Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23](C1CCCCN1)[CH:22]=[CH:21]2>ClCCl.CO>[N:24]1([C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[CH:26][CH:27]=[C:18]([NH:17][C:14](=[O:16])[C:13]#[C:12][C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=4[Cl:1])[CH:19]=3)[N:24]=2)[CH2:25][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc2nc(C3CCCCN3)ccc2c1
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc2nc(N3CCCCC3)ccc2c1

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and 6-amino-2-piperidin-2-ylquinoline. Yield: 170 mg (37.1% of theory); melting point: 176° C.-179° C.; C24H19ClF3N3O (M=457.88); calc.: molecular ion peak (M+H)+: 456/458; found: molecular ion peak (M+H)+: 456/458; Rf value: 0.62 (silica gel, dichloromethane/methanol (19:1)).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[N:10]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH2:30][C:31]#[N:32])[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]([Si](C)(C)C)=[N+:37]=[N-:38].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:35])[N:10]([CH2:11][CH3:12])[CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[C:28]([CH2:30][C:31]2[N:36]=[N:37][NH:38][N:32]=2)[CH:27]=[CH:26][C:25]=1[O:33][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC)C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cc2nn[nH]n2)ccc1OC)C(=O)OCc1ccccc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
(5′-Cyanomethyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-ethyl-carbamic acid benzyl ester (0.209 g, 0.43 mmol), azidotrimethylsilane (0.07 mL, 0.52 mmol), and dibutyltin oxide (0.015 g, 0.04 mmol) were combined in toluene (2.1 mL) and stirred at 110° C. overnight Analytical LCMS indicated that the reaction wasn't proceeding, so additional azidotrimethylsilane (0.04 mL, 0.26 mmol), and dibutyltin oxide (catalytic) was added, and the reaction was stirred at 100° C. overnight. The mixture was cooled to room temperature and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound. M+H is 526.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[N:37]=[C:38]=[O:39]>O1CCCC1>[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[NH:37][C:38]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:39]
Reactant: Cc1onc(-c2ccccc2)c1N=C=O
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 5-methyl-3-phenyl-4-isoxazolyl isocyanate (244 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 229 mg (63.3%) of the desired product as a solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)=[C:2]=[O:3].[CH2:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)=[O:3])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(N=C=O)cc1N1C(=O)c2ccc(Cl)cc2C1=O
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The starting material is prepared as follows: The mixture of 0.5 g of N-(4-isocyanato-o-tolyl)-4-chlorophthalimide and 5ml of benzyl alcohol is heated to 120° under nitrogen for 6 hours and evaporated, to yield the N-(4-benzyloxycarbonylamino-o-tolyl)-4-chlorophthalimide.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:11][CH:12]=2)[O:7]1)[CH2:2][CH3:3].[C:21]([O-:26])(=O)[C:22]([O-])=O>>[NH2:16][C:10]1[CH:11]=[C:21]([CH:22]=[CH:8][CH:9]=1)[O:26][CH2:3][CH2:2][CH2:1][NH:4][CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:11][CH:12]=2)[O:7]1
Reactant: CCCNCC1CCc2ccc(NS(C)(=O)=O)cc2O1
Reactant: O=C([O-])C(=O)[O-]
Product: CS(=O)(=O)Nc1ccc2c(c1)OC(CNCCCOc1cccc(N)c1)CC2

Procedure:
N-(2-Propylaminomethyl-chroman-7-yl)-methanesulfonamide as the oxalate, hemihydrate, mp 204°-205° C.
Reaction SMILES: [ClH:1].C(O)C.[C:5](/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[O:17])=[CH:11][CH:10]=1)#[N:6].[CH2:30](N)[CH2:31][NH2:32].C(=O)([O-])O.[Na+]>C(O)C>[ClH:1].[NH:6]1[CH2:30][CH2:31][N:32]=[C:5]1/[CH:7]=[CH:8]/[C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: N#C/C=C/c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: NCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(Nc1ccc(/C=C/C2=NCCN2)cc1)c1ccc(-c2ccccc2)cc1
Reaction time: 16 h

Procedure:
10.1 N Hydrogen chloride-ethanol solution (30 ml) was added to an ethanol suspension of N-[4-[(E)-2-cyanoethenyl]phenyl][1,1′-biphenyl]-4-carboxamide (250 mg, 0.771 mmol) obtained in Reference Example under room temperature, which was stirred for 16 hours. After the solvent was distilled out under reduced pressure, ethanol was again added to the residue, and then ethylenediamine (0.155 ml, 2.31 mmol) was added at room temperature, which was stirred for 16 hours. Sodium hydrogencarbonate solution was added to the reaction mixture, and the precipitated crude product was washed with water and chloroform. This product was dissolved in methanol. 1 N Hydrochloric acid (4 ml) was added to the solution, and the solvent was distilled out under reduced pressure. Small amount of water was added to the resulting residue, to give the titled compound (124 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccc(C(F)(F)F)nc1)N1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccc(C(F)(F)F)nc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH2:11]I)=[CH:6][C:5]=1[CH3:13]>CN(C=O)C>[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH2:11][NH:2][CH3:1])=[CH:6][C:5]=1[CH3:13]
Reactant: Cc1cc(CI)cc(C)c1Br
Reactant: CN
Solvent: CN(C)C=O
Product: CNCc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.8 %

Procedure:
Methylamine (12.3 ml, 24.60 mmol, 2.0 M solution in methanol) was added dropwise to a solution of 2-bromo-5-iodomethyl-1,3-dimethyl-benzene (400 mg, 1.23 mmol) in anhydrous DMF (12 ml), and the mixture was stirred at room temperature for two days. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was then sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 1-(4-bromo-3,5-dimethylphenyl)-N-methylmethanamine (280 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:61](O)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>ClCCl>[CH2:61]([O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)OCc3ccccc3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 19.9 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.24 g, 0.44 mmol), 1-hydroxybenzotriazole (0.072 g, 0.53 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.102 g, 0.53 mmol) were dissolved in 10 mL of dichloromethane under stirring, and benzyl alcohol (0.1 mL, 0.88 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid benzyl ester 33a (0.056 g, yield 20%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:61])[C:48]([NH:56][C:57]([O:59][CH3:60])=[O:58])([C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)C)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:63](OC(N1CCCC1C(O)=O)=O)(C)(C)C.COC(NC(C1C=CC=CC=1)C(O)=O)=O.COC(NC(C1C=CC=CC=1)(C)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([CH3:63])[CH2:44][N:43]6[C:47](=[O:61])[CH:48]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]6[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(C)(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: COC(=O)NC(C(=O)O)c1ccccc1
Agent: COC(=O)NC(C)(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CC(C)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1

Procedure:
[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-methyl-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester, substituting 4-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and Methoxycarbonylamino-phenyl-acetic acid for 2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI+: calc'd for C48H52N8O6: 836.40 (M+); Found: 837.70 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH3:17]>>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(O)cc1F
Reactant: CCCOCCBr
Product: CCCOCCOc1ccc(OC)c(F)c1

Procedure:
The epoxide starting material is obtained by reacting 3-fluoro-4-methoxyphenol with 1-bromo-2-propoxyethane. After work up of the reaction mixture 2-fluoro-1-methoxy-4-(2-propoxyethoxy)benzene is obtained which is then reacted with sodium thioethoxide giving 2-fluoro-4-(2-propoxyethoxy)phenol which is then reacted with epichlorhydrin in the presence of a catalytic amount of piperidine.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)[CH2:6][P:7]([OH:18])([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])C.[Li+].[OH-].C(OC(=O)C)C>CC#N.O>[C:30]([O:29][C:27]([NH:26][C:23]1[N:22]=[CH:21][C:20]([CH2:19][CH:5]([CH2:6][P:7]([OH:18])([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[C:4]([OH:34])=[O:3])=[CH:25][CH:24]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)CP(=O)(O)CCCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CC(CP(=O)(O)CCCc2ccccc2)C(=O)O)cn1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 76.9 %

Procedure:
To a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl-propyl)-phosphinoyl]-propionic acid ethyl ester (0.240 g 0.489 mmol) in MeCN (3 mL) was added a solution of LiOH (0.059 g 2.45 mmol) in H2O (3 mL). The mixture was then stirred at 20° C. for 1.5 hours. Ethylacetate was added and the mixture was washed with 1 M HCL and brine and filtered to give 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl-propyl)-phosphinoyl]-propionic acid (0.174 g, 77%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1>[C:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Into a solution of 14.6 g (52.6 mmol) of tert-butyl 4-[3-(amino)phenyl]-1-piperidinecarboxylate and 14.7 mL (105 mmol) of triethylamine in 120 mL THF at 0° C. was slowly added 4.5 mL (63.1 mmol) of acetyl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 16.6 g (52.1 mmol, 99%) of desired product: 1H NMR (400 MHz, CDCl3) δ 7.41–7.20 (m, 3H), 6.94 (d, 1H, J=7.5 Hz), 4.21 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 2.16 (s, 3H), 1.78 (m, 2H), 1.56 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]#[N:12])[CH:5]=1.[OH-].[K+]>C1COCC1>[C:11]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[OH:10])[C:3]([OH:13])=[O:2])#[N:12]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl-3-cyano-4-hydroxybenzoate (2.71 g, 15.3 mmol) was dissolved in 50 mL of THF. The solution was chilled in an ice bath, and 2.0M potassium hydroxide (17 mL, 34 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. TLC indicated complete reaction. The THF was removed by rotary evaporation. The aqueous residue was acidified with aqueous trifluoroacetic acid and purified by reverse-phase HPLC (C-18, 0.1% TFA in water and acetonitrile). 3-Cyano-4-hydroxybenzoic acid was obtained as a white powder (2.1 g, 84%) after lyophilization.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[S:6][C@@H:5]2[C@H:7](NC([C@H](N)C3C=CC(O)=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:22]([OH:24])=[O:23].CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].N1C=CC=N1.[Na]>>[CH3:1][C:2]1([CH3:25])[S:6][C@@H:5]2[CH2:7][C:8](=[O:9])[N:4]2[C@H:3]1[C:22]([OH:24])=[O:23]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: [K+]
Agent: [Na]
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O

Procedure:
The free penicillanic acid of the title compound was prepared in the same manner as in Example 11(c), except that amoxycillin trihydrate was used in place of ampicillin. The free acid possessed δ(CD3OD) 1.50, 1.57(2×3H, 2s, gem dimethyls), 4.37 (1H, s, C3 penicillin proton), 5.58 (2H, m, C5 and C6 penicillin protons), 5.78 (1H, s, --CH--CONH--), 6.85(2H, d, J9 Hz, 2 aryl protons), 7.43 (2H, d, J9Hz 2 aryl protons), 7.85 (2H, d, J8Hz, 2 aryl protons), 8.30 (2H, d, J8Hz, 2 aryl protons), 8.61 (1H, s, C3 pyrazole proton). The free acid was converted to the sodium salt in a manner analogous to example 6(b). The sodium salt possessed νmax (Nujol) 1760, 1560 cm-1. MIC against E.coli NCTC 10418 5 μg/ml.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].I(Cl)(Cl)Cl>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][C@H:5]2[C@@H:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C@:9]3([CH2:11][OH:12])[O:4][C@H:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: ClI(Cl)Cl
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Temperature: 60 °C
Reaction time: 4 h
Yield: 136.4 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose and 234 mg of iodine trichloride and the mixture was refluxed with stirring in a water bath at 60° C. for 4 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was then subjected to an after-treatment similar to that described in Example 11 to give 9.85 g (68.2%) of 2,3:4,6-di-O-isopropylidene-L-sorbofuranose (purity ≥98%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C[Si]([N:26]=[N+:27]=[N-:28])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:26]1[C:20]([CH2:19][CH2:18][C:16]2[N:17]=[C:12]([C:4]3[S:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:2](=[O:1])[N:3]=3)[CH:13]=[CH:14][CH:15]=2)=[N:21][N:28]=[N:27]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(CCc3nnn[nH]3)n2)sc2ccccc12
Yield: 70 %

Procedure:
3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionitrile (0.25 g, 0.85 mmol) and trimethylsilylazide (0.20 g, 1.7 mol) were dissolved in toluene (5 ml), and dibutyltin (IV) oxide (0.02 g, 0.08 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs and kept at room temperature. The precipitated crystals were collected by filtration, washed with toluene and recrystallized from ethanol to give the titled compound (0.20 g, 68%) as white crystals.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C:6]([CH3:9])=[CH:5][CH2:4]1)#[N:2].[H][H]>N>[NH2:2][CH2:1][C@H:3]1[CH2:8][CH2:7][C:6]([CH3:9])=[CH:5][CH2:4]1
Reactant: [H][H]
Reactant: CC1=CC[C@@H](C#N)CC1
Agent: N
Product: CC1=CC[C@@H](CN)CC1
Yield: 88 %

Procedure:
605 g of 4(5)-cyano-1-methylcyclohexene were dissolved in 500 ml of liquid ammonia in a stirrer autoclave and hydrogenated at 90° C. and at a hydrogen pressure of 100 bar over 40 g of Raney nickel iron. After evaporating the ammonia, the mixture was filtered from the catalyst and distilled under vacuum. 550 g (88%) of 4(5)-aminomethyl-1-methylcyclohexene, b.p.10 78° to 80° C. were obtained. The ratio by weight of the 4- and 5-isomers was about 80:20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][NH2:31])=[CH:26][CH:25]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: CC(C)(C)C(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=NOc1ccc(F)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 10.8 %

Procedure:
A solution of N-[4-chloro-2-(2,2-dimethylpropionyl)phenyl]trifluoromethanesulfonamide 29C (280 mg, 0.82 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (200 mg, 1.22 mmol) and anhydrous NaOAc (100 mg, 1.22 mmol) in EtOH (20 mL) was stirred for 48 hours at RT. The reaction mixture was concentrated under vacuum and the residue purified by column chromatography (eluting with CH2Cl2/PE, 1:4 to 2:3) to afford N-{4-chloro-2-[1-(4-fluorophenoxyimino)2,2-dimethylpropyl]phenyl}trifluoromethanesulfonamide 198 (40 mg, 11%), as an orange oil. 1H n.m.r. (200 MHz, CDCl3) δ 7.52, d, J=8.8 Hz, 1H; 7.42, dd, J=2.2 and 8.8 Hz, 1H; 7.19, d, J=2.2 Hz, 1H; 7.00, m, 4H; 6.49, br s, 1H; 1.32, s, 9H. HRMS (M+) 452.0576.
Reaction SMILES: [NH2:1][C@H:2]([CH2:9]O)[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[BrH:11]>C(O)(=O)C.C(O)C>[Br:11][CH2:9][C@@H:2]([NH2:1])[CH2:3][C:4]1[NH:8][CH:7]=[N:6][CH:5]=1
Reactant: Br
Reactant: N[C@H](CO)Cc1c[nH]cn1
Solvent: CCO
Solvent: CC(=O)O
Product: N[C@H](CBr)Cc1cnc[nH]1
Temperature: 110 °C

Procedure:
900 mg (S)-histidinol (×2HCl) are dissolved in 20 mL HBr in acetic acid (32%) and heated to 110° C. in the microwave for 6 h. The solvent is eliminated in vacuo, the residue is dissolved in ethanol and again freed from the solvent in vacuo. This crude product is used in the next reaction step without further purification.
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[O:15]([C:22]1[N:27]=[C:26]([CH2:28][SH:29])[CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([Si:3]([CH3:5])([CH3:4])[CH2:2][S:29][CH2:28][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:27]=2)=[CH:7][CH:8]=1)[CH3:14]
Reactant: CCOc1ccc([Si](C)(C)CCl)cc1
Reactant: SCc1cccc(Oc2ccccc2)n1
Product: CCOc1ccc([Si](C)(C)CSCc2cccc(Oc3ccccc3)n2)cc1
Yield: 82.4 %

Procedure:
In the manner described in Example 1, 1.8 grams (8.0 mmoles) of (chloromethyl)(4-ethoxyphenyl)dimethylsilane was reacted with 1.7 grams (8.0 mmoles) of 6-phenoxy-2-pyridine methanethiol giving 3.2 grams of a light orange oil. The product was purified on a Waters® Prep 500A liquid chromatograph (silica gel) eluting with 6 percent ethylacetate in hexane, to yield 2.7 grams of (4-ethoxyphenyl)dimethyl[(((6-phenoxy-2-pyridinyl)methyl)thio)methyl]silane as a clear oil. Analytical data for this product are shown in Table VI.