Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)(=O)C.[H][H]>CO.[Rh]>[C:1]([NH:8][CH:9]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1

Procedure:
N-BOC-a-phenylglycine, methyl ester (1.2 g) is dissolved in methanol (50 ml) containing acetic acid (1 ml). 5% rhodium on aluminum powder (0.60 g) is added and the mixture shaken under 50 psi hydrogen for about 18 hours. The mixture is filtered, evaporated in vacuo , and the residue taken up into ethyl acetate. The organic solution is washed with water, saturated sodium bicarbonate solution, water, brine, dried over magnesium sulfate, filtered, evaporated in vacuo to give N-BOC-a-cyclohexylglycine, methyl ester.
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41](O)=[O:42]>>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:41]([C:37]3[S:36][CH:40]=[CH:39][CH:38]=3)=[O:42])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Reactant: O=C(O)c1cccs1
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)c1cccs1)CC2
Yield: 51.4 %

Procedure:
The compound obtained in Example 3 (483 mg) and thiophen-2-carboxylic acid (158 mg) are treated in the same manner as in Example 5 to give methyl 2-n-butyl-5-(2-thienyl)carbonyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (306 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][O:36][C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(CBr)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=C(COc1ccc(Cl)cc1)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Yield: 100.5 %

Procedure:
To a solution of N,N-dibenzyl-4-(2-bromoacetyl)benzenesulfonamide (10.5 g, 23 mmoles), and p-chlorophenol (2.94 g, 23 mmoles) in methylene chloride (42 ml), potassium carbonate (4.83 g, 34.7 mmoles) and tetrabutylammonium bromide (0.42 g, 1.2 mmoles) in water (140 ml)was added. The reaction mixture was refluxed for 16 hours. After cooling, the mixture was diluted with methylene chloride (150 ml). The organic layer was separated, washed with water, and dried (Na2SO4) The solvent was removed under reduced pressure. N,N-dibenzyl-4-[2-(4-chlorophenoxy)acetyl]benzenesulfonamide (11.7 g) was obtained as a semisolid residue, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:6]=[CH:5]2.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>O1CCOCC1>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:6]=[CH:5]2
Reactant: Clc1ccc2nc(NCCOc3ccccc3)ccc2c1
Reactant: CN(C)CCN
Solvent: C1COCCO1
Product: CN(C)CCNc1ccc2nc(NCCOc3ccccc3)ccc2c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
(6-Chloro-quinolin-2-yl)-(2-phenoxy-ethyl)-amine (100 mg, 0.33 mmol) was dissolved in 1.5 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. N,N-Dimethylethylendiamine (149 mg, 1.69 mmol), sodium tert.-butylate (80 mg, 0.83 mmol), 1,1′-bis(diphenylphosphin)ferrocen (21 mg, 0.037 mmol) and 1,1′-bis(diphenyl-phosphin)ferrocen-palladium(II)chloride (10 mg, 0.012 mmol) were added. The reaction mixture was stirred in a sealed tube at 120° C. overnight. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient). The title compound was obtained as a brown oil (35 mg, 30%), MS: m/e=351.3 (M+H+).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[O:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[Cl:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32](O)=[O:33])[CH:28]=[CH:29][CH:30]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C.O>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:13][C@H:12]([C:14]2[N:15]=[C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[O:17][CH:18]=2)[CH2:11][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1coc(-c2cccs2)n1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(Cl)c1)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1coc(-c2cccs2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-[(thiophen-2-yl)oxazol-4-yl]ethanamine HBr, 47, (3.15 g, 10 mmol) 3-chlorophenyl-acetic acid (1.70 g, 10 mmol) and 1-hydroxybenzotriazole (HOBt) (0.70 g, 5.0 mmol) in DMF (50 mL) at 0° C., is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.90 g, 10 mmol) followed by triethylamine (4.2 mL, 30 mmol). The mixture is stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[F:21].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(COC)OC.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>[Cl:14][C:15]1[CH:16]=[C:17]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([CH3:13])[CH3:12])[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: CC1(C)C(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21
Temperature: 25 °C
Yield: 29.5 %

Procedure:
A solution of 5-bromo-3,3-dimethyl-1,3-dihydro-indol-2-one (0.35 g, 1.46 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g, 0.11 mmol) in dimethoxyethane (10 cm3) was stirred under N2 for 20 min. To this mixture was then added 3-chloro-4-fluorobenzene boronic acid (0.26 g, 1.49 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in water (5 cm3). The solution was brought to reflux for 16 h then cooled to RT, poured into saturated ammonium chloride and extracted with EtOAc (×3). The combined organic extracts were dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane 1:3) to afford the title compound (0.124 g, 0.43 mmol, 30%) as a white solid: m.p. 206.5-207.8° C., 1H NMR (DMSO-d6) δ 1.3 (s, 6H), 6.93 (d, J=8.1 Hz, 1H), 7.45 (dd, J=8.9, 8.9 Hz, 1H), 7.5 (dd, J=8.1, 1.8 Hz, 1H), 7.6 (ddd, J=8.9, 7.1, 2.2 Hz, 1H), 7.7 (d, J=1.8 Hz, 1H), 7.8 (dd, J=7.1, 2.2 Hz, 1H), 10.5 (s, 1H); MS (EI) m/z 289/291 (M)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc[nH]1
Reaction time: 72 h
Yield: 90.9 %

Procedure:
Lit. J. Org. Chem., 44:975 (1979). To a stirred solution of 5.0 g (45.0 mmol) pyrrole-2-carboxylic acid and 31.3 ml (225 mmol) triethylamine in 100 ml DMF was added dropwise 26 ml (225 mmol) benzyl bromide and stirring continued for 72 h at room temperature. The reaction mixture was then concentrated in vacuo and the residue resuspended in dichloromethane and washed twice with saturated sodium bicarbonate solution and twice with water, and the aqueous phases back-extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. Flash chromatography (25% EtOAc in hexane) afforded 8.23 g (90%) of the title compound as a yellow oil. MS m/e (%): 201 (M+, 33), 94 ([M−OBn]+, 22), 91 (Bn+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]=[C:13]2[C:18](=[O:19])[NH:17][NH:16][CH:15]=[C:14]2[N:20]=1.[OH:21]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:10])=[O:21])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]=[C:13]2[C:18](=[O:19])[NH:17][NH:16][CH:15]=[C:14]2[N:20]=1
Reactant: COc1cc(SC)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Reactant: OO
Solvent: CC(=O)O
Product: COc1cc(S(C)=O)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
An amount of 0.21 gm of 2-(2-methoxy-4-methylmercapto-phenyl)-5H-imidazo[4,5-d]pyridazin-4-one is suspended in 10 ml of glacial acetic acid and mixed with 0.08 ml of 30% hydrogen peroxide. The mixture is stirred for 24 hours at ambient temperature and poured onto 20 ml of ice water. It is then stirred until a precipitate has formed. This is subjected to suction filtration and purified by chromatography on silica gel [eluant: methylene chloride/ethanol (100:0 to 100:3)].
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[C:19]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)(=[O:21])[CH3:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[B-][N+](C)(C)C>C(O)(=O)C.CO.C1(C)C=CC=CC=1>[C:19]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:1][C:2]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)=[O:5])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [B-][N+](C)(C)C
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(=O)Nc1ccc(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 18 h

Procedure:
To a small sample of 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (0.01 g, 0.035 mmol) weighed out in a sealable vial toluene was added (200 μL), followed by 4-acetamidobenzaldehyde (0.006 g, 0.035 mmol) and pyridinium p-toluenesulfonate (catalytic amount). A few molecular sieves were added; then the vial was sealed and placed in a shaker at 75° C. After 18 h, the reaction mixture was treated with borane-trimethylamine complex (100 μL of a 1 M solution in acetic acid) and the vial was placed in the shaker at room temperature for an additional 5 h. The reaction mixture was then diluted with methanol and applied to a 0.5 g SCX column, washed with methanol and gravity-eluted with 1 N ammonia in methanol. The product fractions were combined and concentrated in vacuo to a residue which was triturated in acetonitrile to provide the title compound as a yellowish powder (0.015 g, 100%) in 98% purity by LC-MS (method A).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:14])SCCCS1.ClN1C(=[O:34])CCC1=O>C(#N)C.C(OCC)(=O)C.[N+]([O-])([O-])=O.[Ag+]>[O:34]=[C:7]([C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C2(c3ncccn3)SCCCS2)CC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C(=O)c2ncccn2)CC1
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl 4-{[2-(pyrimidin-2-yl)-1,3-dithian-2-yl]carbonyl}piperidine-1-carboxylate (0.51 g, 1.24 mmol) in acetonitrile (10 ml) was added quickly to a well stirred solution of N-chlorosuccinimide (1.10 g, 8.24 mmol) and silver nitrate (1.54 g, 9.06 mmol) in aqueous 80% acetonitrile (30 ml) at room temperature. The mixture was stirred 10 min, then diluted with ethyl acetate, and washed successively with aqueous Na2S2O3 (2 N), 2 N sodium carbonate and brine. The organic layer was separated, dried (MgSO4) and concentrated. The resulting residue was purified on a silica gel column (ethyl acetate/hexane) to give the title compound. LC-MS m/e 320.15 [M+1]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1)[CH2:2][CH3:3].[Cl:18]N1C(=O)CCC1=O>N1C=CC=CC=1>[Cl:18][C:8]1[S:13][CH:12]=[C:11]2[C:7](=[O:14])[N:6]([CH2:15][CH2:16][CH3:17])[C:5]([O:4][CH2:1][CH2:2][CH3:3])=[N:10][C:9]=12
Reactant: CCCOc1nc2ccsc2c(=O)n1CCC
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: CCCOc1nc2c(Cl)scc2c(=O)n1CCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
In a sulfonation flask, 2.02 g (0.008 mol) of 2-propoxy-3-propylthieno[3.2-d]pyrimidin-4-one are added, with stirring, to 10 ml of absolute pyridine. The internal temperature is then raised to 70° C. and then 1.60 g (0.012 mol) of N-chlorosuccinimide (NCS) are added over about 5 min in smallish portions. After stirring for 1 hour at 70-75° C., the pyridine is removed in a water-jet vacuum and the residue is taken up in ethyl acetate. The mixture is washed repeatedly with dilute aqueous hydrochloric acid, dried over sodium sulfate and then the solvent is removed in the water-jet vacuum. The crude product so obtained is purified by column chromatography over silica gel (eluant: n-hexane/ethyl acetate=9:1), giving 2.2 g of 7-chloro-2-propoxy-3-propylthieno[3.4-d]pyrimidin-4-one in the form of a green powder having a melting point of 93-95° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1[CH:24]=[C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)[CH:22]=[C:21]([CH3:29])[N:20]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:28][C:25]([C:23]3[CH:24]=[C:19]([CH3:18])[N:20]=[C:21]([CH3:29])[CH:22]=3)([OH:26])[CH3:27])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Cc1cc(C2(C)CO2)cc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cc(C)nc(C)c2)CCN(C)C1
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF and sodium hydride (120 mg, 3 mmol) was added. The reaction mixture was stirred for 10 min and 2,6-dimethyl-4-(2-methyloxiran-2-yl)pyridine (210.6 mg, 1.3 mmol) was added dropwise to it with constant stirring. The reaction mixture was stirred at RT overnight. The reaction mixture was poured on crushed ice and the precipitate obtained was filtered under vacuum; washed with water and hexane to obtain 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(2,6-dimethylpyridin-4-yl)propan-2-ol (260 mg), which was dissolved in DCM (3 mL) and cooled to 0° C. Thionylchloride (3 mL) was added dropwise to it and the reaction mixture cooled to RT. The reaction mixture was stirred at RT for 2 h. Thionylchloride was evaporated under vacuum by azeotropic distillation with DCM. 1N NaOH solution was added to basify (pH-12-13) the reaction mixture and extracted with EtOAc (40 mL×2). The organic layer was concentrated under vacuum to get the desired product. The crude compound was further purified through reverse phase HPLC. Yield: 13 mg (HCl salt). 1H NMR (CD3OD, D1-HCl salt) δ (ppm): 8.0 (s, 2H), 7.70 (s, 1H), 7.30 (s, 1H), 7.10 (s, 2H), 4.76 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.28 (m, 1H), 3.20 (m, 1H), 3.16 (s, 3H), 2.80 (s, 6H), 2.42 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:25][S:24][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][S:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:26]([OH:28])=[O:27])=O.[CH3:29][N:30]1[C:34]([SH:35])=[N:33][N:32]=[N:31]1>>[CH3:29][N:30]1[C:34]([S:35][CH2:5][C:6]2[CH2:25][S:24][C@@H:9]3[CH:10]([NH:13][C:14](=[O:15])[CH2:16][S:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[C:11](=[O:12])[N:8]3[C:7]=2[C:26]([OH:28])=[O:27])=[N:33][N:32]=[N:31]1
Reactant: Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CSc3ccncc3)[C@H]2SC1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)CSc3ccncc3)[C@H]2SC1

Procedure:
7-(2-(4-pyridylthio)acetamido)cephalosporanic acid is reacted with 1-methyl-1H-tetrazole-5-thiol, yielding 3-(((1-methyl-1H-tetrazol-5-yl)thio)methyl)-7-(2-(4-pyridylthio)acetamido)-3-cephem-4-carboxylic acid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][C:15](Cl)=[O:16])[CH:9]=[CH:10][C:11]=1[F:12]>C(=S)=S>[F:5][C:6]1[CH:7]=[C:8]2[C:9](=[CH:10][C:11]=1[F:12])[C:15](=[O:16])[CH2:14][CH2:13]2
Reactant: O=C(Cl)CCc1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCc2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a carbon disulfide solution (300 mL) containing AlCl3 (76.4 g, 572.6 mmol) at 0° C. was added a carbon disulfide solution (120 mL) of 3-(3,4-difluorophenyl)propanoyl chloride (33.4 g, 163.6 mmol) over 10 min. The solution was stirred for 30 min at 0° C. and heated to reflux for 4 hours. Upon cooling to room temperature the solution was carefully poured onto crushed ice. The carbon disulfide layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residual solid was purified by silica gel column chromatography (5-10% ethyl acetate/hexanes) yielding 19.3 g (114.9 mmol, 70% yield) of 5,6-difluoro-2,3-dihydro-1H-inden-1-one as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm 7.50 (t, 1H, J=8.0 Hz), 7.24 (t, 1H, J=6.6 Hz), 3.09 (t, 2H, J=5.5 Hz), 2.72-2.69 (m, 2H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[C@@H:7]([N:10]1[C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C@@H:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:13][C@H:12]([CH2:30][CH:31]=[CH2:32])[C:11]1=[O:33])[CH2:8][CH3:9])(=[O:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClC(Cl)C.O>[CH2:30]([C@H:12]1[CH2:13][C@H:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:10]([C@H:7]([C:6]2[O:3][C:1]([CH3:2])=[N:4][N:5]=2)[CH2:8][CH3:9])[C:11]1=[O:33])[CH:31]=[CH2:32]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)NNC(C)=O)C1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CC(Cl)Cl
Solvent: O
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)c2nnc(C)o2)C1=O

Procedure:
A solution of 58 mg (0.115 mmol) of (S)-N′-acetyl-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanehydrazide (Example 34, Step A) and Burgess' reagent (110 mg, 0.462 mmol) in dichloroethane (1154 μL) was heated in the microwave at 120° C. for 30 min. Then the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with sat. aq. NaCl and NaHCO3-solutions, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Separation by reversed phase HPLC (55 to 90% MeCN/H2O in 35 min, 29 mg injection each time) provided the title compound as a colorless film. MS (ESI) 484.1 [M+H]+.
Reaction SMILES: C(OC([N:6]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)[C:8]2([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][C:11](=[O:20])[NH:10][CH:9]2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:7]1=[O:35])=O)C.[OH-].[Na+]>CO>[Cl:34][C:31]1[CH:32]=[C:33]2[NH:6][C:7](=[O:35])[C:8]3([CH:13]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:12][C:11](=[O:20])[NH:10][CH:9]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:28]2=[CH:29][CH:30]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)NC(=O)CC2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(C2CCCCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Yield: 28.9 %

Procedure:
In a manner similar to the method described in example 4d, racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.2 g, 0.39 mmol) was reacted with NaOH (28 mg, 0.70 mmol) in methanol to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclohexylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.05 g, 29%).
Reaction SMILES: [H-].[Na+].[CH:3](Br)([CH3:5])[CH3:4].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24]>CN(C)C=O>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]([C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)Br
Reactant: Clc1cccc(Cl)c1Nc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(c1nc2ccccc2[nH]1)c1c(Cl)cccc1Cl
Yield: 7.3 %

Procedure:
In analogy to example 1, (1H-benzoimidazol-2-yl)(2,6-dichlorophenyl)amine (250 mg) was dissolved in dimethylformamide (3 ml), deprotonated with sodium hydride (43 mg) and alkylated with isopropyl bromide (111 mg) in a closed vessel at 100° C. for one hour. Workup and chromatography resulted in 21 mg of the desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.CCOC(C)=O>[N+:27]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([NH:39][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([CH2:17][CH2:16][CH2:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:19][CH:20]=2)(=[O:37])=[O:38])=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: O=C(O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reaction time: 65 h
Yield: 68.6 %

Procedure:
A mixture of 4-[3-(2-benzyloxyphenyl)propyl)benzoic acid 0.2 g), 4-nitrobenzenesulphonamide (0.12 g), DMAP (0.15 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g) was stirred for 65 hours. The mixture was diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate, to give the title compound (0.21 g) mpt. 112°-113° C.