, 20 mmol) was dissolved in methanol (30 mL). 2 N aqueous sodium hydroxide (30 mL, 60 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N hydrochloric acid, and the separated solid was filtered to give the title compound (4.55 g, 98.3%) as a white solid.