Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:27](=[O:28])[N:26]2[C@@H:22]([CH2:23][C@@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:25]2)[C:21](=[O:37])[NH:20][C@@:19]2([C:38](O)=[O:39])[C@@H:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:53]1([S:56]([NH2:59])(=[O:58])=[O:57])[CH2:55][CH2:54]1.[CH2:60]1[CH2:70][CH2:69]N2C(=NCCC2)CC1>C1COCC1>[CH:53]1([S:56]([NH:59][C:38]([C@@:19]23[CH2:18][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][N:11]([CH:70]2[CH2:60][CH2:69]2)[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:27](=[O:28])[N:26]2[C@@H:22]([CH2:23][C@@H:24]([O:29][Si:30]([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:31])[CH3:32])[CH2:25]2)[C:21](=[O:37])[NH:20]3)=[O:39])(=[O:58])=[O:57])[CH2:55][CH2:54]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CNCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C1=O
Reactant: C1CCC2=NCCCN2CC1
Reactant: NS(=O)(=O)C1CC1
Agent: CC(C)(C)OC(=O)N[C@H]1CN(C2CC2)CCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CNCCC/C=C\[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CN(C2CC2)CCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1S,4R,6S,14S,18R)-7-cis-14-tert-Butoxycarbonylamino-18-(tert-butyldimethylsilyloxy)-2,15-dioxo-3,12,16-triazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (490 mg, 0.79 mmol) was dissolved in 15 mL of THF and treated with CDI (179 mg, 1.10 mmol.). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere.) After refluxing the reaction mixture for two hours, it was cooled to rt and treated sequentially with cyclopropylsulfonamide (134 mg, 1.10 mmol.) and DBU (168 mg, 1.10 mmol.). After stirring overnight at rt, the THF was removed by rotary evaporation. The residue was dissolved in water and 1N HCl was added until the pH=5. This aqueous solution was extracted with EtOAc (3×). The combined EtOAc extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. Purification by flash column, eluting with 3% methanol in methylene chloride, gave 300 mg (53%) of (1S,4R,6S,14S,18R)-[7-cis-4-Cyclopropanesulfonylaminocarbonyl-12-cyclopropyl-18-(tert-butyldimethylsilyloxy)-2,15-dioxo-3,12,16-triaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]carbamic acid, tert-butyl ester as a white solid: LC-MS (Phenomenex 10 μm C18 HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nM. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 2.40 min), MS m/z 724 (M++1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][N:27]=1.CS(C)=O>CN(C=O)C>[ClH:25].[CH3:37][O:36][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][C:32]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:29]=[CH:28][N:27]=[C:26]2[CH:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([S:10]([NH:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:12])=[O:11])[CH:14]=2)[NH:18][C:17]1=[O:22]
Reactant: O=C1Cc2cc(S(=O)(=O)NCCN3CCOCC3)ccc2N1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COCCOc1cc2ncnc(C3C(=O)Nc4ccc(S(=O)(=O)NCCN5CCOCC5)cc43)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 5-(2-morpholinoethylaminosulphonyl)oxindole (363 mg, 1.1 mmol) in DMF (3 ml) was added dropwise to a suspension of sodium hydride (89 mg, 2.2 mmol, prewashed with hexane) and the mixture stirred for 30 minutes at ambient temperature. 4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (100 mg, 0.37 mmol), (prepared as described for the starting material in Example 2), was added and the mixture heated at 50° C. for 30 minutes. DMF (5 ml) and DMSO (1.5 ml) were added and the mixture heated at 60° C. for 45 minutes, the volatiles were removed by evaporation and the residue was partitioned between methylene chloride and saturated aqueous ammonium chloride solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60/35/5 followed by 60/30/10). The purified product was triturated with ether, collected by filtration and dried under vacuum. The solid was dissolved in methylene chloride/methanol and SM ethereal hydrogen chloride (1.5 ml) was added. The mixture was stirred for 30 minutes at ambient temperature, the volatiles were removed by evaporation and the solid residue was triturated with ether, collected by filtration and dried under vaccum to give 6-methoxy-7-(2-methoxyethoxy)4-(5-(2-morpholinoethylaminosulphonyl)oxindol-3-yl)quinazoline hydrochloride (110 mg, 46%).
Reaction SMILES: CS(O)(=O)=[O:3].[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:42]=[CH:41][C:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([NH:28][C:29]4[N:34]=[C:33]([C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)[CH:32]=[CH:31][N:30]=4)[CH:22]=3)=[O:19])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1.[OH-:43].[Na+]>OO>[CH3:6][N+:7]1([O-:3])[CH2:12][CH2:11][N+:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([NH:28][C:29]4[N:34]=[C:33]([C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)[CH:32]=[CH:31][N:30]=4)[CH:22]=3)=[O:19])=[CH:41][CH:42]=2)([O-:43])[CH2:9][CH2:8]1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CS(=O)(=O)O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Product: Cc1ccc(NC(=O)c2ccc(C[N+]3([O-])CC[N+](C)([O-])CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 20 °C
Reaction time: 160 h

Procedure:
4-[(4-Methyl-1-piperazinyl)-methyl]-N-{4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl}-benzamide monomethanesulphonate (3.00 g, 5 mmol; prepared as described in WO 99/03854) is added to aqueous hydrogen peroxide (30 mL of 3%) and the resulting solution is stirred at 20° C. for 160 h. The pH of the solution is then adjusted to pH 14 with aqueous sodium hydroxide (4 M) and the resulting suspension is stirred for 1.5 h. The crude product is filtered off, washed with water, dried and purified by column chromatography on silica gel, eluent 25% aqueous ammonia-ethanol-dichloromethane (5:30:70), to give the title compound as a yellow crystalline solid, m.p. 242-244° C.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[CH3:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[NH2:9].O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:9][C:8]1[CH:10]=[C:11]([CH3:13])[C:12]([S:1][C:2]#[N:3])=[C:6]([CH3:5])[CH:7]=1
Reactant: N#C[S-]
Reactant: Cc1cc(C)cc(N)c1
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N)cc(C)c1SC#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
251.2 g (3.30 mol) of ammonium thiocyanate are rapidly added to a solution, maintained under a nitrogen atmosphere, of 121.2 g (1 mol) of 3,5-dimethylaniline in 1.75 l of anhydrous N,N-dimethylformamide. The temperature rises from 18 to 35° C. One and a half hours later, the temperature of the solution having returned to room temperature, 263.3 g (1.65 mol) of anhydrous cupric sulphate are added rapidly. The reaction medium is left stirring at room temperature for 3 days and is then poured into 8 l of water. The pH is brought to 7.5 by addition of 550 g (6.55 mol) of sodium bicarbonate. The medium is then filtered, the solid part being washed with ethyl acetate and the liquid part being extracted with ethyl acetate. The combined organic liquid phases are washed with 500 ml of water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The pasty residue obtained is crystallized from 500 ml of hexane to give 128.8 g (72%) of 4-amino-2,6-dimethylphenyl thiocyanate which is used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C)C=O>[CH2:24]([N:12]1[CH2:13][CH2:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:11]1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: COc1cccc(C2=CCCNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCC=C(c2cccc(OC)c2)C1
Reaction time: 6 h
Yield: 83 %

Procedure:
A mixture of 7 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine hydrochloride, 100 ml of dimethylformamide, 9.8 g of sodium carbonate and 3.75 g of allyl bromide was stirred for 6 hours and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 7-3 benzene-ethyl acetate mixture yielded 5.9 g of 1-allyl-3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[CH2:19]([O:26][C:27]([C:29]1([NH:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)C=C>O1CCCC1>[CH2:19]([O:26][C:27]([C:29]1([NH:35][CH:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:3][CH:1]=[CH2:2])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)CNC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C=CCBr
Product: C=CCC(NC1(C(=O)OCc2ccccc2)CCCCC1)C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (3.03 mL, 21.6 mmol) in dry tetrahydrofuran (75 mL) at -78° C. was added a 2.38M solution of n-butyllithium in hexane (9.07 mL, 21.6 mmol). After 10 minutes, a solution of 1-(tert-butoxycarbonylmethylamino)cyclohexanecarboxylic acid benzyl ester (5.0 g, 14.4 mmol) in tetrahydrofuran (25 mL) was added and the resulting mixture was allowed to warm to -40° C. over 2.5 hours. The mixture was again cooled to -78° C. and allyl bromide was added. The mixture was allowed to warm to 0° C. over 4 hours while stirring and was quenched by addition of a saturated aqueous solution of ammonium chloride. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and evaporated under vacuum to afford an oil. The oil was chromatographed on silica gel eluting with 1% ethyl acetate in methylene chloride to give 1-(1-tert-butoxycarbonylbut-3-enylamino)cyclohexanecarboxylic acid benzyl ester as an oil, 2.0 g (36%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6].Cl.[CH2:16](C(=N)OCC)[CH3:17]>C(O)(=O)C>[CH3:16][C:17]1[N:11]([CH2:12][CH2:13][CH3:14])[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=N)CC
Reactant: CCCNc1ccc(C(=O)O)cc1N
Agent: Cl
Solvent: CC(=O)O
Product: CCCn1c(C)nc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4.5 parts of 3-amino-4-(propylamino)-benzoic acid, 2.6 parts of ethyl ethanecarboximidate hydrochloride and 50 parts of acetic acid is stirred first for 20 minutes at room temperature and further for 10 minutes at reflux. The reaction mixture is evaporated. The residue is crystallized from 2-propanol. The product is filtered off, washed with water and 2-propanol and dried, yielding 1.8 parts of 2-methyl-1-propyl-1H-benzimidazole-5-carboxylic acid; mp.<260° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=C(C3C=CC(OC)=CC=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[CH:21]([C:24]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=O)([CH3:23])[CH3:22]>>[Br:1][C:2]1[C:7]2[N:8]=[C:26]([C:25]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:24]=3[CH:21]([CH3:23])[CH3:22])[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cccc(C(=O)Cl)c1C(C)C
Reactant: COc1ccc(-c2nc3c(Br)cc(OC)cc3s2)cc1
Product: COc1cc(Br)c2nc(-c3cccc(OC)c3C(C)C)sc2c1

Procedure:
The procedure was the same with 4-bromo-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole except using 2-isopropyl-3-methoxy-benzoyl chloride instead of p-anisoyl chloride. Mass spec: MH+=392.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.CS(OS(C)(=O)=O)(=O)=O.CC(=O)OCC.[N:27]1([C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=2[C:35]#[N:36])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:30]1[CH2:29][CH2:28][N:27]([C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=2[C:35]#[N:36])[CH2:32][CH2:31]1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: OCc1cc2ccccc2s1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccccc1N1CCN(Cc2cc3ccccc3s2)CC1

Procedure:
The product from Example 8A (150 mg 0.9 mmol), methane sulfonic anhydride (159 mg, 0.9 mmol), and D1 EA (475 μL 2.7 mmol) were combined. After stirring, 2-(1-piperazinyl)benzonitrile (181 mg, 1.0 mmol) in 2 ml DCM was also combined and stirred at room temperature for 18 hours. The mixture was concentrated and the residue was taken up in hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 2.69 (m, 4H) 3.04 (s, 4H) 3.76 (m, 4H) 3.86 (s, 1H) 6.74 (m, 2H) 7.29 (m, 3H) 7.75 (m, 1H); (ESI) m/z 334 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:25])[CH3:24])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[Cl:26]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:22][C:23](=[O:25])[CH3:24])=[C:8]2[C:16]([Cl:26])=[CH:15][N:14]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2CCC(C)C)c1OC(C)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2CCC(C)C)c1OC(C)=O
Yield: 55.8 %

Procedure:
A solution of 4-acetoxy-7-cyano-1-(3-methyl-butyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (0.44 g, 1.28 mmol) and N-chlorosuccinimide (0.188 g, 1.41 mmol) in 8 mL of N,N′-dimethylformamide was heated at 100° C. for 1 h. Ethyl acetate (100 mL) was added. The organic solution was washed with water, dried over anhydrous sodium sulfate, and concentrated. The crude produce was purified by flash chromatography from silica gel with a gradient of 0-40% ethyl acetate in hexanes to afford 0.27 g of the title compound as a white solid. MS: (+) m/z 378.3 (M+1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[CH2:61]([Cl:63])[Cl:62]>>[NH3:1].[CH2:61]([Cl:63])[Cl:62].[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:22][CH2:23][CH2:24][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(CN2CCCCC2)cc1
Reactant: CC1CCCCN1CCCO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1CCCCN1CCCOc1ccc(CN2CCCCC2)cc1
Product: N
Reaction time: 2 h

Procedure:
A suspension of the product of Example 17 (176 mg), 3-(2-methyl-piperidin-1-yl)-propan-1-ol (145 mg), and polymer supported triphenylphosphine (613 mg; loading: 3 mmol/g) in DCM (5 mL) was treated with di-tert-butylazodicarboxylate (316 mg). After 2 h, the resulting mixture was filtered, and the filtrate was evaporated. Chromatography of the residue (2.5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (60 mg). 1H NMR (400 MHz, CDCl3): 7.20 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 4.01-3.92 (m, 2H), 3.40 (s, 2H), 2.90-2.81 (m, 2H), 2.56-2.47 (m, 1H), 2.40-2.25 (m, 5H), 2.21-2.14 (m, 1H), 1.97-1.88 (m, 2H), 1.70-1.51 (m, 8H), 1.45-1.25 (m, 4H), 1.07 (d, J=6.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=1.C(N(CC)CC)C>CCO>[Cl:9][C:10]1[N:11]=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:13]=[C:14]([N:4]2[CH2:5][CH2:6][O:7][C:2]([CH3:8])([CH3:1])[CH2:3]2)[CH:15]=1
Reactant: CC1(C)CNCCO1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2cc(Cl)nc(N3CCOCC3)n2)CCO1
Temperature: 110 °C

Procedure:
A mixture of 2,2-dimethylmorpholine (2.0 equiv.), 4-(4,6-dichloropyrimidin-2-yl)morpholine (1 equiv.) and triethylamine (6 equiv.) in EtOH (0.2 M) were heated to 110° C. for 25 min in the microwave. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over sodium sulfate. The resulting solution was concentrated and dried under vacuo to give 4-(6-chloro-2-morpholinopyrimidin-4-yl)-2,2-dimethylmorpholine and was used in the next step without further purification. LCMS (m/z) (M+H)=313.2, Rt=0.86 min.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH:12]([CH2:13][C:14]3[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=3)[O:11]C(=O)[NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Li+].[OH-].CO.O.O>[CH:1]1([CH2:7][C@H:8]([NH2:9])[CH:12]([OH:11])[CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ccnc1CC1OC(=O)N[C@H]1CC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ccnc1CC(O)[C@@H](N)CC1CCCCC1

Procedure:
790 mg of 4(S)-cyclohexylmethyl-5(R,S)-(1-methylimidazol-2-yl-methyl)-1,3-oxazolidin-2-one are dissolved in 33 ml of 2N LiOH in MeOH/H2O 1:1; and the solution is heated under reflux for 3 h, then diluted with 150 ml of water and extracted 3 times with 50 ml of CH2Cl2. Drying with Na2SO4 and concentration in vacuo results in the title compound as colorless oil which is used further without purification.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[C:20]=1[Br:25]>CO.C(Cl)(Cl)Cl>[Br:25][C:20]1[C:21]([CH3:24])=[N:22][O:23][C:19]=1[NH:18][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Reactant: Cc1noc(N)c1Br
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl) thiophene-2-sulfonamide was prepared in the same manner as described in Example 10. Reaction of 5-chlorosulfonyl-2-(4-ethylphenyl) thiophene (47.1 mg, 11.16 mmol) with 5-amino-4-bromo-3-methyl isoxazole (29 mg, 0.1 6 mmol) yielded, after flash chromatography using 10% MeOH/CHCl3, a pale brown solid (46 mg, 66% yield), m.p. 172-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.[C:36]1([CH:42]([OH:45])[CH2:43][CH3:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:25](=[O:27])[O:45][CH:42]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:43][CH3:44]
Reactant: CCC(O)c1ccccc1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl)c1ccccc1
Yield: 57.8 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1- phenyl-1-propanol (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (43 mg, yield 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:13]([O:15]C)=[O:14])[C:9](OC)=[O:10])=[C:5]([N+:19]([O-])=O)[CH:4]=1.[H][H]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:7][CH:8]([C:13]([OH:15])=[O:14])[C:9](=[O:10])[NH:19]2)=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: COC(=O)C(Cc1ccc(OC)cc1[N+](=O)[O-])C(=O)OC
Solvent: CCO
Product: COc1ccc2c(c1)NC(=O)C(C(=O)O)C2
Temperature: 80 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
A solution of dimethyl (4-methoxy-2-nitrobenzyl)malonate (19 g) in ethanol (200 ml) was hydrogenated in the presence of 10% palladium-C (2.0 g) at room temperature under one atmosphere of hydrogen for 24 hr. The reaction mixture was further stirred at 80° C. for 24 hr and the catalyst was removed by filtration. The filtrate was concentrated. The residue was dissolved in the combined solvent of THF (250 ml) and methanol (250 ml) and 1 N aqueous sodium hydroxide (126 ml) was added in an ice bath. The reaction mixture was stirred at room temperature for 72 hr and concentrated. The residue was made acidic by adding 1 N aqueous hydrochloric acid and the precipitate was collected by filtration. The crude crystals were washed with acetone to obtain the titled compound (11.7 g).
Reaction SMILES: [C:1]([C:3]([CH2:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]=1[N+:25]([O-:27])=[O:26])([CH2:7][CH2:8][CH:9]=[CH2:10])C(O)=O)#[N:2].CCCCCCC.C(OCC)(=O)C>CC(N(C)C)=O>[N+:25]([C:13]1[CH:14]=[CH:15][C:16]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][C:12]=1[CH2:11][CH:3]([CH2:7][CH2:8][CH:9]=[CH2:10])[C:1]#[N:2])([O-:27])=[O:26]
Reactant: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(=O)N(C)C
Product: C=CCCC(C#N)Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
To a round bottom flask equipped with a stir bar, condenser, and a nitrogen inlet 2-cyano-2-(2-nitro-5-phenoxy-benzyl)-hex-5-enoic acid (4.0 g, 10.92 mmol) was added and dissolved in dimethylacetamide (10 mL). The solution was heated to 150° C. for 3 hours. The reaction mixture was allowed to room temperature, then the solvent was removed under reduced pressure. The resulting crude product was dissolved in ethyl acetate and washed 3 times with 1N HCl followed by one wash with saturated brine solution. The organic layer was separated and dried with anhydrous sodium sulfate and the solvent was removed to yield crude material. The crude material was subjected to flash chromatography (mobile phase 9:1 heptane:ethyl acetate) to yield a yellow oil.