Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][CH2:9][C:5]2[N:4]([CH3:3])[CH:8]=[CH:7][N:6]=2)[N:15]=[CH:14][N:13]=1
Reactant: Cn1ccnc1CO
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccnc1COc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
Sodium hydride (0.30 g as an 80% dispersion by weight in oil) was added to a solution of 1-methyl-2-hydroxymethylimidazole (1.12 g) in tetrahydrofuran (30 ml) and the mixture stirred at room temperature for one hour. A solution of 4,6-dichloropyrimidine (1.48 g) in tetrahydrofuran (10 ml) was added to the reaction mixture dropwise over 30 minutes and the mixture stirred at room temperature for 3 hours and evaporated. The residue was taken up in dichloromethane and the solution extracted into 2M hydrochloric acid. The acidic layer was washed with dichloromethane, basified with saturated aqueous sodium hydrogen carbonate solution and extracted into dichloromethane. The organic layer was dried over Na2SO4 and evaporated to give the title compound (1.2 g), m.p. 126°-128° C. This compound was used directly in subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=2[CH:13]=1.ClC1N=C(NC2C=CC=CC=2C2N(C)C=CN=2)C(Cl)=CN=1.Cl[C:36]1[N:41]=[C:40]([NH:42][C@@H:43]2[C@@H:48]3[CH2:49][C@@H:45]([CH:46]=[CH:47]3)[C@@H:44]2[C:50]([NH2:52])=[O:51])[C:39]([Cl:53])=[CH:38][N:37]=1.[N+](C1C=CC2CCC(=O)CCC=2C=1)([O-])=O>>[Cl:53][C:39]1[C:40]([NH:42][C@@H:43]2[C@@H:48]3[CH2:49][C@@H:45]([CH:46]=[CH:47]3)[C@@H:44]2[C:50]([NH2:52])=[O:51])=[N:41][C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=3[CH:13]=2)=[N:37][CH:38]=1
Reactant: Nc1ccc2c(c1)CCC(O)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Agent: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3ccc4c(c3)CCC(O)CC4)ncc2Cl)[C@H]2C=C[C@@H]1C2

Procedure:
Prepared analogously to Example 216d replacing 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine with 2-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol and (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine was replaced with (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide. 2-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol is a byproduct from the reductive amination of 2-Nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one with various amines. The reaction was carried out in the presence of the desired reductive amination product to provide a crude mixture of amino and alcohol products. The crude mix was then reduced and a mixture of amino and alcohol products were used in the synthesis of target compounds. The mixture was then purified by prep HPLC to afford the desired amino compound as well as (1S,2S,3R,4R)-3-[5-Chloro-2-(7-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide. LC/MS (ESI): 440.22. 1H NMR (400 MHz, DMSO, d6) δ 9.12 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.69 (m, 1H), 7.46 (m, 2H), 7.26 (s, 1H), 6.97 (d, 1H, J=8.08 Hz), 6.35 (m, 1H), 6.27 (m, 1H), 4.58 (m, 1H), 4.15 (m, 1H), 3.72 (m, 1H), 3.31 (s, 2H), 2.88 (s, 1H), 2.78 (m, 3H), 2.11 (d, 1H, J=8.59 Hz), 1.89 (m, 2H), 1.41 (d, 1H, J=8.09 Hz), 1.33 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cncnc1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(OCc2ccccc2)c(-c2cncnc2)c1

Procedure:
A mixture of the product from step (ii) (0.2 g), 5-bromopyrimidine (0.16 g), sodium carbonate (0.21 g) and tetrakistriphenylphosphine palladium (0) (0.05 g) in dioxane (6 ml) was heated under reflux for 48 h. The mixture was partitioned between EtOAc and water, the organics separated, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 20% EtOAc/isohexane. Yield 0.283 g.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]#[CH:23])[CH:19]=[CH:20][CH:21]=1>CO>[C:22]([C:18]1[CH:17]=[C:16]([NH:15][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:20][CH:19]=1)#[CH:23]
Reactant: C#Cc1cccc(N)c1
Reactant: COCCn1ccc2c(Cl)ncnc21
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3c2ccn3CCOC)c1
Yield: 81 %

Procedure:
Utilizing a procedure analogous to that described in Example 47, this product was prepared in 81% yield from 4-chloro-7-(2-methoxy-ethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq) and m-aminophenyl acetylene (1.2 eq) in methanol. M.P. 240-241° C.; LC-MS: 292(MH+); RP18-HPLC RT: 4.16 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[C:12]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:27]2)[CH:11]=1.[F-].[Na+].O>O1CCCC1>[C:22]([CH:19]1[CH2:18][CH2:17][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]=2[N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:27]2)[CH2:21][CH2:20]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCCN1CCN(c2cc(C(=O)OC)ccc2C2CCC(C(C)(C)C)CC2)CC1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCN1CCN(c2cc(CO)ccc2C2CCC(C(C)(C)C)CC2)CC1
Reaction time: 0.92 h
Yield: 102.7 %

Procedure:
Lithium aluminum hydride (29 mg, 0.764 mmol) was suspended in anhydrous tetrahydrofuran (5 mL). To the suspension was added a solution of 4-(4-t-butylcyclohexyl)-3-(4-butylpiperazin-1-yl)benzoic acid methyl ester (308 mg, 0.743 mmol) in anhydrous tetrahydrofuran (5 mL) at room temperature under a nitrogen atmosphere, followed by stirring for 55 minutes. Sodium fluoride (262 mg) was added to the reaction mixture, and water (0.11 mL) was gradually added while blowing nitrogen. After stirring for 1 hour and 35 minutes, insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and anhydrous sodium sulfate was added for drying. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give 295 mg of a crude product of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccccc1
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2snc(C)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-Bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and phenyl boronic acid: MS (m/z) 343.1 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:17]([S:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:16][C:15](F)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N:31]1[C:35](=O)[CH2:34][CH2:33][CH2:32]1>O>[CH2:3]([N:10]1[C:18]2[C:17]([S:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:16][C:15]([NH:10][C:3]3[CH:32]=[CH:33][C:34]([C:35]#[N:31])=[CH:5][CH:4]=3)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C)c(Sc2nc(F)nc3ccn(Cc4ccccc4)c23)c(C)c1
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a stirred suspension of NaH (30 mg, 1.25 mmol) in dry NMP (1.5 mL) was added 4-aminobenzylnitrile (87.4 mg, 0.74 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2-fluoro-4-(mesitylthio)-5H-pyrrolo[3,2-d]pyrimidine (93 mg, 0.25 mmol) in dry NMP (1 mL) and stirred at room temperature for 2 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc×3. The combined organic layers were washed with water, NH4Cl, water×2, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC TLC, eluting with Hexanes:Ethyl acetate (1.5:1) afforded the product as a tan solid (12.6 mg, 11%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Cl[C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[C:14]=1[C:15]([OH:17])=[O:16].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:25][C:18]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=2)[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CCCOc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCCOc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1

Procedure:
A mixture of 24.5 g of 4-propoxyaniline, 19.8 g of 2,6-dichloro-3-nitrobenzoic acid, and 150 ml N,N-dimethylaniline was heated under nitrogen at 100° overnight. The cooled reaction mixture was treated with dilute base and chloroform. After the aqueous layer was washed several times with chloroform, it was treated with hydrochloric acid and the resulting orange needles were collected by filtration and washed with water to give 6-chloro-3-nitro-2-[(4-propoxyphenyl)amino]benzoic acid, mp 194°-196° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=O)[N:3]=1.[CH3:21][NH:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C:5]2=[C:4]([C:18](=[O:20])[NH:25][C@@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH:22][CH3:21])=[O:30])[N:3]=1
Reactant: CNC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 3-bromo-7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (1I) (0.53 g, 1.53 mmol), L-leucine-N-methylamide (0.26 g, 1.80 mmol) and DIEA (0.5 mL, 2.9 mmol) in DMF (20 mL) was added TBTU (0.69 g, 2.15 mmol) in two batches over 10 minutes at 0° C. After stiffing from 0° C. to room temperature for 2 hours, the reaction was quenched with water and evaporated under vacuum. The residue was extracted between saturated aqueous NaHCO3 and EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography with 70% to 100% EtOAc/Hexanes to give the desired product 20C as an oil (48% yield). LCMS (+ESI) m/z 474.1, 475.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)#[N:2].O[N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:12]([O:14][N:34]2[C:35](=[O:44])[C:36]3=[CH:43][CH:42]=[CH:41][CH:40]=[C:37]3[C:38]2=[O:39])=[O:13])[CH2:8][CH2:7]1)#[N:2]
Reactant: N#CC(CCN1CCC(C(=O)O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: N#CC(CCN1CCC(C(=O)ON2C(=O)c3ccccc3C2=O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1

Procedure:
2.12 Grams of 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid are dissolved in 65 ml. of redistilled N,N-dimethylformamide by warming to about 60°C. To the warm solution is added, with stirring, .82 gram of N-hydroxyphthalimide, followed by 1.16 grams of dicyclohexylcarbodiimide. The resultant mixture is stirred at room temperature under calcium chloride, then cooled and filtered. The filtrate is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over potassium carbonate and partially concentrated until a precipitate forms. Filtration and repeated crystallizations of the precipitate from a mixture of chloroform and hexane affords N-[1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carbonyloxy]phthalimide, melting at about 156.5°-157.5°C. The product has the formula ##SPC4##
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:15](O)[CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:34]#[CH:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:56]1(=[O:62])[NH:60][C:59](=[O:61])[CH:58]=[CH:57]1>C1COCC1>[CH2:15]([N:60]1[C:56](=[O:62])[CH:57]=[CH:58][C:59]1=[O:61])[CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:34]#[CH:35]
Reactant: C#CCOCCOCCOCCOCCOCCOCCO
Reactant: O=C1C=CC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CCOCCOCCOCCOCCOCCOCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
Diisopropyl azodicarboxylate (730 μL, 3.43 mmol) was added dropwise into the ice cooled solution of 3,6,9,12,15,18-hexaoxahenicos-20-yn-1-ol 1 (1000 mg, 3.12 mmol), triphenylphosphine (900 mg, 3.43 mmol) and maleimide (456 mg, 4.70 mmol) in anhydrous THF (20 mL) under nitrogen atmosphere (FIG. 3). The resulting brown solution was allowed to war to room temperature and stirred for 1 hour at room temperature. The solvent was evaporated at the reduced pressure and the crude product was purified on a SiO2 column using hexanes/ethylacetate gradient 0-100% to yield 650 mg of yellow oil which was subsequently purified on semipreparative HPLC (System E) to provide 2 free of triphenylphosphine oxide as colorless oil 310 mg (25%). 1H NMR (400 MHz, CDCl3): δ 2.43 (t, J=2.36 Hz, 1H), 3.60-3.72 (m, 24H), 4.20 (d, J=2.37 Hz, 2H), 6.70 (s, 2H); 13C NMR (100.6 MHz, CDCl3): δ 37.2, 58.4, 67.8, 69.1, 70.1, 70.4-70.6, 74.5, 79.7, 134.1, 170.6; MS ESI (m/z): [M+H]+, calcd. for C19H30NO8, 400.19; found 400.0
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([NH:20][CH:21]1[C:53](=[O:54])[N:23]2[CH:24]([C:37]([O:39][CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[C:25]([CH2:29][S:30][C:31]3[N:35]([CH3:36])[N:34]=[N:33][N:32]=3)=[C:26]([CH3:28])[S:27][C@H:22]12)=[O:19]>C(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]([NH:20][CH:21]1[C:53](=[O:54])[N:23]2[C:24]([C:37]([O:39][CH:40]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:38])=[C:25]([CH2:29][S:30][C:31]3[N:35]([CH3:36])[N:34]=[N:33][N:32]=3)[C@@H:26]([CH3:28])[S:27](=[O:9])[C@H:22]12)=[O:19]
Reactant: CC1=C(CSc2nnnn2C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@@H]1C(CSc2nnnn2C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1=O
Reaction time: 1 h
Yield: 47 %

Procedure:
A 217 mg quantity of m-chloroperbenzoic acid was added to a solution of 662 mg of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-(1-methyl-1H-tetrazol-5-yl)thiomethylceph-2-em-4-carboxylate in 30 ml of CH2Cl2 at -10° C., and the mixture was stirred at the same temperature for 1 hour. The reaction solution was washed with 10% Na2S2O3 solution and with saturated aqueous NaCl solution, and dried over MgSO4 to distill off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (5:1) were collected, followed by distilling off the solvent, thus yielding 321 mg (47%) of diphenylmethyl 7-(2-thienylacetamido)-2α-methyl-3-(1-methyl-1H-tetrazol-5-yl)thiomethylceph-3-em-4-carboxylate 1-oxide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[CH:10]([NH:12][C:13]1[NH:17][N:16]=[C:15]([S:18](Cl)(=[O:20])=[O:19])[N:14]=1)=[O:11].[OH-].[Na+].Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][S:18]([C:15]1[N:14]=[C:13]([NH:12][CH:10]=[O:11])[NH:17][N:16]=1)(=[O:19])=[O:20]
Reactant: Nc1c(F)cccc1F
Reactant: O=CNc1nc(S(=O)(=O)Cl)n[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=CNc1nc(S(=O)(=O)Nc2c(F)cccc2F)n[nH]1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a mixture of 1.3 g (10 mmol) of 2,6-difluoroaniline in 4 ml of pyridine was added 1.94 g (9.2 mmol) of 5-formylamino-3-chlorosulfonyl-1,2,4-triazole over a period of 5 minutes. The mixture was heated with stirring to 70° C. for 4 hours. It was then cooled and dispersed between 25 ml of 1N aqueous sodium hydroxide and 50 ml of chloroform. The aqueous layer was acidified with aqueous hydrochloric acid and filtered. The solids collected were dried to obtain 167 g (60 percent of theory) of the title compound, m.p. 258°-260° C. The infrared spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[CH3:48])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1ccccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccccc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and 1-bromo-2-methyl-benzene (13 μl) instead of 4-chloropicolinic acid t-butylamide, in the same manner as in Example 1-D-07, a crude product of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-7-o-tolyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-174) as a pale yellow powder (9 mg, 25%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@@H:29]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][C@H:30]1[CH3:43]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:13])[F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:31][C@@H:30]4[CH3:43])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@H]1N
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and tert-butyl [(1R*,3R*,4R*)-4-amino-3-methylcyclohexyl]carbamate (example C11) the title compound is obtained as pale yellow foam.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].C(OCC)(=O)C>CO.O>[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cc(CO)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
Sodium borohydride (1.36 g, 35.95 mmol) was added to a solution of 4-fluoro-3-nitrobenzaldehyde (2.0 g, 11.83 mmol) in methanol (15 mL) and water (3.0 mL), and the mixture was stirred at room temperature for 3 hours. Water was then added to the reaction mixture, and extraction was performed with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate, and then concentrated under reduced pressure to yield the title compound (2.10 g, 95%) as a pale red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:26](=[O:27])[C:25]5[CH:29]=[CH:30][C:22]([O:21][CH2:20][CH2:19][OH:18])=[CH:23][CH:24]=5)=[CH:10][CH:9]=4)[CH:5]=[N:6]3)=[CH:12][CH:13]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(OCCO)cc1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: O=C(Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(OCCO)cc4)ccc32)cc1)c1ccc(OCCO)cc1

Procedure:
Compound 995 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-(2-hydroxyethoxy)benzoic acid. [M+H]+ calcd for C31H29N4O6: 553.21; found: 553.10.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:12]=1[C:13]([OH:15])=[O:14]>>[F:10][C:11]1[C:19]([N+:1]([O-:4])=[O:2])=[CH:18][CH:17]=[C:16]([F:20])[C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1c(F)cccc1F
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
5.0 mL of conc. HNO3 at 0° C. was slowly treated with 10.0 mL of colic. H2SO4, then 3.2 g (20 mmol) of 2,6-difluoro-benzoic acid. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was poured into a beaker containing ice. The resulting solid was collected by filtration, washed with cold water and dried to produce 4.0 g (80%) of 2,6-difluoro-3-nitro-benzoic acid as a white solid. LCMS: 204 (M+1)+.