Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([O:15][CH2:38][C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C#N)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1ccc(C(=O)Nc2cc(OCC(=O)OCc3ccccc3)ccc2NC(=O)c2cccc(C#N)c2)cc1
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-N2-(4-isopropylbenzoyl)-4-hydroxy-1,2-benzenediamine (502 mg, 1.26 mmol), acetone (15 mL), and potassium carbonate (216 mg, 1.56 mmol) was added by benzyl 2-bromoacetate (0.4 mL, 2.52 mmol). After stirring overnight, the reaction was concentrated and the residue was chromatographed (100% CH2Cl2 to 10% EtOAc/CH2Cl2) to give the title compound as a solid (532 mg, 77%), IR(CHCl3): 2965, 1759, 1654, 1610, 1514, 1175 cm−1; NMR(300 MHz, CDCl3): δ1.28 (s, 3H), 1.30 (s, 3H), 3.00 (m, 1H), 4.50 (s, 2H), 5.22 (s, 2H), 6.71 (d, 1H, J=9.3), 6.93 (s, 1H), 7.31 (m, 7H), 7.54 (d, 1H, J=21), 7.60 (t, 1H, J=7.8), 7.78 (d, 1H, J=8.7), 7.89 (d, 2H, J=8.1), 8.19 (d, 1H, J=8.1), 8.30 (s, 1H), 8.74 (br s, 1H), 9.48 (br s, 1H); MS(FD): 547.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Si:18]([O:14][CH2:13][C@@H:12]([NH:11][C:6]1[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:15])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(N[C@@H](C)CO)c1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1nc(Cl)c([N+](=O)[O-])c(N[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
(2S)-2-[(2-Chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol (3.62 g, 13.9 mmol) was dissolved in 30 mL of dry pyridine under an atmosphere of N2. tert-Butyldimethylsilyl chloride (2.52 g, 16.7 mmol) and DMAP (0.17 g, 1.39 mmol) were added sequentially, and the reaction was heated to 50° C. and stirred overnight. The reaction mixture was then concentrated under reduced pressure. The resulting residue was partitioned between 50 mL of ethyl acetate and 50 mL of H2O. The layers were separated and the organic portion was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was passed through a plug of SiO2, eluting with a mixture of CH2Cl2, ethyl acetate and hexanes, to afford N-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-chloro-5,6-dimethyl-3-nitropyridin-4-amine (4.79 g) as an orange oil.
Reaction SMILES: C(O[C:4](=[NH:18])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)C.[CH:19]([NH:21][NH2:22])=O>O1CCOCC1>[NH:21]1[CH:19]=[N:18][C:4]([CH:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10]2)=[N:22]1
Reactant: CCOC(=N)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NNC=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2nc[nH]n2)CC1
Temperature: 80 °C
Yield: 91.6 %

Procedure:
To a stirred solution of tert-butyl 4-(ethoxy(imino)methyl)piperidine-1-carboxylate (51 g, 198.95 mmol) in dioxane (500 mL), was added formohydrazide (17.92 g, 298.43 mmol). This solution was left to stir at 40° C. overnight under N2 resulting in precipitation of a white solid (hydrazide intermediate). The reaction mixture was then heated to 80° C. for 6 h, cooled to room temperature and concentrated. The residue was dissolved in 500 mL of CH2Cl2 and 300 mL of water was added. The phases were decanted and the organic phase was washed with brine, dried over MgSO4, filtered and concentrated to afford tert-butyl 4-(1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (46.0 g, 92%) as a white solid: 1H NMR Spectrum; (CDCl3) 1.47 (9H, s), 1.76 (2H, m), 1.98-2.11 (2H, m), 2.91 (2H, s), 2.97-3.08 (m, 1H), 4.06-4.23 (2H, m), 8.05 (1H, s); Mass Spectrum [M+H]+=no mass ion.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH2:20][CH2:19][CH:15]([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]2)[CH:7]=[CH:6][N:5]=1
Reactant: NC(=O)C1CCNCC1
Reactant: FC(F)(F)c1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: NC(=O)C1CCN(c2ccnc(C(F)(F)F)n2)CC1
Yield: 69.6 %

Procedure:
A mixture of 4-chloro-2-(trifluoromethyl)pyrimidine (IV, 23.66 g, 0.130 mol), isonipecotamide (V, 16.66 g, 0.130 mol), and sodium carbonate (27.56 g, 0.260 mol) in acetonitrile (250 mL) was refluxed for 4 hr. The mixture was cooled and a solid mass formed. This mass was dissolved in DMF (300 mL) and filtered to remove the inorganics. The solvent was removed in vacuo and the crude product was recrystallized from isopropanol and then from 90% ethanol to give colorless needles (24.8 g, 70%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][NH:3][C:2]1=[O:11].C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl>O>[C:18]([N:8]1[CH2:7][CH2:6][C:5]2([O:1][C:2](=[O:11])[NH:3][CH2:4]2)[CH2:10][CH2:9]1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1NCC2(CCNCC2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1NCC2(CCN(C(=O)OCc3ccccc3)CC2)O1
Reaction time: 18 h
Yield: 81.5 %

Procedure:
To a mixture of 9.5 g 1-oxa-3,8-diazaspiro[4.5]decan-2-one and 75 ml water, at 0°, is added 6.3 g sodium bicarbonate and 10.9 g benzyl chloroformate. The mixture is stirred 18 hours at 0°, acidified with 10 N hydrochloric acid and stirred four hours at room temperature. The mixture is extracted with three 50 ml portions of dichloromethane. Removal of solvent affords 14.4 g 8-carbobenzyloxy-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 126°-128°.
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](=[O:13])[CH3:12].C(OCC)(=O)C>O1CCCC1>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([OH:13])([C:1]#[CH:2])[CH3:12]
Reactant: C#C[Mg]Cl
Reactant: CC(=O)c1cnccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cnccn1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A 0.5 M solution of ethynylmagnesium chloride in tetrahydrofuran (31.90 mmol, Aldrich) is diluted with 50 ml of tetrahydrofuran and then cooled to 0° C. 3 g of 1-pyrazin-2-ylethanone (24.56 mmol, Lancaster) are then added in several fractions, and the mixture is stirred at 0° C. for 4 hours. The mixture is cooled once again with an ice bath and a solution of NH4Claq is added slowly. The mixture is extracted twice with ethyl acetate and the organic phases are then combined, dried over sodium sulphate, filtered, and concentrated under vacuum. The oily residue obtained is purified by silica chromatography (elution with a cyclohexane:ethyl acetate gradient, 70:30 to 50:50) and 2.9 g of the expected product are obtained in the form of a yellow oil (yield=80%).
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH3:39][O:40][C:41]([C:43]1[N:44]([CH3:49])[CH:45]=C(N)[CH:47]=1)=[O:42]>CCCCCCC.C(OCC)(=O)C>[CH3:39][O:40][C:41]([C:43]1[N:44]([CH3:49])[CH:45]=[C:4]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:9][C:8]=2[Cl:36])[CH:47]=1)=[O:42]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: COC(=O)c1cc(N)cn1C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cn1C

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 4-amino-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (commercially available, CAS RN 180258-45-1) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatiographic purification. Light brown foam (70%). MS (ESI): m/z=620.147 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:26][NH:25][CH2:24][CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]=3[N:22]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:26][N:25]([C:42](=[O:44])[CH3:43])[CH2:24][CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]=3[N:22]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: CC(=O)Cl
Reactant: COc1cc(Nc2ncc3c(n2)C(c2ccccc2)CNC3)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc3c(n2)C(c2ccccc2)CN(C(C)=O)C3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
To a suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(8-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-amine hydrochloride (65 mg, 0.15 mmol) in methylen chloride (2 mL) was added at room temperature NN,-diisopropyl ethyl amine (28 mg, 0.22 mmol) and after 2 minutes acetyl chloride (12.5 mg, 0.16 mmol). The reaction was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (20 mg, 30%) as a yellow gum. MS ISP (m/e): 455.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.38 (s, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.20-7.33 (m, 3H), 7.05-7.08 (m, 3H), 6.81 (s, 1H), 6.79 (d, 1H), 5.18 (d, 1H), 4.46 (d, 1H), 4.21 (t, 1H), 3.90 (m, 2H), 3.46 (s, 3H), 2.27 (s, 3H), 1.71 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[CH3:21][O:22][C:23]1[C:31]([CH3:32])=[C:30]2[C:26]([C:27](=[O:33])[O:28][CH2:29]2)=[C:25]([O:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[C:24]=1[CH2:41]/[CH:42]=[C:43](\[CH3:46])/[CH:44]=[O:45].[NH4+].[Cl-]>C1COCC1>[CH3:40][O:39][CH2:38][CH2:37][O:36][CH2:35][O:34][C:25]1[C:24]([CH2:41]/[CH:42]=[C:43](\[CH3:46])/[CH:44]([OH:45])[C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17])=[C:23]([O:22][CH3:21])[C:31]([CH3:32])=[C:30]2[C:26]=1[C:27](=[O:33])[O:28][CH2:29]2
Reactant: CCOC(=O)C(C)C
Reactant: COCCOCOc1c(C/C=C(\C)C=O)c(OC)c(C)c2c1C(=O)OC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(O)/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
Freshly distilled diisopropylamine (0.425 ml) was dissolved in anhydrous THF (10 ml) and cooled to 0° C. n-BuLi (0.63 ml, 2.35M) was added slowly and the reaction was stirred at 0° C. for 20 minutes and cooled to -78°. Ethyl isobutyrate (0.200 ml) was added and the resulting solution was stirred at -78° C. for 40 minutes. A solution of (E)-4-(1,3-dihydro-6-methoxy -4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2-methylbut-2-enaldehyde (365 mg) in THF (10 ml) was added and stirred for 30 min. The reaction mixture was poured to a concentrated solution of NH4Cl, and extracted with ethyl acetate (3×30 ml), the organic layers were dried over Na2SO4, and evaporated to give 420 mg (87%) of ethyl (E)-6-(1,3-dihydro-4-methoxyethoxymethoxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2,2,4-trimethyl-3-hydroxy-4-hexenoate as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH3:17])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18](I)[CH3:19].[Li].C(NC(C)C)(C)C>>[C:1]1([CH2:7][CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH2:17][CH2:18][CH3:19])[CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCI
Reactant: Cc1cnccc1C(C)CCc1ccccc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Product: CCCc1cnccc1C(C)CCc1ccccc1
Yield: 15.6 %

Procedure:
2.1 g (9.35 mmol) of 1-phenyl-3-(3-methyl-4-pyridyl)butane, 1.46 g (9.35 mmol) of ethyl iodide and 2 equivalent of lithium-diisopropylamine were reacted in the same manner as in Example 1. The reaction product was purified to obtain 0.37 g of the desired compound (yield: 15.6%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:29](O)(=O)[CH:30]([CH3:32])[CH3:31].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[CH:30]([C:32]1[O:24][C:23]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C@H:15]3[CH2:16][CH2:17][C@H:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])[CH2:13][CH2:14]3)=[CH:28][CH:27]=2)=[N:25][N:26]=1)([CH3:31])[CH3:29]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NN)cc3)CC2)CC1
Reactant: CC(C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nnc(-c2ccc(O[C@H]3CC[C@H](C(=O)N4CCN(C(C)C)CC4)CC3)cc2)o1

Procedure:
A mixture of 100 mg (0.25 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid hydrazide, 0.06 ml (0.57 mmol) of isobutyric acid and 2 ml of phosphorus oxychloride was refluxed for 3 hr. To the mixture, 1N NaOH solution was added. The mixture was extracted with AcOEt, washed with saturated NaHCO3 solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 19:1. The combined product fractions were evaporated to dryness to yield 40 mg (35%) of the title compound. MS (m/e): 441.1 (MH+).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([O:19]C)=[O:18])=[C:7]2[C:21]2[CH:26]=[CH:25][C:24]([S:27](=[O:36])(=[O:35])[NH:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[CH:23][N:22]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O>C(O)C>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([OH:19])=[O:18])=[C:7]2[C:21]2[CH:26]=[CH:25][C:24]([S:27](=[O:36])(=[O:35])[NH:28][C@@H:29]([CH3:34])[C:30]([F:32])([F:33])[F:31])=[CH:23][N:22]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(-c2ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn2)n(C2CCCC2)c2cc(C)c(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1F)c(C(=O)O)c(-c1ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn1)n2C1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-methyl 1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxylate (0.45 g, 0.85 mmol), 25% aq. NaOH (2.0 mL) in ethanol (4.0 mL) was stirred at 80° C. overnight. The mixture was then treated with water and extracted with ether. The aqueous layer was acidified with 1N HCl to pH 4 and extracted with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and evaporated to give(S)-1-cyclopentyl-5-fluoro-6-methyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-3-carboxylic acid (0.36 g, 82%). MS m/z 514.2 M+H+; 1H NMR (500 MHz, acetone-d6): δ 10.55 (1H, br s), 9.17 (1H, d, J=2.2 Hz), 8.38 (1H, dd, J=8.2 Hz, J=2.2 Hz), 7.96 (1H, dd, J=8.2, 0.8 Hz), 7.89 (1H, d, J=10.7 Hz), 7.70 (br s, 1H), 7.57 (1H, d, J=6.4 Hz), 4.63-4.56 (1H, m), 4.34-4.29 (1H, m), 2.44 (3H, d, J=1.8 Hz), 2.29-2.25 (2H, m), 2.10-1.90 (4H, m), 1.67-1.56 (2H, m), 1.25 (3H, d, J=7.0 Hz).
Reaction SMILES: CS(C)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[OH-].[K+]>C(OC(=O)C)C>[N:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: COc1ccccc1Br
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccccc1-n1ccnc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
To a degassed DMSO (20 mL) solution of imidazole (1.0 g, 15 mmol) was added 2-bromoanisole (1.25 mL, 10 mmol), KOH (1.12 g, 20 mmol) and Cu2O (280 mg, 2 mmol) under nitrogen. The resulting mixture was stirred at 140° C. for 24 hrs under N2. After cooling to room temperature, the mixture was poured into ethylacetate (EA) (50 mL) and filtered. The filtrate was washed with water (50 mL×3) and dried over anhydrous magnesium sulfate. After rotary evaporation, the crude oil was purified via column chromatography on silica gel with eluent of EA/MeOH (9/1, v/v), affording a light yellow liquid (50%). 1H-NMR (400 MHz, CDCl3) δ(ppm) 7.79 (s, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.17 (s, 1H), 7.05 (m, 2H), 3.85 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[C:27]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:47][O:48][C:49]([CH3:55])([CH3:54])[C:50]([NH:52][OH:53])=[O:51]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:47]/[O:48][C:49]([C:50](=[O:51])[NH:52][OH:53])([CH3:55])[CH3:54])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[C:27]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nc(-c5ccccc5)ncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Reactant: CC(C)(ON)C(=O)NO
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(-c4ccccc4)ncc3-c3ccc(O)c(O)c3)CS[C@H]12)c1csc(N)n1)C(=O)NO
Temperature: 25 °C
Reaction time: 22 h
Yield: 82.2 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[(5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (33 mg) (0.05 mmol) and 11 mg (0.065 mMol) 2-(aminooxy)-N-hydroxy-2-methylpropionamide hydrochloride are dissolved in 0.8 ml of absolute dimethylacetamide. After stirring at room temperature for 22 hours the mixture is concentrated in a high vacuum and the residue is crystallized with water. The product is filtered off, washed with water, ethanol and diethyl ether and dried in a high vacuum at room temperature. There are obtained 32 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(hydroxycarbamoyl)-1-methylethoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[C:36](=[N:38]O)[NH2:37]>>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[C:36]1[N:38]=[C:25]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:26][N:37]=1
Reactant: NC(=NO)c1c(F)cccc1F
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(C#N)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4c(F)cccc4F)no3)CN(C(=O)N3CCC(C#N)CC3)C2)cc1

Procedure:
60 mg (0.16 mmol) of the compound from Example 60A and 42 mg (0.24 mmol) of 2,6-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 53 mg (65% of theory)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])[CH:5]=[CH:4][N:3]=1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([Cl:41])[CH:35]=1>>[Cl:41][C:36]1[CH:35]=[C:34]([CH2:33][CH2:32][NH:31][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]4[CH3:25])[CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[CH:5]=[CH:4][N:3]=2)[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: COc1ccc(CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1-c1ccnc(Cl)n1
Product: COc1ccc(CN2CCNC[C@@H]2C)cc1-c1ccnc(NCCc2ccc(O)c(Cl)c2)n1

Procedure:
Intermediate 146 from above was coupled with 4-(2-aminoethyl)-2-chlorophenol following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 468. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.4 (d, 1H) 7.8 (d, 1H) 7.4-7.2 (m, 3H) 7.1 (m, 2H), 6.1 (d, 1H), 3.9 (s, 3H) 3.7-3.6 (m, 4H) 3.5 (d, 2H) 3.4-3.3 (m, 4H), 3.2 (m, 1H), 2.8 (t, 2H), 1.6 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[NH:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[N:10]([CH2:14][C:15]3[C:16]([CH3:25])=[N:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1nc(C(F)(F)F)ccc1CCl
Reactant: O=c1[nH]nc2c(Br)c(Cl)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(Cl)ccn2c1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
To a solution of 8-bromo-7-chloro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (456 mg, 2.0 mmol) in anhydrous DMF (7 mL) was added 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (627 mg, 3.0 mmol), followed by anhydrous potassium carbonate (415 mg, 3.0 mmol). The resulting suspension was stirred under argon at 80° C. for 1.5 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc (30 mL×2). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, and evaporated under reduced pressure to provide crude product as a brown solid. The crude product was purified using a silica gel cartridge (40 g) eluted with a gradient of EtOAc (0-60%) in hexanes to afford the title compound as an off-white solid (733 mg, 87%). HPLC/MS: retention time=3.36 min, [M+H]+=420.1.