Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=2[F:16])[CH2:5][O:4]1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.[Na]>C(O)(C)(C)C>[F:16][C:7]1[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=1[C:3]1([CH2:2][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:5][O:4]1
Reactant: Fc1cc(C(F)(F)F)ccc1C1(CCl)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CC(C)(C)O
Product: Fc1cc(C(F)(F)F)ccc1C1(Cn2cncn2)CO1

Procedure:
A solution of 2-chloromethyl-2-(2-fluoro-4-trifluoromethylphenyl)oxirane (6 g.) in tert-butyl alcohol was treated with sodium 1,2,4-triazole (2.7 g.) and heated at 100° for 1 hour. The mixture was evaporated and the residual gum partitioned between ethyl acetate and water. the organic layer was washed with water, dried and evaporated to dryness. The residual gum was chromatographed on K60 silica gel using chloroform/petroleum ether (b.p. 60°-80°) 1:1 v/v and chloroform as eluting solvents to give 2-(2-fluoro-4-trifluoromethylphenyl)-2-(1,2,4-triazol-1-ylmethyl)oxirane, as a gum with NMR data as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([CH:12](C(C)(C)C(C)C)O[SiH](C)C)=[CH:5]2.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33]([CH3:35])OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:34][C@@H:33]([CH3:35])[N:7]2[C:8]3[CH:9]=[C:10]([F:11])[C:2]([Br:1])=[CH:3][C:4]=3[CH:5]=[C:6]2[CH2:12]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)c1cc2cc(Br)c(F)cc2[nH]1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3cc(Br)c(F)cc3n21

Procedure:
The title compound, ISP-MS: m/e=383.2 ([M+H]+) and m.p. 116-118° C., was prepared in accordance with the general method of example 81e and f) from 5-bromo-2[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-fluoro-1H-indole and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>N1C=CC=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][C:11]([CH3:13])([CH3:14])[C:10]([O:15][C:18](=[O:19])[N:17]([CH3:21])[CH3:16])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(Cc2ccccc2)NC1=O
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)OC1=NN(Cc2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
1-Benzyl-4,4-dimethyl-3-pyrazolidinone [1.2 g] and dimethylcarbamoyl chloride [0.56 mL] were combined in 4 mL pyridine and 1.5 mL triethylamine. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride solution (30 mL), dried over MgSO4, and evaporated. Chromatography on silica gel gave 0.6 g (37%) of pure 1-benzyl-4,4-dimethyl-3-(N,N-dimethylcarbamoyloxy)-2-pyrazoline as a light yellow oil. 1H NMR: 7.6-7.2 (5H, m), 3.8-3.4 (4H, m), 3.2 (6H, s), 1.2 (6H, s).
Reaction SMILES: [FH:1].[Br:2]N1C(=O)CCC1=O.[OH:10][C@H:11]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:17]3[C@H:18]3[CH2:37][C@H:19]3[C@@H:20]2[C:21](=[O:27])[CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:12]1.C(=O)(O)[O-].[K+]>C(Cl)Cl.CN(C)C=O>[F:1][C@H:14]1[C@:13]2([Br:2])[C@:32]([CH3:35])([CH2:33][CH2:34][C@H:11]([OH:10])[CH2:12]2)[C@@H:31]2[C@H:16]([C@H:17]3[C@:28]([CH3:36])([CH2:29][CH2:30]2)[C@@H:20]([C:21](=[O:27])[CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:19]2[CH2:37][C@H:18]32)[CH2:15]1
Reactant: F
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCC(=O)[C@H]1[C@@H]2C[C@@H]2[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)[C@H]1[C@@H]2C[C@@H]2[C@H]2[C@@H]3C[C@@H](F)[C@@]4(Br)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: -15 °C
Reaction time: 0.08 h

Procedure:
2.5 ml of liquid hydrogen fluoride is added to 2.5 ml. of dimethylformamide cooled to -40° C. The reaction mixture is combined with 250 mg. of N-bromosuccinimide, and then 500 mg. of 3β-hydroxy-21-acetoxy-15α,16α-methylene-5-pregnen-20-one, dissolved in 5 ml. of methylene chloride, is introduced into this reaction mixture. The latter is agitated for 5 minutes at -15° C., poured into saturated potassium bicarbonate solution, and extracted with methylene chloride. After drying and evaporation, 700 mg. of crude 6β-fluoro-5-bromo-3β-hydroxy-21-acetoxy-15α,16α-methylene-5α-pregnan-20-one is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[N:35]=[C:36]=[O:37]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[NH:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20])=[O:37]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)ccc4Cl)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-chloro-2-isocyanato-4-(trifluoromethyl)benzene (90 μL, 0.60 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethanol to give the title compound (186 mg, 74%) as a white powder.
Reaction SMILES: CCCCCC.[H-].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([N:26]=[C:27]=[S:28])[C:22]([CH3:29])=[N:21]1>C1COCC1>[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([NH:26][C:27]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=3)[CH:13]=[CH:14]2)=[S:28])[C:22]([CH3:29])=[N:21]1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: Cc1nn(C)c(C)c1N=C=S
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1NC(=S)n1ccc2cc(Cl)ccc21
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A stirred slurry of hexane washed potassium hydride (0.423 g, 10.6 mmol) in 50 mL of dry THF was treated portionwise with 5-chloroindole (1.6 g, 10.6 mmol). The mixture was stirred until a clear solution was obtained. A solution of (1,3,5-trimethyl-pyrazol-4-yl)-isothiocyanate (1.8 g, 10.6 mmol) of step A in 5 mL THF was slowly added and stirring was continued for 1 hour. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residual solid foam was triturated with Et2O-hexane overnight to provide 2.0 g of the title compound as a tan solid, m.p. 165-166° C. (59% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.Br[Mg][CH3:14].C(OCC)C.[Cl-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[N:4][C:3]=1[C:9]([OH:11])([CH3:14])[CH3:10]
Reactant: CC(=O)c1ncc(O)cc1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(O)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-(3-Chloro-5-hydroxypyridin-2-yl)ethanone (0.075 g, 0.0068 mol) was dissolved in THF (2 mL). The mixture was degassed three times then cooled to 0° C. with an ice bath. Then bromo(methyl)magnesium in diethylether (0.3 mL, 0.0009 mol) was added dropwise to the reaction mixture under nitrogen keeping the temperature at 0° C. with an ice bath. When the addition was complete, it was left to warm up to room temperature for 16 hours. Then bromo(methyl)magnesium in diethylether (0.3 mL, 0.0009 mol) was added dropwise to the reaction mixture and was stirred at room temperature for further 3 hours. A saturated aqueous solution of sodium chloride was slowly added to the reaction mixture (10 mL) and then it was extracted with EtOAc (2×10 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to obtain the title compound as a translucent solid (0.049 g, 4% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([N:27]2[CH2:28][CH2:29][CH2:30][C:31]3[N:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)[N:24]=[CH:25][C:26]2=3)=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(Cl)c1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: O=C(Cc1ccc(C(F)(F)F)c(Cl)c1)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 52 %

Procedure:
The compound was from prepared from 3-chloro-4-trifluoromethylphenylacetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with brine and 2×1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-60% EtOAc in hexanes) to provide 68 mg (52%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.45 (s, 0.8H), 7.67 (m, 1H), 7.55 (s, 0.2H), 7.44-7.49 (m, 3H), 7.30 (m, 1H), 7.14-7.21 (m, 2H), 4.04 (s, 0.4H), 3.94 (m, 0.4H), 3.92 (s, 1.6H), 3.77 (m, 1.6H), 2.82-2.87 (m, 2H), 2.04 (m, 2H); MS: (ES) m/z calculated for C21H17ClF4N3O [M+H]+ 438.1, found 438.1.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17](Cl)[N:16]=[N:15][C:14]=3[C:20]([NH2:22])=[O:21])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.O>[N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]4[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[N:16]=[N:15][C:14]=3[C:20](=[O:21])[NH2:22])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2cccn2)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(-n3cccn3)n2)c(C(N)=O)nn1
Temperature: 140 °C
Reaction time: 24 h
Yield: 34.2 %

Procedure:
To a solution of 4-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (131 mg, 415 μmol) in NMP (5 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) and the mixture stirred at 140° C. for 24 h. A second portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (162 mg, 756 μmol) was added and the mixture heated at 140° C. for a further 24 h. The reaction mixture was cooled, and then diluted with water. The mixture was extracted with ethyl acetate (3×50 mL) then the combined organic phases were washed with brine (50 mL), then concentrated in vacuo, and finally purified by chromatography (silica, 12 g RediSep Gold, 2 to 6% of a 99.5:0.5 methanol:ammonium hydroxide solution in dichloromethane, 20 min) to give tert-butyl (1S,2R)-2-(5-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)cyclohexylcarbamate (70 mg, 142 μmol, 34%) as a beige solid. MS (EI/CI) m/z: 494.3 [M+H].
Reaction SMILES: CN(C)C=O.N1CCCCC1.C1(NC(N2C3C(=CC(OC4C=CN=C(NC(=O)OC5C=CC=CC=5)C=4)=CC=3)C=C2)=O)CC1.[CH:44]1([NH:47][C:48]([N:50]2[C:58]3[C:53](=[CH:54][C:55]([O:59][C:60]4[CH:65]=[CH:64][N:63]=[C:62]([NH:66][C:67]([N:69]5[CH2:74][CH2:73][CH:72](N6CCCC6)[CH2:71][CH2:70]5)=[O:68])[CH:61]=4)=[CH:56][CH:57]=3)[CH:52]=[CH:51]2)=[O:49])[CH2:46][CH2:45]1>C(OCC)C>[CH:44]1([NH:47][C:48]([N:50]2[C:58]3[C:53](=[CH:54][C:55]([O:59][C:60]4[CH:65]=[CH:64][N:63]=[C:62]([NH:66][C:67]([N:69]5[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]5)=[O:68])[CH:61]=4)=[CH:56][CH:57]=3)[CH:52]=[CH:51]2)=[O:49])[CH2:46][CH2:45]1
Reactant: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(N2CCCC2)CC1
Agent: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)Oc1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCCCC1
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (5 ml) and piperidine (0.42 ml, 4.2 mmol) were added to a mixture (467 mg) of phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate obtained in Example 68; and the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; the obtained solid was washed with a solvent mixture of hexane:diethyl ether=1:1 to yield the title compound as crystals (241 mg, 0.57 mmol).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22](Cl)(=[O:31])[C:23]1[C:24]([O:29][CH3:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 5 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and o-anisoyl chloride (0.4 g, 2.5 mmol) in THF (30 mL) was cooled to 5° C. Triethylamine (0.5 g, 4.8 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was stirred with 1N HCl (30 mL) and filtered. The solid was slurried with ethanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-methoxy-benzamide (0.8 g, 94%) as a white solid: mp 236-238° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.32-2.66 (m, 2H), 2.86-3.01 (m, 1H), 3.88 (s, 3H, OCH3), 4.39-4.61 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.9 and 13.1 Hz, 1H, CH), 7.02 (t, J=7.4 Hz, 1H, Ar), 7.16 (d, J=8.3 Hz, 1H, Ar), 7.44-7.72 (m, 5H, Ar), 8.77 (t, J=5.6 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.60, 31.17, 46.20, 51.55, 55.82, 111.93, 120.41, 121.51, 123.10, 128.24, 130.22, 130.43, 131.57, 132.17, 134.89, 139.94, 156.87, 165.34, 168.09, 171.00, 172.83; Anal. calcd. for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.59; H, 5.01; N, 10.17.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH3:26][NH:27][CH3:28]>C(O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:27]([CH3:28])[CH3:26])[S:8]1(=[O:25])=[O:24]
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccc(F)cc1F
Reactant: CNC
Solvent: CCO
Product: CN(C)CCOCCN1c2ccccc2N(c2ccc(F)cc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.53 g, 1.2 mmol) was treated with 33% dimethylamine in ethanol to give 2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}-N,N-dimethylethanamine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.157 g, 30%). MS (ES) m/z 397.9 ([M+H]+). HPLC retention time: 7.1 min.
Reaction SMILES: [N:1]([CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([C:13]([C:15]2[N:16]=[CH:17][N:18]3[CH:22]=[C:21]([C:23]4[C@H:24]([CH3:47])[C@@H:25]5[C@@H:42]([C@H:43]([OH:45])[CH3:44])[C:41](=[O:46])[N:26]5[C:27]=4[C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=4)=[O:29])[S:20][C:19]=23)=[O:14])[CH:10]=[N:11][CH:12]=1)=[N+:2]=[N-:3].[I:48][CH2:49][C:50]([NH2:52])=[O:51]>>[I-:48].[N:1]([CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([C:13]([C:15]2[N:16]=[CH:17][N:18]3[CH:22]=[C:21]([C:23]4[C@H:24]([CH3:47])[C@@H:25]5[C@@H:42]([C@H:43]([OH:45])[CH3:44])[C:41](=[O:46])[N:26]5[C:27]=4[C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=4)=[O:29])[S:20][C:19]=23)=[O:14])[CH:10]=[N+:11]([CH2:49][C:50](=[O:51])[NH2:52])[CH:12]=1)=[N+:2]=[N-:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(SCCN=[N+]=[N-])c5)c4s3)[C@H](C)[C@H]12
Reactant: NC(=O)CI
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cc(SCCN=[N+]=[N-])c[n+](CC(N)=O)c5)c4s3)[C@H](C)[C@H]12
Product: [I-]
Yield: 96.4 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-[5-(2-azidoethylthio)-1-carbamoylmethylpyridinium-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate iodide (140 mg) was prepared in the same manner as in step a) of Example 2, except that 114 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-[5-(2-azidoethylthio)pyridin-3-yl]carbonylimidazo[5,1-b]-thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate and 312 mg of 2-iodoacetamide were used as the starting compounds.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C>[CH3:15][C:16]1[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]=[C:11]([CH3:13])[O:10][N:9]=3)=[CH:4][C:3]=2[CH3:14])=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: Cc1nc(-c2ccc(Br)c(C)c2)no1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)c(C)c2)no1

Procedure:
Example 30 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[1,2,4]oxadiazole and N-[4-methyl-3-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 25) using DMF as the solvent.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:27])[CH:18](OC(C)(C)C)N(C)C>CN(C=O)C>[Si:1]([O:8][CH2:9][CH2:10]/[C:11](=[CH:16]\[N:17]([CH3:27])[CH3:18])/[C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COC(=O)CCCO[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)/C(=C/N(C)C)CCO[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Yield: 87 %

Procedure:
A mixture of methyl 4-[tert-butyl(dimethyl)silyl]oxybutanoate (6.8 g, 29.31 mmol) and N,N,N′,N′-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine (5.1 g, 29.31 mmol) in DMF (14 mL) in sealed tube was heated to 100° C. overnight. Added water to the mixture at 0° C. and extracted with ethyl acetate twice. The organic phase was separated and washed with water (2×) and brine and dried with anhydrous Na2SO4. The organic phase was concentrated to give the title compound (7.33 g, 91%). [M+H] Calc'd for C14H29NO3Si, 288. Found, 288.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:6]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[CH2:33]([NH:35][C:36]([NH:11][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[CH:13][CH:12]=1)=[O:37])[CH3:34]
Reactant: CCN=C=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4oc(C)nc4-c4ccc(N)cc4)ccnc32)cc1
Product: CCNC(=O)Nc1ccc(-c2nc(C)oc2-c2ccnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
Following the procedure described for Intermediate 31 with 4-(2-methyl-5-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1,3-oxazol-4-yl)aniline and ethyl isocyanate provided the title compound. ESMS [M+H]+: 516.2
Reaction SMILES: [I-].[Na+].I.[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17](Cl)=[N:16][C:15]([S:22][CH3:23])=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1>O1CCOCC1>[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[N:16][C:15]([S:22][CH3:23])=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CSc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
Sodium iodide (3.9 g, 26 mmol) and hydriodic acid (10 mL, 47% aqueous solution) were added to a mixture of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidine (8.0 g, 26 mmol) and 4-aminobenzotrifluoride (5.06 g, 0.031 mol) in dioxane (100 mL) and the reaction mixture was stirred at 100° C. overnight. Solid thus formed was filtered out, washed with ethyl acetate and diethyl ether and dried in vacuo. Product was obtained as white needle solid (8.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1.C(OCC)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:9]([C:10]#[N:11])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:28]
Reactant: Cc1ccc(CC#N)cc1C
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(C)c(C)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Combine 3,4-dimethylphenylacetonitrile (50.0 mmol) and tetrahydrofuran (140 mL). Cool to about 5° C. Add dropwise a solution of sodium bis(trimethylsilyl)amide (800 mL, 1M in tetrahydrofuran, 800 mmol). When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution via cannula into a cooled (-8° C.) solution of ethyl bromoacetate (84.5 mL, 762 mmol) in tetrahydrofuran (500 mL) at such a rate that the temperature of the reaction mixture does not rise above 20° C. Allow to stir at ambient temperature. After 18 hours, dilute with diethyl ether (1.5 L) and extract with saturated aqueous solution of ammonium chloride, then water, and then saturated aqueous solution of sodium chloride. Dry the organic layer over MgSO4, filter, and concentrate invacuo to give the title compound.