Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:14](=[O:15])[NH:13][CH2:12][CH2:11][N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:4][CH:3]=1.CI.[CH2:25](OC1C=CC(CCl)=CC=1)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2([CH3:25])[C:14](=[O:15])[NH:13][CH2:12][CH2:11][N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1Sc1ccc(Cl)cc1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1(C)Sc1ccc(Cl)cc1

Procedure:
When in the procedure of Example 3a, 27a is substituted for 2 and methyl iodide substituted for p-benzyloxybenzyl chloride, the title compound is obtained.
Reaction SMILES: C(O)C.[NH2:4][OH:5].C[O:7][C:8](=O)[CH:9]([N:14]([CH3:39])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:16])[C:10]([NH:12][CH3:13])=[O:11]>C1COCC1>[OH:5][NH:4][C:8](=[O:7])[CH:9]([N:14]([CH3:39])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:16])[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(OCCCN3CCOCC3)cc2)cc1
Reactant: NO
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(-c2ccc(OCCCN3CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Ethanol (1.0 mL) and a 50% aqueous solution (1.0 mL) of hydroxylamine were added to a THF (1.0 mL) solution of 4-{3-[(4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl-4-yl)oxy]propyl}morpholine (0.11 g) as obtained in Example 4-(4), and the mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative silica gel thin-layer chromatography (chloroform/methanol=90/10), and then recrystallized from ethyl acetate/hexane to obtain N-hydroxy-N′-methyl-2-[methyl({4′-[3-(morpholin-4-yl)propoxy]biphenyl-4-yl}carbonyl)amino]propanediamide (Compound 7, light brown solid) (43 mg, 39%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[H-].[Na+]>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: BrCCCCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCCCCn1c2ccccc2c2ccccc21
Temperature: 25 °C

Procedure:
To a two-necked flask containing carbazole (4.0 g, 23.9 mmol), 1,6-dibromohexane (29.2 g, 120 mmol) in 100 mL of anhydrous THF was added 0.86 g (35.8 mmol) of sodium hydride. This mixture was refluxed under nitrogen for 2 days. The reaction mixture was cooled down to room temperature and extracted with ethyl acetate. The non-reacted 1,6-dibromohexane and carbazole were removed by vacuum distillation (100° C./16 mmHg) and column chromatography (ethyl acetate/hexane=1:30), respectively. Pure N-(6-bromohexyl)carbazole was obtained in a white crystal (4 g, 51%). The 100 mL flask containing 30 mL of dry DMF was cooled down to 0° C. Phosphorous oxychloride (4.4 g, 28.7 mmol) was added dropwise maintaining the temperature below 5° C. The reaction mixture was stirred for 30 min. 1.9 g (5.75 mmol) of N-(6-bromohexyl)carbazole in 20 mL of dry DMF was added to the above solution and the temperature was slowly increased to 90° C. After the solution was heated for 2 days, it was cooled down to room temperature and poured into cold water. The pH of the solution was adjusted to around 7 with aqueous NaOH solution. The product was extracted with methylene chloride, dried over magnesium sulfate, and purified by silica gel column chromatography (ethyl acetate/hexane=1:5). A light brown crystal was obtained. (1.3 g, 72%). 1H-NMR (200 MHz, CDCl3): δ 10.1 (s, 1H, —CHO), 8.62 (m, 1H), 8.17 (m, 1H), 8.02 (m, 1H), 7.59-7.27 (m, 4H), 4.36 (t, 2H, ═NCH2—, J=7.1 Hz), 3.50 (t, 2H, —CH2Cl, J=6.4 Hz), 1.93 (m, 2H), 1.74 (m, 2H), 1.45 (m, 4H). 13C-NMR (100 MHz, CDCl3): δ 191.9, 144.2, 141.3, 128.7, 127.3, 126.9, 124.2, 123.2, 123.1, 120.9, 120.5, 109.5, 109.0, 45.0, 43.4, 32.5, 29.0, 26.7, 26.6. HRMS (EI): m/z=313.1227 (M+), Δ=2.1 ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[F:28].C(N(CC)CC)C>C(O)C.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>[F:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:18][C:11]=2[CH:12]=1)[CH:24]=[O:25]
Reactant: OB(O)c1cc2cc(N3CCCCC3)ccc2o1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cc3cc(N4CCCCC4)ccc3o2)c(F)c1
Yield: 25.2 %

Procedure:
A mixture of 5-(piperidin-1-yl)benzofuran-2-ylboronic acid (50 mg, 0.204 mmol), 4-bromo-3-fluorobenzaldehyde (37 mg, 0.184 mmol), triethylamine (0.56 mL, 4.1 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.02 mmol) in ethanol (5 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (15 mg, 15% yield). ESI-MS: 324.2 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.19 (t, 1H), 7.75 (d, 1H), 7.67 (d, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 7.14-7.11 (m, 2H), 3.13 (m, 4H), 1.77 (m, 4H), 1.59 (m, 2H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27])[CH2:22][OH:23].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][OH:23])[CH:24]=[C:25]([Cl:28])[C:26]=1[O:27][CH:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=1)[C:37]([O:39][CH3:40])=[O:38]
Reactant: OCc1cc(Cl)c(O)c(Cl)c1
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)C(Oc1c(Cl)cc(CO)cc1Cl)c1ccccc1
Yield: 20.4 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 4, 0.400 g (2.07 mmol) of the product of Step C was alkylated with 0.522 g (2.28 mmol) of methyl 2-bromophenylacetate to afford 0.144 g (20%) of the title compound.
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.O>[NH2:19][C:20]1[CH:25]=[C:24]([C:15]2[CH:16]=[CH:17][C:12]([C:2]([F:1])([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6])=[CH:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
Scheme VI, Step A′: Into a 50 mL single neck flask [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (200 mg, 0.53 mmol, prepared in example 1), 3-aminobenzene boronic acid (188 mg, 0.76 mmol), potassium carbonate (104 mg, 0.76 mmol) and tetrakis(triphenyl phosphine)palladium(0) (41 mg, 0.036 mmol) were combined in dioxane/water (20 mL, 3:1). The mixture was heated at 100° C. under stirring for 18 hours. The reaction was cooled to room temperature and poured into H2O. The desired product was extracted with ethyl acetate and the organic layer was separated and washed twice with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield the crude material (276 mg) as a dark oil. The resulting oil was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of Hexane/Ethyl Acetate 1:1 to yield the title compound (164 mg, 90%) as a viscous oil. Ion spray M.S. 351.4 (M*+1).
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([C@@:15]1([CH3:30])[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])#[CH:14].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:14]#[C:13][C@@:15]1([CH3:30])[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21]
Reactant: COC(=O)c1cccc(N)c1Br
Reactant: C#C[C@@]1(C)CCCN1C(=O)OCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(N)c1C#C[C@@]1(C)CCCN1C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
To a suspension of tetrakis(triphenylphosphine)palladium(0)(1.72 g, 1.5 mmol) and CuI (0.29 g, 1.5 mmol) in 54 mL of toluene were added methyl 3-amino-2-bromobenzoate (2.3 g, 10 mmol), (R)-benzyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (3.0 g, 12 mmol), and TEA (7 mL, 50 mmol). The mixture was stirred for 18 h at 100° C. under nitrogen atmosphere. After cooling, water (20 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (20 mL) and dried over MgSO4. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel using CH2Cl2 as eluent to provide 2.31 g of (R)-benzyl 2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[H-].[Na+].[CH2:10]([O:17][C:18](=[O:24])[CH:19](Br)[C:20](=[O:22])[CH3:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([CH:19]([C:20](=[O:22])[CH3:21])[C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:24])[N:3]=1
Reactant: Cc1n[nH]c(C)n1
Reactant: CC(=O)C(Br)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(C(=O)OCc1ccccc1)n1nc(C)nc1C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 3,5-dimethyl-1-H-[1,2,4]-triazole (0.502 g, 5.16 mmol) in THF (36.9 ml) was added NaH (0.199 g, 4.98 mmol). After stirring at RT for 10 mins 2-bromo-3-oxo-butyric acid benzyl ester (step 1) (1.0 g, 3.69 mmol) was added. The mixture was stirred at 40° C. for 30 mins and then allowed to cool to RT. The mixture was absorbed onto silica and purification by chromatography on silica eluting with 0-10% DCM/MeOH afforded the title compound as an orange oil; LC-MS Rt 1.95 mins; MS m/z 288.3 [M+H]+; Method LowpH_v001.
Reaction SMILES: [Cl-].[S:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][CH:34]=1)=O>O1CCCC1.CCCCCC>[S:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:31][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][CH:34]=1
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCS2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(C=C2CCCS2)cc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
(2-Tetrahydrothienyl)triphenylphosphonium chloride (5.8 g) was dissolved in tetrahydrofuran (30 ml), and to the solution was added dropwise a 1.6 M solution of n-butyllithium in hexane (9.5 ml) at −5° C., and then the mixture was stirred at the same temperature for 30 minutes. Then, to the reaction mixture was added dropwise a solution of ethyl 2-(4-formylphenyl)propionate (3.6 g) in tetrahydrofuran (5.0 ml) at −5° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 10% aqueous citric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give the title compound (2.5 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[OH:11]O>C(O)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N+:3]=1[O-:11]
Reactant: NC(=O)c1ccc(N)nc1
Reactant: OO
Solvent: CC(=O)O
Product: NC(=O)c1ccc(N)[n+]([O-])c1
Temperature: 100 °C

Procedure:
6-Aminonicotinamide, 50 g, was dissolved in warm glacial acetic acid, 500 ml. To this clear solution 30% hydrogen peroxide, 80 ml was slowly added with agitation. The mixture was then heated to 100° C. for 5 hours. The light brownish solution thus formed was evaporated to a syrupy residue which crystallized on cooling in an ice water bath. The crystals were washed with acetone and dried. The yield of practically pure 6-aminonicotinamide-1-oxide was 51.6 g. This product had a mobility (Rf) of 0.48 on thin-layer chromatogram using a solvent system of benzene:methanol, 1:1.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]#[C:15][C:16]1[C:17]([O:26][CH3:27])=[CH:18][C:19]([O:24][CH3:25])=[C:20]([CH:23]=1)[CH:21]=[O:22].[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[CH:21]([C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]([O:26][CH3:27])=[C:16]([C:15]#[C:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:28](=[O:30])[CH3:29])[CH:23]=1)=[O:22]
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1NC(C)=O
Temperature: 0 °C
Yield: 77.7 %

Procedure:
Pyridine (453 μL, 5.61 mmol) was added to a suspension of 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 750 mg, 2.67 mmol) in anhydrous methylene chloride (20 mL) and chilled to 0° C. The reaction mixture was treated dropwise with acetyl chloride (9.25 mL, 75.1 mmol). Upon completion the reaction was quenched with IN HCl (10 mL) and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude solid was purified by silica gel chromatography (5% MeOH/CH2Cl2) to yield 671 mg (78%) of N-[2-(5-formyl-2,4-dimethoxyphenylethynyl)phenyl]acetamide as an off-white solid. 1H-NMR (300 MHz, DMSO-d6) 10.15 (s, 1H), 9.23 (br s, 1H), 7.82 (m, 2H), 7.80 (s, 1H), 7.50 (dd, 1H, J=0.9, 7.8 Hz), 7.35 (dt, 1H, J=1.8, 9.3 Hz), 7.12 (t, 1H, J=7.8 Hz), 6.82 (s, 1H), 4.00 (s, 3.99 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32](O)=[O:33])=[O:15])([CH3:4])([CH3:3])[CH3:2].[N:42]1([C:47]2[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[CH:49][CH:48]=2)[CH:46]=[CH:45][CH:44]=[N:43]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[N:42]1([C:47]2[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:32]([C:31]3[CH:35]=[CH:36][N:37]=[C:29]([C:18]4[CH:19]=[C:20]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[CH:21]=[CH:22][C:17]=4[NH:16][C:14]([C:13]4[CH:12]=[C:11]([CH:40]=[CH:39][CH:38]=4)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:41])=[O:15])[CH:30]=3)=[O:33])=[CH:49][CH:48]=2)[CH:46]=[CH:45][CH:44]=[N:43]1
Reactant: NCc1ccc(-n2cccn2)cc1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(-n4cccn4)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed 2-(2-(3-((3-tert-butoxy-3-oxopropylthio) methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid (125 mg, 0.22 mmol, 1.00 equiv), (4-(1H-pyrazol-1-yl)phenyl)methanamine (41 mg, 0.24 mmol, 1.10 equiv), EDC.HCl (62 mg, 0.32 mmol, 1.50 equiv), 4-dimethylaminopyridine (40 mg, 0.33 mmol, 1.51 equiv), and dichloromethane (15 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was extracted with 40 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×15 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was obtained as 0.132 g (83%) of a yellow crude solid.
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[CH3:27].O>CCOCC>[C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH2:26][CH3:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CCC(O)[C@@H](CC)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-2-(trityl-amino)-butyraldehyde (1.5 g, 1 eq, 4.53 mmol) in Et2O (150 mL) under an argon atmosphere at −78° C., was added ethylmagnesium bromide (3 M in Et2O, 1.51 mL, 1 eq, 4.53 mmol) dropwise. The solution was stirred at −78° C. for 2 h, then allowed to warm to room temperature over 16 h. The mixture was recooled to 0° C., H2O (150 mL) added, and the organic phase separated. The aqueous phase was extracted with more Et2O (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (90:10) to afford the title compound as a light yellow oil. Yield: 1.13 g (69%). (57% de 3S,4R: 43% de 3R,4R). 1H-NMR (d6-DMSO, 250 MHz): δ 0.45 & 0.69 (t & m, 6H, J=7.43 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.12-1.29 (m, 4H, —NHCH (CH2CH3)CH (CH2CH3)OH), 2.16 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.54 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.21-3.40 (m, 1H, —NHCH(CH2CH3) CH(CH2CH3)OH), 4.29+4.39 (2×d, 1H, J=4.42 & 5.37 Hz, —NHCH(CH2CH3) CH(CH2CH3)OH), 7.15-7.52 (m, 15H, 3×Ph).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][N:21]([CH3:26])[C:22](=[O:25])[CH2:23][CH3:24])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][N:21]([CH3:26])[C:22](=[O:25])[CH2:23][CH3:24])=[O:19]
Reactant: CCC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 77.2 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N′-methyl-7-oxo-N′-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 226 (0.19 g, 0.52 mml) in methanol (20 mL) was added 5% Pd/C (0.20 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered through Celite, and the filtrate was evaporated to give (2R,5S)-6-hydroxy-N′-methyl-7-oxo-N′-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 227 (0.11 g, 79%) as a brown foam.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2CCCC[C:15]=2[CH:16]=1>CCCCCC.CCOCC>[Li:5][CH:1]1[C:10]2[N:9]=[CH:8][C:7]([CH3:6])=[CH:16][C:15]=2[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]C1CCCc2cc(C)cnc21
Reaction time: 1 h

Procedure:
A solution of 15% w/w n-butyl lithium in hexane (51 ml.) ca. 0.12 m) was added portionwise to a solution of 3-methyl-5,6,7,8-tetrahydroquinoline (14.7 g., 0.1 m) in ether (100 ml.) and the mixture allowed to stand at room temperature for 1 hour to form 8-lithio-3-methyl-5,6,7,8-tetrahydroquinoline. The solution was then added dropwise to a cooled, stirred solution of methylchloroformate (9.45 g., 0.1 m) in ether (100 ml.). The mixture was further treated as described in Example 25 of copending U.S. Ser. No. 460,265 to give methyl-3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate.
Reaction SMILES: C([O:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])[CH:12]=2)=[O:10])=[C:7]([Cl:28])[C:6]=1[Cl:29])C=C.[C:30]1(OC2C=CC=CC=2)[CH:35]=CC=C[CH:31]=1>>[CH2:35]([C:27]1[C:5]([OH:4])=[C:6]([Cl:29])[C:7]([Cl:28])=[C:8]([CH:26]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([S:18]([N:21]=[CH:22][N:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])[CH:12]=1)=[O:10])[CH:30]=[CH2:31]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: C=CCOc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)c(Cl)c1Cl
Product: C=CCc1cc(C(=O)c2ccc(Cl)c(S(=O)(=O)N=CN(C)C)c2)c(Cl)c(Cl)c1O

Procedure:
16.5 g (35 mmol) of 4-allyloxy-3'-dimethylaminomethyleneaminosulfonyl-2,3,4'-trichlorobenzophenone in 200 ml of diphenyl ether are heated at 210° to 215° C. for 1 hour, and the still warm mixture is poured in portions, with stirring, into 1.2 l of petroleum ether. The precipitate is filtered off, washed several times with petroleum ether and recrystallized from methanol. Colorless crystals, melting point 190°-193° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: C1COCCN1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCOCC4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and morpholine. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.33 (d, J=1.95 Hz, 3 H) 3.34 (br. s., 2H) 3.64 (br. s., 6 H) 7.64 (br. s., 1 H) 7.74 (t, J=7.32 Hz, 1 H) 7.90-8.63 (m, 4 H). ESI-MS m/z [M+H]+ 408.3.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([N:11]3[CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[CH3:22])[C:12]3=[O:23])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1>CO.C(Cl)(Cl)Cl.[Pd]>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:13]1[CH2:14][CH2:15][N:11]([C:9]2[S:10][C:6]3[CH:5]=[CH:4][N:3]=[CH:2][C:7]=3[CH:8]=2)[C:12]1=[O:23]
Reactant: Cc1ccncc1N1CCN(c2cc3c(Cl)nccc3s2)C1=O
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2cc3cnccc3s2)C1=O
Reaction time: 12 h
Yield: 13.9 %

Procedure:
10% Pd-C (10 mg) was added to a solution of 1-(4-chloro-thieno[3,2-c]pyridin-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (98A: 80 mg, 0.232 mmol) in methanol (10 mL) under nitrogen atmosphere. The resulting mixture was hydrogenated at 30 PSI (2.04 atm) for 12 hours at room temperature. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was filtered through celite bed, washed with methanol and the filtrate was concentrated under reduced pressure to afford the crude product. Purification by preparative TLC afforded 10 mg of the product (14% yield).