Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:19])[C:3]([C:5]1[N:14]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=1)=[O:36])[CH2:31]2)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH:28]2[CH2:34][CH2:33][CH:32]1[CH2:31][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH:43][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[NH:2][CH3:19])[N:14]([CH:15]5[CH2:16][CH2:17][CH2:18]5)[C:8]=4[N:9]=3)=[CH:41][CH:42]=1)=[O:36])[CH2:29]2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCC1
Product: CNC(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCC1
Yield: 54.2 %

Procedure:
Following general N—C coupling procedure 1, 2-Chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.718 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (262 mg, 0.789 mmol, 1.1 eq) to give 3-[6-(7-Cyclobutyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (218 mg, 50% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H) 1.62 (br. s., 1H) 1.67 (br. s., 1H) 1.77-2.07 (m, 6H) 2.41-2.58 (m, 2H) 3.17 (s, 6H) 3.19-3.29 (m, 2H) 3.64 (br. s., 1H) 4.28 (br. s., 2H) 4.54 (br. s., 1H) 5.01 (dq, J=8.84, 8.67 Hz, 1H) 6.50 (s, 1H) 7.83 (dd, J=8.84, 2.27 Hz, 1H) 8.42 (d, J=2.02 Hz, 2H) 8.67 (d, J=9.09 Hz, 1H) 8.78 (s, 1H); MS m/z 574.9 (M+H)+.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[CH3:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[N:15]=1>COCCOCCOC>[CH3:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:17]=[C:18]([NH:22][C:3]3[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=3)[CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: CSc1nccc(=O)[nH]1
Reactant: Cc1nc(-c2cccc(N)c2)cs1
Solvent: COCCOCCOC
Product: Cc1nc(-c2cccc(Nc3nccc(=O)[nH]3)c2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To 2-(methyl-thio)pyrimidine-4(3H)-one, 1, (1 g, 14.08 mmol) in diglyme (9 mL) is added 3-(2-methylthiazol-4-yl)benzenamine (3.20 g, 16.90 mmol). The resulting mixture is heated to reflux and stirred for 18 hours. A solid forms upon cooling the mixture to room temperature. The solid is washed with hexanes to afford 1.0 g (25% yield) of the desired compound. MS (ESI, pos. ion) m/z: 285 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: OB(O)c1ccncc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(Cl)nc(Cl)nc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a degassed mixture of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), pyridin-4-ylboronic acid (1.1 equiv) and tripotassium phosphate trihydrate (3 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.33 M) was added palladium 1,1-bis(diphenylphosphino)-ferrocene dichloride (0.2 equiv). The reaction mixture was stirred at 100° C. for 2 h. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate in petroleum ether) to afford the desired product (40% yield) as a red solid. MS (ESI) m/z 395.1 [M+1]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([OH:28])[C:26]=1[OH:27])[CH:22]=[O:23]>>[CH2:2]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:28][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[C:26]=1[O:27][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[CH:22]=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: O=Cc1cc(O)c(O)c(O)c1
Product: CCCCCCCCCCCCCCCCOc1cc(C=O)cc(OCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCC

Procedure:
The title compound was prepared according to the method as described in Example 9 above from 1-bromohexadecane and 3,4,5-trihydroxy-benzaldehyde, except the reaction mixture was heated at reflux for 4 days. After cooling, the solid material was removed by filtration and the solid washed with dichloromethane. The combined organic extracts were evaporated under reduced pressure to yield the title compound which was recrystallised from dichloromethane-ethanol.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[C@@H:18]([CH3:21])[CH2:19][OH:20]>>[OH:20][CH2:19][C@H:18]([N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[CH3:21]
Reactant: C[C@H](Cl)CO
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)CO

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and (2S)-2-chloro-1-propanol: MS (ES) m/z 283 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)=[O:10])[CH2:3]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:7]2[CH2:6][CH2:5][N:4]([CH2:8][C:9]([NH:11][C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[N:17]4)=[O:10])[CH2:3][C@@H:2]2[CH3:1])(=[O:32])=[O:31])=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1
Product: C[C@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1S(=O)(=O)c1ccc(C#N)cc1

Procedure:
The title compound was prepared from the product of step (i) (1.4 g) and 4-cyanobenzenesulphonyl chloride (1 g) by the method of Example 58 step (ii) as a white solid. Yield: 0.53 g
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[CH:8]([O:10][C@@H:11]1[C@@H:15]([O:16][CH:17]=[O:18])[C@H:14]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([NH:34][CH2:35][CH2:36][C:37]2[N:38]=[CH:39][N:40]([CH3:42])[CH:41]=2)=[N:23][C:24]=3NC(CC)CC)[O:13][C@@H:12]1[C:43]1[O:47][N:46]=[C:45]([CH2:48][CH3:49])[CH:44]=1)=[O:9]>>[CH:17]([O:16][C@@H:15]1[C@@H:11]([O:10][CH:8]=[O:9])[C@@H:12]([C:43]2[O:47][N:46]=[C:45]([CH2:48][CH3:49])[CH:44]=2)[O:13][C@H:14]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([NH:34][CH2:35][CH2:36][C:37]1[N:38]=[CH:39][N:40]([CH3:42])[CH:41]=1)=[N:23][C:24]=2[NH:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])=[O:18]
Reactant: CCc1cc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(NCCc5cn(C)cn5)nc43)[C@H](OC=O)[C@H]2OC=O)on1
Reactant: CC(C)(C)CCN
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(NCCC(C)(C)C)nc(NCCc5cn(C)cn5)nc43)[C@H](OC=O)[C@H]2OC=O)on1

Procedure:
Example 7 was prepared in an analogous manner to Example 4 using 3,3-dimethylbutylamine (0.006 g, 0.056 mmol) and 2-(1-methyl-1H-imidazol-4-yl)ethylamine (0.035 g, 0.28 mmol; generated as in Example 5) at 90° C. for 5 days. The title compound was afforded after freeze-drying as a brown solid (0.007 g). LC/MS SYSTEM A Rt=3.80 mins, m/z=540 MH+.
Reaction SMILES: [CH2:1]([C:8]1[CH:19]=[CH:18][C:11]([O:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br>C(Cl)Cl.C(N(CC)CC)C>[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][N:15]1[CH2:16][CH2:17][C@@H:13]([O:12][C:11]2[CH:18]=[CH:19][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:14]1
Reactant: COC(=O)CCCBr
Reactant: c1ccc(Cc2ccc(O[C@@H]3CCNC3)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCN1CC[C@@H](Oc2ccc(Cc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
To a solution of (R)-3-(4-Benzyl-phenoxy)-pyrrolidine (126 mg, 0.5 mmol) in anhydrous CH2Cl2 (0.5 mL) was added methyl-4-bromobutyrate (99 mg, 0.55 mmol) in CH2Cl2 (0.5 mL) and triethylamine (101 mg, 1.0 mmol. The resulting mixture was purged with nitrogen and stirred at rt for 16 h. CH2Cl2 was removed in vacuo and crude mixture was partioned between EtOAc and water. EtOAc layer was removed, washed with brine, dried over anhydrous MgSO4 and concentrated. The crude mixture was purified by silica gel flash chromatography (40% EtOA /Hexane) to obtain the product as yellow solid (71 mg, 40%): MS; m/z 354.5 (M+H); 1H NMR (400 MHz, DMSO-d6); δ 1.65-1.72 (m, 2H), 2.18-2.39 (m, 4H), 2.54-2.63 (m, 5H), 2.78-2.82 (m, 1H), 3.57 (s, 3H), 3.85 (s, 2H), 5.78 (m, 1H), 6.78 (d, 2H, J=8.8 Hz), 7.11 (d, 2H, J=8.4Hz), 7.16-7.29 (m, 5H); HPLC (ELSD); 99%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[CH:21][S:20][C:18]=2[N:19]=1>C1COCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([O:12][C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[CH3:3])[C:17]2[CH:22]=[CH:21][S:20][C:18]=2[N:19]=1
Reactant: Clc1nc(Cl)c2ccsc2n1
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(Oc2nc(Cl)nc3sccc23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A stirred suspension of NaH (9.5 mg, 0.24 mmol) in dry THF (1 mL) was added 2,4,6-trimethyl phenol (32.1 mg, 0.24 mmol) and stirred at room-temperature for 30 min under Argon. The reaction mixture was added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (48.1 mg, 0.24 mmol) in dry THF (1.5 mL) at 0° C. and allow it to slowly warmed up to room temperature. After stirring the reaction for 4 h, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (9:1) to give the product as a white solid (71 mg, 97%):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].[OH-].[K+].Cl[CH2:22][C:23]([OH:25])=[O:24]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:12][CH2:13]1)=[O:7]
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OC
Reactant: O=C(O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)N2CCN(CC(=O)O)CC2)cc1OC
Temperature: 50 °C

Procedure:
32 Grams of 4-(3,4-dimethoxybenzoyl)piperazine and 13.1 g of potassium hydroxide were dissolved in 300 ml of dimethylformamide (DMF), then under an ice-cooled condition with stirring, 10 g of α-chloroacetic acid was added thereto, next the reaction mixture was heated at 50° C. for 5 hours with stirring. After completion of the reaction, the reaction mixture was concentrated to dryness, the residue obtained was dissolved in water. The solution obtained was washed with chloroform, the aqueous layer was neutralized with concentrated hydrochloric acid, crystals formed were collected by filtration to obtain 9.8 g of α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]3[C:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([C@H:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:25]([OH:27])=[O:26])[C:14]([CH3:33])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:40](I)[CH3:41]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]3[C:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([C@H:24]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:25]([O:27][CH2:40][CH3:41])=[O:26])[C:14]([CH3:33])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Cc1cc2nc(-c3cccc(Br)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(Br)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of (S)-2-(2-(3-bromophenyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid (104 mg, 0.191 mmol) in DMF, was added Cs2CO3 (152 mg, 0.467 mmol), ethyl iodide (30 μL, 0.343 mmol). The reaction was stirred at room temperature for 2hs. The reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, dry over MgSO4, filtered, purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C28H27BrClNO3S: 572.1 (M+H+); Found: 572.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[Ca+2].[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1)=[C:15]=[S:16]
Reactant: Nc1ccc(S)cc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: S=C=Nc1ccc(S)cc1
Temperature: 35 °C

Procedure:
A solution of 4-aminothiophenol (7.00 g, 0.056 mol) in chloroform (75 ml) was added to a stirred, cooled (0° C.) solution of water (40 ml), chloroform (20 ml), calcium carbonate (6.60 g, 0.066 mol), and thiophosgene (6.95 g, 0.060 mol) at 0°-5° C. The mixture was heated at 35° C. for 1 hour and poured into water (50 ml) before separating the two layers. The organic layer was washed with hydrochloric acid (1%, 100 ml) and dried (MgSO4). The solvent was removed in vacuo to afford an orange semi-solid which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10].[Br:14]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(=O)c1ccccc1C
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=O)c1ccccc1CBr
Yield: 49.3 %

Procedure:
5.34 g (30 millimoles) of methyl 2-methylphenylglyoxylate and 5.34 g (30 millimoles) of N-bromosuccinimide in 1000 l of tetrachloromethane are exposed to a 300 W Hg vapor lamp for one hour. The organic phase is then washed once with water and three times with sodium bicarbonate solution and is dried over sodium sulfate/sodium carbonate. After the solution has been evaporated down, the crude product is chromatographed over silica gel using 1:9 methyl tert-butyl ether/n-hexane. 3.8 g (49%) of the abovementioned compound are obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.[Br:21]Br.O>O>[Br:21][C:18]1[C:17]([Cl:20])=[CH:16][C:5]2[N:6]([C@@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[C:2]([Cl:1])=[N:3][C:4]=2[CH:19]=1
Reactant: BrBr
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(Cl)cc32)[C@H](O)[C@@H]1O
Solvent: O
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Br)c(Cl)cc32)[C@H](O)[C@@H]1O
Reaction time: 3 h

Procedure:
To a suspension of 0.319 g (1.0 mmol) of 2,6-dichloro-1-β-D-ribofuranosylbenzimidazole (67) in 10 mL of H2O, was added dropwise a sat. solution of Br2 /H2O at room temperature. After the addition had been completed, stirring was continued for 3 hr. The reaction mixture was filtered and the solid was washed with portions of H2O, and then recrystallized from MeOH to give 0.335 g (78%, as M MeOH) of 95 as white crystalline needles. MP 140°-142° C. MS (El) m/e 395.9274 (2%, M+ =395.9279). 1H NMR (DMSO-d6): δ8.88 (s, 1,7-H), 8.08 (s, 1,4-H), 5.89 (d, 1,1'-H, J1'-2' =8.0 Hz), 5.49 (d, 1,2'-OH, J2'-2'OH =6.5 Hz), 5.40 (t, 5'-OH, J5'-5'OH =4.0 Hz), 5.28 (d, 1,3'-OH, J3'-3'OH =4.5 Hz), 4.42 (m, 1,2'-H, J2'-3' =5.5 Hz), 4.13 (m, 1,3'-H, J3'-4' =1.5 Hz), 4.01 (m, 1,4'-H, J4'-5' =2.5 Hz), 3.70 (m, 2,5'-H and 5"-H, J5'-5" =12.0 Hz). Anal. Calcd. for C12H11BrCl2N2O4MeOH: C, 36.30; H, 3.51; N, 6.51. Found: C, 35.98; H, 3.60; N, 6.39.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([N+:23]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[C:13]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([NH2:23])[CH:3]=1
Reactant: Cc1c(Cn2cnc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Cc1c(Cn2cnc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of 4-bromo-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (2.5 g, 6.04 mmol) in Methanol (30 mL) in a 250 ml round bottomed flask was added Tin(II)chloride dihydrate (8.17 g, 36.2 mmol) and HCl (1.65 mL, 54.3 mmol). The reaction mixture was left to stir at 80° C. for 1 h. The solvent was removed and diluted with water (100 mL) and this solution was decanted into a 250 mL Erlenmeyer flask. The brown residue in the round bottomed flask was dissolved in 100 mL of EtOAc and washed with 1N NaOH, brine, dried and evaporated to yield a brown solid. The water layer was extracted with EtOAc, washed with 1N NaOH, brine, dried (MgSO4) and evaporated to a brown solid. The solids found to be identical by 1 cms and were combined to yield 4-bromo-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (2.28 g, 5.93 mmol, 98% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.44 (s, 3H) 5.24 (s, 2H) 6.39 (d, J=2.02 Hz, 1H) 6.87 (d, J=8.08 Hz, 1H) 6.92 (d, J=2.02 Hz, 1H) 7.21 (t, J=7.83 Hz, 1H) 7.62 (d, J=7.83 Hz, 1H) 7.69 (s, 1H); LC/MS: MS (ES+) m/e 385 [M+H]+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C@@H:6]2[C@@H:23]([O:24][CH3:25])[C:22](=[O:26])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:32]>CN(C=O)C.C(Cl)Cl>[CH2:1]([S:3]([C:4]1[S:5][C@@H:6]2[C@@H:23]([O:24][CH3:25])[C:22](=[O:26])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)=[O:10])=[O:32])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](OC)[C@H]2S1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](OC)[C@H]2S1
Reaction time: 1 h

Procedure:
A solution of p-nitrobenzyl (5R,6S)-2-ethylthio-6-methoxy-pen-2-em-3-carboxylate (96 mg, 0.24 mmol) in anhydrous DMF (1.2 ml) is diluted with CH2Cl2 (2.4 ml) and cooled in an ice-bath. A solution of 85% m-chloroperoxybenzoic acid (51 mg, 0.25 mmol) in CH2Cl2 (1.2 ml) is added dropwise over 2 minutes to the cold, stirring solution. The resulting mixture is kept at 0° for 60 minutes, and then treated with excess Amberlyst-21 resin and stirred and additional 5 minutes. The mixture is filtered and the filtrate is diluted with CH2Cl2 and washed with 5 portions of H2O. The organic phase is dried over MgSO4, filtered, and evaporated under vacuum to give a crude residue of the title compound which is purified by rapid chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].[Cl:7][C:8]([O:11]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.N1C=CC=CC=1>CCOCC>[Cl:7][C:8]([O:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])=[O:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COCC(C)O
Solvent: c1ccncc1
Solvent: CCOCC
Product: COCC(C)OC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml (10.2 mmol) of 1-methoxy-2-propanol (Fluka, Buchs, Switzerland) is injected slowly into an ice-cold solution of 916 mg (1.1 equivalent) of bis(trichloromethyl)carbonate (triphosgene; Fluka, Buchs, Switzerland) in 35 ml of ether using a syringe. At the same time, 1 ml (1.2 equivalents) of pyridine in 5 ml of ether is added dropwise from a dropping funnel. After the addition has ended, the mixture is left to stir at RT for a further 60 min. The reaction mixture is filtered through wadding and the solvent is carefully evaporated off (35° C. waterbath). The oily residue (title compound) is subjected to further processing without any purification. 1H-NMR (200 MHz; CDCl3)=inter alia 5.05/m (1H); 3.30/s (3H); 1.27/d (3H).
Reaction SMILES: [CH3:1][C:2]1([CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:21][NH:22][CH3:23].[Cl-].[Na+]>O1CCCC1>[OH:17][CH2:18][CH2:19][CH:15]([C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:16]([N:22]([CH3:23])[CH3:21])=[O:20]
Reactant: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21
Reactant: CNC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)C(CCO)C1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A solution of the oil containing the two diasteriomers of dihydro-3-(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)-2(3H)-furanone (described in Example 1, 15 g, 0.055 mole) in tetrahydrofuran (200 ml) and an aqueous solution of dimethylamine (40%, 200 ml) is refluxed for 24 hr. Aqueous sodium chloride solution is added and the solution is extracted with diethyl ether. The organic extract is dried and evaporated to afford an oil consisting of two diastereoisomeric amides of the title compound. The oil is subjected to chromatography on silica gel using acetone-benzene (1:3). The eluates are evaporated and crystallized from benzene-hexane to obtain isomer A of the title compound as crystals (4.5 g), mp 158°-160° C. Further elution of the column with acetone-benzene (1:1), evaporation of the eluates and crystallization of the residue from benzene-hexane gives isomer B of the title compound as crystals (1.5 g), mp 159°-162° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](F)[CH:6]=1>O.CN(C)C=O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([S:2][CH3:1])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of sodium methanethiolate (2.25 g, 70.1 mmol) in water (50 mL) was added dropwise to a solution of 4-bromo-2-fluoro-1-nitrobenzene (6.42 g, 29.2 mmol) in N,N-dimethylformamide (150 mL) at 0° C. and the mixture was stirred for 1 hour. The mixture was filtered and the solid washed with water (3×150 mL) to give the title compound.