Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([O:12][C:13](=[O:34])[CH2:14][NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:31]=[C:30]3[C:25]([C:26](N)=[N:27][CH:28]=[N:29]3)=[CH:24][CH:23]=2)[C:17]1=[O:33])(C)(C)C.[Cl:35][C:36]1[S:40][C:39]([CH:41]=[CH:42][CH2:43]Br)=[CH:38][CH:37]=1.BrCC1[N:48](C(OC(C)(C)C)=O)C2C(C=1)=CC(Cl)=CC=2>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:12][C:13](=[O:34])[CH2:14][N:15]([C@H:16]1[CH2:20][CH2:19][N:18]([CH:21]([NH2:48])[C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[N:27][CH:28]=[N:29]3)=[CH:24][CH:23]=2)[C:17]1=[O:33])[CH2:43][CH:42]=[CH:41][C:39]1[S:40][C:36]([Cl:35])=[CH:37][CH:38]=1
Reactant: Clc1ccc(C=CCBr)s1
Reactant: CC(C)(C)OC(=O)n1c(CBr)cc2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)CN[C@H]1CCN(Cc2ccc3c(N)ncnc3c2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(CC=Cc1ccc(Cl)s1)[C@H]1CCN(C(N)c2ccc3cncnc3c2)C1=O

Procedure:
Same procedure as EXAMPLE 103, but using {[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amino}acetic acid tert-butyl ester trifluoroacetate instead of 3-(S)-amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one hydrochloride, and 3-(5-chlorothiophen-2-yl)allyl bromide instead of added 2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][OH:37])[CH2:31][CH2:30]1.O>CN(C)C1C=CN=CC=1.ClCCl>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]1[CH2:30][CH2:31][CH:32]([CH2:35][CH2:36][O:37][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:33][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(N2CCC(CCO)CC2)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 52.2 %

Procedure:
p-Toluenesulfonyl chloride (0.858 g, 4.50 mmol), triethylamine (0.820 ml, 6.00 mmol) and 4-dimethylaminopyridine (0.0366 g, 0.300 mmol) were added to a solution of 2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethanol (compound of Reference Example 25; 0.804 g, 3.00 mmol) in anhydrous dichloromethane (5 ml), and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (0.661 g, 52%) as a yellow solid.
Reaction SMILES: [C:1]([CH:4]([CH:6]([C:8]([O-:10])=[O:9])O)O)([O-])=O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH+]1C=[CH:30][CH:29]=[CH:28][CH:27]=1.[N+](=[CH2:34])=[N-].[ClH:35]>CN(C)C=O>[CH3:34][O:10][C:8]([C@H:6]([C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:1]=1)[C@@H:25]1[NH:20][CH2:21][CH2:22][CH2:23][CH2:24]1)=[O:9].[ClH:35]
Reactant: c1cc[nH+]cc1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: C=[N+]=[N-]
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](c1ccccc1)[C@H]1CCCCN1
Yield: 67 %

Procedure:
An alternative approach to synthesizing enantiomerically pure d-threo-methylphenidate hydrochloride using an enantiomerically pure starting material, d-pipecolic acid, was reported by Thai et al. in J. Med. Chem. (1998) 41, 591-601. Enantiomerically pure d-pipecolic acid was obtained in 37% yield by recrystallization of the diastereomeric tartrate salt, followed by the separation of the desired amino acid from tartaric acid by ion-exchange chromatography. d-pipecolic acid was protected with a BOC group to afford N—BOC-d-pipecolic acid in 97% yield. The key amino ketone was prepared from N—BOC-d-pipecolic acid in two steps involving its conversion to the N-methoxy-N-methyl amide, followed by a reaction with the amide with phenyllithium. The amino ketone underwent a Wittig olefination with methyltriphenylphosphonium bromide in the presence of potassium tert-butoxide to give the alkene in high yield. The transformation of the obtained alkene to the desired alcohol as a racemic mixture of threo-stereoisomers via a hydroboration/oxidation reaction was critical to introducing the second stereogenic center. Hydroboration with BH3-THF gave a 72:28 mixture of threo and erythro isomers, respectively, from which the threo alcohol was isolated in 64% yield after chromatography. Oxidation of the threo alcohol with pyridinium dichromate (PDC) in dimethylformamide (DMF) followed by esterification of the resulting acid with diazomethane, and N—BOC group deprotection with 3 N methanolic hydrochloric acid furnished d-threo-methylphenidate hydrochloride in 67% yield after recrystallization from a mixture of ethanol and ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2].CC(=CC)C.[O-:23]Cl=O.[Na+]>C(O)(C)(C)C.O>[CH3:2][CH2:1][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([OH:23])=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5]
Reactant: [O-][Cl+][O-]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
To a solution of 0.104 g (0.413 mmol) of 6-Chloro-3-formyl-1H-indole-2-carboxylic acid ethyl ester in a mixture of tert-butanol (10 ml) and H2O (5 ml), was added 2-methyl-2-butene (2 ml) followed by a solution of NaClO2 (0.344 g, 3.80 mmol) and NaH2PO4 (0.399 g, 2.90 mmol) in water (2 ml). The mixture was stirred overnight at RT. The organic solvents were removed, and then the aqueous solution diluted with water, and washed twice with hexane. The ph of the aqueous phase was adjusted to 3 by addition of aq. HCl 1N, and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 15 mg (14%) of 6-chloro-1H-indole-2,3-dicarboxylic acid 2-ethyl ester as alight yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>C(#N)C>[CH:20]1([CH2:19][O:11][C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:22][CH2:21]1
Reactant: COc1cccc(OC)c1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(OC)c1OCC1CC1
Temperature: 80 °C
Yield: 74.4 %

Procedure:
To a stirring solution of 2,6-dimethoxyphenol (2 g, 12.9 mmol) in acetonitrile (50 mL) was added potassium carbonate (3.5 g, 25.8 mmol) and (bromomethyl)cyclopropane (3.5 g, 25.8 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) to afford 2-(Cyclopropylmethoxy)-1,3-dimethoxybenzene as a solid (2 g, 74%).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[C:15]1([CH3:26])[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23](O)=[O:24])=[CH:17][CH:16]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:23](=[O:24])/[CH:22]=[CH:21]/[C:18]2[CH:19]=[CH:20][C:15]([CH3:26])=[CH:16][CH:17]=2)=[N:8]1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: Cc1ccc(/C=C/C(=O)O)cc1
Product: Cc1ccc(/C=C/C(=O)Nc2ccn(CCCCC(C)(F)F)n2)cc1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-p-tolyl-acrylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=348.31.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][Al:8](C)C>C(Cl)Cl>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][Al+2:8]
Reactant: CC(C)C(=O)O
Reactant: C[Al](C)C
Solvent: ClCCl
Product: CC(C)C(=O)[O-]
Product: C[Al+2]

Procedure:
In a sufficiently dried egg-plant type flask provided with a stirrer was charged 0.176 g (2 mmol) of sufficiently purified isobutyric acid, which was sufficiently dried. After completion of the drying, 3.3 ml of methylene chloride was added thereto. Then, under nitrogen atmosphere, 0.9 ml (1 mmol) of trimethylaluminum was slowly added dropwise with ice-cooling and stirring, and the mixture was mixed in the dark at room temperature for 1 hour to obtain a methylene chloride solution of methylaluminum bis(isobutyrate) (1 mmol/3.3 ml).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.COB([C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)O.[Cl-].[Li+].[C:25](=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.COCCOC>[CH3:25][O:22][C:20](=[O:21])[C:17]1[CH:16]=[CH:15][C:14]([C:6]2[C:5]([Cl:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:19][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: COB(O)c1ccc(C(=O)O)cc1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Temperature: 80 °C

Procedure:
In a flask was added 2,4,5-trichloro-pyrimidine (1.3 equivalents, 2.66 g, 14.6 mmol), the commercially available 4-carboxyphenyl boronic acid methyl ester (1.0 equivalent, 2.02 g, 11.2 mmol), tetrakis triphenylphosphine palladium (0.1 equivalent, 1.3 g, 1.12 mmol), lithium chloride (3.0 equivalents, 1.4 g, 33.6 mmol), sodium carbonate (2N, 5 mL) and 1,2-dimethoxyethane (20 mL). The resulting mixture was heat at 80° C. for 24 hours then dissolved in ethyl acetate, washed with hydrochloric acid (1N), brine and dried over sodium sulfate. The crude product was purified by chromatography on silica (ethyl acetate, 10% in hexane) to afford 1.21 g of 4-(2,5-dichloro-pyrimidin-4-yl)-benzoic acid methyl ester as a white solid. The structure was confirmed by 1H NMR.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH3+:5].[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[N:14]=[C:15]=[S:16]>>[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[N:14]=[C:15]1[NH:5][CH2:4][CH2:3][S:16]1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: [NH3+]CCCl
Agent: [Cl-]
Product: Clc1cccc(N=C2NCCS2)c1Cl

Procedure:
2-Chloroethylammonium chloride (Entry 1) was reacted with 2,3-dichlorophenyl isothiocyanate according to Method C1a to give 2-(2,3-dichlorophenylimino)-1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2-(2,3-dichlorophenylimino)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[N:34](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH2:34])=[O:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(=O)O)cc3c2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(N)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
A mixture of 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (1.59 g), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.4 g), 1-hydroxybenzotriazole ammonium salt (1.1 g) and N,N-dimethylformamide (40 mL) was stirred at room temperature for 16 hr. Water was added to the reaction solution, and the precipitated solid was collected by filtration, and washed successively with water, ethanol and diethyl ether to give the title compound (1.6 g, yield 100%) as a pale-yellow solid. The pale-yellow solid was recrystallized from N,N-dimethylformamide-water to give pale-yellow crystals. melting point 251-252° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[CH:32]1([C:35]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:36])[CH2:34][CH2:33]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)C5CC5)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A155) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:10][C:9]([NH:8][C:6]1[CH:7]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)Nc1cc(Cl)nc(N2CCCC2)n1
Reactant: C1CNCCN1
Product: CC(C)(C)Nc1cc(N2CCNCC2)nc(N2CCCC2)n1
Yield: 67.5 %

Procedure:
4-Chloro-6-(1,1-dimethylethylamino)-2-pyrrolidinopyrimidine is reacted with piperazine as described in Example 4 to give the title product in a yield of 67.5%, m.p.: 140°-145° C.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48](=[O:69])[NH:49][CH2:50][CH2:51][N:52](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C:53]([NH2:55])=[NH:54])[CH2:43]1>>[NH:52]([CH2:51][CH2:50][NH:49][C:48]([C@@H:44]1[CH2:43][C@H:42]([S:41][C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([OH:23])=[O:22])[CH2:46][N:45]1[CH3:47])=[O:69])[C:53]([NH2:55])=[NH:54]
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)NCCN(C(=N)N)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)NCCNC(=N)N)N(C)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and (2S,4S)-4-mercapto-1-methyl-2-[2-(4-nitrobenzyloxycarbonylguanidino)ethylcarbamoyl]pyrrolidine (prepared as described in Preparation 103) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([C:34]([O:36][CH2:37][CH3:38])=[O:35])#N>C1COCC1>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[C:13]([CH:15]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C#N
Reactant: CCOC(=O)Cc1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
A solution of 1.000 g (3.243 mmol) of ethyl [1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-acetate was dissolved in 20 ml of THF and cooled to 0° C. Over a period of 10 min, 3.567 ml of lithium bis(trimethylsilyl)amide (3.567 mmol, 1M in THF) were added dropwise. This mixture was stirred at 0° C. for 30 min, 350 μl (3.567 mmol) of ethyl cyanoformate were then added and the mixture was stirred at RT for another 2 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried over Na2SO4, filtered and concentrated. Chromatography on silica gel (heptane/ethyl acetate 1:1) gave the title compound (0.390 g, 32%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:7])[F:1])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCC(F)(F)F

Procedure:
The 4,4,4-trifluoro-1-butanol (Lancaster, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: C[C@@H]1[O:7][C@@H]([O:8][C@H:9]2[C@H:33]([O:34]C)[C@@:32]([OH:37])(C)[C:30](=[O:31])C3C=C4C(=O)C5C=C(OC)C=C(O)C=5C(=O)C4=[C:15]([OH:16])[C:10]2=3)[C@H](OC)[C@H](O)[C@H]1O.CN(C)C=[O:45]>C(Cl)(Cl)Cl.CO>[OH2:7].[O:31]=[CH:30][C@@H:32]([C@H:33]([C@@H:9]([C@@H:10]([CH2:15][OH:16])[OH:45])[OH:8])[OH:34])[OH:37]
Reactant: COc1cc(O)c2c(c1)C(=O)c1cc3c(c(O)c1C2=O)[C@@H](O[C@@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1OC)[C@H](OC)[C@](C)(O)C3=O
Reactant: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 12 h

Procedure:
Between about 36 and 48 hours of fermentation time, steffimycin is added to the fermentation as a dimethylformamide solution (25 mg/ml) to a final medium concentration of 25 mg/l. The fermentation is monitored using tlc on silica gel plates with CHCl3 :CH3OH (925:75) as the developing solvent system. The tlc procedure is conducted at half day intervals between the first half day and five days.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C=CC([C@H]2N3C(SC(C([N:28]4[CH2:49][C@H:48]([F:50])[CH2:47][C@H:29]4[C:30]([N:32]4[CH2:39][C:36]5([CH2:38][CH2:37]5)[N:35]([C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[CH2:34][C@H:33]4C)=[O:31])=O)=C3C(C)C)=N[C@]2(C2C=NC(Cl)=CC=2)C)=CC=1F>ClCCl>[F:50][C@H:48]1[CH2:49][NH:28][C@H:29]([C:30]([N:32]2[CH2:39][C:36]3([CH2:38][CH2:37]3)[N:35]([C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[CH2:34][CH2:33]2)=[O:31])[CH2:47]1
Reactant: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)N(C(=O)C(F)(F)F)C[C@H]2C)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@@H]1C[C@@H](F)CN1)N1CCN(C(=O)C(F)(F)F)C2(CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a dichloromethane (10 ml) solution of the compound (560 mg, 1.32 mmol) obtained in Step 1 above and the resulting mixture was stirred at room temperature for 1 hour. The reaction solvent was concentrated under reduced pressure and then saturated aqueous sodium bicarbonate solution (30 ml) was added, followed by extraction with chloroform three times. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (380 mg, 89%) as a pale yellow solid.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[CH3:7][CH2:8][CH2:9][Br:10]>>[Br-:10].[NH2:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH3:9])[N:3]=1
Reactant: Nn1ccnn1
Reactant: CCCBr
Product: CCCn1cc[n+](N)n1
Product: [Br-]
Yield: 89.9 %

Procedure:
In the same manner as above, 1-amino-1,2,3-triazole (1) 2.00 g (23.8 mmoles) was reacted with n-propyl bromide 13.60 g (110.6 mmoles) at 60° C., resulting in a good yield of 4.43 g (90%) of 1-amino-3-n-propyl-1,2,3-triazolium bromide (2c), mp 128-129° C.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.Br[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[OH:21].[C:22]([O:30][CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([OH:39])[C:33]([CH3:41])([CH3:40])[CH2:32]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCCCCCC>ClC1C=CC=CC=1.CCCCCCC.C(OCC)(=O)C>[C:22]([O:30][CH:31]1[CH2:32][C:33]([CH3:40])([CH3:41])[N:34]([O:39][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[OH:21])[C:35]([CH3:38])([CH3:37])[CH2:36]1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OC1CCCCC1Br
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1O

Procedure:
Tributyltin hydride is added dropwise to a solution of 2-bromocyclohexanol and excess 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine in chlorobenzene. The mixture is heated to facilitate reaction. The crude reaction mixture is passed through silica gel with heptane and then heptane/ethyl acetate to afford the title compound as a mixture os cis/trans isomers.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[N:3]=1.[C:17](O)(=[O:19])[CH3:18].[OH-:21].[Na+]>>[C:17]([O:16][CH2:15][CH2:14][O:13][CH2:12][C:4]1[NH:3][C:2](=[O:21])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: [OH-]
Reactant: Nc1nc(COCCO)nc2nccnc12
Agent: [Na+]
Product: CC(=O)OCCOCc1nc2nccnc2c(=O)[nH]1

Procedure:
A solution of 10.0 g (0.0452 mole) of 4-amino-2-[(2-hydroxyethoxy)methyl]pteridine in 350 ml of 5% aqueous sodium hydroxide is brought gradually to 85° C and maintained at this temperature for 1 hour 30 minutes. After cooling, the solution obtained is acidified with acetic acid to pH 5.5, and is then concentrated to dryness under reduced pressure. The residue is taken up in 500 ml of isopropanol. The insoluble inorganic portion is removed by filtration. The isopropanolic solution is concentrated to dryness under reduced pressure. The solid residue is treated with 250 ml of acetic anhydride and this mixture is refluxed for 1 hour. After cooling, inorganic salts are removed by filtration; the filtrate is concentrated to dryness under reduced pressure. The residue is purified by 4 successive recrystallizations from ethanol in the presence of Norit. Yld: 1.2 g (10%), m.p. 157°-159° C.
Reaction SMILES: C[Mg+].[Br-].[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].[C:20](=O)(O)[O-].[Na+]>CCOCC.C1COCC1.ClCCl>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH:12][C:13](=[O:15])[CH3:14])=[CH2:20])=[N:9][CH:10]=1
Reactant: N#Cc1ccc(F)cn1
Reactant: O=C([O-])O
Reactant: CC(=O)OC(C)=O
Agent: C[Mg+]
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(NC(C)=O)c1ccc(F)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0° C. 5-fluoropyridine-2-carbonitrile (Intermediate 1, 53.6 g, 425.82 mmol) in THF (170 ml) was added dropwise. The reaction was stirred at 0° C. for 30 minutes, then diluted with dichloromethane (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in dichloromethane (100 ml) was added dropwise at 0° C. After addition, the reaction was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and extracted with EtOAc (2×200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane:EtOAc=2.5:1) to give the title compound as a white solid (26.6 g, 35%). 1H NMR (400 MHz) δ 9.37 (s, 1H), 8.57 (d, J=2.8 Hz, 1H), 7.81 (m, 2H), 6.01 (s, 1H), 5.52 (s, 1H), 2.08 (s, 3H). MS: Calculated: 180. Found: [M+H]+ 181.