Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24]O)=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2].C(N(CC)CC)C.CS([Cl:40])(=O)=O.[Cl-].[Li+]>ClCCl>[CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][Cl:40])=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)Oc1cccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)Oc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a stirred solution of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-methanol (2.7 g, 7.08 mmol) in dichloromethane (14 mL) was added triethylamine (3.0 mL, 21.2 mmol) and methanesulphonyl chloride (1.24 mL, 15.6 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and lithium chloride (1.4 g, 33 mmol) was added at this temperature. The reaction mixture was stirred at room temperature for 15 hrs and diluted with dichloromethane (150 mL). The reaction mixture was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 1-(3-sec-butoxy-benzyl)-4-chloromethyl-6,7-dimethoxy-isoquinoline (2.1 g, 74% yield) as a brown oil. The crude product was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([NH2:12])[CH:5]=1.Br.Br[CH2:15][C:16]([C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=1)=O.C([O-])(O)=O.[Na+].O1CCOCC1>O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([NH2:12])[C:7]2[C:8]([N:9]=1)=[N:10][C:16]([C:18]1[C:23]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH:15][N:11]=2
Reactant: O=C(CBr)c1ncccc1C(F)(F)F
Reactant: COCc1cc(N)c(N)c(N)n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCc1cc(N)c2ncc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Methoxymethyl-2,3,4-triamino-pyridine (353 mg, 2.10 mmol), 2-bromo-1-(3-trifluoromethyl-pyridin-2-yl)-ethanone hydrobromide (771 mg, 2.21 mmol; synthesis described in Example 2E, below), and NaHCO3 (554 mg, 6.59 mmol) are dissolved into a solution of dioxane (20 mL) and water (20 mL). The reaction mixture is stirred 1 hour at room temperature and 3 hours at 100° C. The mixture is cooled and filtered through Celite. The Celite bed is washed with EtOAc (20 mL). The aqueous mixture is extracted with EtOAc (4×100 mL). The combined organic extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure and the crude product purified by column chromatography on silica gel eluting with acetone/hexanes (1:1) to yield the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH2:10][CH3:11])[CH:3]=1.C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: C1COCCN1
Reactant: CCc1cc(Br)ccc1CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(Br)ccc1CN1CCOCC1
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-ethyl-benzene (3.67 g, 13.2 mmol) in CH3CN (66 mL) was added triethylamine (2.76 mL, 19.8 mmol) and morpholine (1.38 mL, 15.8 mmol). The mixture was stirred for 1.5 hours, at which time the volatiles were removed in vacuo to yield a pale yellow solid (3.7 g, 97%). 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 3 H), 2.40 (m, 4 H), 2.68 (q, J=7.7 Hz, 2 H), 3.40 (s, 2 H), 3.65 (m, 4 H), 7.13 (m, 1 H), 7.22 (d, J=2.1 Hz, 1 H), 7.30 (d, J=2.1 Hz, 1 H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1)(=O)=O.O>CN(C)C=O>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][N:1]=[N+:2]=[N-:3])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCCc1ccc(CCOC2CCCCO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccc(CCOC2CCCCO2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Sodium azide (1.73 g, 26.61 mmol) was added to a solution of 4-(2-(tetrahydropyran-2-yloxy)ethyl)phenethyl methanesulfonate (5.24 g, 15.95 mmol) in N,N-dimethylformamide (50 ml). The mixture was stirred at 100° C. for 1 hour. Water (40 ml) was added to the reaction mixture. The mixture was extracted with ethyl ether and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting9 with n-hexane/ethyl acetate (=20/1) to give the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)-1-(2-azidoethyl)benzene (4.30 g, 98%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][NH:3]1.[H-].[Na+].[CH2:14](I)[CH3:15].O>CN(C=O)C>[CH2:14]([N:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:7][C:2]1=[O:1])[CH3:15]
Reactant: COC(=O)c1ccc(=O)[nH]c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)OC)ccc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
Methyl 2-oxo-1,2-dihydropyridinecarboxylate-5- (400 mg, 2.61 mmol) obtained in Step 3 was dissolved in DMF (3 mL), and 55% sodium hydride (125 mg, 2.87 mmol) and ethyl iodide (0.230 mL, 2.87 mmol) were added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford methyl 1-ethyl-2-oxo-1,2-dihydropyridine-5-carboxylate (375 mg, 79%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH2:15][C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28][CH2:27][N:26]([CH2:29][C:30](O)=[O:31])[C:25]2=[O:33])=[CH:20][CH:19]=1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:14][N:13]([C:30](=[O:31])[CH2:29][N:26]3[CH2:27][CH2:28][C:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)[C:25]3=[O:33])[CH2:12]2)[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC3(CC2)CNC3)cc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccccc3)CC2)C1
Reaction time: 8 h

Procedure:
7-Benzyl-2,7-diazaspiro[3.5]nonane (0.237 g, 0.749 mmol), 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.248 g, 0.749 mmol; Example 58D), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.199 mL, 1.123 mmol) and N-methylmorpholine (0.247 mL, 2.247 mmol) were stirred together in dichloromethane (2 mL). After stirring overnight, the reaction was diluted with dichloromethane (20 mL) and washed with 1 N HCl (10 mL) and brine (10 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the title compound eluted with a gradient of 0.4% methanol/dichloromethane containing 0.2 N NH3 to 6% methanol/dichloromethane containing 0.2 N NH3 (Flow=40 mL/minute) over 40 minutes. 1H NMR (300 MHz, CDCl3) δ 7.39-7.15 (m, 9H), 6.99 (t, J=8.2, 4H), 3.97 (s, 2H), 3.72 (d, J=20.0, 4H), 3.53 (t, J=6.5, 2H), 3.46 (s, 2H), 2.75 (t, J=6.4, 2H), 2.32 (s, 4H), 1.73 (s, 4H); MS (ESI+) m/z 530.2 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19]O.C(N(CC)CC)C.[S:42](Cl)([CH3:45])(=[O:44])=[O:43]>C(Cl)Cl>[CH3:45][S:42]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][S:42]([CH3:45])(=[O:44])=[O:43])(=[O:44])=[O:43]
Reactant: CC(C)(C)OC(=O)N(CCCCO)CCCCCCCCN(CCCCO)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCCCCCCCN(CCCCS(C)(=O)=O)C(=O)OC(C)(C)C)CCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cool to 0° C. a mixture containing 3.0 gm of the product of Step F, 3.3 ml of triethylamine and 70 ml of CH2Cl2. In a dropwise fashion add 1.22 ml of mesylchloride in 10 ml of CH2Cl2, and stir the resulting mixture at 0° C. for 11/2 hours. Pour the mixture into 100 ml of CH2Cl2, wash with 200 ml of 1N AcOH, 100 ml of water, 100 ml of sat'd sodium bicarbonate, dry over MgSO4 and remove the solvent in vacuo. Flash chromatograph the residue, eluting from silica gel with 60% EtOAc/hexane to obtain 3.5 gm of the desired product. Rf is 0.39.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.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.O>[CH3:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[C:3]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:33][CH:32]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CN1CCCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCCN(C)CC2)cn1

Procedure:
A mixture of 5-bromo-6-(4-methyl-1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 146.1, 74 mg, 0.150 mmol), (6-methylpyridin-3-yl)boronic acid (20.6 mg, 0.150 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon. Pd(PPh3)2Cl2 (5.3 mg, 0.0075 mmol) was added and the mixture was subjected to MW irradiation at 125° C. for 30 min. The RM was evaporated to dryness under reduced pressure and the residue was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative HPLC. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=1.55 min, m/2z=243.6 [M+2H]+, m/z=484.2 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[C:5]#[C:6][C:7](=[N:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]([F:11])(F)F)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:41][C:42]([CH3:46])([CH3:45])[CH2:43][NH2:44]>CS(C)=O>[C:42]([C:43]1[C:8]([F:11])=[C:7]([NH:12][C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:32][CH2:33][CH3:34])[N:44]=1)([CH3:46])([CH3:45])[CH3:41]
Reactant: CCOC(C#CC(=NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F)OCC
Reactant: CC(C)(C)CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(C(C)(C)C)n1
Yield: 101.8 %

Procedure:
Using the procedure of Example 9, N-(5,5-diethoxy-1,1,1-trifluoropent-3-yn-2-ylidene)-1,1,1-triphenylmethanamine (2.328 g, 5 mmol), cesium carbonate (4.07 g, 12.50 mmol), 2,2-dimethylpropan-1-amine (1.307 g, 15.00 mmol) and anhydrous DMSO (20 mL) gave 2-(tert-butyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine (2.61 g, 97%) as an off-white solid: mp 168-169.5° C.; 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 15H), 6.16 (d, J=6.1 Hz, 1H), 5.71 (d, J=5.2 Hz, 1H), 5.01 (s, 1H), 3.29 (dd, J=9.5, 7.1 Hz, 2H), 3.17 (dq, J=9.4, 7.0 Hz, 2H), 1.36 (d, J=1.3 Hz, 9H), 1.01 (t, J=7.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 151.67 (d, J=9.9 Hz), 150.42 (d, J=5.9 Hz), 147.83 (d, J=249.5 Hz), 144.45, 141.00 (d, J=10.3 Hz), 128.91, 128.14, 127.12, 107.63, 102.63, 71.04, 61.35, 36.75 (d, J=5.1 Hz), 29.00 (d, J=3.5 Hz), 15.09; 19F NMR (376 MHz, CDCl3) δ −145.99; HRMS-ESI (m/z) [M+H]+ calcd for C33H37FN2O3, 512.2839. found, 512.2851.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:12][C:6]1[C:7](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:8]([OH:10])=[O:9])[CH3:18]
Reactant: CCO
Reactant: COc1ccc(O)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(OC)cc1C(=O)O
Yield: 58 %

Procedure:
5-Methoxysalicylic acid (2.00 g) was suspended in ethanol (28 ml), and thionyl chloride (2.11 g) was gradually added dropwise to the suspension. Thereafter, the mixture was heated under reflux for 2 hr. The solvent was removed therefrom by distillation under the reduced pressure. Water was added to the residue, and the mixture was neutralized with a 20% aqueous sodium hydroxide solution and was then extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-methoxysalicylic acid (1.37 g, yield 58%).
Reaction SMILES: [C:1]1([CH:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:70][CH2:71][CH2:72][CH:73]([O:77][CH2:78][CH3:79])[O:74][CH2:75][CH3:76]>CN(C=O)C.C(OCC)(=O)C>[N:31]12[CH2:32][CH2:33][CH:34]([CH2:35][CH2:36]1)[C@@H:29]([O:28][C:26](=[O:27])[NH:25][CH:7]([C:8]1[CH:24]=[CH:23][CH:22]=[C:10]([O:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:70][CH2:71][CH2:72][CH:73]([O:77][CH2:78][CH3:79])[O:74][CH2:75][CH3:76])=[CH:15][CH:14]=3)[CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:30]2
Reactant: O=C(NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Reactant: CCOC(CCN)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(CCNC(=O)c1ccc(COc2cccc(C(NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a stirred solution of 4-((3-(phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)methyl)benzoic acid (0.300 g, 0.57 mmol) in DMF (2.5 mL), was added HATU (0.262 g, 0.69 mmol) and diisopropylethylamine (0.250 mL, 1.43 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. 1-Amino-3,3-diethoxypropane (0.139 mL, 0.86 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated sodium hydrogen carbonate and brine (×2). The organic phase was dried wih anhydrous sodium sulfate, and filtered, and the solvent was evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 100% ethyl acetate in iso-hexane to afford the title compound (0.347 g, 99%), which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[K+].[CH3:14][C:15]([CH:17]=O)=O.O>C(O)C>[CH3:17][C:15]1[CH:14]=[N:11][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:10]=1
Reactant: CC(=O)C=O
Reactant: Nc1cccc([N+](=O)[O-])c1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cnc2c([N+](=O)[O-])cccc2n1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 3-nitro-1,2-phenylenediamine (2.67 g) and a 2N KOH (8.7 mL) in ethanol (250 mL) was added a 40% aqueous solution of pyruvic aldehyde (17.72 g) at 60° C. The mixture was heated under reflux for 10 minutes, and thereto was added water (150 mL). The mixture was cooled to room temperature, and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with cold water, and dried under reduced pressure to give 2-methyl-5-nitroquinoxaline (2.21 g, 67%) as pale brown solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[C:16]([O:18]CC)=[O:17])[N:12]=[CH:11][CH:10]=[N:9]2)=[O:5])C.[OH-].[K+].O>O1CCOCC1.CC(OC(C)=O)=O>[N:9]1[C:8]2[CH:7]=[C:6]3[C:4](=[O:5])[O:18][C:16](=[O:17])[C:15]3=[CH:14][C:13]=2[N:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cc2nccnc2cc1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc3nccnc3cc21
Yield: 72 %

Procedure:
11.8 g (43.0 mmol) quinoxaline-6,7-dicarboxylic acid diethyl ester and 5.0 g (86 mmol) KOH dissolved in 100 ml dioxane and 50 ml water is stirred at ambient temperature during 20 hours. After evaporation of the dioxane, the solution is made slightly acidic (pH ˜5) with HCl 2N and is extracted with methylene chloride. After evaporation of the organic phase, 6.6 g diacide is isolated. This product is directly dissolved in 25 ml acetanhydride and heated at reflux during 8 hours. Acetanhydride is evaporated and 6.2 g furo[3,4-g]quinoxaline-6,8-dione is isolated. Without purification, this material is dissolved in 50 ml methanol and heated at reflux during 1 hour. After evaporation of the solvent, the residue is crystallised in diisopropyl ether to give 6.25 g of the title compound (63%): 1H-NMR (DMSO-d6, 400 MHz): 3.73 ppm (s, 3H), 8.20 (s, 1H), 8.35 (s, 1H), 9.0 (2 s, 2H), 13.6 (s, b, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>C1COCC1.C(Cl)Cl>[C:19]([NH:18][C:14]1[CH:13]=[C:12]([CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:26]([O:25][CH3:24])[CH:27]=3)[CH2:11][CH2:10]2)[CH:17]=[CH:16][CH:15]=1)(=[O:23])[CH:20]([CH3:21])[CH3:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1OC

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3,4-dimethoxybenzoyl chloride: ESMS m/e: 482.0 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C@H:8]([OH:19])[C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C@H:8]([O:19][S:30]([CH3:29])(=[O:32])=[O:31])[C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](c1ccc(Cl)c(Cl)c1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](c1ccc(Cl)c(Cl)c1)[C@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of (2R,3R)-1-(tert-butyl-dimethyl-silyloxy)-3-(3,4-dichloro-phenyl)-butan-2-ol (4.63 g, 13.2 mmol) in DCM (44 mL) at 0° C. were added Et3N (4.6 mL, 33.0 mmol), DMAP (81.0 mg, 0.7 mmol), and MsCl (2.2 ml, 28.4 mmol). The mixture was stirred overnight at rt. The reaction was quenched with water (100 mL) and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to yield an orange oil. The product was purified by flash chromatography (Et2O/hexanes) to afford 4.99 g (88%) of the desired product as a colorless liquid. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=8.3, 1H), 7.35 (d, J=2.1, 1H), 7.12 (dd, J=8.3, 2.1, 1H), 4.72-4.69 (m, 1H), 3.71 (dd, J=11.4, 5.7, 1H), 3.64 (dd, J=11.4, 4.3, 1H), 3.24-3.18 (m, 1H), 2.81 (s, 3H), 1.36 (d, J=7.2, 3H), 0.90 (s, 9H), 0.06 (s, 3H), 0.06 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2)[CH3:22]>CN(C=O)C>[CH2:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:16])[CH2:27]2)[CH3:22]
Reactant: CCNc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: CCNc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 60.4 %

Procedure:
141 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 253 mg of 5-ethylaminoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 128 mg of the target compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]([C@H:22]([NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])CO)[CH2:16][C:17]([O:19][CH2:20]C)=[O:18])=[O:13])=[CH:6]2>O1CCOCC1>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:16][C:17](=[O:18])[O:19][CH2:20][C@H:22]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:13])=[CH:6]2
Reactant: CCOC(=O)C[C@@H](NC(=O)c1cc2cc(Cl)ccc2[nH]1)[C@@H](CO)NC(=O)c1nc2c(s1)CN(C)CC2
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@@H]3COC(=O)C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Yield: 151.1 %

Procedure:
A 4N dioxane solution (20 ml) of hydrochloric acid was added to the compound (0.31 g) obtained in Example 176, and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated, and the resultant residue was recrystallized from diethyl ether to obtain the title compound (0.23 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.CCOC(C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[O:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: Oc1cccnc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A brown solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (2.01 g, 9.61 mmol) and 3-hydroxypyridine (0.923 g, 9.71 mmol) in dry DMF (15 ml) under Ar was treated with cesium carbonate (3.28 g, 10.07 mmol) at once and the brown mixture was stirred at RT for 2 h. H2O (50 mL) and EtOAc (50 mL) were added and the organic layer was isolated. The water layer was extracted with EtOAc (2×30 mL). The combined organic layer was washed with H2O (3×40 mL), brine (40 mL), dried (MgSO4), filtered and concentrated to dryness to give a light yellow solid. Yield: 2.62 g (96%).