Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: CNc1cccc(C)n1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N(C)C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), methyl-(6-methyl-pyridin-2-yl)-amine (88 mg, 0.72 mmol), BOP (137 mg, 0.31 mmol), DIEA (265 μL, 1.44 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-(6-methyl-pyridin-2-yl)-amide: MS m/z: 519.0 (M+H).
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8]1[C:17]([O:18][CH2:19][CH3:20])=[C:16]([O:21][CH2:22][CH3:23])[CH:15]=[C:14]2[C:9]=1[CH2:10][O:11][C:12]2=[O:13])[CH3:6].[N+:24]([O-])([OH:26])=[O:25]>O>[CH2:5]([O:7][C:8]1[C:17]([O:18][CH2:19][CH3:20])=[C:16]([O:21][CH2:22][CH3:23])[C:15]([N+:24]([O-:26])=[O:25])=[C:14]2[C:9]=1[CH2:10][O:11][C:12]2=[O:13])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc2c(c(OCC)c1OCC)COC2=O
Solvent: O
Solvent: CC(=O)O
Product: CCOc1c2c(c([N+](=O)[O-])c(OCC)c1OCC)C(=O)OC2
Reaction time: 8 h
Yield: 35 %

Procedure:
Glacial acetic acid (14 ml) was added to 5.32 g (0.02 mole) of 4,5,6-triethoxyphthalide. Into the reaction mixture on a water bath at 30-35° C., 14 ml of fuming nitric acid, d=1.52, was gradually added dropwise over a time period of 9 hours. After completion of the addition, the reaction mixture was allowed to stand overnight at room temperature and thereafter 80 ml of water was added to deposit crystals. The crystals were filtered out, washed thoroughly with water and dried. There was obtained 2.20 g of 4,5,6-triethoxy-7-nitrophthalide having a melting point of 82.5-84.5° C. with a yield of 35%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:10]([OH:17])[CH2:11]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]1[O:17][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)COS(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-methanesulfonyloxybutane(the 2-hydroxy-1-sulfonate compound: the 1-hydroxy-2-sulfonate compound: the diol compound: the 1,2-disulfonate compund=97.1:0.1:0.4:2.3 according to the HPLC area ratio) 50 g dissolved in ethyl acetate 510 ml was added 28% sodium methylate methanol solution 58.2 g under ice-cooling and stirred for 10 min. The reaction solution was diluted with water and adjusted with 6N-HCl to pH7 to separate an organic phase, which was distilled to remove the solvent. The concentrated residue was mixed with n-heptane, stirred at the ambient temperature for 1 hr to deposit crystals, which were filtered to remove. The filtrate was washed with water to separate an organic phase, which was mixed with active charcoal 2 g, stirred at the ambient temperature for 1 hr and filtered to remove charcoal. The filtrate was cooled down to −20° C. to deposit crystals, which were filtered and dried in vacuum to obtain the N-tert-butoxycarbonyl-3(S)-amino-1,2(R)-epoxy-4-phenylbutane(98.5% according to the HPLC area ratio) 28.8 g. The diol compound and the 1,2-disulfonate compound contained in a concentration of 0.5% or less in the crystals according to the HPLC area ratio respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[NH2:5].[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([NH:22][C:23]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:24])=[O:21]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
At room temperature, 6.4 g of 3-chloro-4-(4-chlorophenoxy)aniline is dissolved in 50 ml of toluene. Subsequently, 4.7 g of 2,6-difluorobenzoyl isocyanate is dripped in, whereupon the temperature rises by 15° C. The mixture is then stirred for 1 hour at 50° C. and allowed to cool; the precipitate is then filtered off. There is obtained 8.5 g of N-(2,6-difluorobenzoyl)-N'-[4-(4-chlorophenoxy)-3-chlorophenyl]-urea of m.p. 194°-196° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:33][CH2:32][N:24]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=3[CH:31]=[C:23]2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:60][O:59][CH2:58]4)[CH2:53][CH2:52]3)=[CH:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[CH:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:58][O:59][CH2:60]4)[CH2:53][CH2:52]3)=[CH:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 53.2 %

Procedure:
Following Example 148b, 464 mg of 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a and 420 mg of 188e were reacted to give 188f as a yellow solid (360 mg, 54%). LCMS: [M+H]+ 678
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][NH:12][C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)[C:11]1=[O:21]
Reactant: COC(=O)CCCCCCCBr
Reactant: Cc1ccc(-n2c(-c3ccccc3)c[nH]c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(C)cc2)c1=O

Procedure:
The product is produced as described in example 1 from 2.25 g of NaH (80% suspension in mineral oil), 18.7 g of 1-(4-methylphenyl)-5-phenyl-4-imidazolin-2-one, 150 cc. of DMF, 17.8 g of 8-bromocaprylic acid methyl ester and 2.25 g of NaJ.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[CH:1]1([CH2:4][CH2:5][O:6][C:14]2[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=2[C:12]#[N:13])[CH2:3][CH2:2]1
Reactant: OCCC1CC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OCCC2CC2)cccc1[N+](=O)[O-]
Yield: 85 %

Procedure:
Prepared as in Example 187c from 2-cyclopropylethanol and 2,6-dinitrobenzonitrile in 85% yield as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 0.15-0.20 (m, 2H), 0.43-0.47 (m, 2H), 0.84-0.89 (m, 1H), 1.69 (q, J=6.8 Hz, 2H), 4.31 (t, J=6.4 Hz, 2H), 7.73-7.76 (m, 1H), 7.86-7.93 (m, 2H). MS 233 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2nc(Cl)ncc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
A solution of 2,4,5-trichloropyrimidine (1.0 g, 5.4 mmol) and 4-methoxyphenol (0.64 g, 5.2 mmol) in NMP (2.5 ml) was treated with anhydrous potassium carbonate (1.65 g, 12 mmol). The reaction mixture was allowed to stir at ambient temperature for 18 hours. The reaction was partitioned between water and ethyl acetate. The organic layer was evaporated and the residue purified by column chromatography eluting with 10% ethyl acetate in isohexane to afford a solid product (1.33 g, 90%). NMR: 3.78 (s, 3H), 7.00 (d, 2H), 7.20 (d, 2H), 8.77 (s, 1H); MS (M+H)+271, 273.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:14]([O:22][CH3:23])(=[O:21])[C:15]#[C:16][C:17]([O:19][CH3:20])=[O:18]>C1(C)C=CC=CC=1>[C:9]([O:8][C:7]([NH:6][C:2]1[CH:3]=[CH:4][C:5]([OH:1])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:15]=1[C:14]([O:22][CH3:23])=[O:21])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1ccco1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(O)ccc(NC(=O)OC(C)(C)C)c1C(=O)OC
Yield: 37 %

Procedure:
A solution of tert-butyl furan-2-ylcarbamate C3-2 (55.0 g, 300.2 mmol) and dimethyl but-2-ynedioate (73.5 mL, 600.4 mmol) in toluene (100 mL) was heated at 45° C. for 4 hrs. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, PE to EA:PE (1:20, v:v)) to give compound C3-2 as a light yellow solid (36.1 g, yield: 37%). 1H NMR (DMSO-d6, 400 MHz) δ: 1.41 (s, 9H), 3.69 (s, 3H), 3.73 (s, 3H), 7.02 (d, J=8.8 Hz, 1H), 7.35 (d, J=9.2 Hz, 1H), 8.93 (s, 1H), 10.07 (s, 1H); MS (ESI+): m/z 238 (M-87).
Reaction SMILES: NC1C2C3C=CC=CC=3SC=2NC2C=C(F)C=CC=2N=1.[ClH:21].FC1C=CC2N=[C:28]([N:39]3[CH2:44][CH2:43][N:42](CCC)[CH2:41][CH2:40]3)[C:29]3C4C=CC=CC=4S[C:30]=3NC=2C=1>CS(C)=O>[ClH:21].[CH2:28]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH2:29][CH3:30]
Reactant: CCCN1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)CC1
Agent: Cl
Agent: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Solvent: CS(C)=O
Product: CCCN1CCNCC1

Procedure:
In the same manner as in Example 42 and using 12-amino-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.1 hydrochloride (1.5 g), N-n-propylpiperazine (17 g), dimethyl sulfoxide (10 ml) and hydrochloric acid, crude crystals (850 mg) of 8-fluoro-12-(4-propylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine were obtained. The crude crystals were dissolved in ethyl acetate (12 ml) and a solution of 5.5 mol/l hydrochloric acid in ether was added to give 8-fluoro-12-(4-propylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.2 hydrochloride.1.5 hydrate (757 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:12])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][CH:14]([S:16](Cl)(=[O:18])=[O:17])[CH3:15]>N1C=CC=CC=1.CCOCC>[CH:14]([S:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH2:11])=[O:10])=[CH:6][CH:7]=1)(=[O:18])=[O:17])([CH3:15])[CH3:13]
Reactant: C[C@@H](C(N)=O)c1ccc(N)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C(N)=O)c1ccc(NS(=O)(=O)C(C)C)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
(2R)-2-(4-Aminophenyl)propanamide (0.5 g, 3.05 mmol) was dissolved in pyridine (2 mL) and 2-propanesulfonyl chloride (0.53 mL, 3.66 mmol) was added. The resulting solution was refluxed for 4 h and left overnight at room temperature. After the complete disappearance of the starting amide, the solution was diluted with Et2O (10 mL) and the organic layer washed with 1N HCl (2×5 mL), with H2O (2×5 mL), dried over Na2SO4, filtered and evaporated under vacuum to give (2R)-2-{(4-[(isopropylsulfonyl)amino]phenyl}propanamide as pale yellow solid (667 mg, 2.47 mmol). Yield 81%. mp 125-127° C.; [α]D25 (c=0.3, CH3OH): −12.7°; 1H-NMR (DMSO-d6) δ 9.65 (bs, 1H, SO2NH), 7.40 (bs, 1H, CONH2), 7.25 (d, 2H, J=7 Hz), 7.12 (d, 2H, J=7 Hz), 6.80 (bs, 1H, CONH2), 3.52 (q, 1H, J=7 Hz), 3.15 (m, 1H), 1.22 (d, 3H, J=7 Hz), 1.18 (d, 6H, J=7 Hz).
Reaction SMILES: O[C@@H:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[C:5]1[CH2:6][CH2:7][C:8](=[O:19])[C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(OC=C(OC(C)=COC(C)C)C)(C)C.P(Cl)(Cl)(Cl)=O>C(Cl)Cl.CCOCC>[O:19]=[C:8]1[CH2:7][CH2:6][C:5](/[CH:4]=[CH:3]/[CH2:2][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCC[C@H](O)/C=C/C1=C(CCCCCCC(=O)O)C(=O)CC1
Agent: CC(=COC(C)C)OC(C)=COC(C)C
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCC/C=C/C1=C(CCCCCCC(=O)O)C(=O)CC1

Procedure:
To a 250 ml roundbottom borosilicate flask containing 0.4 g of 15(S)-hydroxy-9-oxo-8(12),13-trans-prostadienoic acid in 15 ml of methylene chloride is added 5 ml of isopropoxyisopropenyl ether and 0.01 ml of phosphorus oxychloride and the flask's contents allowed to react at 20° C for 36 hours. Next, the reaction product is diluted with 25 ml of ether and washed with 50% brine and saturated brine until the solution is neutral. Next, the residue is extracted with methylene chloride, filtered, and freed of solvent under reduced pressure, dried over anhydrous magnesium sulfate, the give 15(S)-(dimethyl' isopropoxy' methyloxy)-9-oxo-8(12),13-trans-prostadienoic acid.
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH:2]1[C:10]([O:12]C)=[O:11].C1COCC1.O.[OH-].[Li+:28]>CO>[C:17]([O:16][C:14]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH:2]1[C:10]([O-:12])=[O:11])=[O:15])([CH3:20])([CH3:18])[CH3:19].[Li+:28]
Reactant: COC(=O)C1Cc2cccnc2N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL round-bottomed flask, 1-tert-butyl 2-methyl 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (prepared using methods of M Boehringer, et al. U.S. Pat. No. 7,417,144) (3.0 g, 10.8 mmol, Eq: 1.00) was combined with THF (18 mL) and MeOH (12 mL) to give a colorless solution. Lithium hydroxide monohydrate (452 mg, 10.8 mmol, Eq: 1.00) was added and the reaction was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo to give lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate as an off-white solid (2.9 g), m/z=265 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:24]([CH3:26])[CH3:25])[CH:14]=2)[O:11][CH3:12])=[CH:21][CH:22]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc(OC(C)C)c1

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(3-hydroxy-phenyl)-2-methoxy-acetamide was alkylated with 2-iodopropane/cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-(3-isopropoxy-phenyl)-2-methoxy-acetamide as a colorless oil. MS 339.2 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:17])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:28]C=2C=1.N>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:17])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([NH2:28])=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1N1CC(C(=O)O)CC1=O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1N1CC(C(N)=O)CC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.1 %

Procedure:
A mixture of 1-(3-bromo-2-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid (Intermediate 41-10, 100 mg, 0.335 mmol), EDC (129 mg, 0.671 mmol), HOBT (103 mg, 0.671 mmol) and 28% aqueous ammonia in THF (2 mL) was stirred at rt for 5 h. The mixture was diluted with ethyl acetate, washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was purified by column chromatography (eluting with 90:10 DCM-methanol) to provide 1-(3-bromo-2-methylphenyl)-5-oxopyrrolidine-3-carboxamide as a white solid (26 mg, 26%). Mass spectrum m/z 297, 299 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:48][CH:49]1[C@H:53]2[C@H:54](OC3CCCCO3)[N:55](C(OC(C)(C)C)=O)[C:56]3[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH2:51][CH2:50]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[C@H:21]2[C@H:22](OC3CCCCO3)[N:23](C(OC(C)(C)C)=O)[C:24]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:48][CH:49]1[C@@H:53]2[CH:54]=[N:55][C:56]3[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH2:51][CH2:50]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[C@@H:21]2[CH:22]=[N:23][C:24]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][CH2:18]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 94.4 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8f (191 mg, 0.18 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9f (106 mg, 0.17 mmol, 97%) as a solid: [α]20D=+467° (c=0.14, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.34-1.53 (m, 8H, 14-H, 14′-H, 15-H, 15′-H), 1.78-1.91 (m, 4H, 13-H, 13′-H), 1.96-2.10 (m, 4H, 2-H, 2′-H), 2.25-2.38 (m, 4H, 1-H, 1′-H), 3.54-3.63 (m, 2H, 3-H, 3′-H), 3.70-3.76 (m, 2H, 11a-H, 11a′-H), 3.77-3.88 (m, 2H, 3-H, 3′-H), 3.90 (s, 6H, 7-OMe, 7′-OMe), 4.04-4.17 (m, 4H, 12-H, 12′-H), 6.81 (s, 2H, 9-H, 9′-H), 7.52 (s, 2H, 6-H, 6′-H), 7.67 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 29.0, 29.1, 29.6, 46.6, 53.7, 56.0, 69.0, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.3, 164.6; IR (neat): 3326, 2937, 1599, 1506, 1448, 1387, 1262, 1217, 1092, 1023 cm−1; MS (FAB) m/z (relative intensity) 667 ([M+2×MeOH]+., 7), 635 ([M+MeOH]+., 15), 603 (M+., 100).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[C:27]1([C:33]2[CH:34]=[C:35]([C:39]([C:41]3[N:42]=[CH:43][N:44]4[CH:48]=[C:47]([Sn](CCCC)(CCCC)CCCC)[S:46][C:45]=34)=[O:40])[CH:36]=[N:37][CH:38]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:47]3[S:46][C:45]4=[C:41]([C:39]([C:35]5[CH:36]=[N:37][CH:38]=[C:33]([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:34]=5)=[O:40])[N:42]=[CH:43][N:44]4[CH:48]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(-c4ccccc4)c3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(-c6ccccc6)c5)c4s3)[C@H](C)[C@H]12
Yield: 14.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-phenylpyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (47 mg) was prepared in substantially the same manner as in step a) of Example 1, except that 270 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 293 mg of 7-(5-phenylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(C=CC=1)N.C1(C2C=C(NC(=O)OC3C=CC=CC=3)ON=2)CC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]2[C:50](=[CH:51][C:52]=1[O:53][CH3:54])[N:49]=[CH:48][N:47]=[C:46]2[O:55][C:56]1[CH:57]=[C:58]([NH:62][C:63]([NH:65][C:66]2[O:70][N:69]=[C:68]([CH:71]([CH3:73])[CH3:72])[CH:67]=2)=[O:64])[CH:59]=[CH:60][CH:61]=1>>[CH:71]1([C:68]2[CH:67]=[C:66]([NH:65][C:63]([NH:62][C:58]3[CH:59]=[CH:60][CH:61]=[C:56]([O:55][C:46]4[C:45]5[C:50](=[CH:51][C:52]([O:53][CH3:54])=[C:43]([O:42][CH3:41])[CH:44]=5)[N:49]=[CH:48][N:47]=4)[CH:57]=3)=[O:64])[O:70][N:69]=2)[CH2:73][CH2:72]1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: O=C(Nc1cc(C2CC2)no1)Oc1ccccc1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CC5)no4)c3)c2cc1OC
Yield: 49 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) and phenyl 3-cyclopropylisoxazol-5-ylcarbamate from the previous step (88 mg, 0.36 mmol) were reacted according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-cyclopropylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea as a colorless solid (65 mg, 49%). 1H NMR (300 MHz, DMSO-d6) δ 10.17 (brs, 1H), 9.05 (brs, 1H), 8.56 (s, 1H), 7.56 (s, 2H), 7.38-7.44 (m, 2H), 7.29 (m, 1H), 6.99 (m, 1H), 5.77 (s, 1H), 3.98-4.00 (2×s, 6H), 1.91 (m, 1H), 0.94-0.99 (m, 2H), 0.71-0.75 (m, 2H); LC-MS (ESI) m/z 448 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16](C(OCC)=O)[N:15]([CH3:24])[C:14]3=[O:25])[CH:10]=[N:9]2)=[C:5]([CH3:26])[O:4][N:3]=1.CN(C=O)C.C(#N)C.Cl>CO>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:14](=[O:25])[N:15]([CH3:24])[NH:16][C:17]3=[O:18])[CH:10]=[N:9]2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CCOC(=O)n1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(C)c2=O)cn1
Yield: 90 %

Procedure:
Ethyl 4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-methyl-3,5-dioxo-1,2,4-triazolidine-1-carboxylate (3.2 g, 8.8 mmol) was stirred in a (1/1) mixture of MeOH/1N aqueous NaOH (100 mL) at ambient temperature for 30 minutes. The mixture was acidified with aqueous 1N HCl (150 mL), extracted with ethyl acetate (3×, 100 mL), dried over sodium sulfate, filtered and concentrated to afford 4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,2,4-triazolidine-3,5-dione (2.3 g, 89%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ2.18 (s, 3H), 2.44 (s, 3H), 3.05 (s, 3H), 5.17 (s, 2H), 7.94 (s, 1H), 8.13 (s, 1H).