Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[OH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(O)C>[CH3:10][N:4]1[C:5]([N:24]2[CH2:25][CH2:26][CH:21]([OH:20])[CH2:22][CH2:23]2)=[C:6]([N+:7]([O-:9])=[O:8])[CH:2]=[N:3]1
Reactant: Cn1cc([N+](=O)[O-])c(Cl)n1
Reactant: Oc1ccncc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(O)CC1
Temperature: 130 °C
Yield: 104.6 %

Procedure:
To a solution of 3-chloro-1-methyl-4-nitro-1H-pyrazole (1.0 g, 6.17 mmol) in ethanol (10 mL) was added DIPEA (2 mL, 11.4 mmol) followed by 4-hydroxypyridine (686 mg, 6.79 mmol). The reaction mixture was heated at 130° C. in the microwave for 60 min before the solvents were removed under reduced pressure. Purification of the residue via silica gel column chromatography (75-100% EtOAc/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-ol as a bright yellow oil (1.46 g). To a solution of this oil (1.40 g, 6.17 mmol) in DCM (40 mL) was added portionwise Dess-Martin periodinane (3.1 g, 7.41 mmol). The reaction mixture was stirred at room temperature for 3 hr, diluted with DCM (100 mL) and washed with saturated aqueous sodium hydrogencarbonate (30 mL), followed by saturated aqueous sodium thiosulphate (30 mL), saturated aqueous sodium hydrogencarbonate (30 mL) and brine (30 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (50-75% EtOAc/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.32 g, 95% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 3.86 (s, 3H), 3.54 (t, J=6.0 Hz, 4H), 2.65 (t, J=6.0 Hz, 4H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C@H:15]1[C@@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17][N:16]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:5])=[O:4])[CH3:2].[H][H]>CO.C1COCC1.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:7]([C@H:15]2[C@@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17][N:16]2[C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH:8]=1
Reactant: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)CC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)CC
Yield: 102.2 %

Procedure:
To 35F (2.2 g) in methanol (50 mL) and THF (30 mL) was added 10% Pd/C (580 mg). The mixture was hydrogenated with a hydrogen balloon for 6.0 h. The Pd/C was removed by filtration and the filtrate was concentrated to afford 35H (2.1 g, 95% yield). 1H NMR (500 MHz, DMSO-d6, 100° C.) δ ppm 0.88 (t, J=6.87 Hz, 3H) 1.16 (t, J=7.42 Hz, 3H) 1.26 (s, 9H) 2.07-2.13 (m, 2H) 3.13-3.21 (m, 2H) 3.49 (br s, 1H) 3.63-3.75 (m, 4H) 5.69 (d, J=8.25 Hz, 1H) 6.50-6.55 (m, 2H) 7.44 (d, J=8.79 Hz, 1H); LC-MS 427 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: FC(F)(F)CCBr
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCC(F)(F)F)CC4)cc3F)ncc2Cl)n[nH]1
Reaction time: 8 h

Procedure:
The mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol), 3-bromo-1,1,1-trifluoropropane (85.0 uL, 0.60 mmol) and triethylamine (102.0 uL, 0.60 mmol) in 2 mL of DMF was stirred overnight. The reaction mixture was purified by preparative RP-HPLC to afford 5-chloro-N2-(2-fluoro-5-methyl-4-(1-(3,3,3-trifluoropropyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine. ESMS m/z 512.2 (M+H+).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH:8]1C=CC=CC=1.CO.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH2:25][CH:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)[CH3:27]>CC(O)=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH2:25][CH:26]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:8])=[O:33])=[CH:35][CH:36]=1)[CH3:27]
Reactant: c1ccccc1
Reactant: COc1ccc(Br)c(CC(C)c2ccc(C(=O)O)cc2)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(C)Cc2cc(OC)ccc2Br)cc1

Procedure:
(Trimethylsilyl)diazomethane (2.0M hexanes, 4.8 mL) was added dropwise to a benzene/MeOH solution (7/3, 50 mL) containing the intermediate from Step A (2.8 g, 8.0 mmol). After 20 minutes AcOH was added dropwise to quench the excess reagent. The solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.98 (d, J=8.2 Hz, 2H); 7.43 (d, J=8.2 Hz, 1H); 7.29 (d, J=8.2 Hz, 2H); 6.63 (dd, J=3.0, 8.7 Hz, 1H); 6.50 (d, J=3.0 Hz, 1H); 3.93 (s, 3H); 3.68 (s, 3H); 3.26-3.19 (m, 1H); 2.96 (d, J=7.0 Hz, 2H); 1.34 (d, J=6.9 Hz, 3H). LCMS1 4.14 min. (M-31)=331
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][C@H:17]([F:20])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:27])[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][C@H:17]([F:20])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](F)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CC[C@H](F)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[(3S)-3-fluoropyrrolidin-l-yl]quinolin-7-yl}ethanone (0.10 g, 0.34 mmol) and ammonium acetate (0.263 g, 3.42 mmol) in methanol (1.5 mL) and acetonitrile (1.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.064 g, 1.0 mmol). The reaction was heated at 65° C. overnight, cooled to room temperature and quenched with sat. NaHCO3 solution and extracted with Ethyl acetate. The combined organic layers were dried over MgSO4, concentrated and purified on a preparative LCMS (pH=10) to give the desired product. LCMS calculated for C15H18ClFN3 (M+H)+: m/z=294.1; Found: 294.0.
Reaction SMILES: [Li]N1C(C)(C)CCCC1(C)C.[Li]CCCC.[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[Te:27][CH:28]=[CH:29][CH:30]=2)=[C:22]([F:31])[C:21]=1[F:32])[CH3:18].[CH:33](N1CCOCC1)=[O:34].Cl>C1COCC1.O>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[Te:27][C:28]([CH:33]=[O:34])=[CH:29][CH:30]=2)=[C:22]([F:31])[C:21]=1[F:32])[CH3:18]
Reactant: O=CN1CCOCC1
Reactant: CCOc1ccc(-c2ccc[te]2)c(F)c1F
Agent: Cl
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(C=O)[te]2)c(F)c1F
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of LiTMP (comprising 3.9 ml (22.9 mmol) of TMP and 14.0 ml (22.3 mmol, 15% soln. in hexane) of n-BuLi) is added to 6.8 g (20.3 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)tellurophene in 70 ml of THF at 0° C. The mixture is stirred at this temperature for 1 h. The solution is cooled to −60° C., and N-formylmorpholine is added. The reaction mixture is warmed to 0° C. and stirred for 1 h. Water and 2 N hydrochloric acid are added, and the mixture is extracted with MTBE. The organic phase is washed with sodium chloride and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is recrystallised from toluene. Drying in vacuo gives 5-(4-ethoxy-2,3-difluorophenyl)tellurophene-2-carbaldehyde as a brown solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Br:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[C:35]([C:37](Cl)=[O:38])=[CH:34][CH:33]=[CH:32]2>>[Br:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[C:35]([C:37]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]1)=[O:38])=[CH:34][CH:33]=[CH:32]2
Reactant: O=C(Cl)c1cccc2cccc(Br)c12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5cccc(Br)c45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 8-bromonaphthalene-1-carbonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.[NH2:31][OH:32]>CS(C)=O.O>[OH:32][N:31]=[C:27]([C:26]1[CH:29]=[CH:30][C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:20](=[CH:21][C:11]3=4)[CH2:19][CH2:18][O:17]5)[C:2]2=[O:1])=[CH:24][CH:25]=1)[NH2:28]
Reactant: NO
Reactant: N#Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Solvent: CS(C)=O
Solvent: O
Product: NC(=NO)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirred solution of 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (1.30 g, 32.9 mmol) in dimethyl sulfoxide (10 mL) was added 50% wt solution of hydroxylamine in water (2 mL). The reaction was heated with stirring at 80° C. for 1 h, then cooled to ambient temperature and the product was precipitated by adding distilled water (25 mL). The solid was filtered and air dried to afford N′-hydroxy-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide (1.32 g, 93%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 7.40-7.03 (m, 13H), 6.99-6.92 (m, 2H), 6.79-6.74 (m, 2H), 6.58-6.50 (m, 1H), 5.10 (s, 1H); MS (ES+) m/z 428.0 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[Cl:15][C:16]1[CH:17]=[C:18]([C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25])[CH:19]=[CH:20][C:21]=1[F:22].S(Cl)(Cl)=O>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]([CH3:28])([CH3:27])[C:24]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:25])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CC(C)(C(=O)O)c1ccc(F)c(Cl)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Diethyl malonate (5.68 mL, 37.6 mmol) was dissolved in ACN (75 mL) at 0° C. MgCl2 (3.93 g, 41.3 mmol) was added to the reaction mixture in one portion and TEA (10.5 mL, 75.1 mmol) was added dropwise. 2-(3-chloro-4-fluorophenyl)-2-methylpropanoic acid (7.73 g, 35.7 mmol) was converted to the acid chloride by reaction with thionyl chloride at 65° C. for 1 hour, and the resulting acid chloride was concentrated under reduced pressure. The acid chloride was then dissolved in ACN and added dropwise via addition funnel to the initial reaction mixture. The resulting mixture was stirred at ambient temperature for 2 hours and then quenched with water, acidified with 5N HCl, diluted with 100 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed with water (2×50 mL), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (7.17 g) as a light yellow oil after flash chromatography. MS m/e=359 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1[CH:13]=[C:12]2[C:14]([O:16][C:17](=O)[C:10]3=[C:11]2[C:6](=[CH:7][C:8]([N+:19]([O-:21])=[O:20])=[CH:9]3)[CH:5]=1)=[O:15]>N1C=CC=CC=1.O>[OH:3][N:2]1[C:17](=[O:16])[C:10]2[CH:9]=[C:8]([N+:19]([O-:21])=[O:20])[CH:7]=[C:6]3[C:11]=2[C:12](=[CH:13][CH:4]=[CH:5]3)[C:14]1=[O:15]
Reactant: NO
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C1c2cccc3cc([N+](=O)[O-])cc(c23)C(=O)N1O
Yield: 99.2 %

Procedure:
Hydroxylamine hydrochloride (0.9 g, 13.0 mmol) was added to a suspension of 3-nitro-1,8-naphthalic anhydride (2.0 g, 8.2 mmol) in pyridine (30 mL). The mixture was refluxed for 3 hours and concentrated in vacuo to give a brown solid. The solid was suspended in water, stirred, filtered, and dried to give 2.1 g of the title compound, mp 277-279° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.O.[CH3:19]O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH3:19])=[O:12]
Reactant: CO
Reactant: O=C(O)Cc1c(F)cc(F)cc1F
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2,4,6-trifluorobenzeneacetic acid (5.00 g, 26.3 mmol) in methanol (25 mL) was stirred at ambient temperature, and thionyl chloride (6 mL, ˜3 eq.) was added dropwise, causing the temperature of the reaction mixture to reach 60° C. The reaction mixture was allowed to cool to ambient temperature and was stirred for 3 h. Water (25 mL) was added with ice cooling. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with water (2×), with saturated aqueous sodium bicarbonate solution and with brine, and dried over MgSO4. Concentration provided the title product as a clear oil (5.38 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C@@H:14]([OH:17])[CH2:15][CH3:16])[N:11]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:9]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.[CH3:28][CH2:29]N(CC)CC.S1C=CC=C1>C1COCC1.[Pd]>[F:26][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[N:9]=[C:8]([C:6]3[CH:7]=[CH:2][N:3]=[C:4]([CH3:27])[CH:5]=3)[N:12]([CH2:13][CH:14]([OH:17])[CH2:15][CH2:16][CH2:28][CH3:29])[N:11]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CC[C@H](O)Cn1nc(Nc2ccc(F)c(F)c2)nc1-c1cc(C)nc(Cl)c1
Reactant: CCN(CC)CC
Agent: [Pd]
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: CCCCC(O)Cn1nc(Nc2ccc(F)c(F)c2)nc1-c1ccnc(C)c1

Procedure:
A mixture of intermediate, 1-[5-(2-chloro-6-methyl-pyridin-4-yl)-3-(3,4-difluoro-phenylamino)-[1,2,4]triazol-1-yl]-hexan-2-ol (prepared according to D4) (1.5 g; 3.5 mmol) and Et3N (2 ml) in THF (40 ml) was hydrogenated with Pd/C 10% (0.020 g) as a catalyst in the presence of thiophene solution (0.1 ml; 4% in DIPE). After uptake of H2 (1 equiv) had ceased, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was suspended in DIPE and filtrated. The crystals were dried in a vacuum oven at 70° C. overnight.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][O:15][S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Cl)nc2)nc1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Cl)nc3)oc2C)cc1
Reaction time: 8 h

Procedure:
The crude 2-[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethanol from step C is dissolved in methylene chloride (50 mL), then TsCl, DMAP and triethyl amine are added and stirred overnight. The reaction mixture is washed with water, brine and concentrated. Column chromatography on silica gel gave the title compound (0.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[C:14]([NH:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)(=[O:16])[CH3:15].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:24][C:20]1[CH:19]=[C:18]([NH:17][C:14](=[O:16])[CH3:15])[CH:23]=[CH:22][CH:21]=1)([O-:3])=[O:2]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a mixture of 3,4-dinitrofluorobenzene (1.0 g, 5.4 mmol, 1.0 eq.) and 3-acetamidophenol (0.8 g, 5.4 mmol, 1.0 eq.) in 10 mL of anhydrous DMF, K2CO3 (0.7 g, 5.4 mmol, 1.0 eq) was added. The reaction mixture was heated to 120° C. and stirred for 16 h. The mixture was cooled to RT and EtOAc was added (100 mL). After washing with H2O (100 mL), the organic layer was dried (MgSO4), filtered and concentrated. The resulting crude material was purified by column chromatography (20-100% EtOAc in hexanes) to obtain pure N-[3-(3,4-dinitro-phenoxy)-phenyl]-acetamide.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][O:32][CH2:33][CH3:34])[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:36]([O:38][CH2:39][CH2:40][CH3:41])=[O:37]>ClCCl>[CH2:33]([O:32][CH2:31][C:20]1[N:21]([CH2:22][C:23]([CH3:25])([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:24])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:36](=[O:37])[O:38][CH2:39][CH2:40][CH3:41])[C:18]=2[N:19]=1)[CH3:34]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: CCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)Nc1nc2ccccc2c2c1nc(COCC)n2CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
Triethylamine (2.67 mL, 5 eq) was added to a chilled (ice/water bath) suspension of N-{2-[4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (1.5 g, 1 eq) in dichloromethane (150 mL). A solution of propyl chloroformate (1.55 g, 3.3 eq) in dichloromethane (5 mL) was added dropwise to give a clear solution. The reaction mixture was allowed to come to ambient temperature with stirring for 24 hours. The reaction mixture was washed sequentially with water (150 mL), 4% sodium carbonate (150 mL), water (150 mL), and brine (150 mL). The organic layer was concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-20% CMA in chloroform, 1500 mL) followed by recrystallization from diethyl ether to provide 1.23 g of propyl 2-ethoxymethyl-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white powder, mp 177-179° C. Anal calcd for C22H31N5O5S: C, 55.33; H, 6.54; N, 14.66. Found: C, 55.41; H, 6.47; N, 14.45.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7](Cl)=[N:6][C:5]=1[Cl:12].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:14])=[N:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: CB1OB(C)OB(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+]
Solvent: O
Product: COC(=O)c1cc(F)c(C)nc1Cl
Temperature: 110 °C
Yield: 45.8 %

Procedure:
A mixture of 2,6-dichloro-5-fluoro-nicotinic acid methyl ester (1.00 g 4.46 mmol), trimethylboroxin (0.620 mL, 4.40 mmol), tetrakis(triphenylphosphine)palladium (0.500 g, 0.433 mmol) and potassium carbonate (1.50 g, 12.0 mmol) is heated at 110° C. overnight. The mixture is cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic phase is washed with water followed by brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography using a gradient of 0-30% EtOAc/heptane to provide 0.410 g (45.1%) of 2-chloro-5-fluoro-6-methyl-nicotinic acid methyl ester as a solid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[OH:17][C:18]1[CH:19]=[CH:20][C:21]2[N:43]([CH:44]=1)[C:24]1[N:25]([C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)[C:26](=[O:33])[C:27]3[C:32]([C:23]=1[N:22]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3>CN(C=O)C>[N:5]1([CH2:4][CH2:3][O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:43]([CH:44]=2)[C:24]2[N:25]([C:34]4[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=4)[C:26](=[O:33])[C:27]4[C:32]([C:23]=2[N:22]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=c1c2ccccc2c2nc3ccc(O)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c2nc3ccc(OCCN4CCOCC4)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Yield: 39.9 %

Procedure:
4-(2-Chloroethyl)morpholine hydrochloride (1.2 equiv., 0.806 mmol, 0.121 g) and potassium carbonate (3 equiv., 2.01 mmol, 0.278 g) were added to a solution compound 10 (1.0 equiv., 6.71 mmol, 0.250 g) in DMF (3 ml). The mixture was heated at reflux for 2 h. The reaction product was precipitated by the addition of water, filtered off and washed with isopropanol and isopropyl ether successively to give 9-[2-(4-morpholinyl)-ethoxy]-6-(4-nitrophenyl)-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (79) (0.156 g, yield=46%, purity (LC)=95%) as a brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27]([C:24]4[CH:25]=[CH:26][O:22][CH:23]=4)=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccoc1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 3-furoic acid using method B. NMR; δH CDCl3 8.10,(1H, s), 7.97,(1H, s), 7.78,(2H, d), 7.64,(1H, dd), 7.47,(1H, m), 7.38,(1H, d), 7.33,(2H, d), 7.24,(1H, d), 6.80,(1H, s), 6.36,(1H, t), 3.32,(2H, m), 2.21,(3H, s), 1.06,(1H, m), 0.57,(2H, m), 0.28,(2m). LCMS: retention time 3.38 min, MH+375.
Reaction SMILES: [S:1]1[CH2:5][CH:4]=[C:3]2[CH:6]=[C:7]([C:9](O)=O)[CH:8]=[C:2]12.[CH3:12][O:13][C:14]1[C:15]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:16][C:17]2[O:21][CH2:20][CH2:19][C:18]=2[CH:22]=1.C([O-])(=O)/C=C/C([O-])=O>>[S:1]1[CH2:5][CH:4]=[C:3]2[CH:6]=[C:7]([CH2:9][N:26]3[CH2:27][CH2:28][N:23]([C:15]4[C:14]([O:13][CH3:12])=[CH:22][C:18]5[CH2:19][CH2:20][O:21][C:17]=5[CH:16]=4)[CH2:24][CH2:25]3)[CH:8]=[C:2]12
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Reactant: O=C(O)C1=CC2=CCSC2=C1
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: COc1cc2c(cc1N1CCN(CC3=CC4=CCSC4=C3)CC1)OCC2

Procedure:
Prepared as described in Example 9, starting from (cyclopenta[b]thien-5-yl)carboxylic acid (Preparation 8) and 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of the title compound melts at 186°-190° C. (ethanol).