Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28](Cl)[CH:27]=[N:26]1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:18][CH:17]=2)[CH:27]=[N:26]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CO)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(OCc2ccc(CCCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Reaction time: 12 h
Yield: 88.6 %

Procedure:
To a dry 25 mL round bottom flask, fitted with a reflux condenser, was added the product of Example 2D (0.41 g, 1.4 mmol), 2-tert-butyl-4,5-dichloro-2H-pyridazin-3-one (0.93 g, 4.2 mmol), cesium carbonate (1.37 g, 4.2 mmol), and anhydrous dimethylformamide (11 mL). The reaction flask was placed in a 68° C. oil bath and the reaction was stirred for 12 hours. The reaction flask was removed from the oil bath and allowed to cool. The mixture was diluted with ethyl acetate, transferred to a separatory funnel and washed with water (25 mL, 5×). The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 1.3 g of crude product. Column chromatography [silica gel; eluent hexanes-ethyl acetate (9:1)] provided the desired product (594 mg, 89%). 1H (CDCl3) δ(ppm): 0.05 (s, 6H); 0.90 (s, 9H); 1.64 (s, 9H); 2.65 (t, 2H); 3.64 (t, 2H); 5.23 (s, 2H); 7.23 (d, 2H); 7.33 (d, 2H); 7.74 (s, 1H). 13C (CDCl3) δ(ppm): 18.57, 26.19, 27.75, 28.09, 32.58, 35.61, 63.14, 66.57, 72.14, 118.46, 125.41, 127.44, 129.23, 132.38, 143.72, 154.02, 159.30.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-chloro-5-nitro-benzoic acid (10 g, 49.6 mmol), oxalyl chloride was added dropwise (12.6 g, 2.0 equiv.). The resulting yellow solution was stirred at room temperature under argon overnight. The solvent was removed under vacuum to give a yellowish solid (10.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[N:27]([CH2:30][CH2:31][C:32]([OH:34])=O)[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[CH2:35]([NH2:38])[CH2:36][CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[N:27]([CH2:30][CH2:31][C:32]([NH:38][CH2:35][CH2:36][CH3:37])=[O:34])[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: O=C(O)CCn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21
Product: CCCNC(=O)CCn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21
Yield: 76 %

Procedure:
Following a similar procedure to that described in example 48, but using 3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]propionic acid (obtained in example 47) instead of 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetic acid, and propylamine instead of morpholine, the title compound was obtained (yield: 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[FH:14].F.F.C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([OH:11])[C@H:10]([F:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](F)C1
Temperature: 90 °C

Procedure:
A mixture of 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (5.4 mmol, from Example 316) and triethylamine trihydrofluoride (5.4 mmol) was heated at 90° C. for 2 h, then cooled to rt. Aq. Na2CO3 was added and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4), concentrated and purified by silica gel chromatography (0-40% EtOAc in heptane) to afford (trans)-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1ccc2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5-methoxy-1H-indole (500 mg, 3.40 mmol) in dry DMF (8 ml), cooled at 0° C., sodium hydride (60% w/w dispersion in mineral oil, 136 mg, 3.40 mmol) was slowly added portionwise and the reaction was stirred at 0° C. for 45 minutes; then methyl 2-bromoacetate (315 μl, 3.40 mmol) was added dropwise, and the reaction was stirred at room temperature for 15 hours. Water was slowly added, and the product was extracted with Et2O and then with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4 and evaporated to dryness. The title compound was obtained and used for the next step without further purification (745 mg, 3.40 mmol, quantitative yield). MS/ESI+ 220.1 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:6]=[CH:5]2.C[O-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH3:16][CH:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:3]=2)[CH:8]=1)[C:13]([OH:15])=[O:14]
Reactant: ClCc1ccccc1
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of 6-hydroxy-α-methyl-2-naphthaleneacetic acid (6.48 g, 30 mmol) in methanol (100 ml) is added sodium methoxide (60 mm). After 10 minutes the solvent is removed and replaced with dimethylformamide (100 ml). Benzyl chloride (7.6 g, 60 mmol) is then added and the reaction mixture is stirred overnight at room temperature. The reaction is then heated at 150° C. for 1 hour. The solvent is then removed and the residue is partitioned between water and methylene chloride. The organic layer is washed with water, dried over magnesium sulfate and evaporated to 11.5 g of crude product. This crude product is extracted with 100 ml hot hexane which affords 3.5 g of white crystals. A final recrystallization from methanol affords 2.5 g of white crystals of the intermediate ethyl ester (21% yield, m.p. 76°-78° C.).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.13) (0.31 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.18 g, 0.8 mmol) according to the general procedure VI. Obtained as an off-white solid (0.08 g, 26%). MS (ISP) 397.3 [(M+H)+]; mp 230-232° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1nc(CCCOc1ccccc1)n2CCCCNC(=O)N1CCOCC1
Yield: 31.1 %

Procedure:
Using the general method of Example 143 except that pyridine was used in place of chloroform, 1-(4-aminobutyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.25 g, 3.2 mmol) was reacted with 4-morpholinecarbonyl chloride (0.41 mL, 3.5 mmol) to provide 0.50 g of N-{4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4, 5-c]quinolin-1-yl]butyl}morpholine-4-carboxamide as a light brown solid, m.p. 71.5-72.1° C. Analysis: Calculated for C28H34N6O3.0.5H2O: %C, 65.73; %H, 6.90; %N, 16.43; Found: %C, 65.43; %H, 6.90; %N, 16.29.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[O:15][C:14]2=O>C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[C:14](=[O:15])[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([F:10])[CH:12]=3)[C:16]2=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C1OC(=O)c2cc(F)ccc21
Solvent: CC(=O)O
Product: Cc1c(Br)cccc1N1C(=O)c2ccc(F)cc2C1=O
Temperature: 100 °C
Yield: 65.4 %

Procedure:
A mixture of 3-bromo-2-methylaniline (200 mg, 1.075 mmol) and 5-fluoroisobenzofuran-1,3-dione (179 mg, 1.075 mmol) in acetic acid (2 mL) was heated at 100° C. for 4.5 h. The mixture was concentrated and the residue was purified by column chromatography (eluting with a gradient from hexane to 60:40 hexane-EtOAc) to give 2-(3-bromo-2-methylphenyl)-5-fluoroisoindoline-1,3-dione as a white solid (235 mg, 59%). Mass spectrum m/z 334, 336 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].I[CH2:26][CH2:27][F:28].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:26][CH2:27][F:28])[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCOc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a stirred solution of 1-[3-(ethyloxy)-4-nitrophenyl]-4-(4-piperidinyl)piperazine (0.28 g, 0.83 mmol) and 1-iodo-2-fluoroethane (0.29 g, 1.67 mmol) in acetonitrile (17 mL) was added Na2CO3 (0.106 g, 1.0 mmol). The reaction was stirred under N2 and heated to reflux for 4 h. The temperature was lowered to 75° C. and the reaction was stirred overnight (approximately 16 h). The reaction was cooled to rt and then concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound of step B (206 mg, 0.54 mmol, 65%) as a yellow solid. MS (ESI): 381 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.O>CN(C)C=O>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:11]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: BrCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
2,4,5-Triphenylimidazole (5 g) was added to a suspension of sodium hydride (1.0 g) (50% dispersion in oil, washed with hexane) in dry dimethylformamide (80 ml) under nitrogen. The reaction was stirred at 45° C. for 1 h, cooled and added, over 1 h to a solution of 1,8-dibromo-octane (30 g) in dry dimethylformamide (100 ml) under nitrogen. The reaction was stirred at room temperature for 24 h, water was carefully added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (500 ml), washed with water (250 ml), 2N aqueous hydrochloric acid (250 ml), saturated sodium chloride solution (250 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Distillation to remove 1,8-dibromooctane and chromatography on silica gel eluted with dichloromethane gave 1-(8-bromooctyl)-2,4,5-triphenylimidazole (4.1 g, 50%) as an oil; NMR d (CDCl3) 0.9-1.7 (12H, m, 6×CH2), 3.3 (2H, t, BrCH2), 3.9 (2H, t, N--CH2), 7.1-7.7(15H, m, 3×Ph) ppm.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:18][CH2:17][CH2:16][N:15]2[CH2:19][CH:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)[CH2:21][N:8]([CH2:9][CH2:10][CH2:11][N:12]([CH2:30][C:31]([OH:33])=[O:32])[CH2:13][CH2:14]2)[CH2:7][CH2:6]1)([OH:3])=[O:2].[C:34](Cl)(Cl)=[S:35]>Cl.C(Cl)(Cl)Cl>[C:1]([CH2:4][N:5]1[CH2:18][CH2:17][CH2:16][N:15]2[CH2:19][CH:20]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]=[C:34]=[S:35])=[CH:27][CH:28]=3)[CH2:21][N:8]([CH2:9][CH2:10][CH2:11][N:12]([CH2:30][C:31]([OH:33])=[O:32])[CH2:13][CH2:14]2)[CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: Nc1ccc(CC2CN3CCCN(CC(=O)O)CCN(CCCN(CC(=O)O)CC3)C2)cc1
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)CN1CCCN2CCN(CC(=O)O)CCCN(CC1)CC(Cc1ccc(N=C=S)cc1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 143 %

Procedure:
A solution of compound 28 (1.21 g, 1.75 mmol) in 0.5 M HCl (50 mL) was carefully added to thiophosgene (CSCl2) (4.03 mL, 6.04 g, 52.5 mmol) in CHCl3 (50 mL). The reaction mixture was stirred for 5 hours at room temperature and the layers were allowed to separate. The aqueous layer was removed and the organic CHCl3 layer was then washed with water (2×50 mL). The combined aqueous layers were washed with CHCl3 (3×50 mL) to remove unreacted thiophosgene. Finally, the aqueous layer was lyophilized to afford white crystalline solid 29 (1.26 g, 98% yield).
Reaction SMILES: C1([ClH]P([ClH]C2C=CC=CC=2)(Cl)=O)C=CC=CC=1.[OH:18][C@@H:19]([C@H:21]1[C:42](=[O:43])[N:23]2[CH:24]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C:25](=O)[C@H:26]([CH3:27])[C@H:22]12)[CH3:20].[SH:44][C@@H:45]1[CH2:49][N:48]([C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=2)=[O:51])[C@H:47]([C:63]([N:65]2[CH2:68][CH:67]([NH:69][C:70]([O:72][CH2:73][C:74]3[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=3)=[O:71])[CH2:66]2)=[O:64])[CH2:46]1>C(#N)C.C(OCC)(=O)C>[N+:80]([C:77]1[CH:76]=[CH:75][C:74]([CH2:73][O:72][C:70]([NH:69][CH:67]2[CH2:66][N:65]([C:63]([C@@H:47]3[CH2:46][C@H:45]([S:44][C:25]4[C@H:26]([CH3:27])[C@@H:22]5[C@@H:21]([C@H:19]([OH:18])[CH3:20])[C:42](=[O:43])[N:23]5[C:24]=4[C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=4)=[O:30])[CH2:49][N:48]3[C:50]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=3)=[O:51])=[O:64])[CH2:68]2)=[O:71])=[CH:79][CH:78]=1)([O-:82])=[O:81]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: O=C(NC1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 32.3 %

Procedure:
167 μl of diphenylphosphoric acid chloride and 140 μl of ditsopropylethylamine were added dropwise at the same time, whilst ice-cooling, to a solution of 278 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 4 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, a solution of 430 mg of (2S,4S)-4-mercapto-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 113) in 4 ml of dry acetonitrile and 134 μl of ditsopropylethylamine were added dropwise at the same time to the mixture, whilst ice-cooling. The resulting mixture was then stirred at the same temperature for 2 hours, after which it was left to stand overnight whilst ice-cooling. The reaction mixture was then diluted with ethyl acetate and washed with water and with an aqueous solution of sodium chloride. The ethyl acetate layer was dehydrated over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the fractions obtained by elution with a 98:2 by volume mixture of ethyl acetate and methanol were combined and concentrated by evaporation under reduced pressure, to give 224 mg of the title compound, as a powder.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:15][CH3:16])=[N:13][NH:14][C:10]=2[CH:9]=[C:8]([NH:17][C:18]([NH:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[O:19])[N:7]=1)(=[O:3])[CH3:2].[B-](F)(F)(F)[F:30].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(O)(C(F)(F)F)=O>CO>[C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:15][CH3:16])=[N:13][NH:14][C:10]=2[C:9]([F:30])=[C:8]([NH:17][C:18]([NH:20][C@@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])=[O:19])[N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(COC(C)=O)c12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1n[nH]c2c(F)c(NC(=O)N[C@H](C)c3ccccc3)nc(COC(C)=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
(R)-(3-methoxy-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (108 mg, 0.282 mmol, Example 257, derived from Intermediate 41B according to Scheme 3/Method A) was dissolved in MeOH (1 mL) and charged with selectfluor (150 mg, 0.423 mmol). The reaction was allowed to stir overnight at rt. The solvents were removed in vacuo and the residue was purified on RP-HPLC 30×150 mm column (25-60% CH3CN/H2O w/0.1% TFA) to provide (R)-(7-fluoro-3-methoxy-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (60 mg, 0.149 mmol, 53.1% yield) as TFA salt.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28](Cl)[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C=CC=CC1=O>[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28]([O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Oc2nc(N)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
To a solution of 2,4,6-trimethylphenol (161 mg, 1.16 mmol) in 1-methyl-2-pyridone (2 mL) in a sealed tube was added NaH (46 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (100 mg, 0.39 mmol) in 1-methyl-2-pyridone (1 mL) was added to the mixture. The mixture was heated at 150° C. for 16 h and cooled to room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 107 mg (77%) of 7-benzyl-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine.
Reaction SMILES: [C:1]([CH2:3][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].[H][H]>C(O)C.C(O)(=O)C.[Pt](=O)=O>[NH2:2][CH2:1][CH2:3][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC#N)CC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(O)(CCN)CC1

Procedure:
A solution of tert-butyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate (example 89, step a) (1.4 g) in a mixture of ethanol (20 mL) and acetic acid (20 mL) was hydrogenated at 4 atmospheres pressure of hydrogen in the presence of platinum(IV) oxide (0.25 g) for 4 hours. The catalyst was filtered off and the solvents removed under reduced pressure. The residue was partitioned between dilute aqueous NaOH and ethyl acetate and the organic layer dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 1.1 g. Used directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].I[CH2:24][CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:24][CH2:25][CH3:26])[N:12]=1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2OC)c2cccc(F)c21
Yield: 99.2 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.300 g, 1.10 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and iodopropane (0.195 mL, 2.00 mmol) to give the title compound (0.343 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[CH2:25]Br)=[O:5])[CH3:2].[CH2:27]([O:29][C:30](=[O:40])[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH3:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[CH2:25][N:32]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:31][C:30]([O:29][CH2:27][CH3:28])=[O:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccccc2)c1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(-c2ccc(F)cc2)n1-c1ccccc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 4-bromo-2-bromomethyl-5-(4-fluoro-phenyl)-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 625 (M+Na+).