Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:18][CH:14]4[CH2:15][CH:16]([CH2:17]2)[C:12]([NH2:19])([CH2:13]4)[CH2:11]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.O>[CH2:26]([O:33][C:34](=[O:35])[NH:19][C:12]12[CH2:13][CH:14]3[CH2:18][C:10]([C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=4)([CH2:17][CH:16]1[CH2:15]3)[CH2:11]2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2)OCc1ccccc1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a stirred mixture of 1-(4-nitrophenyl)tricyclo[3.3.1.03,7]nonan-3-amine (2.0 g, 8.0 mmol) obtained in step III, K2CO3 (3.5 g, 24 mmol) in THF (80 mL), cooled to ice-bath temperature was added benzylchloroformate (50% w/v in Toluene, 2.2 mL, 12 mmol). After stirring the reaction mixture at r.t for 2 h, it was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain benzyl[2-(4-nitrophenyl)hexahydro-2,5-methanopentalen-3a(1H)-yl]carbamate as an off-white solid (2.1 g) in 70% yield. M.R: 104.1-105.9° C.; m/z (M+1) 393; IR cm−1 3440, 2952, 1714, 1518, 1349, 1216, 757; 1H NMR (CDCl3) 300 MHz δ 8.12 (d, J=8.8 Hz, 2H), 7.50-7.27 (m, 7H), 5.20-5.0 (s (br), 2H), 2.65-2.55 (m, 1H), 2.50-1.55 (m, 11H). 13C NMR (CDCl3) 75 MHz δ 155.1, 154.2, 146.1, 136.4, 131.1, 128.5 (2C), 128.1 (2C), 126.6 (2C), 123.4 (2C), 66.3, 64.4, 49.248.0, 47.5, 43.8, 42.1, 40.8, 37.0.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[I:25]I.Cl>CCCCCC.C1COCC1>[CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([F:19])[C:15]([I:25])=[C:16]([F:18])[CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: II
Reactant: CCCCCC1CCC(c2cc(F)cc(F)c2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC1CCC(c2cc(F)c(I)c(F)c2)CC1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of (4-pentyl-cyclohexyl)-3,5-difluorobenzene (10 mmol) and 150 ml of THF, was added dropwise 7.5 ml of a solution of n-butyl lithium (corresponding to 12 mmol) in hexane while keeping them at a temperature lower than −70° C., and stirred at the same temperature for 30 min. While keeping the solution at a temperature lower than −70° C., iodine (30 mmol) was added thereto. Then, the solution was stirred for 1.5 hours, temperature of the solution was gradually backed up to room temperature, and then the solution was stirred for 2 hours. After 12 ml of 1N hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted once with toluene and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: heptane) to give a (4-pentyl-cyclohexyl)-3,5-difluoro-4-iodobenzene (8.3 mmol).
Reaction SMILES: [OH-].[Na+].C([C:5]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)([CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([O-:8])=[O:7])C.O.Cl>CO>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([CH:5]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]([OH:8])=[O:7])=[CH:19][CH:18]=1
Reactant: CCC(C(=O)[O-])(c1ccc(Br)cc1)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(c1ccc(Br)cc1)C1CCCC1

Procedure:
386 ml (96.4 mmol) of 10% strength aqueous sodium hydroxide solution were added to a solution of 30 g (96.4 mmol) of (+/−)-ethyl(4-bromophenyl)(cyclopentyl)acetate in 655 ml of methanol, and the mixture was heated under reflux for 3 h. After cooling, the solution was stirred into 2 liters of water, adjusted to pH 1-2 by addition of dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and concentrated. This gave 27.2 g (92% of theory) of the title compound.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:19]CCOCC1C=CC=CC=1>>[CH2:5]([O:6][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:10]=[CH2:19])[CH:12]=1)[C:4]1[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=1
Reactant: O=Cc1cccc(O)c1
Reactant: BrCc1ccccc1
Reactant: BrCCCOCc1ccccc1
Product: C=Cc1cccc(OCc2ccccc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 20 using 3-hydroxybenzaldehyde and benzyl bromide instead of 4-hydroxybenzaldehyde and benzyl 3-bromopropyl ether, respectively.
Reaction SMILES: [CH3:1][CH:2]([CH:6]1[C:10]2=[C:11]([S:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:12]3[C:13]([CH:23]([CH3:25])[CH3:24])=[CH:14][C:15]([C:18]4[N:19]=[N:20][NH:21][N:22]=4)=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH2:34]1COCC1>>[CH3:1][CH:2]([CH:6]1[C:10]2=[C:11]([S:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:12]3[C:13]([CH:23]([CH3:24])[CH3:25])=[CH:14][C:15]([C:18]4[N:19]=[N:20][N:21]([CH3:34])[N:22]=4)=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH3:1][CH:2]([CH:6]1[C:10]2=[C:11]([S:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:12]3[C:13]([CH:23]([CH3:24])[CH3:25])=[CH:14][C:15]([C:18]4[N:19]([CH3:34])[N:20]=[N:21][N:22]=4)=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4]
Reactant: C1CCOC1
Reactant: CC(C)c1cc(-c2nn[nH]n2)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1C(C)C(=O)[O-]
Product: CC(C)c1cc(-c2nnn(C)n2)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1C(C)C(=O)[O-]
Product: CC(C)c1cc(-c2nnnn2C)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1C(C)C(=O)[O-]
Reaction time: 0.08 h

Procedure:
A solution of the compound of Step 1 in THF (10 mL) was treated with an excess of CH2N2 at 0° C. The reaction mixture was stirred for 5 minutes and the solvent removed. The residue was purified by silica gel chromatography eluted with 50% EtOAc/hexane to give 65 mg of (+/−)-methyl[9-[(4-chlorophenyl)thio]-8-isopropyl-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate and 150 mg of (+/−)-methyl[9-[(4-chlorophenyl)thio]-8-isopropyl-6-(1-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1.[OH2:26]>C(Cl)Cl>[CH2:1]([S:3]([CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[O:23])=[O:26])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: CCSCc1cccc(NC(C)=O)c1
Solvent: ClCCl
Product: CCS(=O)(=O)Cc1cccc(NC(C)=O)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of N-(3-(ethylthiomethyl)phenyl)acetamide (1 g, 5 mmol) in DCM (10 mL) was added mCPBA (2.4 g, 14 mol). The reaction mixture was stirred at 40° C. overnight. Then water was added, the organic layer was separated and washed with an aqueous of NaHCO3, dried over Na2SO4, concentrated and purified by silica gel chromatography (petroleum ether:EtOAc=1:0 to 5:1) to give N-(3-(ethylsulfonylmethyl)phenyl)acetamide (1 g, 87% yield) as a white solid. 1H NMR: (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.61 (s, 1H), 7.41 (d, 1H), 7.24 (t, 1H), 7.14 (d, 1H), 4.14 (s, 2H), 2.90-2.85 (m, 2H), 2.12 (s, 3H), 1.34 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:29][CH:26]2[CH2:28][CH2:27]2)=[O:11])[CH:7]=1
Reactant: NC1CC1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NC2CC2)c1
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (500 mg, 1.4 mmol) and cyclopropyl amine (0.5 ml, 7 mmol) in DMF (5 ml), added PyBOP (730 mg, 1.4 mmol) then triethyl amine (0.4 ml, 3 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as white powder. MS calcd for (C18H20BN3O5S): 401.12. MS found (ESI negative): (M−H)−=400.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.84 (s, 1H), 8.14 (d, J=4 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.11 (dd, J=8.4 Hz, 1H), 6.43 (d, J=2 Hz, 1H), 6.36 (dd, J=8.4 Hz, 1H), 4.88 (s, 2H), 3.74 (s, 2H), 2.67 (m, 1H), 0.64 (m, 2H), 0.44 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[C:22]([N:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:27]1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:55])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[NH2:54])=C[CH:41]=1>CN(C=O)C.C(Cl)Cl>[CH3:25][N:24]([C:22]1[CH:21]=[CH:20][C:16]([C:17]([NH:54][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[C:47]([NH:46][C:43]2[CH:44]=[CH:45][C:40]([Cl:39])=[CH:41][N:27]=2)=[O:55])=[O:19])=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:23]=1)[CH3:26]
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Reactant: CN(C)c1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
To a mixture of 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(N,N-dimethyl-amino)benzoic acid (950 mg, 2.61 mmol), pyridine (0.23 mL, 2.86 mmol), DMF (1 drop) and methylene chloride (15 mL) was added oxalyl chloride (0.24 mL, 2.73 mmol) dropwise. After 15 minutes, more pyridine (0.23 mL, 2.86 mmol) was added, followed by the N-(4-chlorophenyl)-2-aminobenzamide (645 mg, 2.61 mmol). The reaction was stirred for 1 hour, diluted with methylene chloride, washed with 50% saturated aqueous sodium bicarbonate, and dried over Na2 SO4. The organic solution was concentrated, chromatographed (2000 g silica, 5% EtOAc/CH2Cl2 to 15% EtOAc/CH2Cl2), and triturated with ether to give the desired product (1.32 g, 83%).
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[OH:13]O>O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[N+:1]1([O-:13])[C:2]([C:10]([OH:12])=[O:11])=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: OO
Reactant: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc(C(=O)O)[n+]1[O-]
Temperature: 90 °C

Procedure:
50 g of pyridine-2,6-dicarboxylic acid was suspended in 275 g of water. 47 g of 30% hydrogen peroxide aqueous solution and 2.8 g of sodium tungstate were added to the resulting suspension. The suspension was heated to a temperature of 90° C. for 24 hours. As a result, the carboxylic acid as starting material was gradually dissolved in the aqueous solution during heating, and fresh crystals were then deposited. 24 g of 30% hydrogen peroxide aqueous solution was further added to the solution. The solution was heated for 12 hours and then allowed to cool to obtain 48 g of colorless prismatic creptais of pyridine-2,6-dicarboxylic acid N-oxide.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([CH3:15])[CH3:14])=[O:5])#[N:2].CO[C:18](OC)([N:20]([CH3:22])[CH3:21])[CH3:19]>>[C:1](/[C:3](=[C:18](/[N:20]([CH3:22])[CH3:21])\[CH3:19])/[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([CH3:15])[CH3:14])=[O:5])#[N:2]
Reactant: CC(C)c1ccccc1NC(=O)CC#N
Reactant: COC(C)(OC)N(C)C
Product: C/C(=C(\C#N)C(=O)Nc1ccccc1C(C)C)N(C)C

Procedure:
As for Example 1, 2-cyano-2'-isopropylacetanilide, off-white crystals, m.p. 74°-78° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylacetamide dimethylacetal to yield 2-cyano-3-dimethylamino-2'-isopropylcrotonanilide as colorless prisms, m.p. 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.[C:19](OC(=O)C)(=[O:21])[CH3:20].Cl>O1CCCC1.C(OCC)C>[C:19]([C:8]1[S:7][C:6]2[C:10]([Cl:11])=[C:2]([Cl:1])[C:3]([O:12][CH3:13])=[CH:4][C:5]=2[CH:9]=1)(=[O:21])[CH3:20]
Reactant: COc1cc2ccsc2c(Cl)c1Cl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2cc(C(C)=O)sc2c(Cl)c1Cl
Reaction time: 2 h

Procedure:
To a solution of 5.0 g of 6,7-dichloro-5-methoxybenzo[b]thiophene in 30 ml of dry tetrahydrofuran and 10 ml dry ethyl ether under nitrogen at -20° is added 11.7 ml of 2.2M n-butyllithium, while the temperature is maintained at -20°. After stirring for 2 hours at this temperature, the reaction mixture is added dropwise through a transfer needle to a stirred solution of 22 ml of freshly distilled acetic anhydride in 40 ml of dry tetrahydrofuran at -20°. Five minutes after the addition, the reaction mixture is poured onto 100 ml 10% hydrochloric acid. The mixture is extracted twice with dichloromethane, the organic layers are collected and dried and the solvent is removed to give a solid. The solid is washed with ethyl ether to give 1.5 g of 2-acetyl-6,7-dichloro-5-methoxybenzo[b]thiophene as a fluffy solid. Recrystallization of the residue obtained by evaporation of the filtrate from ethyl ether-hexane gives an additional 0.6 g of 2-acetyl-6,7-dichloro-5-methoxybenzo[b]thiophene.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][CH2:19][C:20](Cl)=O>C1(C)C=CC=CC=1>[Cl:18][CH2:19][C:20]1[O:10][N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: O=C(Cl)CCl
Reactant: NC(=NO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClCc1nc(-c2ccccc2)no1
Temperature: 25 °C

Procedure:
A solution of benzamidoxime (0.77 g, 5.68 mmol) and triethylamine (0.95 mL, 0.82 mmol) in toluene (10 mL) was treated with 0.45 mL (5.65 mmol) of chloroacetyl chloride at room temperature for 30 min., refluxed for 18 hours, cooled to room temperature and concentrated in vacuo. The residue was diluted with water, and extracted with ethyl acetate. The organic extracts were then washed with water and dried with MgSO4. Concentration in vacuo gave an oil which was chromatographed on silica gel using ethyl acetate, hexanes (1.9), giving 0.24 of the title compound as a light yellow oil which solidified on standing. 1H NMR (250 MHz, CDCl3) δ 8.1 (m, 2H), 7.5 (m, 3H), 4.8 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[O:19]C[N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C@H:16]2[CH:30]([CH3:32])[CH3:31])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20]([NH:17][C@@H:16]([CH:30]([CH3:32])[CH3:31])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:19])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)[C@@H]1N(C(=O)OCc2ccccc2)COC1(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.2 %

Procedure:
In tetrahydrofuran (4 mL) was dissolved (4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-isopropyl-5-hydroxyoxazolidine (1.38 g) prepared in Example 8, and to the solution were added water (5 mL) and conc. hydrochloric acid (2 mL). The mixture was stirred at room temperature for 24 hours. The reaction was diluted with toluene and the aqueous layer was discarded. The organic layer was washed with water three times. The organic layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=2/1) to give the title compound (466 mg) as pale yellow crystals in a yield of 36%.
Reaction SMILES: ClC1C(C([CH2:10][C:11]([O:13][CH3:14])=[O:12])=S)=CC(N=C2N3N(CCCC3)C(=O)S2)=C(F)C=1.[Cl:27][C:28]1[CH:36]=[C:35]([F:37])[C:34]([N+:38]([O-:40])=[O:39])=[CH:33][C:29]=1[C:30](Cl)=[O:31].COC(=O)C[SH:45]>C(OCC)(=O)C>[CH3:14][O:13][C:11]([CH2:10][O:31][C:30](=[S:45])[C:29]1[CH:33]=[C:34]([N+:38]([O-:40])=[O:39])[C:35]([F:37])=[CH:36][C:28]=1[Cl:27])=[O:12]
Reactant: COC(=O)CC(=S)c1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl
Reactant: COC(=O)CS
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: CCOC(C)=O
Product: COC(=O)COC(=S)c1cc([N+](=O)[O-])c(F)cc1Cl
Reaction time: 18 h

Procedure:
The preparation of 9-[4-chloro-2-fluoro-5-(methoxycarbonylmethylthiocarbonyl)-phenylimino]-8-thia-1,6-diazabicyclo[4.3.0]nonan-7-one is given by way of example: ##STR22## 48 g of 2-chloro-4-fluoro-5-nitrobenzoic acid chloride are added dropwise, with stirring, at room temperature to a solution of 20 ml of thioglycolic acid methyl ester in 100 ml of ethyl acetate. The batch is stirred for 18 hours and then the solvent is evaporated off in vacuo to yield 19 g of 2-chloro-4-fluoro-5-nitrothiobenzoic acid (methoxycarbonylmethyl) ester in the form of an oil having nD23 : 1.5709.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([OH:13])[CH:10]=[C:11]([CH3:12])[C:5]=2[N:4]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([O:13][C:9]2[CH:10]=[C:11]([CH3:12])[C:5]3[N:4]=[C:3]([O:2][CH3:1])[NH:7][C:6]=3[CH:8]=2)[CH:20]=1
Reactant: COc1nc2c(C)cc(O)cc2[nH]1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
74 mg (0.42 mmol) 2-methoxy-4-methyl-1H-benzo[d]imidazol-6-ol and 68 mg (0.44 mmol) 4,6-dichloropyrimidine were placed in 2.0 mL DMF. 0.12 g (0.88 mmol) potassium carbonate were added and the mixture was stirred for 4 h at 50° C. The reaction mixture was combined with ice water, the substance was extracted with ethyl acetate and evaporated down i.vac.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1.[OH:12][CH2:13][CH:14]([CH2:17]O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]([CH:7]2[O:12][CH2:13][CH:14]([CH2:15][OH:16])[CH2:17][O:8]2)=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Reactant: OCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1ncc([N+](=O)[O-])c1C1OCC(CO)CO1
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (718 mg, 4.63 mmol, intermediate 3) in toluene (100 mL) was added 2-(hydroxymethyl)propane-1,3-diol (700 mg, 6.73 mmol) followed by p-toluenesulfonic acid (88 mg, 0.463 mmol). The reaction mixture was heated at reflux for 18 hr whilst azeotropically removing the water. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and washed with a saturated aqueous NaHCO3 (50 mL). The organic layer was washed with water (20 mL) and brine (20 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methanol (trans isomer) as the first eluting isomer as a colourless solid (220 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 6.42 (s, 1H), 4.34 (dd, J=11.6, 4.7 Hz, 2H), 4.12 (s, 3H), 3.81 (t, J=11.5 Hz, 2H), 3.56 (t, J=5.1 Hz, 2H), 2.53-2.38 (m, 1H), 1.67 (t, J=4.6 Hz, 1H).
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=C[CH:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])[O:22][CH2:23][CH3:24]>C(O)C>[CH2:2]([O:20][CH:19]([O:22][CH2:23][CH3:24])[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1)[CH3:3]
Reactant: CCOC([O-])[O-]
Reactant: O=Cc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(OCC)c1ccncc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.2 %

Procedure:
p-Toluenesulfonic acid monohydrate (11.8 g, 62.0 mmol) was dissolved in dry ethanol (80 mL) at rt. 4-Pyridinecarboxaldehyde (4.71 mL, 50.0 mmol) was added, followed by ethyl orthoformate (20.79 mL, 125.0 mmol). The mixture was stirred at rt for 17 hours. The mixture was concentrated and the residue was basified with aqueous saturated NaHCO3 solution to ˜pH 8, extracted with EtOAc (150 mL), washed with brine, dried over Na2SO4, filtered, evaporated, and dried under high vacuum to give a liquid product. (9.06 g, yield 97.2%). LCMS: (FA) ES+ 182. 1H NMR (400 MHz, CDCl3) δ: 8.60-8.62 (m, 2H), 7.38-7.40 (m, 2H), 5.50 (s, 1H), 3.53-3.62 (m, 4H), 1.23-1.27 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[C:31]([OH:33])=O)[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.O[N:40]1C2C=CC=CC=2N=N1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19][C@H:18]2[C:31]([NH2:40])=[O:33])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A 3 L round bottom flask was charged with (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (75.5 g, 0.158 mol), EDC*HCl (33.5 g, 0.175 mol), 1-hydroxybenzotriazole (23.6 g, 0.175 mol), and dichloromethane (1 L). The reaction was stirred at room temperature for 2 h, during which time it changed from a white suspension to a clear solution. Ammonia (gas) was bubbled into the solution until the pH was strongly basic (paper) and the reaction was stirred for 10 min; this ammonia addition was repeated and the reaction was stirred for an additional 10 min. Water was added. The organic phase was washed with sat. NaHCO3, NaH2PO4, and brine before being concentrated in vacuo. The residue was slurried with acetonitrile (0.5 L) and then concentrated in to give (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxamide as a white solid (75.9 g, ˜100%), which was used in the next step without further purification. LC/MS for primary peak: [M-Boc+H]+=375.3; [M±H]+=475.4; [M-tBu+H]+=419.3. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.25 (m, 2H), 3.70 (m, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 2.91 (m, 1H), 2.38 (m, 1H), 2.12 (m, 1H), 1.9-2.05 (m, 2H), 1.65-1.9 (m, 4H), 1.46 (s, 9H).