Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([C:15]([O-:17])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]=[C:53]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58]>ClCCl>[CH3:67][C:65]([CH3:68])([O:64][C:63]([NH:62][C:53]([NH:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][NH:43][C:15](=[O:17])[CH:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:54][C:55]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:61])=[O:69])[CH3:66]
Reactant: CC(C)(C)OC(=O)NC(=NCCCCCCCCN)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(OCc1ccccc1)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)C(OCc1ccccc1)C(=O)NCCCCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
2.6 g (10.9.10-3 mol) of ethyl 2-phenylmethoxypropanedioate are dissolved in 50 ml of dichloromethane and the mixture is cooled to 0° C. 4.34 g (22.10-3 mol) of N,N'-dicyclohexylcarbodiimide and 0.57 g (4.10-3 mol) of 1-hydroxybenzotriazole are added, the mixture is stirred for 0.5 hour, a solution of 4.21 g (10.9. 10-3 mol) of bis(1,1-dimethylethyl) [[(8-aminooctyl)imino]methylene]biscarbamate in 15 ml of dichloromethane is then added and the mixture is stirred at room temperature for 48 hours. The reaction medium is concentrated under reduced pressure and the residue is then purified by chromatography on silica using a methylcyclohexane/ethyl acetate mixture (7/3) as the eluent to give 2.7 g (yield=40.8%) of the expected product in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].I[CH2:10][CH2:11][CH2:12][CH:13]1[S:17][C:16]2[C:18]([CH3:28])=[C:19]([O:24][CH2:25][O:26][CH3:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1.O>CN(C)C=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][CH2:10][CH2:11][CH2:12][CH:13]1[S:17][C:16]2[C:18]([CH3:28])=[C:19]([O:24][CH2:25][O:26][CH3:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1
Reactant: COCOc1c(C)c(C)c2c(c1C)SC(CCCI)O2
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1c(C)c(C)c2c(c1C)SC(CCCOCCN(C)C)O2
Temperature: 50 °C

Procedure:
210 mg of 2-dimethylaminoethanol were dissolved in 3 ml of dimethylformamide, and then 100 mg of a 50% w/w oily suspension of sodium hydride were added to the solution. This reaction mixture was then heated for 1 hour at 50° C. The reaction mixture was then cooled with ice, and a solution of 900 mg of 2-(3-iodopropyl)-5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 86) in 2 ml of dimethylformamide was added dropwise, while stirring. After completion of the dropwise addition, the temperature of the reaction mixture was gradually raised, and then the mixture was heated for a further 2 hours at 50° C. The reaction mixture was then poured into water, and the resulting precipitate was extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure. The residual crude oily reaction product was separated by silica gel column chromatography. The fraction eluted with benzene was removed, while the fraction eluted with a 20:1 by volume mixture of ethyl acetate and triethylamine was subjected to silica gel Lobar column chromatography, eluted with the same eluent, to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[OH:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:16]=[CH:15][CH:14]=[C:4]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Reactant: OB(O)c1ccc(O)cc1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(O)cc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 2 using tert-butyl N-(3-bromobenzyl)carbamate instead of tert-butyl N-(4-bromobenzyl)carbamate and 4-hydroxyphenylboronic acid instead of 3-benzyloxyphenylboronic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)cc1C
Temperature: 25 °C

Procedure:
After 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml and with saturated sodium bicarbonate solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The crude extract was dissolved in hexane 10 ml and ethyl acetate 5 ml, and the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 321.6 mg.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>>[N+:8]([C:7]1[C:2]([O:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: OC1CCOCC1
Reactant: O=[N+]([O-])c1cccnc1F
Product: O=[N+]([O-])c1cccnc1OC1CCOCC1

Procedure:
Prepared analogously to I.1 from 2-fluor-3-nitropyridine and tetrahydro-pyran-4-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C@@H:6]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])[CH2:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)([O-:41])=[O:40].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:39]([C:42]1[CH:43]=[CH:44][C:45]([C:46]([O:17][C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[C@@H:6]([CH2:7][N+:8]([O-:10])=[O:9])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:47])=[CH:49][CH:50]=1)([O-:41])=[O:40]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])C[C@@H](c1ccc(Cl)cc1)[C@H]1CCCC[C@H]1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CCCC[C@H]1[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
9.1 g (32.1 mmol) of rac-(1S*)-cis-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexanol, 16.8 g (64.2 mmol) of triphenylphosphine and 10.8 g (64.2 mmol) of p-nitrobenzoic acid are dissolved in 180 ml of tetrahydrofuran. To this solution is added dropwise with 30 minutes a solution of 11.3 g (64.2 mmol) of diethyl azodicarboxylate in 80 ml of tetrahydrofuran and the mixture is subsequently stirred at room temperature for 5 hours. After distilling off the solvent the residue obtained is chromatographed on a 30-fold amount of silica gel while eluting with toluene/hexane (1:2). By recrystallization of the product obtained from methylene chloride/hexane there is obtained rac-(1R*)-trans-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexyl p-nitrobenzoate in the form of colourless crystals of m.p. 146°-148°.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([O:13]CC)=[O:12].Cl>[OH-].[Na+]>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1cnc2n(c1=O)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc2n(c1=O)CCC2
Yield: 66.7 %

Procedure:
10.4 g of ethyl 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate are dissolved in 50 ml of a 5% by W/V sodium hydroxide solution and after two hours the pH of the reaction mixture is adjusted to 2.5 with 36% by W/V hydrochloric acid solution. The precipitated crystals are filtered and washed with a small amount of cold water. 6.0 g (66.7%) of 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylic acid are obtained, melting at 146° to 148° C. (decomposition).
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)C.CI.[CH2:16]=[CH:17][CH:18]=[CH2:19]>C(OCC)(=O)C>[CH3:13][C:7]1[C:8](=[O:12])[C:9]([CH3:11])=[CH:10][C:5]2([CH2:19][CH2:18][CH:17]=[CH:16][CH2:4]2)[CH:6]=1
Reactant: C=CC=C
Reactant: Cc1cc(CN(C)C)cc(C)c1O
Solvent: CCOC(C)=O
Solvent: CI
Product: CC1=CC2(C=C(C)C1=O)CC=CCC2
Temperature: 130 °C
Yield: 79.9 %

Procedure:
To a 250 mL glass reaction vessel containing an ethyl acetate (120 mLs) solution of N,N-dimethyl,2,6-dimethyl-4-aminomethylphenol (7.16 g; 40 mmols), there was added methyl iodide (40 mmols) to give a colorless slurry. The vessel was sealed and 1,3-butadiene (200 mmols) was introduced into the vessel. The reaction mixture was heated to 130° C. and the pressure was increased from atmospheric to 70 psig. The reaction mixture was maintained at these conditions for approximately 5 hours. The reaction vessel was cooled to room temperature. After cooling, the reaction mixture was filtered to remove ammonium iodide salt by-product. The filtrate was concentrated to afford a viscous oil which was purified by column chromatography (ethyl acetate/silica gel) to give 6.02 g of 2,4-dimethylspiro[5.5]undeca-1,4,8-trien-3-one (76% yield by vapor phase chromatography).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][CH2:24][OH:25])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C)C=O>[C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][CH2:24][O:25][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCCO)(C(=O)OC(C)(C)C)CC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@@](CCCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 59.5 h
Yield: 48.6 %

Procedure:
(3S)-3-(3-Hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (46 g) and imidazole (11.9 g) were dissolved in dimethylformamide (600 mL). After addition of tert-butyldimethylsilyl chloride (23.2 g) under ice-cooling, the mixture was stirred at room temperature for 59.5 hours. The reaction solution was extracted with a 10% citric acid solution and ethyl acetate. Then, the organic layer was sequentially washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→8:2→2:1) to give 29.7 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][N:18]([CH3:33])[C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:18]([CH3:33])[CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: CN(C)c1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:34]([N:36]3[C@H:40]([C:41](=[O:53])[NH:42][C@H:43]4[C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[CH2:46][CH2:45][CH2:44]4)[CH2:39][Si:38]([CH3:55])([CH3:54])[CH2:37]3)=[O:35])[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:23][CH:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:34]([N:36]3[C@H:40]([C:41](=[O:53])[NH:42][C@H:43]4[C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[CH2:46][CH2:45][CH2:44]4)[CH2:39][Si:38]([CH3:54])([CH3:55])[CH2:37]3)=[O:35])[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2C[Si](C)(C)C[C@H]2C(=O)N[C@@H]2CCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si]1(C)C[C@@H](C(=O)N[C@@H]2CCCc3ccccc32)N(C(=O)[C@H](Cc2ccc(C(=O)O)cc2)NC(=O)OCC2c3ccccc3-c3ccccc32)C1
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl 4-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-3-oxopropyl)benzoate (0.17 g, 0.22 mmol) in CH2Cl2 (10 mL) was added TFA (1 mL) at rt. After 4 h, the reaction mixture was concentrated in vacuo to obtain the title compound (150 mg, 82% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 12.37 (br. s., 1H), 8.05 (d, J=8.4 Hz, 2H), 7.76 (d, J=7.5 Hz, 2H), 7.56 (dd, J=7.3, 4.4 Hz, 2H), 7.44-7.05 (m, 11H), 6.62-6.52 (m, 2H), 5.23-5.09 (m, 2H), 4.94 (t, J=6.9 Hz, 1H), 4.38-4.11 (m, 3H), 3.33 (d, J=13.2 Hz, 1H), 3.20 (dd, J=14.1, 4.8 Hz, 1H), 3.03-2.93 (m, 2H), 2.86-2.74 (m, 2H), 2.11-2.01 (m, 1H), 1.92-1.79 (m, 3H), 1.27 (d, J=6.6 Hz, 2H), 0.45 (s, 3H), 0.32 (s, 3H); MS(ESI+) m/z 702.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:17][CH2:16]2)=[C:11](C)[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC([N+]([O-])=O)=[C:39]([O:41]C)C=1>>[NH2:1][C:2](=[N:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:19][CH2:20]2)=[CH:13][C:14]=1[O:41][CH3:39])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Product: COc1cc(N2CCN(C(=O)NCCCCC3CCSS3)CC2)ccc1N=C(N)c1cccs1
Yield: 4 %

Procedure:
The experimental protocol used is the same as that described for the compound of Example 6, 5-chloro-2-nitroanisole replacing 2-fluoro-5-nitrotoluene. A pale yellow foam is obtained (yield 4%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[C:6]1=[O:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]2)[C:6]1=[O:17]
Reactant: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1C1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: O=C1CCC(N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CC1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
Dissolve 3-(2,4-dichloro-benzyl)-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (14.56 g, 37.90 mmol) in acetone (400 mL) with stirring at room temperature. Add p-toluene sulfonic acid (6.53 g, 37.90 mmol) and stir the reaction at room temperature for 48 hours. Then add water and extract the aqueous layer with ethyl acetate (3×400 mL). Combine the organic layers and dry with Na2SO4. Filter and concentrate to give 12.95 g (100%) of the crude title compound as a white solid: Mass spectrum (ion spray): m/z=340.1, 342.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)=[C:11]([CH3:31])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1C=[N+]([C@@H]2[O:42][C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl-].[Mg+2].[Cl-].C(#N)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:24][CH2:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28]4)=[O:22])=[CH:17][CH:16]=3)=[C:11]([CH2:31][OH:42])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1)N1CCS(=O)(=O)CC1
Yield: 18 %

Procedure:
A solution of {6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1,1-dioxo-1-thiomorpholin-4-yl)-methanone (44.5 mg, 0.096 mmol) in DMSO (2 mL) was added to a suspension of CYP3A4 (800 nmol)) and NADP in a total volume of 1000 mL reaction buffer (823 mL 0.1M K+ phosphate buffer pH 7.4, 50 mL 1M trisodium citrate, 10 mL 1M magnesium chloride, 2.5 mL 20 mM NADP). The mixture was shaken in a 2 L baffled Erlenmeyer flask at 220 rpm at 27° C. for 4 h, by which time the ratio of substrate:product (12:8 at 3 h, and 11:9 at 4 h) remained almost constant (reaction monitoring: 0.2 mL suspension was treated with 0.2 mL acetonitrile, centrifuged at 13,200 rpm for 2 min, and supernatant was analyzed by HPLC). The suspension (1000 mL) was extracted with 2 L ethyl acetate. The solvent was distilled off and the residue was dissolved in 100 mL water. This was applied to a 10 g reverse phase C18 cartridge which was eluted with a step gradient of acetonitrile in water (15 mL aliquots). Metabolite containing fractions eluting at 35% MeCN were pooled as appropriate and after removal of organic solvent by rotary evaporation were freeze dried to afford the title compound (8.4 mg, 18%) as a white solid. MS: m/e=536.1 [M+CH3COO]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.[C:24]([Cu])#[N:25].CCOC(C)=O>CN1CCCC1=O.[Cu]I>[CH:17]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6](=[CH:5][C:4]3[CH:21]=[C:22]([CH:23]=[CH:2][CH:3]=3)[C:24]#[N:25])[C:7]=2[CH:20]=[CH:19][CH:18]=1
Reactant: N#C[Cu]
Reactant: Brc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reaction time: 1 h
Yield: 71.5 %

Procedure:
Purge a solution of 5-(3-bromo-benzylidene)-10,11-dihydro-5H-dibenzo-[a,d]cycloheptene (4.2 g, 11.6 mmol) in N-methylpyrrolidinone (80 mL) with nitrogen for 10 minutes. Add CuI (6.7 g, 35 mmol) and CuCN (3.1 g, 35 mmol) and heat to 130° C. After 1 hour, cool the reaction to ambient temperature and shake with aqueous FeCl3 (200 mL) and EtOAc (200 mL). Wash the organic layer with water, dry with MgSO4 and concentrate to obtain 6.4 g crude product. Purify on silica gel using EtOAc/hexane to obtain 2.55 g (71%) title compound as a white solid, mp 115.7° C. 1H NMR (CDCl3) δ 3.02 (br d, 2H), 3.40 (br d, 2H), 6.77 (s, 1H), 6.93 (dd, 1H), 7.02-7.49 (m,11H); MS (EI) 307. HPLC shows 98% purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8].[OH:27]O>>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)=[O:27])[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8]
Reactant: Nc1c(Br)cc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1Br
Reactant: OO
Product: Nc1c(Br)cc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1Br

Procedure:
Prepared analogous to Example 123 from 6-[4-(3,5-dibromo-4-amino-phenylmercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](=[CH:24][N:25]([CH3:27])[CH3:26])[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C1CCN=C(c2c(F)cccc2F)c2cc(Cl)ccc21
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C1CN=C(c2c(F)cccc2F)c2cc(Cl)ccc2C1=O

Procedure:
8-Chloro-1-(2,6-difluoro-phenyl)-3,4-dihydro-benzo[c]azepin-5-one (4aa) (4.2 g, 15 mmol) was dissolved in toluene (100 mL) and N,N-dimethylformamide dimethyl acetal (19 mL) and heated at 80° C. for 2 h. The solution was evaporated in vacuo and the resulting residue was purified by column chromatography (silica gel, 0 to 75% EtOAc/hexanes) to afford 5aa (2.6 g, 78%) as a pale brown solid MS m/z=361 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClC(Cl)C>[CH:25]1([NH:31][C:32]([NH:1][C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:5]3=[N:6][CH:7]=2)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C=NC1CCCCC1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(N)nc12
Solvent: CC(Cl)Cl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(NC(=O)NC3CCCCC3)nc12
Yield: 75.8 %

Procedure:
A solution of 1-[2-amino-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.100 g, 0.287 mmol) and cyclohexyl isocyanate (0.37 mL, 2.9 mmol) in 3 mL of dichloroethane was stirred at reflux for 19 h, then concentrated to a residue. Column chromatography (10→50% EtOAc/hexanes) afforded 0.103 g (76%) of 1-cyclohexyl-3-[7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a brown solid.