Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]12[CH2:34][C:30]([CH2:35]O)([CH2:31][CH2:32][CH2:33]1)[CH2:29][CH2:28][CH2:27]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:26]12[CH2:34][C:30]([CH2:35][O:7][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=3[O:12][CH3:13])([CH2:31][CH2:32][CH2:33]1)[CH2:29][CH2:28][CH2:27]2
Reactant: OCC12CCCN(CCC1)C2
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(N)c(Cl)cc1C(=O)OCC12CCCN(CCC1)C2
Reaction time: 1 h
Yield: 57.3 %

Procedure:
A solution of 4-amino-5-chloro-2-methoxybenzoic acid (2.02 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.70 g, 10.5 mmol), stirred for one hour, then degassed with a stream of nitrogen over 10 minutes. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.3.1]nonane-5-methanol (1.71 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (10.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The above prepared suspension was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated in vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little 2-propanol and saturated aqueous sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo and recrystallized from acetonitrile (2 crops) to afford 1.94 g (57%) of pale yellow solid; mp 152.5°-154.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]([OH:22])=O)=[N:10]2)=[CH:5][CH:4]=1.[N:23]([CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)=[N+:24]=[N-:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:12][C:11]([C:20]([N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]3[CH2:27][CH2:26][N:23]=[N+:24]=[N-:25])=[O:22])=[N:10]2)=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=NCCC1CCCCN1
Reactant: COc1ccc(-n2nc(C(=O)O)cc2-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)N3CCCCC3CCN=[N+]=[N-])cc2-c2ccccc2)cn1
Reaction time: 14 h

Procedure:
1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carboxylic acid (191 mg) obtained from Referential Example 41, 2-(2-azidoethyl)piperidine (100 mg) obtained from Referential Example 80, 1-hydroxybenzotriazole (88 mg), and triethylamine (316 μL) were dissolved in methylene chloride (10 mL). To the resultant mixture, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (186 mg) was added at room temperature, followed by stirring for 14 hours. The residue obtained by removal through evaporation of the reaction solvent under reduced pressure was partitioned between water and ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The residue obtained by removal through evaporation of the solvent under reduced pressure was purified through silica gel thin-layer chromatography (hexane-ethyl acetate), to thereby give the title compound as an oily product (227 mg, 81%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH2:16][NH:17]C(OC(C)(C)C)=O)[O:13][N:12]=2)=[CH:3]1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH2:16][NH2:17])[O:13][N:12]=2)=[CH:3]1
Reactant: Cn1cc(-c2noc(CNC(=O)OC(C)(C)C)n2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2noc(CN)n2)c2ccccc21
Temperature: 25 °C

Procedure:
1-Methyl-3-[5-t-butoxycarbonylaminomethyl-1,2,4-oxadiazol-3-yl]indole (300mg) was dissolved in CH2Cl2 (10 ml) at 0° C., trifluoroacetic acid (0.5 ml) was then added and the reaction mixture allowed to warm to room temperature over 30 mins. The reaction mixture was stirred at room temperature for twelve hours before evaporation at reduced pressure. The residue was recrystallised from cold CH2Cl2 to afford white crystals (150 mg) mp 178° C.; Found C, 48.74; H, 3.74; N 15.97 C14H13N4O3F3 requires C, 49.13; H, 3.83; N, 16.37%; δH (360 MHz, DMSO), 3.92 (3 H, s, NMe), 4.58 (2 H, s, CH2N), 7.24-7.35 (2 H, m, H-5, H-6), 7.60 (1 H, d, J=7, H-4), 8.07 (1 H, d, J=7, H-7), 8.10 (1 H, s, H-2); M/Z 228 (M+, free base 70%), 171(100), 156(80).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[S:23]1[C:27]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)=[CH:26][N:25]=[CH:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:32][C:31]4[CH:30]=[CH:29][C:28]([C:27]5[S:23][CH:24]=[N:25][CH:26]=5)=[CH:35][CH:34]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1ccc(-c2cncs2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccc(-c5cncs5)cc4)c23)c1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 567 mg (3.0 mmol) of 4-(thiazol-5-yl)-benzaldehyde to form 4-(3-chloro-phenylamino)-3-[{4-(thiazol-5yl)-phenyl}-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H, analogous working-up and digestion in diethyl ether yield 4-(3-chloro-phenylamino)-3-[4-(thiazol-5-yl)-benzylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p. 235° C.; TLC: Rf=0.42 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=8.5; FABMS: (M+H)+=434.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[OH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[C:8]#[N:9].[OH-].[Na+].C(=O)=O>O.COCCOC>[F:3][CH:2]([F:4])[O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(O)cccc1F
Reactant: FC(F)Cl
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1c(F)cccc1OC(F)F
Reaction time: 1 h

Procedure:
6.3 g of chlorodifluoromethane were passed into a stirred mixture of 10.0 g of 2-hydroxy-6-fluorobenzonitrile, 50 ml of 1,2-dimethoxyethane and 25 ml of NaOH (33%) at 75° C. (the reflux condenser was cooled with dry ice), and stirring was continued for one hour at 70-75° C. After cooling, the batch was diluted with 300 ml of water and extracted three times using in each case 150 ml of tert-butyl methyl ether. After the solvent had been vaporated, 6.5 9 of the desired product were obtained as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]([NH:28]C(=O)OC(C)(C)C)([CH3:27])[CH3:26])=[CH:19][CH:18]=1>ClCCl>[CH3:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[C:10]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]([CH3:26])([CH3:27])[NH2:28])=[CH:19][CH:18]=1
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl [2-({6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 79, 202.1 mg) was dissolved in dichloromethane (2 mL) to give a pale yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The solvent was evaporated under vacuum to afford a yellow oil which was charged on a 5 g SCX cartridge. It was then flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (144.4 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[C:5]([O:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH3:24]
Reactant: CCOC(=O)CCc1cc(O)ccc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.65 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (0.46 g), anhydrous potassium carbonate (0.30 g) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over, anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.89 g, 95%) of 3-[2-ethoxy-5-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 136-137° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([C:11]([CH3:13])=[CH2:12])[C:6]=2[CH:14]=1.C[O-].[Na+].[O:18]1[CH2:20][CH2:19]1>C(O)C>[OH:18][CH2:19][CH2:20][N:9]1[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:6]=2[N:7]([C:11]([CH3:13])=[CH2:12])[C:8]1=[O:10]
Reactant: C=C(C)n1c(=O)[nH]c2ccc(C)cc21
Reactant: C1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C=C(C)n1c(=O)n(CCO)c2ccc(C)cc21
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred mixture of 37.6 parts of 1,3-dihydro-6-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one, 2 parts of sodium methoxide solution 30% and 320 parts of absolute ethanol is added a solution of 22 parts of oxirane in 40 parts of absolute ethanol. Stirring is continued first overnight at room temperature and further for 3 hours at reflux. The ethanol is evaporated, yielding 46 parts (100%) of 1,3-dihydro-1-(2-hydroxyethyl)-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[S:12][C:11]([S:13]([NH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:47]([O:55][CH3:56])(=[O:54])[CH2:48][CH2:49][CH2:50][C:51]([O-])=[O:52].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:51](=[O:52])[CH2:50][CH2:49][CH2:48][C:47]([O:55][CH3:56])=[O:54])[S:3][C:4]=1[C:8]1[S:12][C:11]([S:13]([NH:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:15])=[O:14])=[CH:10][CH:9]=1
Reactant: Cc1nc(N)sc1-c1ccc(S(=O)(=O)NCCN2CCOCC2)s1
Reactant: COC(=O)CCCC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CCCC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCCN3CCOCC3)s2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.3 %

Procedure:
To a degassed solution of 5-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-(2-morpholin-4-ylethyl)thiophene-2-sulfonamide (6) (100 mg; 0.22 mmol; 1 eq) in anhydrous THF (10 ml), N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (104.4 mg; 0.33 mmol; 1.50 eq), mono-methyl glutarate (68 μl; 0.54 mmol; 2.50 eq) and N,N-diisopropylethylamine (148 μl; 0.87 mmol; 4 eq) are added successively. The reaction mixture is stirred at room temperature for three days. Solvents are evaporated under vacuum. The resulting crude product is dissolved in EtOAc and washed with NH4Cl sat. solution, water, brine and dried over MgSO4. After evaporation of the solvents, the crude product is purified by flash chromatography (CH3C1/MeOH gradient from 1/0 to 1/1 over 40 min), affording Compound (7) as a yellow solid (68.5 mg; 61.18%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:19])=O>C1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCOCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: O=C(Cl)CCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the acid 29 (4.98 g, 24 mmol) in dry benzene (40 ml), was added oxalyl chloride (2.5 ml, 28.8 mmol, 1.2 equiv) dropwise. A drying tube was placed on the flask and the reaction was stirred for 90 min at room temperature. The reaction was concentrated in vacuo and used directly in the next step: 1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (m, 5H), 4.50 (s, 2H), 3.51-3.40 (t, 3J=6.4 Hz, 2H), 2.95-2.90 (t, 3J=7.2 Hz, 3H), 1.87-1.78 (m, 2H), 1.71-1.63 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 173.958, 138.519, 128.949, 128.787, 128.630, 127.862, 73.197, 69.551, 47.032, 28.618, 22.329.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=2[C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:5]([CH3:28])[CH:4]=1.C1C(=O)N([Br:36])C(=O)C1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:28][C:5]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=2[C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:7]([CH2:9][Br:36])[CH:8]=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C(=O)c2cc(C#N)ccc2-c2c(C)cc(OC)cc2C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=O)c2cc(C#N)ccc2-c2c(C)cccc2CBr)cc1
Yield: 93.6 %

Procedure:
To a refluxing solution of the compound from Step D (45.5 g, 122 mmol) and AIBN (1.0 g) in CCl4 (2.5 L) was added a mixture of NBS (23.0 g, 129 mmol) and AIBN (1.0 g) in ten equal portions. The reaction mixture was refluxed for 2 h after the addition of the last portion of NBS/AIBN. The reaction mixture was concentrated to approximately 1 L and washed 3 times with water (1 L). The organic layer was dried with anhydrous Na2SO4, filtered and the solvent removed. Toluene (200 ml) was added to the residue and then evaporated. Repeating this procedure gave 48 g of the title compound that was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH:7]=[CH:8][C:9](O)=[S:10])[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[CH2:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH:7]=[CH:8][C:9]([Cl:24])=[S:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccccc1C=CC(O)=S
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCc1ccccc1C=CC(=S)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methylene chloride (564 ml) is added to 2-n-butylthiocinnamic acid (40.0 g, 0.69 mol) and cooled in an ice bath. To the mixture is added DMF (13.1 ml, 0.169 mol) and then oxalyl chloride (34.0 ml, 0.389 mol) dropwise with the vigorous evolution of gas. After the oxalyl chloride addition is complete, the ice bath is removed and the reaction stirred at room temperature for 2 hours to afford 2-n-butylthiocinnamic acid chloride. Methylhydroxylamine hydrochloride salt (56.5 g, 0.677 mol) is dissolved in THF (50 ml) and water (70 ml) and further THF (96 ml) is added. The acid chloride is added dropwise then stopped so an additional THF (175 ml) and water (35 ml) can be added for solubility. The acid chloride addition is then continued with the reaction mixture being cooled in an ice bath. After the addition is complete, the reaction mixture is stirred at room temperature overnight.
Reaction SMILES: ClCl.[CH3:3][S:4][CH3:5].[C:6]12([O:16][C:17]3[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=3)[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.C(N(CC)CC)C>C(Cl)Cl>[C:6]12([O:16][C:17]3[CH:18]=[CH:19][C:20]([NH2:21])=[C:22]([CH2:3][S:4][CH3:5])[CH:23]=3)[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2
Reactant: CSC
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Agent: ClCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1cc(OC23CC4CC(CC(C4)C2)C3)ccc1N
Temperature: 25 °C

Procedure:
To 6.2 g. (0.088 mole) of chlorine in 240 ml. of CH2Cl2 in a one-liter 3-neck flask cooled to -70° to -73° was added dropwise with stirring a cold (~-70°) solution of 5.7 g. (0.092 mole) of dimethyl sulfide in 20 ml. of CH2Cl2. The solution was stirred for several minutes, and then a solution of 21.4 g. (0.088 mole) of 4-(1-adamantyloxy)-aniline and 8.9 g. (0.088 mole) of triethylamine in 400 ml. of CH2Cl2 cooled either to -70° or to -40° to -50° was added dropwise rapidly. Then the mixture was either stirred at -70° and gradually allowed to warm to room temperature during four hours and then cooled again to -65° or it was stirred at -70° for two hours followed in either case by the addition of 51.8 g. of 25% sodium methoxide in methanol solution, removal of the cold bath, and stirring at room temperature for 12 to 18 hours.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17]C(=O)O[C:13]2=[O:14]>>[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[C:13]([NH:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4])=[O:14]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: N[C@H](CO)Cc1ccccc1
Product: Nc1ccccc1C(=O)N[C@H](CO)Cc1ccccc1

Procedure:
The product was prepared by the method of procedure 1a from 5 g (S)-(-)-2-amino-3-phenyl-1-propanol and isatoic anhydride. 3.6 g of the product were obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:32]=[C:20]1[CH2:21][C:22]([C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[C:30]#[N:31])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)=[CH:10][C:9]=2[NH:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccsc4)cc3NC(=O)C2)c1

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-thiophen-3-yl-phenyl}-carbamic acid tert.-butyl ester (Example K4) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige solid (54 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH:4]=[CH2:5].N1C=CN=C1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:26]([O:1][CH2:2][C@@H:3]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH:4]=[CH2:5])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(1-hydroxybut-3-en-2-yl)isoindoline-1,3-dione (Intermediate 1, 69.4 g, 319.49 mmol) and imidazole (26.1 g, 383.39 mmol) in methylene chloride (160 mL), at ambient temperature under an atmosphere of nitrogen, was added tert-butyldimethylchlorosilane (55.4 g, 367.41 mmol) as a solid. This addition was performed over approximately ten minutes. Warming of the mixture was observed during this addition. After two hours stirring, the solution was poured into a saturated solution of aqueous sodium bicarbonate (approximately 150 mL); this biphasic mixture was shaken, and the organic layer was separated. The aqueous layer was back-extracted three times with 200 mL methylene chloride each time. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The desired product was obtained as a pale yellow solid after drying overnight under high vacuum (107 g, 101%).
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[CH2:13][CH2:12][C:9]2([O:11][CH2:10]2)[CH:8]([C:14]2([CH3:22])[CH:16]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[O:15]2)[CH:7]1[O:23][CH3:24])([OH:3])=O.C(N(CC)CC)C.C(C(Cl)=O)(C)(C)C.[CH2:39]([NH2:42])[CH2:40][CH3:41]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:24][O:23][CH:7]1[CH:6]([O:5][CH2:4][C:1](=[O:3])[NH:42][CH2:39][CH2:40][CH3:41])[CH2:13][CH2:12][C:9]2([O:11][CH2:10]2)[CH:8]1[C:14]1([CH3:22])[CH:16]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[O:15]1
Reactant: COC1C(OCC(=O)O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: CCCN
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)COC1CCC2(CO2)C(C2(C)OC2CC=C(C)C)C1OC
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a mixture of 6-carboxymethoxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]-octane (9.0 mg), triethylamine (2.5 mg), and 4-dimethylaminopyridine (0.6 mg) in dichloromethane (1 ml) was added dropwise tert-butylcarbonyl chloride (3.5 mg) under ice cooling. The mixture was stirred for half an hour at ambient temperature and propylamine (2.9 mg) was added. After stirred for 2 hours at the same temperature, the solution was washed with water, aqueous HCl solution, saturated aqueous NaHCO3 solution, and brine successively. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (diethyl ether-ethyl acetate =1-1) to give 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-propylcarbamoylmethoxy-1-oxaspiro[2,5]octane (7.6 mg).