Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1)[OH:6])[CH3:2].[CH2:25]([Br:27])[CH3:26].CO>C(#N)C>[Br-:27].[CH2:1]([N+:3]([CH2:25][CH3:26])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH:5]([OH:6])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCCN(CC)CC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: CCBr
Solvent: CO
Solvent: CC#N
Product: CCCCCCC[N+](CC)(CC)CC(O)c1ccc(NS(C)(=O)=O)cc1
Product: [Br-]
Reaction time: 72 h

Procedure:
A stirred solution of N-[4-[2-(ethylheptylamino)-1-hydroxyethyl]phenyl]methanesulfonamide of Example 5 (1.5 g, 0.0042 mol) in acetonitrile (15 ml) is treated with ethyl bromide (6.12 ml, 0.082 mol) and refluxed under N2 for 4 days. Additional ethyl bromide is added and reflux is continued for 3 days. The reaction is still incomplete by TLC on silica gel with 5% MeOH-1% NH4OH--CH2Cl2. The mixture is concentrated and mixed with a solution of NaHCO3 (200 mg) in water and Et2O. The aqueous layer is extracted with Et2O and the Et2O extracts are washed with water. The combined water solution is made alkaline with 1N potassium hydroxide, saturated with potassium bromide and extracted with CH2Cl2. The CH2Cl2 extracts are washed with saturated potassium bromide. The combined aqueous layer is acidified with hydrogen bromide and extracted with CH2Cl2. These extracts are washed with saturated potassium bromide, dried (Na2SO4) and concentrated. This material is pure by HPLC on an RP-18 Spheri-10 column using a gradient of 50% H2O to 35% H2O--CH3CN with both solvents containing 0.2% TFA to yield N,N-diethyl-N-heptyl-β-hydroxy-4-[(methylsulfonyl)amino]benzeneethanaminium bromide.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5](S(O)(=O)=O)=[CH:6][CH:7]=1.CC(=O)CCC(=O)C.[NH2:20][C:21]1[N:22]=[N:23][C:24]([Cl:27])=[CH:25][CH:26]=1.C>C1(C)C=CC=CC=1>[Cl:27][C:24]1[N:23]=[N:22][C:21]([N:20]2[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]2[CH3:2])=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Cl)nn1
Temperature: 140 °C

Procedure:
A mixture of p-TSA (117 mg, 0.618 mmol), 2,5-hexanedione (4.36 mL, 37.1 mmol) and 3-amino-6-chloropyridazine (4.00 g, 30.9 mmol) in toluene (150 mL) was heated at 140° C. for 5 h in a round bottom flask equipped with a condenser and Dean-Stark apparatus. The reaction mixture was cooled to rt and charcoal was added. The mixture was filtered through CELITE and concentrated in vacuo to afford the title compound i-6a. m/z (ES) 208 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[N:4](C)[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[I:19]C1C=CC(N2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:1][C:2]1[C:3](=[O:18])[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]([I:19])=[CH:7][CH:6]=2
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Reactant: O=C1C(=O)N(c2ccc(I)cc2)c2ccccc21
Product: CCOC(=O)c1c(O)c(=O)[nH]c2ccc(I)cc12

Procedure:
Intermediate 26 was prepared as a white powder the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 4-iodo-phenylindoline-2,3-dione. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.41 (1 H, br. s.), 10.52 (1 H, br. s.), 7.33-8.21 (2 H, m), 7.14 (1 H, d, J=8.3 Hz), 4.41 (2 H, q, J=6.9 Hz), 3.34 (1 H, br. s.), 2.51 (1 H, br. s.), 1.33 (3 H, t, J=7.1 Hz). LC-MS (ESI) m/z 359.9 (M+H), RT=3.48 min (Method A).
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][C:6]([O:17][CH2:18][CH3:19])=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH3:16])C.CCOC(C)=O.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:18]([O:17][C:6]1[CH:5]=[C:4]([OH:20])[C:13]2[C:8](=[C:9]([CH3:16])[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]=1)[CH3:19]
Reactant: CCOC(=O)CC(=Nc1cccc(OC)c1C)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOc1cc(O)c2ccc(OC)c(C)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
3-Ethoxy-3-(3-methoxy-2-methyl-phenylimino)-propionic acid ethyl ester (1.56 g, 5.57 mmol) was dissolved in diphenyl ether then placed in a 300° C. sand bath. The internal temperature was kept between 240-250° C. for 15 minutes then the reaction was cooled to room temperature. The crude material was directly loaded onto a silica gel column (0→60% EtOAc/hexane) to afford 2-ethoxy-7-methoxy-8-methyl-quinolin-4-ol (882 mg, 68%). LCMS found 234.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[S:11](=[O:15])(=[O:14])([OH:13])[OH:12].[N+:16]([O-])([OH:18])=[O:17]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[N+:16]([C:6]1[CH:7]=[C:8]([S:11]([OH:13])(=[O:15])=[O:12])[CH:9]=[CH:10][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4])([O-:18])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: CCCCc1ccccc1
Reactant: O=[N+]([O-])O
Product: CCCCc1ccc(S(=O)(=O)O)cc1
Product: CCCCc1ccc(S(=O)(=O)O)cc1[N+](=O)[O-]

Procedure:
4-n-butylbenzenesulfonic acid is prepared by sulfonating 4n-butylbenzene with concentrated sulfuric acid at 180° C. as in previous reactions. Nitration of this compound with a mixture of sulfuric acid and nitric acid on a steam bath yielded 3-nitro-4-n-butylbenzenesulfonic acid. Hydrogenation of this in 50% ethanol/water over palladium on charcoal afforded 3-amino-4-n-butylbenzenesulfonic acid. Structural verification was obtained by carbon magnetic resonance, proton magnetic resonance and infra-red analysis.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+].C(#N)C>Cl[Pd-2](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>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:19]3[CH:20]=[CH:21][C:22]([CH:23]=[O:24])=[C:17]([F:16])[CH:18]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Reactant: O=Cc1ccc(B(O)O)cc1F
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc(C=O)c(F)c3)n2n1
Temperature: 160 °C
Yield: 69.9 %

Procedure:
A mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (300 mg, 1.1 mmol), 3-fluoro-4-formylphenylboronic acid (230 mg, 1.3 mmol), dichloro-bis(triphenylphosphino) palladium (II) (40 mg, 0.055 mmol), potassium carbonate (230 mg, 1.7 mmol), acetonitrile (1.5 mL) and H2O (0.5 mL) was heated in a sealed conical vessel at 160° C. for 1000 s by microwave irradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic layers were concentrated under reduced pressure to afford an oil that was purified by reverse phase HPLC to afford 4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzaldehyde (240 mg, 68%) as a yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.39 (s, 1H), 8.28 (dd, J=12.9, 1.5 Hz, 1H), 7.91-8.01 (m, 3H), 7.73 (d, J=9.6 Hz, 1H), 6.54 (d, J=9.6 Hz, 1H), 3.48 (td, J=7.2, 5.8 Hz, 2H), 1.69-1.80 (m, 2H), 1.46-1.57 (m, 2H), 1.03 (t, J=7.5 Hz, 3H); LCMS (ESI) m/e 313.2 [(M+H)+, calcd for C17H18FN4O 313.1].
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)S(O)(=O)=O.O>ClCCCl>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[C:13]([F:21])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: F[B-](F)(F)F
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Solvent: O
Product: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(F)c21
Temperature: 75 °C
Reaction time: 60 h
Yield: 22.8 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75° C. The product mixture was poured into water (200 mL), extracted with EtOAc (200 mL), the organic phase washed with saturated aqueous NaHCO3 (2×100 mL), brine (100 mL), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexane, silica) resulting in 0.6 g of a white solid. MS calculated for C13H12ClF4NO+H: 310, observed: 310.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:19])[N:4]([CH3:18])[C:5]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[H-].[Na+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26]Br>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([OH:1])[C:3](=[O:19])[N:4]([CH3:18])[C:5]=2[C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:10]1=[O:12]
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: CN(C)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
4-Hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (0.43 g, 0.0016 mol) was dissolved in 10 mL dry DMF and 100 mg NaH was added. The mixture was allowed to stir until the bubbles ceased, then 3-chloro-4-fluoro benzyl bromide (0.362 g, 0.0016 mole) was added. The reaction was quenched with 30 mL of a 10% aq KHSO4 solution and diluted with 100 mL chloroform. The reaction was further diluted with 100 mL brine and allowed to stir vigorously for 30 minutes. The layers were separated and the aqueous layer was washed with chloroform. The organic fractions were combined and dried over NaSO4, filtered and concentrated under high vacuum to remove the DMF (yield 0.5 g, 75%). HPLC analysis showed 85% purity. The solid product was crystallized first from isopropanol, then from ethanol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc(N2CCNCC2)n1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nccc(N2CCN(C(=O)c3ccccc3)CC2)n1
Yield: 31.6 %

Procedure:
1 g of 2-methyl-4-piperazino-pyrimidine was dissolved in 50 ml of acetone, and 2 g of potassium carbonate and 0.8 g of benzoyl chloride were added. The suspension was refluxed for 6 h until starting compound was no longer detectable. After filtration, the filtrate was concentrated in vacuo, and the residue was recrystallized from dichloromethane/petroleum ether. 0.5 g of 2-methyl-4-(4-benzoyl-piperazino)-pyrimidine was obtained. (Melting point: 147° C.)
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:9]1([C:2]2[O:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: OCc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCc1ccc(-c2ccccc2)o1
Temperature: 80 °C
Yield: 34.6 %

Procedure:
The 5-bromo-2-hydroxymethylfuran prepared in Example 327A (1.012 g, 5.72 mmol) was dissolved in 10 mL of DMF and PdCl2 (PPh3)2 (401 mg, 0.57 mmol) was added followed by phenylboronic acid (1.39 g, 11.4 mmol) and Cs2CO3 (3.71 g, 11.4 mmol) and the reaction was heated at 80° C. under N2 for 12 hours. The reaction mixture was taken up in ethyl acetate and washed with water (3×) and brine (3×), dried over Na2SO4, filtered and evaporated to a brown oil that was purified by flash chromatography (50% ethyl acetate-hexanes) to give the desired compound (345 mg, 35%) as an oil.
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])[CH:4]=1)#[N:2].[CH2:25]([O:27][CH2:28][CH2:29][NH2:30])[CH3:26]>>[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]([NH:30][CH2:29][CH2:28][O:27][CH2:25][CH3:26])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCOCCN
Product: CCOCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-ethoxyethylamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=6.95 Hz, 3 H) 2.43 (s, 3 H) 3.42-3.49 (m, 4 H) 3.49-3.55 (m, 2 H) 7.66 (dd, J=8.08, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.75-7.85 (m, 1 H) 8.06-8.27 (m, 1 H) 8.42 (d, J=6.82 Hz, 2 H) 8.80 (t, J=5.18 Hz, 1 H) 8.88-8.96 (m, 1 H) 12.86-13.47 (m, 1 H). MS m/z [M+H]+ 392.2.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([S:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[F:33])(=[O:42])=[O:41])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(S(=O)(=O)c3ccccc3F)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and 2-fluorobenzene-1-sulfonyl chloride to give 5,7-difluoro-2-(4-(2-fluorophenylsulfonyl)-piperazin-1-yl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 2.00 (br s, 3H), 3.04 (t, J=4.4 Hz, 4H), 3.26 (br s, 4H), 3.33-3.37 (m, 4H), 3.68 (t, J=4.0 Hz, 4H), 6.48 (s, 1H), 7.14-7.19 (m, 1H), 7.26-7.29 (m, 1H), 7.45-7.54 (m, 3H), 7.77 (d, J=2.4 Hz, 2H), 7.81-7.85 (m, 1H), 8.35 (s, 1H). Mass Spectrum (ESI) m/e=599.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([NH:15][CH:16]=O)[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].[C:24](=O)([O-])[O-:25].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([NH:15][CH2:16][CH:24]=[O:25])[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23]
Reactant: CCOC(=O)c1cn(NC=O)c2c(OC)c(F)c(F)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(NCC=O)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
The whole (0.0018 mole) of the ethyl 6,7-difluoro-1-(formylamino)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XVI) [prepared as described in Step (D2) above] was dissolved in 8 ml of dimethylformamide. 0.51 g (0.0037 mole) of potassium carbonate and 0.78 g (0.0052 mole) of methyl iodide were then added to the solution, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the solvent was distilled from the mixture under reduced pressure. The residue was extracted with chloroform, and the chloroform extract was washed with water, dried and concentrated by evaporation under reduced pressure to give 0.5 g of ethyl 6,7-difluoro-1-(N-formylmethylamino)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XVII, R10 =methyl) as a colorless powder.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>CN1C(=O)CCC1>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-fluoro-2-nitroaniline (1 g), 1-methylpiperazine (0.752 mL) and TEA (1.86 mL) in NMP (1.5 mL) was heated at 100° C. in a microwave oven for 20 h. After cooling down, H2O (50 mL) was added, the resulting suspension was stirred for 20 min and filtrated off. The yellow solid was washed with water and dried under high vacuo (1.45 g). LC-MS (B): tR=0.47 min; [M+H]+: 237.19.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][O:13][C:12]([CH2:19][CH2:20][OH:21])([CH2:16][CH2:17][CH3:18])[C:5]=1[NH:6]2.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][O:13][C:12]([CH2:19][CH2:20][O:21][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])([CH2:16][CH2:17][CH3:18])[C:5]=1[NH:6]2
Reactant: CCCC1(CCO)OCCc2c1[nH]c1c(F)ccc(Br)c21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC1(CCO[Si](C)(C)C(C)(C)C)OCCc2c1[nH]c1c(F)ccc(Br)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of (5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acid ethyl ester (2.0 g, 5.02 mmol) in THF (10 mL) was added LAH (5.27 mL of 1.0 M in THF, 5.27 mmol) slowly at room temperature. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was quenched by the addition of H2O (0.5 mL) and then 10% NaOH (0.5 mL) was added to the mixture. Na2SO4 was added to the mixture and the resulting mixture was filtered. The filtrate was concentrated to give 1.79 g (100%) of 2-(5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol as yellow oil. A mixture of 2-(5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.79 g, 5.02 mmol), imidazole (0.854 g, 12.55 mmol) and tert-butyldimethylsilyl chloride (0.909 g, 6.03 mmol) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (100 mL). The organic solution was washed with H2O (5×100 mL) and brine (100 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, 7% EtOAc in hexanes) to give 2.29 g (97%) of title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 8.97 (bs, 1H), 6.95 (dd, J=8.37, 4.17 Hz, 1H), 6.57 (d, J=10.41, 8.37 Hz, 1H), 3.98–3.54 (m, 4H), 3.00 (m, 2H), 2.00–0.90 (m, 6H), 0.80 (s, 9H), 0.74 (d, J=7.32 Hz, 3H), 0.06 (s, 3H), 0.03 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:19])=[CH:8]2.C(N(CC)CC)C.CS(C)=O>O>[CH3:19][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[C:10]([CH:17]=[O:18])[C:11]3[C:16]([C:3]=2[CH:2]=[O:1])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=1
Reactant: Cc1ccc2c(CO)c3ccccc3c(C=O)c2c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(C=O)c3ccccc3c(C=O)c2c1
Reaction time: 1 h

Procedure:
To a solution of 1.25 g. of 10-(hydroxymethyl)-2-methyl-9-anthraldehyde in a mixture of 14 ml. of triethylamine and 20 ml. of dry dimethylsulfoxide is added a solution of 4.80 g. of sulfur trioxide pyridine complex in 20 ml. of dry dimethylsulfoxide. The reaction mixture is stirred for one hour and then poured into 200 ml. of water. The solid is collected and washed with water, giving 1.18 g. of the desired product as orange crystals, mp. 150°-152° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[OH:30])[CH:5]=[CH:6][C:7]=1[C@H:8]([NH:10][C:11]([C:13]1([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14]1)=[O:12])[CH3:9].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[C:4]1[CH:5]=[CH:6][C:7]([C@H:8]([NH:10][C:11]([C:13]2([NH:16][C:17](=[O:22])[C:18]([F:19])([F:21])[F:20])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[C:2]([F:1])[CH:3]=1)(=[O:41])=[O:40]
Reactant: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc(F)c2O)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc(F)c2OS(C)(=O)=O)cc1F
Reaction time: 16 h

Procedure:
N-[(1R)-1-(3,3′-difluoro-2′-hydroxy-1,1′-biphenyl-4-yl)ethyl]-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide (0.040 g, 0.093 mmol) and triethylamine (0.019 g, 0.187 mmol) were dissolved in CH2Cl2 (2 mL) and cooled to −78 C. To this solution was added methanesulfonyl chloride (0.012 g, 0.103 mmol) and the reaction was allowed to stir for 16 hours. The reaction was concentrated under reduced pressure, diluted with methanol and purified by reverse phase chromatography using a gradient from 95/5H2O/CH3CN to 5/95H2O/CH3CN. Product was lyophilized to yield the title compound as a solid. High resolution mass spectrometry: C21H19F5N2O5S requires: 507.1076, found: 507.1002. 1H NMR (400 MHz, (CD3)2SO) δ 9.79 (s, 1H), 8.30 (d, J=7.5 Hz, 1H), 7.44-7.54 (m, 3H), 7.30-7.39 (m, 3H), 5.23 (qn, J=7.5 Hz, 1H), 2.99 (s, 1H), 1.4.2 (d, J=7.5 Hz, 3H), 1.32-1.38 (m, 2H), 0.92-1.06 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8](Cl)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:8]([CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1c(Cl)ccc([N+](=O)[O-])c1N
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(N)c1C(=O)OC
Temperature: 60 °C
Yield: 76.1 %

Procedure:
A mixture of methyl 2-amino-6-chloro-3-nitrobenzoate (4.11 g, 17.8 mmol), diethyl malonate (4.85 g, 30.3 mmol) and solid K2CO3 (powder, 9.11 g, 65.9 mmol) in DMF (71 mL) was heated at 60° C. for 10 h. The reaction mixture was poured into aqueous 1N HCl solution (400 mL) and the resulting solution was extracted with EtOAc (2×250 mL). The combined organic layers were washed with water (3×150 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (10-40μ silica gel; hexane:EtOAc 3:1) provided the title compound (4.80 g, 76% yield) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([N:9]=[O:10])[C:3]([NH:5][N+:6]([O-:8])=[O:7])=[NH:4].[OH2:11]>>[CH3:1][N:2]([N+:9]([O-:11])=[O:10])[C:3]([NH:5][N+:6]([O-:8])=[O:7])=[NH:4]
Reactant: O
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Product: CN(C(=N)N[N+](=O)[O-])[N+](=O)[O-]

Procedure:
About 25 mg of N-methyl-N'-nitro-N-nitrosoguanidine (Aldrich Chemie BDR) were added to a 10 ml tared graduated cylinder supplied with a glass stopper. Water was supplied so as to obtain a total volume of 10 ml, and the N-methyl-N'-nitro-N-nitrosoguanidine was dissolved therein by shaking. 10×1 ml of stock solution were obtained from this solution.