Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][N:11]=1)(=[O:9])=[O:8].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:59][C:60]1[N:64]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[N:63]=[C:62]([CH3:71])[CH:61]=1.CN(C)C(=O)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:71][C:62]1[CH:61]=[C:60]([NH:59][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)(=[O:9])=[O:8])=[N:11][CH:12]=2)[N:64]([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[N:63]=1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cn1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Product: Cc1cc(Nc2ccc(S(=O)(=O)Nc3nccs3)nc2)n(-c2ccccc2)n1
Temperature: 120 °C
Yield: 61.1 %

Procedure:
Into a Vial was added the 5-Bromo-pyridine-2-sulfonic acid thiazol-2-ylamide (75 mg, 0.00023 mol), 9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (16 mg, 0.000028 mol), Tris(dibenzylideneacetone)dipalladium(0) (8.6 mg, 0.0000094 mol), 5-AMINO-3-METHYL-1-PHENYLPYRAZOLE (49 mg, 0.00028 mol) and N,N-Dimethylacetamide (3.0 mL, 0.032 mol). The mixture was sparged with argon for ˜5 min. Sodium tert-butoxide (68 mg, 0.00070 mol) was added and the reaction mixture was heated at 120° C. for 30 min in microwave. The reaction mixture was filtered through celite. The filtrate was diluted with Ethyl acetate and washed with 0.1 N HCl solution, water (3×) and brine, dried over sodium sulfate, filtered and was concentrated to give the crude product that was purified on ISCO (0% to 100% Ethyl acetate in CHCl3). 58 mg of the product was obtained as a light brown solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](I)=[CH:7][C:8]2[CH:14]([CH3:15])[CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11][CH2:10][C:9]=2[N:22]=1)[CH:2]=[CH2:3].CC([O-])=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(N(C)C)=O>[CH3:3][C:2]1[C:6]2=[CH:7][C:8]3[CH:14]([CH3:15])[CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11][CH2:10][C:9]=3[N:22]=[C:5]2[O:4][CH:1]=1
Reactant: C=CCOc1nc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1coc2nc3c(cc12)C(C)CN(C(=O)C(F)(F)F)CC3
Temperature: 125 °C
Yield: 31.9 %

Procedure:
A mixture of 2-(allyloxy)-3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (300 mg, 682 μmol), Pd(PPh3)2Cl2 (120 mg, 170 μmol), NaOAc (168 mg, 2.04 mmol) and DMA (20 ml) was heated for 30 min at 125 ° C. The reaction mixture was concentrated in vacuo and purified by column chromatography to give 68.0 mg (32%) of 3,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H -furo[3′,2′:5,6]pyrido[2,3-d]azepine. H-NMR (CDCl3) δ 7.68 (2× s, 1H), 7.46 (2× s, 1H), 4.25-3.25 (m, 7H), 2.24 (2× d, 3H), 1.44 (2×d, 3H) ppm. A mixture of 3,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-furo[3′,2′:5,6]pyrido[2,3-d]azepine (62.0 mg, 199 μmol), K2CO3 (80 mg) and MeOH (6 ml) was heated for 1 h at 60° C. The reaction mixture was concentrated in vacuo and purified by column chromatography to give 19.6 mg (46%) of 3,5-dimethyl-6,7,8,9-tetrahydro-5H-furo[3′,2′:5,6]pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.69 (s, 1H), 7.47 (d, 1H), 3.63-3.33 (m, 5H), 3.06 (t, 1H), 2.87 (t, 1H), 2.25 (d, 3H), 1.54 (d, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>>[CH:3]1[C:4]2[NH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([CH:15]=[O:16])=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(-c2ccc3c(c2)[nH]c2ccccc23)cc1
Yield: 53 %

Procedure:
10.0 g of 2-bromo-9H-carbazole (4.06 10−2 mol), 9.22 g of 4-formylphenylboronic acid (6.15 10−2 mol), 0.63 g of tetrakistriphenylpalladium (5.5 10−4 mol), 42.0 g of potassium carbonate (3 10−1 mol) are initially introduced. After flushing through 300 ml of water with argon, 400 ml of THF is added. The reaction mixture is stirred under reflux for 2 days. After filtration through Celite, the organic phase is separated, dried over Na2CO4, and the aqueous phase is washed 2× with CH2Cl2 and dried over Na2SO4. Column chromatography with toluene as eluent give 2.0 g (53%) of clean product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.Cl[C:12]1[C:13]2[S:20][CH:19]=[CH:18][C:14]=2[N:15]=[CH:16][N:17]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:12]2[C:13]3[S:20][CH:19]=[CH:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:5][CH:6]=1
Reactant: Clc1ncnc2ccsc12
Reactant: NCCc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1ccc(CCNc2ncnc3ccsc23)cc1

Procedure:
A solution of 4-(2-amino-ethyl)-phenylamine (compound 12.1; 0.1 mmol.), compound 6.2 (1.0 equivalent) and DIEA (2.5 equivalents) was heated in n-butanol (2 mL) at 135° C. for 2 hours. The reaction mixture was cooled and partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried and concentrated under reduced pressure to give crude [2-(4-amino-phenyl)-ethyl]-thieno[3,2-d]pyrimidin-4-yl-amine (compound 12.2) which was used without purification for the next step.
Reaction SMILES: CI.[CH2:3]([C:6]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:17])[CH:4]=[CH2:5].[C:18](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[CH2:3]([C:6]1[C:15]([O:16][CH3:18])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:17])[CH:4]=[CH2:5]
Reactant: C=CCc1c(O)ccc2c1CCCC2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCc1c(OC)ccc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
901 μl of methyl iodide was added to a mixture consisting of 1.46 g of 5-allyl-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one, 1.20 g of potassium carbonate, and 15 ml of N,N-dimethylformamide. The obtained mixture was stirred at room temperature under nitrogen atmosphere overnight. Thereafter, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with water (5 times) and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.51 g of the subject compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=3)[NH:15][N:14]=1)[CH:7]=[CH:6]2.[OH:24]O.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH2:23])=[O:24])[CH:20]=3)[NH:15][N:14]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(-c3n[nH]c4ccc(C#N)cc34)ccc2c1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2cc(-c3n[nH]c4ccc(C(N)=O)cc34)ccc2c1
Temperature: 45 °C
Yield: 20 %

Procedure:
A mixture of 3-(6-methoxy-2-naphthyl)-1H-indazole-5-carbonitrile (0.230 g, 0.77 mmol), 95% ethanol (6 mL), aqueous 30% hydrogen peroxide (3 mL), and 6.0 N aqueous sodium hydroxide (1 mL, mmol) was heated at 45° C. for 3 h. The reaction mixture was diluted with water (30 mL) and acidified to pH 6 with 3 N hydrochloric acid. The solid was filtered and dried in a vacuum oven to give product (0.050 g, 20% yield): 1H NMR (DMSO-d6) δ 13.45 (s, 1H), 8.72 (s, 1H), 8.50 (s, 1H), 8.18 (s, 1H), 8.15 (d, 1H), 8.02 (d, 1H), 7.95 (d, 1H), 7.61 (d, 1H), 7.37 (m, 2H), 7.22 (dd, 1H); ES-MS (m/z) 318 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:26][CH:14]4[CH2:15][N:16]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:17][CH:13]4[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:3]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:26][CH:14]4[CH2:15][N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH2:17][CH:13]4[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CN(CC(=O)OC(C)(C)C)CC4C3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CN(CC(=O)O)CC4C3)cc12
Reaction time: 1 h

Procedure:
A solution of Example 293A (0.685 g, 1.423 mmol) and trifluoroacetic acid (2.74 mL, 35.6 mmol) in dichloromethane (12 mL) was stirred for 18 hours. The mixture was concentrated and the residue was dissolved in 5 mL dichloromethane and treated with 8 mL 2M hydrogen chloride in ether. The suspension was sonicated, diluted with ether, and stirred for 1 hour. The solid was filtered, washed with ether and vacuum oven-dried to give the title compound as a hydrochloride salt. MS (trifluoroacetic acid salt via HPLC) (ESI+) m/z 426.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[N+:12]([O-])([OH:14])=[O:13]>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:3]=12
Reactant: Fc1cnc2[nH]ccc2c1F
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2ncc(F)c(F)c12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79.8 %

Procedure:
4,5-Difluoro-1H-pyrrolo[2,3-b]pyridine (0.63 g, 4.09 mmol) was added slowly to fuming nitric acid (8.18 mL, 164 mmol) at 0° C. and stirred slowly for 5 minutes. Ice (20 g) was added followed by water (40 mL). The solid formed was collected by filtration to give 4,5-difluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.65 g, 80% yield) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:9](=O)[NH:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1.[OH-].[K+].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C.O=P(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:12])[C:10]2[C:9]([N:18]3[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2nc[nH]c(=O)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2C(C)(C)CC3)CC1
Temperature: 80 °C
Yield: 47.4 %

Procedure:
A mixture of ethyl 2,2-dimethyl-5-oxocyclopentanecarboxylate (3.426 g) and ammonium acetate (14.33 g) in EtOH (100 mL) was heated at 85° C. (bath) for 1 hour. The contents were concentrated. The residue was partitioned between water and DCM. The organic phase was separated. The aqueous solution was extracted with DCM. The combined DCM solutions were washed with water and dried (Na2SO4). Upon filtration and concentration, solid ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate (2.933 g) was yielded. The ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate was mixed with ammonium formate (5.054 g) and formamide (7 mL) and heated at 150° C. for 16 hours. The mixture was diluted with water and extracted with 5:1 DCM-IPA. The combined extracts were dried (Na2SO4) and concentrated to give 5,5-dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one as a viscous oil (1.185 g). 5,5-Dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (1.063 g) was dissolved in acetonitrile (20 mL) with POCl3 (1.78 mL). The mixture was heated at 80° C. for 10 hours. The mixture was cooled to 0° C. 50% KOH (15.3 mL) was added dropwise. t-Butyl piperazine-1-carboxylate (3.615 g) was added. The mixture was heated at 80° C. for 24 hours. The contents were concentrated. Water was added. The mixture was extracted with DCM (2×) and dried (Na2SO4). The crude material was purified with flash chromatography to give tert-butyl 4-(5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.021 g). 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.57 (s, 1H), 3.56-3.54 (m, 4H), 3.37-3.34 (m, 4H), 2.90 (t, J=7.3 Hz, 2H), 1.89 (t, J=7.3 Hz), 3H) 1.48 (s, 9H), 1.40 (s, 6H). MS: 333.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15]Br)=[CH:8][CH:7]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C(O)C>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])=[CH:8][CH:7]=1)[CH3:18]
Reactant: CCNCC
Reactant: BrCCCCc1ccc(CCCCBr)cc1
Solvent: CCO
Product: CCN(CC)CCCCc1ccc(CCCCN(CC)CC)cc1
Yield: 69.8 %

Procedure:
First, 1.05 g of 1,4-bis(4-bromobutyl)benzene and 1.1 g of diethylamine were dissolved in absolute ethanol, and the mixture was refluxed for an hour and then evaporated under a reduced pressure to remove the solvent. After adding chloroform, the mixture was evaporated under a reduced pressure. After adding ethyl acetate the mixture was extracted with 15 ml of 1N hydrochloric acid. The aqueous extract was alkalized with 10% sodium hydroxide, and extracted with total 70 ml of chloroform. The organic extract was washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain 0.70 g of the title compound as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[C:13]([O:25][CH3:26])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5]([I:27])=[CH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([I:27])[C:6]=3[O:10][CH:9]=2)=[CH:12][C:13]=1[O:25][CH3:26]
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1N
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Tert-butyl 4-(4-amino-7-iodofuro[32-c]pyridin-3-yl)-2-methoxyphenylcarbamate (3.98 g 8.28 mmol) was added to a 20% solution of trifluoroacetic acid in dichloro-methane (150 mL). The mixture was stirred for two hours and then the solvent was removed in vacuo. To the residue was added water (15 mL) and dichloromethane (25 mL). The mixture was adjusted to pH 12 with 1 N aqueous sodium hydroxide and the layers were separated. The aqueous layer was extracted with dichloromethane (2×10 mL) and the combined organic layers were dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound (2.534 g, 80%). 1H NMR (DMSO-d6, 400 MHz) □ 8.03 (s, 1H) 7.94 (s, 1H) 6.91 (d, 1H) 6.82 (dd, 1H) 6.75 (d, 1H) 5.69-5.77 (bs, 2H) 4.96-5.05 (bs, 2H) 3.81 (s, 3H); RP-HPLC (Conditions f) Rt 11.22 min.; MS: MH+ 382.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:11]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=2)[CH2:11]1
Reactant: [N-]=[N+]=N[C@H]1CCCC[C@H]1N1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CCCC[C@H]1N1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a Parr hydrogenation bottle was added N-(2-{[(3R)-1-(cis-2-azidocyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (0.745 g, 1.70 mmol), dissolved in methanol (20 mL), followed by the addition of 10% Pd/C (0.15 g). This mixture was hydrogenated at 50 psi for 3 h. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo to give 0.70 g of N-(2-{[(3R)-1-(cis-2-aminocyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide. MS (EI) calcd: (M+H)+=413.2; found: 413.3.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.Cl.N[C@H](C([NH:14][CH:15]1[C:21](=[O:22])[N:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:16]1=[O:35])=O)C>>[CH:1]1([CH2:4][C:5]([NH:14][C@H:15]([C:21]([C:15]2([NH2:14])[C:21](=[O:22])[N:20]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:16]2=[O:35])=[O:22])[CH3:16])=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(O)CC1CC1
Reactant: CC(C)CN1C(=O)C(NC(=O)[C@H](C)N)C(=O)N(CC(C)C)c2ccccc21
Agent: Cl
Product: CC(C)CN1C(=O)C(N)(C(=O)[C@H](C)NC(=O)CC2CC2)C(=O)N(CC(C)C)c2ccccc21

Procedure:
Following General Procedure I above using cyclopropylacetic acid (Lancaster) and 3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-S), the title compound was prepared as a white solid (melting point=190-191° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 3:4) and a second flash chromatography eluting with EtOAc/Toluene (7:3). Rf=0.28 (EtOAc/Toluene, 7:3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])(=[O:14])=[O:13])[CH:3]=1.Cl.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]([CH3:36])[CH2:34][NH2:35])=[CH:29][CH:28]=1)([O-:26])=[O:25].[N+](C1C=CC(CC#N)=CC=1)([O-])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:35][CH2:34][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=2)[CH3:36])=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])(=[O:14])=[O:13])[CH:3]=1
Reactant: CC(CN)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F
Agent: Cl
Agent: N#CCc1ccc([N+](=O)[O-])cc1
Product: CC(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F)c1ccc([N+](=O)[O-])cc1

Procedure:
This compound was prepared from 4-chloro-2-(2,6-difluoro-benzenesulfonylamino)-benzoic acid and 2-(4-nitro-phenyl)-propylamine hydrochloride (prepared as in EXAMPLE 5, substituting 4-nitrophenylacetonitrile in Part A) as in Example 1, Part C. HPLC: RT=10.37 min. MS (ESI−): mass calcd. for C22H18ClF2N3O5S, 509.9; m/z found, 509 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.63 (s, 1H), 8.18 (d, J=8.6, 1H), 7.69 (d, J=1.7, 1H), 7.56-7.46 (m, 1H), 7.42 (d, J=8.6, 2H), 7.15 (d, J=8.5, 1H), 7.02-6.94 (m, 1H), 6.19-6.17 (br m, 1H), 3.79-3.70 (m, 1H), 3.57-3.49 (m, 1H), 3.33-3.23 (m, 1H), 1.38 (d, J=6.9, 3H).
Reaction SMILES: [NH3:1].CC(O)C.[CH3:6][C:7]1[N:12]=[C:11](SC)[N:10]=[C:9]([C:15]2[C:16]([NH:32][C:33]3[C:34]4[CH:35]=[N:36][N:37](C5CCCCO5)[C:38]=4[CH:39]=[CH:40][CH:41]=3)=[N:17][CH:18]=[C:19]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)[CH:20]=2)[N:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[NH2:1][C:11]1[N:12]=[C:7]([CH3:6])[N:8]=[C:9]([C:15]2[C:16]([NH:32][C:33]3[C:34]4[CH:35]=[N:36][NH:37][C:38]=4[CH:39]=[CH:40][CH:41]=3)=[N:17][CH:18]=[C:19]([CH2:21][N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]3)[CH:20]=2)[N:10]=1
Reactant: CSc1nc(C)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2Nc2cccc3c2cnn3C2CCCCO2)n1
Reactant: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1nc(N)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2Nc2cccc3[nH]ncc23)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 22.88 %

Procedure:
2 M NH3 in 2-propanol (2.00 mL, 92 mmol) was added to N-(3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (97 mg, 0.159 mmol) and the mixture was sealed and heated at 90° C. overnight. After cooling, the precipitate was collected and dried to give a yellow solid which was dissolved in DCM (3.00 mL, 46.6 mmol) and then TFA (1.50 mL, 19.47 mmol) was slowly added. The mixture was stirred at rt for 1 h and then concentrated, adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (DCM to 10% MeOH in DCM) to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)-1H-indazol-4-amine (18 mg, 0.036 mmol, 22.88% yield) as a yellow solid. LCMS (API-ES) m/z 495 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 13.10 (br. s., 1H) 12.27 (s, 1H) 8.75 (s, 1H) 8.32 (br. s., 1H) 8.19 (s, 1H) 8.13 (d, J=7.04 Hz, 1H) 7.78 (br. s., 2H) 7.31 (t, J=8.31 Hz, 1H) 7.15 (d, J=8.22 Hz, 1H) 3.53 (s, 2H) 3.12 (br. s., 4H) 2.87 (s, 3H) 2.57 (s, 3H) 2.37-2.49 (m, 4H).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13])(=O)[CH2:2][CH3:3].[CH2:14]([O:17][NH2:18])[CH:15]=[CH2:16]>CN(C)C=O>[CH2:14]([O:17][NH:18][C:1](=[C:5]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13])[CH2:2][CH3:3])[CH:15]=[CH2:16]
Reactant: CCC(=O)C1C(=O)NC(=O)NC1=O
Reactant: C=CCON
Solvent: CN(C)C=O
Product: C=CCONC(CC)=C1C(=O)NC(=O)NC1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
1.8 g of 5-propionylbarbituric acid was dissolved in 30 ml of dimethylformamide and after the temperature of said solution was raised to 40° C, 1.5 g of allyloxyamine was added to it and the resulting solution was stirred at 40° C during 3 hours and then, about 10 ml of said dimethylformamide was distilled off and after 50 ml of ethanol was added to it, the separated crystal was filtered and recrystallized from ethanol and thereby, 2.1 g of the desired compound was obtained as a white columns.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:32][C:8]([CH2:9][C:10]2[CH:15]([C:16]([OH:18])=[O:17])[N:14]3[C:19](=[O:30])[C@@H:20]([C:21](=[O:29])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@H:13]3[S:12][C:11]=2[NH2:31])=[CH:7][CH:6]=1)=[O:4].C(O[CH2:37][CH3:38])(=O)C>CO>[C:23]1([CH:22]([O:17][C:16]([CH:15]2[N:14]3[C:19](=[O:30])[C@@H:20]([C:21](=[O:29])[CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:13]3[S:12][C:11]([NH2:31])=[C:10]2[CH2:9][C:8]2[O:32][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[O:18])[C:38]2[CH:37]=[CH:3][CH:5]=[CH:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(CC2=C(N)S[C@@H]3[C@H](C(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)o1
Solvent: CO
Product: COC(=O)c1ccc(CC2=C(N)S[C@@H]3[C@H](C(=O)Cc4ccccc4)C(=O)N3C2C(=O)OC(c2ccccc2)c2ccccc2)o1

Procedure:
A solution of 6.85 g of crystallised 3-(5-methoxycarbonyl-furfuryl)-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid in 50 ml of methanol is treated with 100 ml of ethyl acetate and the methanol is almost completely removed under reduced pressure. A total of 6.0 g of crude diphenyldiazomethane is then added in small amounts. The reaction mixture is freed from solvent after a total reaction period of 60 minutes at room temperature. The residual oil is triturated with 500 ml of petroleum ether, the undissolved material is filtered off and crystallised from 100 ml of hot ethyl acetate. The first crystalline fraction is recrystallised twice from a mixture of methylene chloride and cyclohexane to yield the 3-(5-methoxycarbonyl-furfuryl)-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid diphenylmethyl ester in the form of colourless felted needles, m.p. 164°-166°; [α]D20 = + 267° ± 1° (c = 1.134 in chloroform): thin-layer chromatogram (silica gel): Rf = 0.71 (system: toluene/ethyl acetate 1:1), Rf = 0.60 (system: toluene/ethyl acetate 2:1), Rf = 0.70 (system: toluene/acetone 2:1), Rf = 0.49 (system: toluene/acetone 4:1) and Rf = 0.30 (system toluene/acetone 9:1); ultraviolet absorption spectrum (in 95% ethanol): λmax = 268 mμ (ε = 21000) and λmin = 234 mμ (ε = 11000); infrared absorption spectrum (in mineral oil): characteristic bands at 2,98μ, 5,61μ, 5,74μ, 6,03μ, 6,53μ, 7,59μ, 8,26μ, 8,54μ, 8,72μ, 9,81μ, 10,14μ, 13,13μ and 14,42μ.