Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH2:15])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20].CNC(=O)C(CO)NC(=O)C1C(I)=C(N)C(I)=[C:31]([C:38](O)=[O:39])C=1I.C(Cl)(=O)C>CC(N(C)C)=O>[CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH:15][C:38](=[O:39])[CH3:31])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20]
Reactant: CNC(=O)CCNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CNC(=O)C(CO)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CNC(=O)CCNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Yield: 58.8 %

Procedure:
99.5 g. (0.15 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-β-alanine methylamide . 1.1 H2O (IV f), m.p. 250°-252° C. (decomposition) in 190 ml. of dimethylacetamide yield, after reaction with 40.0 ml. of acetyl chloride analogously to Example 1, 60.4 g. (58.8%) of the desired compound. A sample for analysis is purified in alcohol by way of the dimethylammonium salt; m.p. 288°-289° C. (under decomposition).
Reaction SMILES: C(N(CC)CC)C.[C:8]([S:12][CH3:13])(=[S:11])[CH2:9][CH3:10].C(O[C@H:18]1[NH:21][C:20](=[O:22])[C@@H:19]1[C@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH3:24])(=O)C.Cl>C(#N)C.[Cl-].[Zn+2].[Cl-].ClCCl>[Si:26]([O:25][C@@H:23]([C@@H:19]1[C@@H:18]([C@H:9]([C:8]([S:12][CH3:13])=[S:11])[CH3:10])[NH:21][C:20]1=[O:22])[CH3:24])([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:27])[CH3:28]
Reactant: CCC(=S)SC
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSC(=S)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a suspension of anhydrous zinc chloride (45.3 g) in acetonitrile (450 ml) cooled to 0° C. was added triethylamine (101 g). After stirring for 30 minutes at 0° C., the solution was cooled to -35° C. and a mixture of methyl dithiopropionate (20.0 g) and (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-oxoazetidine (23.9 g) in acetonitrile (90 ml) was added thereto. The reaction mixture was stirred at -20° C. for 2 hours, warmed to 0° C., and additionally stirred for 30 minutes at 0° C. The mixture was poured into a stirred mixture of dichloromethane (800 ml) and 1N hydrochloric acid (1000 ml). The organic layer was separated, washed with water, aqueous sodium bicarbonate solution and brine, and dried. The solution was concentrated under reduced pressure and the solid residue was washed with n-hexane to afford (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine (20.1 g) as a yellow crystal.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16].[H-].[Na+]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)CCCCBr
Reactant: Cc1c(N)cccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(Br)cccc1N1CCCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A solution of 3-bromo-2-methylaniline (1 g, 5.37 mmol) in DCM (15 mL) was treated with TEA (0.749 mL, 5.37 mmol) and then dropwise with a solution of 5-bromopentanoyl chloride (1.072 g, 5.37 mmol) in DCM (4 mL). The mixture was stirred at rt for 30 min, then was diluted with DCM, washed with water and brine, and dried and concentrated. The residue was dissolved in THF (100 mL) and added to a suspension of sodium hydride (60% oil dispersion, pre-washed with hexane, 0.430 g, 10.75 mmol) in THF (50 mL). The resulting mixture was stirred overnight at rt. The mixture was concentrated and the residue was acidified with 1 M hydrochloric acid. The mixture was extracted with DCM and the organic phase was washed with water, dried and concentrated to give 1-(3-bromo-2-methylphenyl)piperidin-2-one as a tan oil (1.4 g, 97%). 1H NMR (400 MHz, chloroform-d) δ 7.49-7.54 (1 H, m), 7.07-7.13 (2 H, m), 3.38-3.60 (2 H, m), 2.54-2.59 (2 H, m), 2.26 (3 H, s), 1.91-2.02 (4H, m). Mass spectrum m/z 268, 270 (M+H)+.
Reaction SMILES: ClCCN1CCOCC1.CS([O:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)(=O)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([C:37]2[N:46]=[C:45]([NH:47][C:48]3[CH:52]=[C:51]([CH3:53])[NH:50][N:49]=3)[C:44]3[C:39](=[CH:40][C:41](OC4CCCCN4C([O-])=O)=[CH:42][CH:43]=3)[N:38]=2)[OH:36])=[CH:31][CH:30]=1.Cl.O1CCOCC1>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([C:37]2[N:46]=[C:45]([NH:47][C:48]3[CH:52]=[C:51]([CH3:53])[NH:50][N:49]=3)[C:44]3[C:39](=[CH:40][C:41]([O:14][CH:15]4[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[CH:42][CH:43]=3)[N:38]=2)[OH:36])=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(OC4CCCCN4C(=O)[O-])ccc23)n[nH]1
Agent: Cl
Agent: ClCCN1CCOCC1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(OC4CCNCC4)ccc23)n[nH]1
Reaction time: 20 h
Yield: 21 %

Procedure:
Intermediate compound (R,S)-tert-butyl 4-(2-(4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yloxy)piperidine-1-carboxylate was obtained (105 mg) following the procedure described in Example 38 for the synthesis of (R,S)-(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-morpholinoethoxy)quinazolin-2-yl)methanol, substituting 4-(2-chloroethyl)morpholine in Example 38 with tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate. To the crude tert-butyl 4-(2-(((4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yloxy)piperidine-1-carboxylate (100 mg, 18.2 mmol) in a flask at 0° C. was added 4N HCl/dioxane (5 mL). After stirring for 20 h, the solvent was removed and the residue was shaken with DCM and aq sodium bicarbonate. The solvents were removed, and the remaining residue was extracted with MeOH/DCM. The extracts were concentrated and the residue was chromatographed on reverse phase HPLC to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(piperidin-4-yloxy)quinazolin-2-yl)methanol as a white solid (32 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (m, 2H) 1.89 (s, 13H) 1.89 (s., 3H) 1.98 (m, 2H) 2.68 (m, 2H) 2.99 (m, 2H) 4.66 (m, 4H) 5.62 (s, 1H) 5.76 (s, 1H) 6.36 (b., 1H) 7.08-7.18 (m, 4H) 7.52 (m, 2H) 8.45 (m., 1H), 10.29 (bs, 1H). LC-MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[C:22]([NH:33][CH3:34])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH3:34])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CNc1nc2ccc(OC)cc2cc1CCl
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (200 mg, 0.86 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-methylquinolin-2-amine hydrochloride SLA 28154 (234 mg, 0.86 mmol) at RT followed by a 2 N aq. LiOH solution (0.86 mL, 1.72 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with a mixture CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 21 mg of 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.40 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 39 as a yellow solid (20.0 mg, 5% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3=[C:11]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[C:26][Si](C)(C)C)=[CH:21][C:20]=4[F:31])[N:12]([CH3:17])[C:13](=[O:16])[C:14]([CH3:15])=[C:7]3[N:6]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:41])[CH3:40])[CH:35]=[CH:36][CH:37]=3)[C:5]2=[O:42])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CO.CN(C)C=O.Cl>O>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3=[C:11]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][C:20]=4[F:31])[N:12]([CH3:17])[C:13](=[O:16])[C:14]([CH3:15])=[C:7]3[N:6]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:41])[CH3:40])[CH:35]=[CH:36][CH:37]=3)[C:5]2=[O:42])[CH2:2][CH2:3]1
Reactant: CC(=O)Nc1cccc(-n2c(=O)n(C3CC3)c(=O)c3c(Nc4ccc(C#C[Si](C)(C)C)cc4F)n(C)c(=O)c(C)c32)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1ccc(Nc2c3c(=O)n(C4CC4)c(=O)n(-c4cccc(NC(C)=O)c4)c3c(C)c(=O)n2C)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To N-{3-[3-cyclopropyl-5-(2-fluoro-4-trimethylsilanylethynylphenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide 61 (1.00 g) obtained in Step 2 and potassium carbonate (236 mg) was added methanol/N,N-dimethylformamide [1:1 (volume ratio), 10.0 ml], and the mixture was stirred at room temperature for 20 hrs. The mixture was neutralized with 2N hydrochloric acid, water (10.0 ml) was added, and the mixture was stirred at room temperature for 1 hr. The crystals were collected by filtration and dried to give N-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide 62 (815 mg, yield 93%) as pale-yellow crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1c[nH]c2ccccc12)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 43 %

Procedure:
The title compound is prepared from 1H-indole-3-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 43% of theory; LC (method 4): tR=2.01 min; Mass spectrum (ESI+): m/z=331 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][O:22][CH2:23][O:24][C:25]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][C:26]=1[C:27]([NH:29][C:30]1[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1C=CC=CC=1>[Br:1][CH2:53][C:50]1[CH:51]=[CH:52][C:25]([O:24][CH2:23][O:22][CH3:21])=[C:26]([CH:49]=1)[C:27]([NH:29][C:30]1[CH:42]=[C:41]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28]
Reactant: COCOc1ccc(C)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COCOc1ccc(CBr)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 69 %

Procedure:
N-Bromosuccinimide (0.25 g) and azobisisobutyronitrile (0.023 g) were sequentially added to a benzene (6.3 mL) solution of the obtained tert-butyl 2-(2-(methoxymethoxy)-5-methylbenzamido)-4-phenylbenzoate (0.63 g), followed by heating to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and then a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% hexane/ethyl acetate] to obtain 0.51 g of tert-butyl 2-(5-(bromomethyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Cl:13][C:14]1[CH:19]=[C:18]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:17]=[CH:16][C:15]=1[C:27](=O)[CH3:28].[OH-:30].[K+].Cl>CCO.O.O>[Cl:13][C:14]1[CH:19]=[C:18]([CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:17]=[CH:16][C:15]=1[C:27]1[CH:28]=[C:5]([C:6]([OH:11])=[O:30])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]=1
Reactant: CC(=O)c1ccc(CN2CCOCC2)cc1Cl
Reactant: [OH-]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ccc(CN3CCOCC3)cc2Cl)nc2ccc(F)cc12
Temperature: 125 °C
Reaction time: 16 h
Yield: 29.4 %

Procedure:
A mixture of 5-fluoroisatin (702 mg, 4.25 mmol) and 1-(2-chloro-4-(morpholinomethyl)phenyl)ethanone (1.08 g, 4.25 mmol) (preparation 17) was prepared in EtOH/water (1:1) (10 ml) and then KOH (2.38 g, 42.49 mmol) was added and the resulting mixture heated under microwave irradiation at mw, 125° C. for 20 mins. The mixture was then diluted with water (10 ml) acidified to pH3 with 2M aqueous HCl, stirred for 16 h at room temperature and the resulting precipitate filtered, washed with water (2×10 ml) and concentrated under reduced pressure to afford 2-(2-chloro-4-(morpholinomethyl)phenyl)-6-fluoroquinoline-4-carboxylic acid as an orange solid (503 mg, 1.25 mmol, 30%).
Reaction SMILES: [N+:1]([C:4]([CH3:10])([CH:6]([OH:9])[CH2:7][CH3:8])[CH3:5])([O-:3])=[O:2].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([O-:18])([O:9][CH:6]([CH2:7][CH3:8])[C:4]([CH3:10])([N+:1]([O-:3])=[O:2])[CH3:5])=[O:17]
Reactant: CCC(O)C(C)(C)[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCC(O[N+](=O)[O-])C(C)(C)[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2-nitro-2-methyl-3-pentanol, 20 grams, was added to a mixture of 120 ml of concentrated sulfuric acid and 40 grams of 90% nitric acid over a 30-minute period at 6°-9° C. After 1/2 hour the acid solution was added to 800 ml of ice water.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>CN(C=O)C>[Br:3][C:4]1[N:5]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
NaH (1.4 eq, 60% dispersion in mineral oil) was added to a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in published International Patent application WO 2004/065367, from commercially available methyl indole-6-carboxylate) in DMF (0.2 M) and the solution stirred at RT for 1 h. Then tert-butyl bromoacetate (1.1 eq) was added and the mixture stirred at RT for 40 min. The solvent was removed in vacuo and the residue taken up in EtOAc. The organic phase was washed with H2O (twice) and then brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound as a brownish solid (90%); MS (ES+) m/z 450 (M+H)+, m/z 452 (M+H)+
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH3:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Br:36]N1C(=O)CCC1=O.ClCCl>C1C=CC=CC=1.[Cl-].[Na+].O.O[C@@H]([C@H]1C(=O)N2C(C(OCOC(=O)C(C)(C)C)=O)=C(C3SC4=C(C(=O)CC)N=CN4C=3)[C@H](C)[C@H]12)C>[Br:36][C:18]1[N:13]2[C:14]([S:15][C:11]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]4[C:7]=3[C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[CH:12]2)=[C:16]([S:19][CH3:20])[N:17]=1
Reactant: CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: O=C1CCC(=O)N1Br
Agent: CCC(=O)c1ncn2cc(C3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O
Product: CSc1nc(Br)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
4Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (77 mg) was dissolved in 5 ml of benzene at room temperature. N-bromosuccinimide (33 mg) and 5 mg of 2, 2′-azobis(isobutyronitrile) were added to the solution. The mixture was stirred for 10 min. Dichloromethane (10 ml) and 10 ml of semisaturated brine were added thereto, followed by separation. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 70 mg of 4-nitrobenzyl (1S,5R,6S)-2-(5-bromo-7-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@H:15]2[C:21](=[O:22])[N:20]3[C@@H:16]2[CH2:17][C:18](=O)[C@@H:19]3[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:63][C:64]1[S:65][CH:66]=[C:67]([C@@H:69]2[CH2:73][C@H:72]([SH:74])[CH2:71][N:70]2[C:75]([O:77][CH2:78][C:79]2[CH:84]=[CH:83][C:82]([N+:85]([O-:87])=[O:86])=[CH:81][CH:80]=2)=[O:76])[N:68]=1>ClCCl>[NH2:63][C:64]1[S:65][CH:66]=[C:67]([C@@H:69]2[CH2:73][C@H:72]([S:74][C:18]3[CH2:17][C@H:16]4[N:20]([C:21](=[O:22])[C@@H:15]4[C@H:13]([O:12][C:10]([O:9][CH2:8][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:38][CH:37]=4)=[O:11])[CH3:14])[C:19]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH2:71][N:70]2[C:75]([O:77][CH2:78][C:79]2[CH:84]=[CH:83][C:82]([N+:85]([O-:87])=[O:86])=[CH:81][CH:80]=2)=[O:76])[N:68]=1
Reactant: Nc1nc([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cs1
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](c4csc(N)n4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1- (4-nitrobenzyloxycarbonyloxy)ethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (1.92 g) in dichloromethane (50 ml) were added N,N-diisopropyl-N-ethylamine (0.76 ml) and trifluoromethanesulfonic anhydride (0.73 ml) at -30° C., and the solution was stirred at the same temperature for 30 minutes. To this solution was added (2S, 4S)-2-(2-aminothiazol-4-yl)-4-mercapto-1- (4-nitrobenzyloxycarbonyl)pyrrolidine (1.13 g) in dichloromethane (20 ml) at -30° C. and the solution was stirred at 0° C. for 3 hours. The mixture was washed in turn with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (5:1 V/V) to give 4-nitrobenzyl (5R,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl) -1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-(4-nitrobenzyloxycarbonyloxy) ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.85 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>CN(C=O)C>[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(Br)cc1)c1ccccc1

Procedure:
Prepared by reacting 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with 1.5 equivalents of 4-bromo-aniline in DMF (110° C., for 2 hours), subsequent treatment with piperidine (20° C., 0.5 hours) and precipitation with water.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:21][CH3:22])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)[CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCN(CCCOc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCN(CCCOc1ccc(N)cc1)C(=O)OC(C)(C)C
Yield: 99.9 %

Procedure:
A solution of ethyl-[3-(4-nitrophenoxy)propyl]carbamic acid tert-butyl ester (2.9 g) (from step A above) in ethanol (70 mL) was treated with 10% Pd/C (442 mg) and stirred for 2 hours under 40 psi of hydrogen. The mixture was filtered through a celite pad. The pad was washed with ethanol and the combined solution was evaporated in vacuo to yield [3-(4-aminophenoxy)propyl]-ethyl-carbamic acid tert-butyl ester (2.63 g, 88%). HRMS, Observed: 317.1839; Calcd for M+Na: 317.1835
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10](F)=[CH:9][C:8]=2F)[N:5]=[CH:4][N:3]=1.[Cl:15]C1C=CC=CC=1N1C=NC=N1.C([Li])CCC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:15])[N:5]=[CH:4][N:3]=1
Reactant: Clc1ccccc1-n1cncn1
Reactant: Fc1ccc(-n2ncnc2Cl)c(F)c1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Product: Clc1ccccc1-n1ncnc1Cl

Procedure:
Following the procedure for 5-chloro-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole, 1-(2-chloro-phenyl)-1H-[1,2,4]triazole was reacted with n-butyllithium and hexachloroethane to give 5-Chloro-1-(2-chloro-phenyl)-1H-[1,2,4]triazole as a white solid. 1H NMR δ (ppm) (CDCl3): 8.05 (1 H, s), 7.61-7.58 (1 H, m), 7.55-7.48 (1 H, m), 7.46-7.43 (2 H, m).