Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CNC(=O)CCNC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCNC1
Yield: 89.9 %

Procedure:
To a solution of 1.84 g of 3-(benzyloxycarbonyl)amino-N-({(3R)-1-(tert-butoxycarbonyl)-3-piperidyl}methyl)propanamide in 2 ml of chloroform, 2 ml of trifluoroacetic acid was added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was distilled off under reduced pressure, and the residue was rendered basic with, 4N aqueous sodium hydroxide solution. Extracting the product with chloroform, the product was dried over anhydrous sodium sulfate. Upon distilling the solvent off under reduced pressure, 1.26 g of the title compound was obtained.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14]1>>[OH:19][CH2:18][CH:15]1[CH2:16][CH2:17][N:13]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: OCC1CCNC1
Reactant: CCOC(=O)c1ccc(F)cc1
Product: CCOC(=O)c1ccc(N2CCC(CO)C2)cc1

Procedure:
Ethyl 4-fluorobenzoate and pyrrolidin-3-ylmethanol were coupled following the procedure outlined in example 28 to give ethyl 4-[3-(hydroxymethyl)pyrrolidin-1-yl]benzoate. MS (ESI): 250.0 (M+H). A similar reaction sequence as outlined in example 26 was followed using the above alcohol. 1H NMR (500 MHz, DMSO) δ 12.03 (br s, 1H), 7.76 (d, 2H), 7.25 (d, 1H), 7.21 (d, 1H), 6.89 (d, 1H), 6.56 (d, 2H), 6.38 (d, 1H), 4.05-3.95 (m, 2H), 3.90 (s, 2H), 3.56 (dd, 1H), 3.49-3.42 (m, 1H), 3.38 (dd, 1H), 3.27 (dd, 1H), 2.86-2.78 (m, 1H), 2.77 (t, 2H), 2.26-2.17 (m, 1H), 2.00-1.92 (m, 1H), 1.64-1.53 (m, 2H), 0.92 (s, 9H), 0.91 (t, 3H). MS (ESI): 449.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:14][CH:13]=[CH2:12])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1cc(Br)ccc1O
Reaction time: 72 h
Yield: 90.7 %

Procedure:
A mixture of 5-bromosalicylic acid (10 g, 46 mmol), allyl bromide (6.12 g, 51 mmol) and sodium bicarbonate (4.65 g, 55 mmol) in 50 ml of DMF was stirred under a drying tube for 72 hr. The reaction mixture was poured into water, extracted with ethyl acetate. and the organic layer dried over MgSO4. Concentration under vacuum gave 10.73 g (91%) of product (1-Scheme 2) with the expected NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>CCCCCCC.CCOC(C)=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1COc2cc(F)ccc2N1
Yield: 93.1 %

Procedure:
2-Amino-5-fluorophenol (111MF10) (10.3 g, 81 mmol), 2-chloroacetyl chloride (10.1 g, 89 mmol) and K2CO3 (23.5 g, 170 mmol) were mixed according to GP1. CC (SiO2; Heptane/EtOAc 4:1-4) to give the title compound (111MF12) (12.6 g, 93%); 1H NMR (DMSO) δ 10.68 (s, 1H), 6.83-6.91 (m, 2H), 6.75-6.80 (m, 1H), 4.57 (s, 2H); 13C NMR (DMSO) δ 164.2, 157.8 (d, J=238.6 Hz), 144.0 (d, J=12.4 Hz), 123.9 (d, J=2.7 Hz), 116.3 (d, J=9.6 Hz), 108.6 (d, J=22.7 Hz), 104.0 (d, J=26.5 Hz), 66.7.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:35]2[CH:36]=[CH:37][S:33][CH:34]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Reactant: OB(O)c1ccsc1
Product: COc1c(-c2ccsc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Yield: 33 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with thiophen-3-yl boronic acid (8.1 mg, 0.063 mmol) as described in Example 63, Part B to give the title compound as an off-solid (8.6 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=1.84 Hz, 1H) 7.93 (d, J=2.94 Hz, 1H) 7.87 (d, J=7.72 Hz, 1H) 7.53-7.75 (m, 6H) 7.49 (t, J=6.25 Hz, 1H) 7.39 (d, J=2.57 Hz, 1H) 6.57 (s, 1H) 5.68 (dd, J=7.91, 2.02 Hz, 1H) 4.19 (d, J=5.15 Hz, 2H) 3.47 (s, 2H) 3.21 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: CN(C=O)C.C(Cl)(C([Cl:10])=O)=O.[CH3:12][O:13][C:14]1[C:19]2[C:20]3[N:21]=[CH:22][NH:23][C:24](=O)[C:25]=3[S:26][C:18]=2[CH:17]=[CH:16][CH:15]=1>ClCCCl>[Cl:10][C:24]1[C:25]2[S:26][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[C:19]=3[C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: COc1cccc2sc3c(=O)[nH]cnc3c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cccc2sc3c(Cl)ncnc3c12
Temperature: 25 °C
Yield: 66.1 %

Procedure:
DMF (0.125 mL, 1.7 mmol) is added dropwise to a solution of (COCl)2 (0.15 mL, 1.68 mmol) in 1,2-dichloroethane (4.5 mL) at r.t. After gas evolution ceases, 9-methoxy-4-oxo-3H-benzothieno[3,2-d]pyrimidine (73.2 mg, 0.32 mmol) is added. The resulting mixture is heated at reflux for 4 hr. After the reaction is cooled to r.t., the black tar is filtered off. The filtrate is stripped to dryness and then mixed with water. A yellow solid forms and is collected via filtration. The solid is washed with water and air dried to give 4-chloro-9-methoxybenzothieno[3,2-d]pyrimidine (53 mg, 66%). 1H NMR (DMSO) δ9.17 (1H, s), 7.82-7.78 (2H, m), 7.3-7.2 (1H, m) , 4.06 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[C:15]4=[N:16][CH:17]=[CH:18][CH:19]=[C:14]4[C:13]([C:20]([O:22]C)=[O:21])=[CH:12]3)[C:5]=2[CH:4]=[CH:3]1.O1CCCC1.[Li]>O>[CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[C:15]4=[N:16][CH:17]=[CH:18][CH:19]=[C:14]4[C:13]([C:20]([OH:22])=[O:21])=[CH:12]3)[C:5]=2[CH:4]=[CH:3]1
Reactant: COC(=O)c1cn(-c2ncnc3c2ccn3C)c2ncccc12
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2c(-n3cc(C(=O)O)c4cccnc43)ncnc21
Temperature: 5 °C
Yield: 85.7 %

Procedure:
To 1.2 g (3.7 mmol) of methyl 1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate were successively added 13.5 cm3 of tetrahydrofuran, 0.47 g (11.2 mmol) of lithium hydroxyde, monohydrate and 13.5 cm3 of distilled water. The reaction mixture was heated at reflux temperature for 4 hours and then concentrated to dryness in vacuo (2.7 kPa). The residue was dissolved into 72 cm3 of distilled water and the mixture was extracted with 35 cm3 of ethyl acetate. The aqueous phase was cooled to about 5° C. and 10 cm3 of 1N hydrochloric acid were added dropwise (pH ca. 3). The resulting precipitate was filtered, washed twice with 20 cm3 of distilled water and dried in vacuo at about 50° C. to yield 0.93 g of 1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid as off-white crystals. mp>260° C.; IR spectrum (KBr): 3461; 3152; 2951; 2571; 1678; 1590; 1544; 1452; 1263; 1204; 916; 808; 774; 746; 681 and 607 cm−1.
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-:3])=[O:2].[I:12]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:12][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:6]
Reactant: II
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(O)ccc(I)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of 1 g (6.4 mmol) of 2-nitroresorcinol, 1.42 g (6.4 mmol) of silver trifluoroacetate and 1.64 g (6.4 mmol) of iodine in 25 mL of chloroform was stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with 20 mL of dichloromethane. The combined filtrate was washed with 10% aqueous sodium metabisulfite, water, brine and dried over anhydrous magnesium sulfate, evaporated to dryness to give 1.6 g of crude 4-iodo-2-nitroresorcinol [H11 NMR (CDCl3) 6.52 (d, 1H, CH, J=8.9 Hz); 7.85 (d, 1H, CH, J=8.9 Hz); 10.67 (s, 1H, OH); 11.43 (s, 1H, OH)] which was used in the next step without further purification. To a mixture of above product in 10 mL of anhydrous dimethylformamide 1.77 g (12.8 mmol) of anhydrous potassium carbonate was added at room temperature followed by 3 mL (48 mmol) of methyl iodide. After stirring overnight at room temperature resulting mixture was diluted to 150 mL with ethyl acetate, washed with water (3×15 mL) brine and dried over anhydrous magnesium sulfate, filtered off and filtrate evaporated to dryness to give 1.6 g of crude product, which was purified by flash column chromatography (silica gel hexane dichloromethane 7:3) to give 1.1 g (56%) of the title compound as a colourless crystals. H1 NMR (CDCl3) 3.87 (s, 3H, OMe); 3.91 (s, 1H, OMe); 6.6 (d, 1H, CH, J=8.9 Hz); 7.75 (d, 1H, CH, J=8.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:23]([C:25]2([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]2)=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:43][CH2:44][CH2:45][N:46]1[CH2:52][CH:51]([OH:53])[C:48]2([CH2:50][CH2:49]2)[CH2:47]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:53][CH:51]1[C:48]2([CH2:50][CH2:49]2)[CH2:47][N:46]([CH2:45][CH2:44][CH2:43][O:21][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([N:22]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[C:23]([C:25]5([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]5)=[O:24])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][C:16]=2[O:19][CH3:20])[CH2:52]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (240 mg, 0.475 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (236 mg, 0.95 mmol) and Cs2CO3 (463 mg, 1.425 mmol). The reaction was then stirred at rt for 2 days. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (15 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as a white solid (250 mg, 80%).
Reaction SMILES: CNC(O[N:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]=[C:7]1[C:16]([F:19])([F:18])[F:17])=O.[ClH:20].O>CO>[Cl:20][C:11]1[N:10]=[C:9]2[N:8]=[C:7]([C:16]([F:19])([F:18])[F:17])[NH:6][C:14]2=[CH:13][C:12]=1[Cl:15]
Reactant: CNC(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reactant: Cl
Solvent: O
Solvent: CO
Product: FC(F)(F)c1nc2nc(Cl)c(Cl)cc2[nH]1
Reaction time: 3 h

Procedure:
1-(Methylcarbamoyloxy)-6-chloro-2-(trifluoromethyl) -1H-imidazo [4,5-b] pyridine (250 milligrams) in 2.5milliliters of methanol was saturated with HCl. The reaction mixture was permitted to stand for three hours, then poured into water and filtered to separate the desired 5,6-dichloro-2-(trifluoromethyl)-1H-imidazo[ 4,5-b] pyridine, m.p., 280° -30° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH3:20])[C:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][C:14](OC)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[BH4-].[Na+].CO>C(O)(C)(C)C>[CH2:1]([N:8]([CH2:19][CH3:20])[C:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN(CC)C(=O)CCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CO
Product: CCCCCCCN(CC)C(=O)CCCCCO
Yield: 35.8 %

Procedure:
A mixture of a solution of 3.1 gms of the N-heptyl-N-ethyladipamic acid, methyl ester in 40 ml of tert-butanol and 800 mg of sodium borohydride is heated to reflux, following which 7.8 ml of methanol is added dropwise. The reaction mixture is stirred at reflux for 18 hours and then partitioned between water and CH2Cl2. After separation, the organic layer is dried over MgSO4, filtered, and concentrated under vacuum. The residue obtained is flash chromatographed on normal phase silica gel with a 4/1 ratio of hexane and ethyl acetate to yield 1.0 gms of N-heptyl-N-ethyl(6-hydroxy)hexanamide.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Product: O=C(Cc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2NC1=O

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3(R,S)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylacetyl chloride. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.: m.p. 238°-240° C.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[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])=[N+]=[N-].[C:25]([O:28][C:29]([CH3:31])=[CH2:30])(=[O:27])[CH3:26]>ClCCl>[C:25]([O:28][C:29]1([CH3:31])[CH2:30][N:1]1[C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[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])(=[O:27])[CH3:26]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Reactant: C=C(C)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC1(C)CN1C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Yield: 17 %

Procedure:
Two solutions of p-nitrobenzyl 2-azidocarbapen-2-em-3-carboxylate (52 mg and 24 mg, 231 micromol) and 2-acetoxy-1-propene (0.25 ml each) in dichloromethane were kept 2.5 days at ambient temperature. The mixtures were combined, filtered through florisil, and evaporated under vacuum. The residue was chromatographed on four 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plates developed with 5:1 (v/v) diethyl ether-ethyl acetate. The band centered at Rf 0.25 was eluted with ethyl acetate and the eluate evaporated under vacuum to provide 15.9 mg (17%) p-nitrobenzyl 2-(2-acetoxy-2-methylaziridin-1-yl)-carbapen-2-em-3-carboxylate; IR (CH2Cl2): 1770, 1735 cm-1, NMR (CDCl3): δ 1.69 s (3H), 2.11 s (3H), 2.16 d (J=7 Hz, 1H), 2.22 d (J=7 Hz, 1H), 2.74 dd (J=8 Hz, J2 =17 Hz, 1H), 2.79 dd (J1 =3 Hz, J2 =16 Hz, 1H), 2.84 dd (J1 =5 Hz, J2 =17 Hz, 1H), 3.21 dd (J1 =6 Hz, J2 =16 Hz, 1H), 4.30 m (1H), 5.29 d (J=12 Hz, 1H), 5.35 d (J=12 Hz, 1H), 7.57 d (J=9 Hz, 2H), 8.29 d (J=9 Hz, 2H); MS (m/e): 402 (M+), 359, 342, 316, 300, 274, 258, 222.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][C:13]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[C:16]([Br:27])=[CH:15][C:14]=1[C:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[C:31]([CH3:41])[O:30][N:29]=1)C1C=CC=CC=1>ClCCl>[Br:27][C:16]1[CH:15]=[C:14]([C:28]2[C:32]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)=[C:31]([CH3:41])[O:30][N:29]=2)[C:13]([OH:12])=[CH:18][C:17]=1[OH:19]
Reactant: COc1ccc(-c2c(-c3cc(Br)c(OCc4ccccc4)cc3OCc3ccccc3)noc2C)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3cc(Br)c(O)cc3O)noc2C)cc1
Reaction time: 1 h
Yield: 43 %

Procedure:
Boron trichloride solution (1M in dichloromethane, 1 ml, 1 mmol) was added to a solution of 3-(2,4-Bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-5-methyl-isoxazole (38 mg, 0.068 mmol) in dichloromethane (1 ml), and stirring was continued for 1 h. The reaction mixture was partitioned between water (20 ml) and dichloromethane (2×20 ml) and the combined organic phases were dried over anhydrous magnesium sulphate and concentrated in vacuo to leave a brown oil. The crude product was purified by column chromatography, silica (10 g), eluting with hexane, followed by hexane/diethyl ether (3:1 then 1:1), to give 4-Bromo-6-[4-(4-methoxy-phenyl)-5-methyl-isoxazol-3-yl]-benzene-1,3-diol as a colourless oil (11 mg, 43%).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.I[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]#[N:33])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]#[N:33])[CH:25]=2)=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: N#Cc1ccc(I)cc1C#N
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: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(C#N)c(C#N)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 23.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.197 g, Example 33), 4-iodo-1,2-dicyanobenzene (0.421 g, Can. J. Chem., 1985, 63, 3057), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium (0) (0.054 g) in ethanol (3 ml). The reaction mixture was heated in a sealed vial at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure and the residue purified by chromatography over silica eluting with ethyl acetate. The residue was further purified by chromatography over silica gel eluting with dichloromethane:2-propanol (19:1). The residue was then further purified by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution. The HPLC fractions were concentrated under reduced pressure, the residue dissolved in dichloromethane, filtered and concentrated under reduced pressure. The residue was triturated with ether to give the title to compound as a solid (0.060 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH2:13]([OH:15])[CH3:14].[ClH:16]>C(Cl)(Cl)Cl>[ClH:16].[CH2:13]([O:15][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1)[CH3:14]
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccc(C(F)(F)F)cc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of 4-trifluoromethyl-benzonitrile (5.16 g, 30.2 mmol) and ethanol (1.39 ml, 30.2 mmol) in chloroform (15 ml) was saturated with a dry stream of HCl gas for 15 min. at −5° C. and the mixture allowed to stand 1 week at 4° C. The product was precipitated with ether, and the suspension stirred for 30 min. at −15°C., then filtered and washed with ether. The solid product was dried at r.t. under high vacuum overnight to afford the title compound (7.1 g, 28 mmol, 93% yield) as a white solid. MS: m/e=217 (M+), 172 (M+-EtOH)
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].C(O)(C)C.Cl[CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>O>[CH2:17]([O:16][C:14]([CH2:13][C:12]1[N:2]=[C:1]([SH:3])[S:4][CH:11]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)Cc1csc(S)n1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
To 180.0 g (1.63 mols) of ammonium dithiocarbamate was added 1.5 liters of isopropyl alcohol, the mixture was stirred and then 268.9 g (1.63 mols) of ethyl 4-chloro-3-oxobutanoate was added dropwise to the mixture. After stirring the resultant mixture for 3 hours under refluxing, 300 ml of water was added to the reaction mixture, the mixture was cooled to room temperature and crystals formed were collected by filtration under a reduced pressure to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate to obtain 188 g (yield 57%) of 4-ethoxycarbonylmethyl-2-mercaptothiazole.
Reaction SMILES: [Cl:1][C:2]1[C:11](I)=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[K+].[F:15][C:16]([F:19])([F:18])I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:10][C:5]2[NH:6][C:7]([S:9][C:16]([F:19])([F:18])[F:15])=[N:8][C:4]=2[CH:3]=1
Reactant: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1
Reactant: FC(F)(F)I
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)Sc1nc2cc(Cl)c(-c3ccc(Cl)cc3)cc2[nH]1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Compound number 102 (i.e., 6-chloro-5-(4-chlorophenyl)-2-trifluoromethylthiobenzimidazole) was prepared as follows. A 250-mL 3-necked round-bottom flask was charged with a solution of 5-chloro-6-iodo-2,3-dihydro-1H-1,3-benzodiazole-2-thione (2 g, 6.44 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) and potassium hydroxide (1.1 g, 3.00 equiv). Trifluoro(iodo)methane was introduced to the above. The resulting solution was stirred for 3 h at 120° C. in an oil bath. The resulting solution was diluted with 250 mL of ethyl acetate. The resulting mixture was washed with 3×200 mL of water and 2×200 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 400 mg (16%) of 5-chloro-6-iodo-2-[(trifluoromethyl)sulfanyl]-1H-1,3-benzodiazole as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]([CH3:23])[CH3:22])[C:13]3=[O:24])=[N:10][C:6]=2[CH:5]=1.[CH:32]1(N)C[CH2:33]1>>[CH:1]1([NH:2][CH2:3][C:4]2[CH:31]=[CH:30][C:7]3[N:8]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:9]([CH2:11][N:12]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=5[N:14]([CH:21]([CH3:23])[CH3:22])[C:13]4=[O:24])=[N:10][C:6]=3[CH:5]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: CNCc1ccc2c(c1)nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CNC3CC3)ccc21

Procedure:
1-[5-Cyclopropylaminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one was prepared by the same procedure as 1-[5-methylaminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one, except using cyclopropylamine.