Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[N:14][C:13]([N:16]2[CH:20]=[C:19]([CH3:21])[N:18]=[N:17]2)=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.Cl[C:23]([C:25]([O:27][CH3:28])=[O:26])=[O:24]>C(Cl)Cl.C[N+]([O-])=O>[CH3:28][O:27][C:25](=[O:26])[C:23]([C:9]1[C:8]2[C:12](=[C:13]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[N:17]3)[N:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][CH:10]=1)=[O:24]
Reactant: COc1cnc(-n2cc(C)nn2)c2[nH]ccc12
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2c(-n3cc(C)nn3)ncc(OC)c12
Temperature: 0 °C
Reaction time: 18 h
Yield: 17.3 %

Procedure:
To a solution of AlCl3 (1.382 g, 10.36 mmol) in CH2Cl2 (4 mL) and MeNO2 (1 mL) was added 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindole (0.155 g, 0.677 mmol) as a solid. After dissolution of the starting material (ca. 5 min), ClCOCO2Me (0.29 mL, 3.15 mmol) was added and the mixture was allowed to stir for 18 h. Another portion of ClCOCO2Me (0.29 mL, 3.15 mmol) was then added and stirring continued for a further 24 h. The mixture was subsequently cooled to 0° C., quenched by the slow addition of 1 M aqueous NH4OAc and then extracted with EtOAc. The aqueous layer was separated and acidified with 6 M HCl and then the resultant precipitate was filtered and dried to give the title acid (0.158 g, 69%): LCMS: m/e 302 (M+H)+. The organic layer was washed (H2O, brine), dried (Na2SO4) and evaporated to give 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid methyl ester (0.037 g, 15%): LCMS: m/e 316 (M+H)+. This material was hydrolyzed by dissolving in MeOH (2 mL) and treating with 1M NaOH (0.3 mL). The mixture was allowed to stir for 4 h, at which point the solvent was removed and the residue diluted with H2O (4 mL). The mixture was then acidified to pH 1 using 6N HCl and the precipitated acid was filtered and dried to give a further 0.021 g of the title compound. Total yield=0.179 g (78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16]S(C)(=O)=O)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[F:21][C:22]1[CH:23]=[C:24](O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:25]3[CH:24]=[CH:23][C:22]([F:21])=[C:27]([F:28])[CH:26]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: Oc1ccc(F)c(F)c1
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Product: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccc(F)c(F)c2)C1
Yield: 89.9 %

Procedure:
The title compound (D109) (87 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63) (100 mg, 0.311 mmol) and 3,4-Difluorophenol (36.87 mg, 0.284 mmol).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18](O)[CH2:17]4)=[CH:11][CH2:10]1)[CH3:8])[CH3:3].C(N(S(F)(F)F)CC)C.O>C(Cl)Cl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH:19]=[CH:18][CH2:17]4)=[CH:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)CC1CC3
Agent: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC=CCC1CC3
Temperature: -78 °C

Procedure:
The title compound was prepared by using a method analogous to a method described in J Chemical Research (miniprint) (1979) 4714-4755. Cholesta-8,14-diene-3β-ol (1.17 g, 3 mmol) was dissolved in 10 ml of methylenechloride and cooled to −78° C. Over 10 min a solution of diethylaminosulfur trifluoride (1.4 g, 8,7 mmol) in 10 ml of methylenechloride was added at −78° C. The mixture was stirred and was then slowly heated to the room temperature. The reaction mixture was added 15 ml water while stirring was continued. The organic phase was separated and washed with 30 ml of 5% NaHCO3 and then with water. The organic phase was dried with MgSO4 and evaporated to dryness. The residue was purified by column chromatography using heptane for a first fraction A giving cholesta-2,8,14-triene, 0.23 g. Melting point: 104.7° C. Elementary analysis: Cal C: 88.45; H: 11.55. Found C: 88.58; H: 11.89. NMR: Hd: 5.64 (m 2H; C2—H; C3—H)d 5.35 (s,1H C 15H). Cd: 125.95 (C3), 125.67 (C2).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[F:33])(C)(C)C.[ClH:35].O1CCOCC1>>[ClH:35].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[F:33]
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(F)c1
Yield: 100 %

Procedure:
[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-carbamic acid tert-butyl ester from Example E8.1 (237 mg, 0.51 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (205 mg, 100%).
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]([N+:23]([O-])=O)=[C:8]([CH:22]=1)[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=1)(=O)C.[CH2:26]([O:28]CC)[CH3:27]>C(O)C.ClCCl.[Pd]>[C:26]([C:5]1[CH:4]=[CH:22][C:8]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:11]=2)=[C:7]([CH:6]=1)[NH2:23])(=[O:28])[CH3:27]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Nc2cccc(-c3cccnc3)c2)c1
Reactant: CCOCC
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)c1ccc(Nc2cccc(-c3cccnc3)c2)c(N)c1
Yield: 80 %

Procedure:
30a from Example 12 (2 g, 6 mmol) is suspended in a mixture of ethanol (50 ml) and dichloromethane (10 ml) and is hydrogenated at ambient pressure using palladium (5% on activated carbon) as the catalyst. Filtration of the resulting solution through celite followed by evaporation of solvent leaves an oil. Trituration with a mixture of diethyl ether and petroleum ether (1:1) affords 1.46 g pure 31a (80%). Mp 175-176° C.
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH2:7][CH:8]1[C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1)C>C(O)C>[N:2]1[NH:5][CH2:7][CH:8]2[CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=12
Reactant: CN(C)CC1COc2ccccc2C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1ccc2c(c1)OCC1CNN=C21
Temperature: 0 °C
Yield: 105.5 %

Procedure:
Hydrazine monohydrate (7.2 g) was dissolved in ethanol (10 ml). Thereto was dropwise added a solution of 3-(N,N-dimethylaminomethyl)-4-chromanone (6.7 g) dissolved in ethanol (10 ml) in a nitrogen atmosphere at room temperature. The resulting mixture was refluxed for 4 hours with heating. The reaction mixture was poured into ice water. Extraction with chloroform was conducted, followed by drying and concentration, to obtain 6 g of a title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOC(C)=O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:13][CH:14]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cn2)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2nccs2)cc(-c2ccc(C)cn2)c1
Temperature: 135 °C

Procedure:
A stirred mixture of methyl 3-hydroxy-5-(5-methylpyridin-2-yl)benzoate (290 mg, 1.2 mmol), 2-bromothiazole (410 mg, 2.5 mmol), potassium carbonate (346 mg, 2.5 mmol), and dimethyl sulfoxide (5 mL) was heated at 135° C. overnight. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The organic phase was washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-30% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([Br:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].[N:12]1[C:21]2[C:16](=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[Br:11][C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH:15]=[CH:14][CH:13]=[N:12]3)[S:3][CH:4]=1
Reactant: COC(=O)c1c(Br)csc1N
Reactant: O=C(O)Cc1cccc2ncccc12
Product: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2ncccc12
Yield: 49 %

Procedure:
The title compound was prepared from methyl 2-amino-4-bromothiophene-3-carboxylate (660 mg, 2.8 mmol) and 2-(quinolin-5-yl)acetic acid using protocol A. 560 mg (49% yield). Method [1]: rt=1.666 min; MH+ 405/407.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH:16](O)=[O:17].C(O)(=O)C.C(OC(=O)C)(=O)C>COCCOC>[CH:16]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[N:9]=[CH:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:17]
Reactant: Clc1ccc(NN=Cc2cccs2)cc1
Reactant: O=CO
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Product: O=CN(N=Cc1cccs1)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
5.29 g of 1 was dissolved in 25 ml of 1,2-dimethoxyethane. The solution was treated with 5.4 g of the mixed anhydrides of formic acid and acetic acid, prepared by mixing the appropriate amounts of formic acid and acetic anhydride, and distilling the product. The resulting mixture was held overnight at room temperature. The solvent was evaporated and the residue was extracted with chloroform. The extract was washed with sodium bicarbonate solution, dried and the solvent evaporated. The residue was treated with charcoal in hexane; the mixture was filtered and the filtrate let stand. 2 crystallized out, mp 103°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:29]#[N:30]>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:29]#[N:30]
Reactant: COc1ccc2cc3ncc(C#N)c(Cl)c3cc2c1
Reactant: Nc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc3ncc(C#N)c(Nc4ccc(Cl)cc4Cl)c3cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
According to the procedure of Example 14, a reaction mixture of 657.8 mg (4.06 mmol) of 2,4-dichloroaniline and 162.4 mg (4.06 mmol) of sodium hydride in 18 mL of anhydrous DMF is stirred at room temperature for 0.5 hour. To the mixture is added 494.0 mg (1.84 mmol) of 4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile. The resulting mixture is heated at 55° C. for 1 hour. After work up, 624.6 mg (86.2%) of 4-(2,4-dichloroanilino)-7-methoxybenzo[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp 215-217° C.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:24])=[N:10][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([C:32]5[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:30]([F:29])[CH:31]=5)=[CH:3][C:4]([C:25]([F:26])([F:27])[F:28])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:24])[CH2:13]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5Cl)C[C@H]4C)[nH]c23)cc1F

Procedure:
7-Bromo-2-[(2R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (95 mg, 0.2 mmol, Example 77) and 3-fluoro-4-methoxyphenylboronic acid (43 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 520 (M+1).
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]1([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2].[Cl-].C[N:17](C)C=O>C1C=CC=CC=1>[CH:1]([O:4][CH2:5][C:6]1([C:12]([NH2:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)OCC1(C(=O)O)CCCCC1
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(C)OCC1(C(N)=O)CCCCC1

Procedure:
10 g of 1-isopropyloxymethyl 1-cyclohexyl carboxylic acid dissolved in 50 cm3 of benzene were heated under reflux for 5 hours together with 15 cm3 of thionyle chloride in the presence of 0.3 cm3 of dimethylformamide.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([NH:9][NH2:10])[CH2:5][CH2:4]1.CN1CCCC1=O.CCN(C(C)C)C(C)C.[Br:27][C:28]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:31]([NH:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[C:30]([C:45](=O)/[CH:46]=[CH:47]/N(C)C)[CH:29]=1>O>[Br:27][C:28]1[C:33]([C:34]([F:37])([F:35])[F:36])=[CH:32][C:31]([NH:38][C:39](=[O:44])[C:40]([F:41])([F:42])[F:43])=[C:30]([C:45]2[N:9]([CH:6]3[CH2:7][CH2:8][O:3][CH2:4][CH2:5]3)[N:10]=[CH:47][CH:46]=2)[CH:29]=1
Reactant: NNC1CCOCC1
Reactant: CN(C)/C=C/C(=O)c1cc(Br)c(C(F)(F)F)cc1NC(=O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc(C(F)(F)F)c(Br)cc1-c1ccnn1C1CCOCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.1 %

Procedure:
To a mixture of 6.0 g of tetrahydro-2H-pyran-4-ylhydrazine dihydrochloride and 175 mL of N-methylpyrrolidone was added 11 mL of DIPEA, followed by stirring at room temperature for 20 minutes. To the reaction mixture was added 8.86 g of N-{4-bromo-2-[(2E)-3-(dimethylamino)prop-2-enoyl]-5-(trifluoromethyl)phenyl}-2,2,2-trifluoroacetamide, followed by stirring at 110° C. for 1 hour. To the reaction mixture was added water, followed by extraction with isopropyl acetate, and the organic layer was washed with saturated brine. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol). The obtained oil was triturated with diethyl ether/n-hexane to obtain 4.19 g of N-{4-bromo-2-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-5-(trifluoromethyl)phenyl}-2,2,2-trifluoroacetamide.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28]CC3C=CC([N+]([O-])=O)=CC=3)=[O:27])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].I[CH2:42][C:43]([NH2:45])=[O:44].C(OCC)(=O)C>CC(C)=O>[C:43]([CH2:42][N+:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:19][C:16]1[N:17]=[CH:18][N:13]2[CH:12]=[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:39](=[O:40])[N:6]4[C:7]=3[C:26]([O-:28])=[O:27])[S:15][C:14]=12)(=[O:44])[NH2:45]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(Sc5ccccn5)c4s3)[C@H](C)[C@H]12
Reactant: NC(=O)CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(Sc5cccc[n+]5CC(N)=O)c4s3)[C@H](C)[C@H]12
Temperature: 40 °C
Reaction time: 96 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-2-yl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (42.2 mg) was dissolved in 2 ml of acetone. 2-Iodoacetamide (140 mg) was added to the solution. The mixture was stirred at 40° C. for 4 days. Ethyl acetate (4 ml) was added to the reaction solution, and the resultant precipitate was collected, and was reacted in the same manner as in Example 1c). The reaction product was purified by column chromatography on Cosmosil 40C18-PREP (a 10 to 25% aqueous methanol solution). In this case, the first eluted fraction in two major products was collected to prepare 1.44 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][N:15]=1.N>>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([C:18]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1cccc(C(N)=NO)c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: N
Product: N#Cc1cccc(-c2noc(-c3ccc(Cl)nc3)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 4B using 3-cyano-N′-hydroxybenzimidamide (Example 4A) and 6-chloronicotinoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.87 (m, 2H), 8.17 (m, 1H), 8.4 (m, 1H), 8.43 (d, J=1.7 Hz, 1H), 8.6 (m, 1H), 9.25 (d, J=1.7 Hz, 1H) ppm; MS (DCl/NH3) m/z 283 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:10]=[N:9][C:8](SC)=[N:7][C:6]=2[N:13]=1.[CH3:14][O:15][CH2:16][CH2:17][NH2:18]>CCOC(C)=O>[CH3:14][O:15][CH2:16][CH2:17][NH:18][C:8]1[N:9]=[CH:10][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:13][C:6]=2[N:7]=1
Reactant: COCCN
Reactant: CSc1ncc2ccc(C)nc2n1
Solvent: CCOC(C)=O
Product: COCCNc1ncc2ccc(C)nc2n1
Temperature: 25 °C
Yield: 91 %

Procedure:
Heat a solution of 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine (2.6 g, 13.6 mmol) and 2-methoxyethanamine (6 mL) with microwave irradiation at 180° C. for 2 h. Cool the mixture to RT, dissolve in EtOAc, wash with water, then brine, dry over Na2SO4 and concentrate under reduced pressure to give N-(2-methoxyethyl)-7-methylpyrido[2,3-d]pyrimidin-2-amine (2.7 g, 91%). Treat a solution of N-(2-methoxyethyl)-7-methylpyrido[2,3-d]pyrimidin-2-amine (2.35 g, 10.7 mmol) in THF (100 mL) portion wise with NBS (1.8 g, 10.7 mmol) and stir at RT for 2 h. Concentrate the reaction mixture to dryness, dissolve in EtOAc, wash with water, then brine, dry the organics over Na2SO4, concentrate and purify by HPLC to afford the title compound (0.55 g, 26%). MS (m/z): 297.0 (M+1+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[CH:17]=O.Cl>CO>[CH3:23][O:22][C:20]1[CH:19]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:15]=[C:14]([O:13][CH3:12])[CH:21]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: COc1cc(C=C2Oc3cc(O)ccc3C2=O)cc(OC)c1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3,5-dimethoxybenzaldehyde 1.23 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.42 g.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][O:20]C3=O)=[C:10]3[S:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].[OH-].[K+].O>CO.C1COCC1>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][CH2:16][CH2:17][NH:18][CH2:22][CH2:21][OH:20])=[C:10]3[S:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=4[C:8]([C:9]=23)=[N:7]1)[CH3:34]
Reactant: CCN(CC)CCn1nc2c3c(c(NCCN4CCOC4=O)ccc31)Sc1ccc(OC)cc1-2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCn1nc2c3c(c(NCCNCCO)ccc31)Sc1ccc(OC)cc1-2
Yield: 82.6 %

Procedure:
A mixture of 8.0 g (0.017 mol) of 3-[2-[[2[2-(diethylamino)ethyl]-9-methoxy-2H[1]benzothiopyrano-[4,3,2-cd]indazol-5-yl]amino]ethyl]-2-oxazolidinone, 70 ml of 2N KOH in MeOH, 35 ml of THF, and 35 ml of H2O was treated and the product isolated as described in Example 56 to furnish 6.4 g of the product, mp 111°-115° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([C:21]([NH:23]O)=[NH:22])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:28]C(=O)C)(=[O:27])[CH3:26].[H][H]>C(O)(=O)C.[Pd]>[C:25]([O-:28])(=[O:27])[CH3:26].[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([C:21]([NH2:23])=[NH2+:22])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C(=N)NO)n2)c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)[O-]
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C(N)=[NH2+])n2)c1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 147.7 %

Procedure:
To a mixture of 6-(3-tert-butylsulfamoyl-phenyl)-N-hydroxy-pyridine-2-carboxamidine (Example C.7) (830 mg, 2.38 mmol) in acetic acid (10 ml) at 23° C. was added acetic anhydride (0.34 ml, 3.57 mmol) and the mixture was stirred at 23° C. for 10 min, then 10% Pd on charcoal (84 mg, 0.79 mmol) was added and the mixture was hydrogenated (1 bar hydrogen) at 23° C. for 24 h. The catalyst was filtered off, washed with acetic acid and the solvents were evaporated to give the title compound (1.38 g, 148%, contains excess acetic acid) as a light yellow oil, which was used without further purification (cf. Synth. Commun. 1996, 26(23), 4351). MS (ISP) 333.1 [(M+H)+].
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=1)=[O:36]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:34][C:35](=[O:36])[NH:37][C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=3)[C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(OCCO[Si](C)(C)C(C)(C)C)cccc3[nH]2)CC1
Product: CC(C)N1CCC(NC(=O)c2nc3c(OCCO[Si](C)(C)C(C)(C)C)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 108 (v) starting from 670.0 mg (1.45 mmol) 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide and 362.8 mg (1.45 mmol) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide. Final purification by flash-chromatography on silica gel using ethyl acetate as eluent gave the title compound as a brown oil.