Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[C:20]([CH3:22])[C:19]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28]CCCCC>CN(C)C=O>[CH2:26]([N:25]1[CH:28]=[CH:22][C:20]2[N:21]=[C:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:11][CH2:12]3)[N:17]=[CH:18][C:19]=2[C:23]1=[O:24])[CH3:27]
Reactant: CCNC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1C
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Yield: 87 %

Procedure:
After washing 240 mg of sodium hydride (60% in oil, 6 mmol) with hexane, it was suspended in 3 ml of N,N-dimethylformamide (DMF). Thereafter, a DMF solution (10 ml) of 1.7 g (5 mmol) of 2-(4-benzylpiperazino)-N-ethyl-4-methylpyrimidine-5-carboxylic acid amide (Referential Example 5) was added and the reactants were reacted at 150° C. for 1.5 hours. After distilling off DMF under reduced pressure, 100 ml of water was added, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried with magnesium sulfate, and ethyl acetate was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 1.5 g of the intended product as light yellowish crystals (yield: 87%).
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:23][CH2:24][CH3:25])=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:14]=2)[CH:5]=1.[C:27]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH3:28].[Li]>>[C:31]([O:30][C:27](=[O:29])[CH2:28][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:23][CH2:24][CH3:25])=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:14]=2)[CH:5]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CCCc1sc(-c2cccc(C(=O)OC)c2)nc1COC1CCCCO1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CCCc1sc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc1COC1CCCCO1

Procedure:
3-[5-Propyl-4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-benzoic acid methyl ester (0.34 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-oxo-3-[3-[5-propyl-4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.42 g) as a pale-yellow oil.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21]1([CH3:37])[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[N:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1>C1COCC1>[C:33]1([CH3:36])[CH:34]=[CH:35][C:30]([NH:29][C:28]([O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4][C:3]2([CH3:20])[CH3:19])=[N:27][C:24]2[CH:23]=[CH:22][C:21]([CH3:37])=[CH:26][CH:25]=2)=[CH:31][CH:32]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: Cc1ccc(N=C=Nc2ccc(C)cc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(N=C(Nc2ccc(C)cc2)ON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.3 %

Procedure:
1-Hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine (5.75 g, 20.7 mmol) [prepared as described in Example 6] and di-p-tolylcarbodiimide (4.8 g, 21.6 mmol) are dissolved in THF (40 ml) and the solution is stirred at room temperature for 17 hours. The solvent is evaporated and the residue is chromatographed on silica gel with hexane-ethyl acetate (9:1). The pure fractions are recrystallized from acetonitrile to afford 6.55 g of the title compound as a colorless solid, mp. 124-128° C.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[OH-].[Na+:38]>O>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[Na+:38]
Reactant: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A suspension of the product of Example 42G in water (3 mL) and treated with 0.997N sodium hydroxide solution (0.410 mL) and stirred at 25° C. for 1 hour. The solution was lyophilized to give 209 mg (74%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 m, 1 H) 0.70 (s, 9 H) 0.81 m, 1 H) 1.38 (s, 3 H) 1.71 m, 1 H) 2.16 (m, 1 H) 2.90 (s, 3H) 7.28 m, 3 H) 7.44 m, 3 H) 8.05 (d, J=7.35 Hz, 1 H) 9.87 (s, 1 H) 15.44 (s, 1 H); MS (ESI−) m/z 530 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[CH2:11]([N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:27])[CH:15]=[N:14]1)[CH3:12].C([O-])([O-])=O.[K+].[K+]>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>[CH2:11]([N:13]1[C:17]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[C:16]([CH3:27])[CH:15]=[N:14]1)[CH3:12]
Reactant: COC(=O)c1cc(Br)cs1
Reactant: CCn1ncc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCn1ncc(C)c1-c1csc(C(=O)OC)c1
Temperature: 70 °C
Yield: 79.3 %

Procedure:
A mixture of methyl 4-bromo-2-thiophenecarboxylate (300 mg, 1.36 mmol), 1-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (449 mg, 1.9 mmol), Pd(Ph3P)4 (157 mg, 0.136 mmol), and K2CO3 (536 mg, 4.07 mmol) was heated at 70° C. for 2 h, concentrated and purified on silica (EtOAc/Hex, 10-30%) to afford the title compound (0.27 g, 79%) as a syrup: LC-MS m/z=251 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]([O-:16])=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].[OH-].[K+].C(O)C>O>[Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: O=C([O-])COc1cc2ccsc2c(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1cc2ccsc2c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7.5 g of ethyl [(6,7-dichlorobenzo[b]thien-5-yl oxy]acetate, 15 g of potassium hydroxide pellets, 125 ml of ethanol and 125 ml of water is refluxed for 1 hour. Ethanol is removed under reduced pressure at 60° and the aqueous suspension is acidified with conc hydrochloric acid. The slurry is stirred at room temperature for 30 min. and extracted with ether (3×250 ml-portions). The combined ether extracts are washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an off-white crystalline mass. Recrystallization of the crude product from acetone-cyclohexane gives 6.5 g of [(6,7-dichlorobenzo[b]thien-5-yl)oxy]acetic acid as an off-white powder, mp 166°-167°.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@@H:28]1[NH:33][CH2:32][CH2:31][N:30]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[CH2:32][CH2:31][N:30]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][C@@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@H]1CN(c2ccc3ccccc3n2)CCN1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@H]1CN(c2ccc3ccccc3n2)CCN1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[(S)-3-methyl-piperazin-1-yl]-quinoline
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[C:18]([SiH2:22][O:23][C:24]([CH3:33])([CH3:32])[C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([SiH2:22][O:23][C:24]([CH3:33])([CH3:32])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:2]2[N:3]=[CH:4][C:5]3[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[C:6]=3[N:7]=2)=[N:29][CH:30]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(N)nc1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(Nc2ncc3cc(C#N)n(C4CCCC4)c3n2)nc1
Yield: 66 %

Procedure:
Following Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (95 mg, 0.385 mmol) and 5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (101 mg, 0.424 mmol) (Example C) gave 114 mg of 2-[5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile [following SiO2 chromatography eluting with 1-2% MeOH/dichloromethane and subsequent trituration with diethyl ether].
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C([Li:24])CCC.CCCCCC>CCOCC>[C:3]1([Li:24])[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:2]=1
Reactant: Brc1ccc2c3ccccc3c3ccccc3c2c1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]c1cccc2c3ccccc3c3ccccc3c12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into a suspension of 2-bromotriphenylene (7.28 g, 23.70 mmol) in ether (50 mL) was added n-butyllithium solution in hexane (14.81 mL, 23.70 mmol) dropwise at −78° C. The suspension was gradually warmed to 0° C. and stirred for 3 hours to yield a solution of triphenylenyllithium. In a separate flask a solution of 3-bromophenyllithium was prepared by dropwise addition of n-butyllithium solution in hexane (14.81 mL, 23.70 mmol) into a solution of 1,3-dibromobenzene (2.87 mL, 23.70 mmol) in ether (50 mL). The solution was stirred at this temperature for 2.5 hours before being transferred into a solution of dichlorodiphenylsilane (4.88 mL, 23.70 mmol) in ether (30 mL) at −78° C. After stirring for another 2 h, the triphenylenyllithium solution prepared above was introduced dropwise into the flask containing the dichlorophenylsilane. The reaction mixture was allowed to gradually warm to room temperature and was stirred overnight. The mixture was quenched with water and the organic phase was isolated. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (85/15, v/v) as eluent to yield (3-bromophenyl)diphenyl(triphenylen-2-yl)silane (8.5 g, 75%) as a white powder.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Br:16])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:25]=[O:26])C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C.CO>[Br:16][C:11]1[CH:12]=[C:13]([CH:14]=[C:9]([O:8][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:6])[CH3:7])[CH:10]=1)[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(C=O)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl-(3,5-dibromo-phenoxy)-dimethyl-silane (22 g; 60.08 mmol) was dissolved in THF (200 mL) in a dried reaction flask under an atmosphere of nitrogen. The mixture was cooled to −78° C. and n-BuLi (1.6 N in hexane; 41.25 mL; 66.09 mmol) was added while the temperature was kept between −60 and −78° C. The mixture was stirred for 15 min. and DMF (4.83 g; 66.08 mmol) was added. The reaction mixture was stirred for 1 h and methanol (5 mL) followed by saturated ammonium chloride was added. Ethyl acetate (200 mL) was added and the organic phase was separated from the aqueous phase. The organic phase was washed with water, dried, and evaporated to dryness. The crude product was purified by flash chromatography (heptane:dichloromethane (1:1). Yield 7 g. HPLC-MS: m/z: 317.0 (M+1); Rt: 2.7 min.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(=O)([O-])[OH:29].[Na+].C(OO)(C)(C)C>ClCCCl>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:29])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C([O-])O
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Agent: CC(C)(C)OO
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 25 °C
Yield: 114.2 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone (100 mg, 0.25 mmol, 1.0 equiv; Example 24) in anhydrous 1,2-dichloroethane (2 mL) was added sodium hydrogen carbonate (11 mg, 0.125 mmol, 0.5 equiv; [CAS RN 144-55-8]), tert-butyl hydroperoxide (189 mg, 227 μL, 1.25 mmol, 5.0 equiv, 5.5 M solution in decane; [CAS RN 75-91-2], TBHP) and dirhodium caprolactamate (1.7 mg, 0.0025 mmol, 0.01 equiv; [CAS RN 138984-26-6]; prepared according to M. P. Doyle, L. J. Westrum, W. N. E. Wolthuis, M. M. See, W. P. Boone, V. Bagheri, M. M. Pearson, J. Am. Chem. Soc. 1993, 115, 958-964). The reaction mixture was stirred at rt over night. Removal of the solvent mixture under reduced pressure and purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate followed by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 59 mg (57%) of the title compound as a white solid. MS (ISP): 413.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[CH:45]=O.[B][B][B][B][B][B][B][B][B][B].C(O)(C(F)(F)F)=O>>[CH2:31]([N:30]([CH2:33][CH3:34])[C:28](=[O:29])[C:25]1[CH:24]=[CH:23][C:22]([C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:45][C:36]3[CH:37]=[CH:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:35]=3)[CH:3]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:27][CH:26]=1)[CH3:32]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(N)c2)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1ccc2ccccc2n1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NCc3ccc4ccccc4n3)c2)N2CCNCC2)cc1
Yield: 70.9 %

Procedure:
Using the same method as for COMPOUND 17 and using INTERMEDIATE 5a (209 mg, 0.45 mmol), 2-quinolinecarboxaldehyde (77.6 mg, 0.49 mmol), and decaborane (16.4 mg, 0.13 mmol) afforded COMPOUND 54 (162 mg, 38% yield) as its TFA salt. This material was lyophilized from CH3CN/H2O to produce a yellow solid. Purity (HPLC): >98%; Optical purity (Chiral HPLC): >99%; 1H NMR (400 MHz, CD3OD) δ 1.07 (br t, J=6.7 Hz, 3H), 1.23 (br t, J=6.6 Hz, 3H), 2.59 (br s, 4H), 3.18 (br t, J=4.4 Hz, 6H), 3.52 (br q, J=7.2 Hz, 2H), 4.30 (s, 1H), 4.89 (s, 2H), 6.58 (dd, J=7.9, 2.1 Hz, 1H), 6.72 (s, 1H), 6.82 (d, J=7.4 Hz, 1H), 7.04-7.12 (m, 3H), 7.36 (d, J=8.2 Hz, 2H), 7.85-7.93 (m, 2H), 8.09 (td, J=7.8, 1.2 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.87 (d, J=8.6 Hz, 1H). Found: C, 50.15; H, 4.57; N, 7.46. C32H37N5O×1.1 H2O×3.6 CF3COOH has C, 50.20; H, 4.60; N, 7.47%. [α]D17=+20.8 deg [c 0.726, MeOH].
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[N:11][C:6]=2[S:5](=[O:14])(=[O:13])[N:4]=[CH:3]1.[BH4-].[Na+]>C(O)(C)C.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[N:11][C:6]=2[S:5](=[O:14])(=[O:13])[NH:4][CH2:3]1
Reactant: Cc1cnc2c(c1)N(C)C=NS2(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cc1cnc2c(c1)N(C)CNS2(=O)=O
Reaction time: 0.5 h

Procedure:
A solution of 0.5 g of 4,6-dimethyl-4H- pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 76) in 25 cm3 of a 1/1 isopropanol/chloroform mixture is treated, in small portions, with 0.4 g of sodium borohydride with good stirring and under an inert atmosphere. After 30 minutes at ambient temperature, the excess borohydride is destroyed by addition of a few drops of acetic acid and the solvent is removed under reduced pressure. The residue is taken up in 10 cm3 of water and the pH of the mixture is brought to neutrality. The precipitate obtained is collected on a filter, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24].[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24]
Reactant: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To a solution of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate (214 mg, 0.48 mmol) in a mixture of THF (10 ml) and H2O (5 ml) was added a solution of LiOH (57.5 mg, 2.40 mmol) in H2O (2.4 ml). After stirring at room temperature for 4 h, the reaction was concentrated, acidified with 1 M HCl solution, and extracted with EtOAc (2×20 ml). The organic solution was dried over MgSO4 and concentrated to give 184 mg (100%) of 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylic acid as an orange solid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7])=O.Cl.[NH2:19][OH:20]>C(O)C>[OH:20][N:19]=[CH:1][C:3]1[C:4]([CH3:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1C
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1C

Procedure:
11.55 g of methyl 3-formyl-4-methylsulfonyl-2-methylbenzoate was dissolved in 100 ml of ethanol, and 4.70 g of hydroxylamine hydrochloride was added. The resulting solution was reacted for 1.5 hours at room temperature and further heated at reflux for an hour. The reaction solution was cooled down. Ethanol was then distilled out under reduced pressure. The obtained residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure to give 12.31 g of a crude product as viscous oil. The crude product was purified by column chromatography on silica gel with n-hexane/ethyl acetate=2/1 to give the title compound as white crystals. m.p. 123~129° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:30]1([O:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1>[CH3:24][C@H:19]1[CH2:20][O:21][CH2:22][CH2:23][N:18]1[C:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37]([O:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])=[CH:7][CH:6]=2)[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=1
Reactant: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 2-(4-aminophenyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate (400 mg) was dissolved in dioxane (10 mL) and sodium bicarbonate (154 mg) and phenylchloroformate (0.154 mL) added dropwise. The mixture was stirred at RT for 16 hours then the dioxane removed under reduced pressure and the residue partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated to give the desired material as a brown foam (624 mg).
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[C:14]([OH:16])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][NH2:18]>[NH4+].[Cl-].CCOC(C)=O>[C:2]1([C:1]2[C:9]3[CH:13]=[CH:12][O:11][C:10]=3[C:14]([OH:16])=[N:18][N:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccoc1C(=O)O
Reactant: NN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: Oc1nnc(-c2ccccc2)c2ccoc12

Procedure:
A brown solution of 3-benzoylfuran-2-carboxylic acid (0.770 g, 3.56 mmol) and anhydrous hydrazine (0.568 ml, 17.8 mmol) was heated to 100° C. in a sealed tube for approx. 72 h. The reaction was cooled, and diluted with sat'd aq. NH4Cl and EtOAc. The organic layer was washed with sat'd aq. NH4Cl and brine, and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-phenylfuro[3,2-d]pyridazin-7-ol which was carried on without further purification. MS m/z=213 [M+H]+. Calc'd for C12H8H2O2: 212.2.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](O)(=[O:18])[C:16]#[CH:17].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])[C:16]#[CH:17]
Reactant: OCCCCCCCc1ccccc1
Reactant: C#CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C#CC(=O)OCCCCCCCc1ccccc1
Yield: 57.9 %

Procedure:
A mixture of 0.5 g of 7-phenylheptanol, 0.27 g of propiolic acid, 0.005 g of p-toluenesulfonic acid and 25 ml of benzene was refluxed with stirring for six hours while water formed was removed by a Dean-Stark water separator. After the reaction was completed, the reaction solution was washed successively with a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 0.368 g of 7-phenylheptyl propiolate (compound 3).