Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:9]=2[CH3:25])=[O:7])=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:25][C:9]1[N:10]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:11]2[C:16]([C:8]=1[C:6](=[O:7])[C:5]1[CH:26]=[CH:27][C:2]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:3][CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: Cc1c(C(=O)c2ccc(F)cc2)c2ccccc2n1CCN1CCOCC1
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCNc1ccc(C(=O)c2c(C)n(CCN3CCOCC3)c3ccccc23)cc1
Temperature: 0 °C
Yield: 36.9 %

Procedure:
A mixture of 10 g. (0.027 mole) of 3-(4-fluorobenzoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole, (Example 1Q) 2.5 g. (0.033 mole) of 2-methoxyethylamine and 7.6 g. (0.054 mole) of potassium carbonate in 15 ml of DMSO was heated at 95° C. under nitrogen and the mixture then poured into ice water. The solid which separated was collected, dissolved in methylene dichloride and the solution washed with brine, dried over magnesium sulfate, filtered and taken to dryness in vacuo. Recrystallization of the residue from ethyl acetate-ether afforded 4.2 g (37%) of 2-methyl-3-[4-(2-methoxyethylamino)benzoyl]-1-[2-(4-morpholinyl)ethyl]-1H-indole, m.p. 121°-123° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:10]1)(=[O:8])=[O:7].[CH3:36]C(S(Cl)(=O)=O)CC>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][NH:29][S:30]([CH:33]([CH2:35][CH3:36])[CH3:34])(=[O:31])=[O:32])[CH2:10]1)(=[O:7])=[O:8]
Reactant: CC(C)S(=O)(=O)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: CCC(C)S(=O)(=O)Cl
Product: CCC(C)S(=O)(=O)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1

Procedure:
According to the procedure for Example 237, the reaction of 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (Example 237, Step 2) and butane-2-sulfonyl chloride (Sigma-Aldrich, St. Louis, Mo.) gave N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2-butanesulfonamide as a mixture of 4 compounds.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:37](=[O:36])[CH2:38][OH:39])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f21) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[CH:16]1([C:19]2[CH:20]=[C:21]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:22](=[O:43])[N:23]3[C:28]=2[C:27]([CH3:29])=[C:26]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH:24]3)[CH2:18][CH2:17]1.O>CN(C=O)C.[Ag-]=O.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>[C:11]([O:10][C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][N:23]3[C:28]([C:27]=2[CH3:29])=[C:19]([CH:16]2[CH2:18][CH2:17]2)[CH:20]=[C:21]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:22]3=[O:43])=[CH:3][CH:4]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccn2c(=O)c(C(=O)OCC)cc(C3CC3)c2c1C
Agent: O=[Ag-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(=O)OC(C)(C)C)nc3)ccn2c1=O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 13.3 %

Procedure:
73 mg of tert-butyl (5-bromopyridin-2-yl)carbamate was dissolved in 1 ml of DMF. 62 mg of silver (I) oxide and 31 mg of tetrakis(triphenylphosphine)palladium were added to the obtained solution, and they were stirred at 100° C. in argon atmosphere for 5 minutes. 1 ml of a solution of 100 mg of ethyl 1-cyclopropyl-9-methyl-4-oxo-8-tributylstannyl-4H-quinolizine-3-carboxylate in DMF was added dropwise to the reaction mixture, and they were stirred at that temperature for 1 hour. The reaction mixture was poured into water. After the extraction with chloroform, the organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by the silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain 11 mg of ethyl 8-(6-tert-butoxycarbonylaminopyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][N:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][C:17]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:19]=2)[C:14]1=[O:27])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][N:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][C:17]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:19]=2)[C:14]1=[O:27]
Reactant: COC(=O)c1ccc2ccn(Cc3cccc(NC(=O)OC(C)(C)C)c3)c(=O)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc2ccn(Cc3cccc(N)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-{3-[(tert-butoxycarbonyl)amino]benzyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.23 g, 0.57 mmol) in methylene chloride (5 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (7 mL, 28 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated to dryness to afford methyl 2-(3-aminobenzyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.20 g, quant.). LC-MS: (FA) ES+ 309.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(OCC)(=O)C>[CH:10]1[C:11]2[N:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[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: c1ccc2c(c1)[nH]c1ccccc12
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCCCCCn1c2ccccc2c2ccccc21
Temperature: 150 °C

Procedure:
To a 500 ml three-neck round bottom flask was added 25 g. carbazole, 218 g. dimethyl formamide, 45.5 g. potassium carbonate and 43 g. 6-chloro-1-hexanol. The reaction mixture was heated at 150° C. for 6 hours, and cooled to room temperature. 500 g. ethyl acetate was added, washed with 250 g water, then 250 g water with 50 g concentrated HCl, then 250 g. saturated brine. The solvent was removed on a rotary evaporator to yield 58 g of a brown semi-solid. The crude product was purified using a silica gel flash chromatography column with dichloromethane as the elutant. The concentrated product fractions yielded 33.3 g. of a white solid product; ˜90% pure by gas chromatography.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[N:29]1([C:35]2([C:38](O)=[O:39])[CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:25])[F:26])(=[O:16])=[O:15])[CH2:11][N:10]2[C:38]([C:35]2([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:36][CH2:37]2)=[O:39])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3OC(F)(F)F)CN2)CC1
Reactant: O=C(O)C1(N2CCCCC2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3OC(F)(F)F)CN2C(=O)C2(N3CCCCC3)CC2)CC1
Yield: 61 %

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)pyrrolidine-2-carboxamide 7D with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)pyrrolidine-2-carboxamide as a light yellow solid (61%). MS ISP (m/e): 555.3 (100) [(M+H)]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](C(OCC)=O)([CH3:13])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C)CN(Cc2ccccc2)CC1=O
Agent: Cl
Product: CC1CN(Cc2ccccc2)CC1=O
Yield: 91 %

Procedure:
A mixture of 48.0 g (0.184 mole) of 1-benzyl-4-ethoxycarbonyl-4-methyl-3-pyrrolidone [prepared as described in Step (3) above] and 80 ml of concentrated hydrochloric acid was heated under reflux for 24 hours. The reaction mixture was then filtered, and the filtrate was concentrated by evaporation under reduced pressure. The residue was diluted with water and made alkaline by adding a 50% w/v aqueous solution of sodium hydroxide to pH 10, after which it was extracted with diethyl ether. The diethyl ether extract was dried and the solvent was then distilled from the extract under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 2.5:7.5 by volume mixture of ethyl acetate and toluene, to give 31.7 g of 1-benzyl-4-methyl-3-pyrrolidone as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH:16]([CH3:18])[CH3:17])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22].O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]2[N:6]([CH:16]([CH3:18])[CH3:17])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)c([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5-Chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)benzimidazole (2.7 g) was dissolved in acetic acid (15 ml). To the solution was added fuming nitric acid (3 ml) at 0° C. and then the mixture was stirred at 60° C. for 1 hour. The reaction mixture was poured into water and the mixture was made basic with an aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography [eluted with chloroform-methanol (10:1, v/v)] to give 5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-6-nitrobenzimidazole (1.8 g). A part of the obtained product was recrystallized from acetonitrile, which showed the following physical properties:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[NH2:30][CH:31]1[C:41](=[O:42])[N:33]2[C:34]([C:38]([OH:40])=[O:39])=[CH:35][CH2:36][S:37][C@H:32]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]([NH:30][CH:31]2[C:41](=[O:42])[N:33]3[C:34]([C:38]([OH:40])=[O:39])=[CH:35][CH2:36][S:37][C@H:32]23)=[O:17])[N:13]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reaction time: 1.5 h
Yield: 60.2 %

Procedure:
N,N-Dimethylformamide (0.19 g.), phosphorylchloride (0.40 g.), 2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 0.72 g.) and ethyl acetate (8.5 ml.) were treated in a similar manner to that of Example 1-(1) to give an activated acid solution. The solution was added to a solution of 7-amino-3-cephem-4-carboxylic acid (0.40 g.), trimethylsilylacetamide (1.35 g.), and bis(trimethylsilyl)acetamide (1.2 ml.) in ethyl acetate (4 ml.) at -10° C., and stirred at the same temperature for 1.5 hours. Water (10 ml.) and ethyl acetate (7 ml.) were added to the resultant solution, and the ethyl acetate layer was separated, extracted with a saturated aqueous solution of sodium bicarbonate (10 ml.). The extract with adjusted to pH 5.0 with 85% phosphoric acid and extracted with ethyl acetate (50 ml.). The extract was dried over magnesium sulfate and concentrated in vacuo to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert butoxycarbonylaminoethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.65 g.).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][O:23][CH3:24])[C:17](=[O:20])[NH:18][N:19]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][N:18]1[C:17](=[O:20])[N:16]([CH2:21][CH2:22][O:23][CH3:24])[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)=[N:19]1)[CH3:7]
Reactant: COCCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCOC)c1=O

Procedure:
527 mg (4.30 mmol) of ethyl chloroacetate are added to 1.09 g (4.30 mmol) of 5-(4-chlorophenyl)-4-(2-methoxyethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 49A and 1.19 g (8.59 mmol) of potassium carbonate in 20 ml acetonitrile and the mixture is heated under reflux for 3 hours with stirring. After purification of the resulting crude product by preparative HPLC [Method 9] 810 mg (42% of theory) of the target compound are obtained.
Reaction SMILES: [CH3:1][C:2]12[CH:10]([CH:11]([CH3:16])[CH2:12][CH:13]3[CH2:15][O:14]3)[CH2:9][CH2:8][CH:7]1[CH:6]([OH:17])[CH2:5][CH2:4][CH2:3]2.C(OCC)(=O)C.[CH3:24][Si:25](C1NC=CN=1)([CH3:27])[CH3:26]>O>[CH3:24][Si:25]([O:17][CH:6]1[CH2:5][CH2:4][CH2:3][C:2]2([CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]2[CH:11]([CH3:16])[CH2:12][CH:13]1[CH2:15][O:14]1)([CH3:27])[CH3:26]
Reactant: C[Si](C)(C)c1ncc[nH]1
Reactant: CC(CC1CO1)C1CCC2C(O)CCCC12C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CC1CO1)C1CCC2C(O[Si](C)(C)C)CCCC12C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.4 g of [1R-[1alpha(R*,S*), 3a beta, 4beta, 7a alpha]]-Octahydro-7a-methyl-1-(1-methyl-2-oxiranylethyl)-1H-inden-4-ol and 40 mL of ethyl acetate is added 1.64 g of trimethylsilylimidazole. The mixture was stirred under a dry argon atmosphere at room temperature for 20 minutes then poured into 100 mL of cold water and extracted 3×25 mL of heptane/ethyl acetate (1:1). The extracts were washed with 3×50 Ml of water and dried over anhydrous sodium sulfate. The mixture was filtered and solvent removed in vacuo. Chromatography on silica gel (2.5×100 cm Altex column, 40-60μ silica gel) eluting with hexane/ethyl acetate (6:1) gave 1.81 g (99%) of [1R-[1alpha(R*,S*),3a beta, 4beta, 7a alpha]]-Octahydro-7a-methyl-1-(1-methyl-2-oxiranylethyl)-1H-inden-4-ol trimethylsilyl ether. This material which contained traces of starting material and slowly reverted to starting material on standing was used with no further purification.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17]OS(C)(=O)=O)[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Na+].[I-:35]>CN(C=O)C>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][I:35])[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: [I-]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCI
Temperature: 60 °C
Reaction time: 6 h
Yield: 80.1 %

Procedure:
To a solution of (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-6-methyl-8-(2(methylsulfonyloxy)ethyl)-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (350 mg, 0.71 mmol) in DMF (3 mL) at room temperature (about 22° C.) was added NaI (1.06 g, 7.06 mmol), and the resulting reaction mixture was heated to 60° C. and stirred for 6 h. The reaction mixture was partitioned between sat'd aqueous NaHCO3 solution (20 mL) and EtOAc (25 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (2×25 mL) and the combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude residue was purified via column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (300 mg, 81%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 5.43-5.15 (m, 2H), 5.07 (t, J=9.8 Hz, 1H), 4.95-4.75 (m, 2H), 3.72-3.51 (m, 1H), 3.24 (ddd, J=10.6, 6.6, 4.3 Hz, 1H), 3.00-2.87 (m, 1H), 2.82 (td, J=10.9, 3.0 Hz, 1H), 2.62 (hept, J=7.0 Hz, 1H), 2.35-2.21 (m, 1H), 1.86-1.69 (m, 1H), 1.45 (s, 9H), 1.28 (d, J=6.3 Hz, 3H), 1.22 (dd, J=7.0, 3.9 Hz, 6H); ESIMS m/z 550 ([M+Na]+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[N:10]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]3)[C:9]=2[CH:31]=1)(=[O:4])=[O:3].NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:23][CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][N:10]2[C:9]3[CH:31]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12][C:11]2=[O:14])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(S(C)(=O)=O)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: CS(=O)(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2

Procedure:
tert-Butyl (1-{2-[6-(methylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)carbamate (Intermediate 100) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[OH:7])=[O:5].[OH-].[K+]>CO>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:6]1[C:4](=[O:5])[C:3]([CH3:17])([CH3:16])[CH2:2][O:7]1
Reactant: CC(C)(CCl)C(=O)N(O)Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CON(Cc2ccccc2Cl)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
One method for production of COMMAND® is disclosed in U.S. Pat. No. 4,405,357. Such preparation includes adding to a stirred solution of 6.3 grams (0.023 mole) of 3-chloro-N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide in 45 ml of methanol dropwise a solution of 1.5 grams (0.023 mole) KOH (85% pure) in 25 ml methanol. The addition required 15 minutes and the temperature rose from 24° to 32° C. Upon completion of addition the reaction mixture was stirred for 18 hours at ambient temperature. By-product KCl was removed by filtering the mixture. The filtrate was poured into 500 ml of ice-water. The mixture was extracted with two portions of 250 ml each of methylene chloride. The combined extracts were dried with MgSO4 and filtered. Under reduced pressure the filtrate was concentrated to give 5.2 grams of 2-(2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone as an
Reaction SMILES: S1(=O)(=O)C=CC=N1.BrCC(O)CN1C2C=CC=C3C=CC=C(C=23)S1(=O)=O.[S:27]1(=[O:40])(=[O:39])[C:31]2=[CH:32][CH:33]=[CH:34][C:35]3=[CH:36][CH:37]=[CH:38][C:29](=[C:30]23)[NH:28]1.[H-].[Na+].Br[CH2:44][CH:45]([CH3:48])[CH2:46][Cl:47]>CN(C)C=O>[Cl:47][CH2:46][CH:45]([CH3:48])[CH2:44][N:28]1[C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([C:30]=23)[S:27]1(=[O:39])=[O:40]
Reactant: O=S1(=O)Nc2cccc3cccc1c23
Reactant: CC(CCl)CBr
Agent: O=S1(=O)C=CC=N1
Agent: O=S1(=O)c2cccc3cccc(c23)N1CC(O)CBr
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(CCl)CN1c2cccc3cccc(c23)S1(=O)=O

Procedure:
2-(3- Chloro-2-methylpropyl)naphthol1,8-cd]isothiazole 1,1-dioxide may be prepared in the following manner: the experiment is carried out as in Example 56 for the preparation of 2-(3-bromo-2-hydroxypropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide, starting with naphtho[1,8-cd]isothiazole 1,1-dioxide (10.3 g) in dimethylformamide (125 cc), sodium hydride (2.4 g) in a 50% dispersion in vaseline oil, and 1-bromo-3-chloro-2-methylpropane (5.9 cc). After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and cyclohexane (80-20 vol) as eluant, 2-(3-chloro-2-methylpropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (10.4 g) is obtained, in the form of a green oil, which is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[O:22]=[C:23]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:24](O)=[O:25]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[C:24](=[O:25])[C@@H:23]([OH:22])[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Reactant: O=C(O)C(=O)c1cccnc1
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2cccnc2)cc1C
Yield: 13.1 %

Procedure:
In analogy to example 7, (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (250 mg, 0.85 mmol) and oxo-pyridin-3-yl-acetic acid (343 mg, 1.27 mmol, CAS 39684-37-2) were coupled together to afford the title compound (48 mg, 27%) as a colourless solid. MS m/e: 430.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[C:23]1([NH:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:32][CH2:31][CH2:30][NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Reactant: NCCNc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccccc2)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester and N-phenylethylenediamine in DME. ES-MS m/e (%): 320 (M+H+, 100).