Azzindani/Open_Reaction_Data huggingface dataset:
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: O=Cc1ccc(B(O)O)cc1F
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
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: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.C([Cu])#N.C([O:19][C@@H:20]1[CH2:24][C@H:23](O)[CH:22]=[CH:21]1)(=O)C>C1COCC1.[NH4+].[Cl-]>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C@H:23]2[CH2:24][C@H:20]([OH:19])[CH:21]=[CH:22]2)[CH:3]=1
Reactant: Ic1cccnc1
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: O[C@@H]1C=C[C@@H](c2cccnc2)C1
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of 3-Iodopyridine (13.0 g, 63.3 mmol) in THF (30 mL) was added i-PrMgCl (38.0 mL, 76.0 mmol) at 3-9° C. After stirring was continued at room temperature for 30 min, CuCN (567 mg, 6.33 mmol) was added to the solution at 2° C. After stirring was continued at 3° C. for 30 min, to the resulting solution were added (1R,4S)-4-hydroxycyclopent-2-enyl acetate (3.00 g, 21.1 mmol) in THF (30 mL). The whole mixture was stirred at the room temperature for 2 h, and diluted with saturated NH4Cl with vigorous stirring. The products were extracted with EtOAc three times, and the combined layers were dried over Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (NH, Hexane/EtOAc=4/1) to yield (1S,4S)-4-(3-pyridyl)-2-cyclopenten-1-ol (1.88 g, 55%) as yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:38])([CH3:37])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:37][C:3]([CH3:38])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:9][CH:10]=1)[CH:2]=[O:1]
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of 4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.01 g) in methylene chloride (10 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.26 g), and the mixture was stirred for 1 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.79 g, 79%).
Reaction SMILES: [CH2:1]([CH:3]([C:9](=O)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:16].N.S([O-])([O-])(=O)=O.[Na+].[Na+]>CO>[NH2:16]/[C:9](/[CH3:10])=[C:3](/[CH2:1][CH3:2])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: [NH4+]
Reactant: CCOC(=O)C(CC)C(C)=O
Agent: CC(=O)[O-]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CCOC(=O)/C(CC)=C(/C)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A 100-mL round bottom flask was charged with ethyl 2-ethyl-3-oxo-butanoate (5 g, 90% purity, 28 mmol), ammonium acetate (22 g, 280 mmol, 10 eq.), ammonia (2N in EtOH, 14 ml, 1 eq.), anhydrous sodium sulfate (8 g, 56 mmol, 2 eq.) and MeOH (30 ml). The resulting mixture was stirred at room temperature overnight. The volatile material was removed under reduced pressure and the residue was treated with dichloromethane (40 ml). Insoluble material was removed by filtration and washed with dichloromethane (2×20 ml). The organics was washed with aqueous sodium bicarbonate, dried over Na2SO4. Removal of solvent gave ethyl (Z)-3-amino-2-ethyl-but-2-enoate (4.1 g, 82% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]1[C:52]2[C:47](=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=2)[CH:46]=[C:45]([C:54]2[CH:55]=[C:56]([NH:61]/[C:62](/[NH2:65])=[N:63]/O)[CH:57]=[CH:58][C:59]=2[CH3:60])[C:44]1=[O:66]>CN(C=O)C>[OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]1[O:6][N:63]=[C:62]([NH:61][C:56]2[CH:57]=[CH:58][C:59]([CH3:60])=[C:54]([C:45]3[C:44](=[O:66])[N:43]([CH3:42])[C:52]4[C:47]([CH:46]=3)=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=4)[CH:55]=2)[N:65]=1
Reactant: CC(C)(O)CC(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(CC(C)(C)O)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-hydroxy-3-methylbutanoic acid (6 mg, 0.06 mmol) in DMF (1 mL) were added DIPEA (31 μL, 0.18 mmol) and HATU (23 mg, 0.06 mmol). After stirring at rt for 15 min, 17 (20 mg, 0.06 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 3-(5-(5-(2-hydroxy-2-methylpropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A56). MS m/z 420.4 (M+1).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14].O.Cl>C(O)C.[Cl-].[Cl-].[Zn+2]>[NH2:7][C:3]1[CH:2]=[C:1]2[C:6]([C:11]([C:10]([F:20])([F:19])[F:9])=[CH:12][C:13](=[O:14])[NH:8]2)=[CH:5][CH:4]=1
Reactant: Nc1cccc(N)c1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(C(F)(F)F)cc(=O)[nH]c2c1
Yield: 31.4 %

Procedure:
m-Phenylenediamine (28.84 g, 0.26 mole), ethyl trifluoroacetoacetate (49.12 g, 0.26 mole), and ZnCl2 (44 g) were refluxed in 280 ml ethanol containing 10 ml isopropanol for 18 hours. The reaction mixture was poured into 1600 ml iced water containing 10 ml. conc. HCl and let stand at room temperature 2 hours. The solid was filtered, washed with water and air dried. The product was recrystallized from 800 ml boiling ethanol to give 18.63 g (31%) 7-amino-4-trifluoromethylquinolone (AFQ).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)=O>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(Br)cn1
Product: N#Cc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Yield: 83.5 %

Procedure:
The procedure of Referential Example 1 was repeated, except that 2-amino-5-bromopyridine (692 mg) and 2-bromo-4′-cyanoacetophenone (450 mg) were used, to thereby yield the title compound (500 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:18]([OH:20])=O)[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[NH:35]1[C:34]([NH:33][C:18]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([N:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=3)[N:6]=2)=[O:20])=[N:38][N:37]=[N:36]1
Reactant: COc1cc(C(=O)O)nc(-c2ccc(N(C)C)cc2)c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc(N(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of 4-methoxy-6-(4-dimethylaminophenyl)-2-pyridinecarboxylic acid (0.44 g) in dimethylformamide (6 ml) is added carbonyldiimidazole (0.29 g), and the mixture is agitated at room temperature for one hour. To the mixture is added 5-aminotetrazole (0.15 g), and the mixture is heated at 70° C. for one hour. After cooling, the reaction mixture is poured into ice-water. The resulting precipitates are collected by filtration and washed with water and ethanol to give N-(5-tetrazolyl)-4-methoxy-6-(4-dimethylaminophenyl)-2-pyridinecarboxamide (0.36 g). M.P. 261°-263° C. (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=O)=[CH:14][CH:13]=1.[OH-].[K+]>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:6]3[C:5](=[CH:4][CH:3]=[C:2]([CH3:10])[CH:7]=3)[NH:8][CH:19]=2)=[CH:14][CH:13]=1
Reactant: O=CCc1ccc(F)cc1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2[nH]cc(-c3ccc(F)cc3)c2c1
Temperature: 80 °C
Yield: 47 %

Procedure:
A mixture of p-tolyl hydrazine hydrochloride (3 g, 0.0189 mol), 4-fluorophenyl acetaldehyde (3 g, 0.0227 mol) and ethanol (50 mL) was heated at 80° C. for 1 h. After completion of reaction (monitored by TLC), the mixture was cooled to RT, basified with potassium hydroxide solution, and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (15% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a brown colored oil (2 g, 47% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[C:16]2[O:15][CH:14]=[C:13]([CH2:17][C:18](OC)=[O:19])[C:12]=2[CH:11]=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])O.[Na+]>C1COCC1>[OH:19][CH2:18][CH2:17][C:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[C:16]=2[O:15][CH:14]=1
Reactant: COC(=O)Cc1coc2c(OC3CCCCO3)cccc12
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCc1coc2c(OC3CCCCO3)cccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
Methyl (7-tetrahydropyranyloxybenzofuran-3-yl)acetate (355 mg) was dissolved in THF (4 ml) and the solution was cooled to 0° C. To this solution, lithium aluminum hydride (47 mg) was added and the solution was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution and the solution was filtered through Celite. The filtrate was poured into water layer (30 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated saline, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (289 mg, yield: 90%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:18](=O)[CH3:19])[C:3]=1[O:21][CH2:22][CH3:23].[CH3:24][CH2:25][O:26][C:27]([CH:29](P(OCC)(OCC)=O)[F:30])=[O:28].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:16])([CH3:15])[CH3:17])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:19])=[C:29](/[F:30])\[C:27]([O:26][CH2:25][CH3:24])=[O:28])[C:3]=1[O:21][CH2:22][CH3:23]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-114, 98 mg, 0.26 mmol) and triethyl-2-fluoro-2-phosphonoacetate (250 mg, 1.03 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 0.65 mL, 1.03 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: C(N1C2C(=CC(N)=CC=2)CC1)(=O)C.[C:14]([N:17]1[C:25]2[CH:24]=[C:23]3[C:26](=[O:30])[C:27](=[O:29])[NH:28][C:22]3=[CH:21][C:20]=2[CH2:19][CH2:18]1)(=[O:16])[CH3:15].[CH:31]1[C:36]([NH:37][NH2:38])=[CH:35][CH:34]=[C:33]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:32]=1.Cl>>[C:14]([N:17]1[C:25]2[CH:24]=[C:23]3[C:26](=[O:30])[C:27](=[O:29])[NH:28][C:22]3=[CH:21][C:20]=2[CH2:19][CH2:18]1)(=[O:16])[CH3:15].[C:14]([N:17]1[C:25]2[CH:24]=[C:23]3[C:26](=[N:38][NH:37][C:36]4[CH:35]=[CH:34][C:33]([S:39]([NH2:42])(=[O:40])=[O:41])=[CH:32][CH:31]=4)[C:27](=[O:29])[NH:28][C:22]3=[CH:21][C:20]=2[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: CC(=O)N1CCc2cc(N)ccc21
Agent: CC(=O)N1CCc2cc3c(cc21)C(=O)C(=O)N3
Agent: Cl
Product: CC(=O)N1CCc2cc3c(cc21)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N3

Procedure:
5-Acetyl-1,5,6,7-tetrahydro-pyrrolo[2,3-f]indole-2,3-dione was prepared from 1-acetyl-5-aminoindoline according to Procedure A in 90% yield: mp>250° C.; 1H NMR (DMSO-d6): δ 2.11 (s, 3H), 3.16 (t, J=8.4 Hz, 2H), 4.06 (t, J=8.4 Hz, 2H), 6.78 (s, 1H), 8.02 (s, 1H), 10.87 (s, 1H); APCI-MS: m/z 229 (M−H)−. Anal. Calcd for C12H10N2O3.0.3H2O: C, 61.17; H, 4.53; N, 11.89. Found: C, 60.91; H, 4.62; N, 12.10. The title compound was prepared from 5-acetyl-1,5,6,7-tetrahydro-pyrrolo[2,3-f]indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 53% yield: mp>250° C.; 1H NMR (DMSO-d6): d2.13 (s, 3H), 3.13 (t, J=8.4 Hz, 2H), 4.06 (t, J=8.4 Hz, 2H), 6.79 (s, 1H), 7.22 (s, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 8.24 (s, 1H), 10.96 (s, 1H), 12.78 (s, 1H); APCI-MS: m/z 422 (M+Na)+. Anal. Calcd for C18H17N5O4S: C, 54.13; H, 4.29; N, 17.53; S, 8.03. Found: C, 53.85; H, 4.23; N, 17.28; S, 7.89.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:14]Br>CCOC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Br:14])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CCOC(C)=O
Product: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2,4-dinitroaniline (2.2 g, 12 mmol) in 40 ml of ACOH was added 1.0 ml of Br2 dropwise and reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, yielding a dark residue which was diluted with EtOAc and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo to provide 2.9 g (11 mmol, 92%) of 2,4-dinitro-6-bromo-aniline which was characterized by NMR and used in a following reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:11])=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:2]/[C:1]([C:4]1[C:5]([CH3:11])=[N:6][C:7]([N:10]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cnc(N)nc1C
Reactant: COC(OC)N(C)C
Product: Cc1nc(N=CN(C)C)ncc1C(=O)/C=C/N(C)C
Yield: 61 %

Procedure:
A solution of 5-acetyl-2-Amino-4-methypyrimidine (Alfa Aesar) (1.00 g, 6.62 mmol) in DMF-DMA (35.4 mL, 265 mmol) was heated at 120° C. for 18 hours. The reaction mixture was concentrated in vacuo, then was purified by Biotage™ silica gel chromatography [50 g SNAP column, 2-10% MeOH/DCM] to obtain a pale yellow solid as the desired product, which was dried over high vacuum for 1 hour (1.06 g, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3 H) 2.86 (br. s., 3 H) 3.03 (s, 3 H) 3.10 (br. s., 3 H) 3.13 (s, 3 H) 5.40 (d, J=12.63 Hz, 1 H) 7.50 (d, J=12.63 Hz, 1 H) 8.48 (s, 1 H) 8.64 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:21](OCC)(OCC)OCC>C(O)=O>[C:15]1([CH2:14][CH2:13][N:12]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[N:1]=[CH:21]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cnc2ccccc2c1NCCc1ccccc1
Solvent: O=CO
Product: c1ccc(CCn2cnc3cnc4ccccc4c32)cc1

Procedure:
Using the method of Example 31, 3-amino-4-[2-(phenyl)ethylamino]quinoline was reacted with triethyl orthoformate and formic acid to provide 1-[2-(phenyl)ethyl]-1H-imidazo[4,5-c]quinoline, m.p. 105°-108° C.
Reaction SMILES: [OH:1][CH:2]([CH2:20][OH:21])[CH:3]([NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O[CH:23]([CH2:43]O)[CH:24](NC(C1NC2C(C=1)=CC=CC=2)=O)C1C=CC=CC=1.ClC1C=CC(C(O)=O)=CC=1.C(Cl)(=O)C(Cl)=O.NC(C1C=CC=CC=1)C(O)CO>C(N(CC)CC)C>[CH:23]([O:1][CH:2]([CH3:3])[CH3:20])([CH3:43])[CH3:24].[OH:1][CH:2]([CH2:20][OH:21])[CH:3]([NH:10][C:11](=[O:19])[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NC(c1ccccc1)C(O)CO)c1cc2ccccc2[nH]1
Agent: NC(c1ccccc1)C(O)CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(NC(c1ccccc1)C(O)CO)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: CC(C)OC(C)C

Procedure:
N-[(1RS, 2RS)-2,3-Dihydroxy-1-phenylpropyl]-4-chlorobenzamide may be prepared in the following manner: working as in Example 8 for the preparation of N-[(1RS, 2RS)-2,3-dihydroxy-1-phenylpropyl]-2-indolecarboxamide, but starting with 4-chlorobenzoic acid (2.57 g), oxalyl dichloride (1.55 cc), (2RS, 3RS)-3-amino-3-phenyl-1,2-propanediol (2.5 g) and triethylamine (8.3 cc), and after the precipitate is washed with distilled water and then with diisopropyl ether, N-[(1RS, 2RS)-2,3-dihydroxy-1-phenylpropyl]-4-chloro-benzamide (3.2 g), m.p. 142° C., is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]1=[O:15].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(#N)C>[CH3:23][S:24]([O:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]1=[O:15])(=[O:26])=[O:25]
Reactant: O=c1nc2n(c(=O)n1CCO)CCCC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)OCCn1c(=O)nc2n(c1=O)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To an ice-cooled solution of 1.80 g of 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione prepared in Reference Example 27 and 1.20 g of triethylamine in 25 ml of acetonitrile, 1.17 g of methanesufonyl chloride was added dropwise. After stirring for 30 minutes, the mixture was concentrated to dryness, and the residue was extracted with chloroform. Concentration of the chloroform solution gave 2.34 g of the entitled compound as an yellow oil.
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9][C:10]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[F:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9][C:10]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1Nc1ccc(F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a suspension of ethanol 3.0 mL of methyl 2-(4-fluoroanilino)-4-phenoxybenzoate 36 mg was added 10% sodium hydroxide aqueous solution 1.0 mL at room temperature, and it was stirred at 60° C. for 1 hour and 30 minutes. After the reaction mixture was cooled to room temperature,10% sodium hydroxide aqueous solution 1.0 mL was added, and it was heated and refluxed for 30 minutes. After the reaction mixture was cooled to room temperature,10% citric acid aqueous solution and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and insoluble matter was filtrated. The solvent of filtrate was removed under reduced pressure, hexane was added to the residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-phenoxybenzoic acid 10 mg of white solid.
Reaction SMILES: C(CO[C:6]1[C:11]2[CH2:12][C:13](=[CH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][C:27]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)([OH:30])[CH2:26][CH2:25]3)[C:14]3[C:15]([O:20][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[N:16][CH:17]=[CH:18][CH:19]=3)(O)=O.C(CCC1C2C[C:50](=CCCN3CCC(C4C=CC(Cl)=CC=4)(O)CC3)[C:51]3[C:52]([O:57]C=2C=CC=1)=[N:53]C=CC=3)(O)=O>>[C:52]([CH2:51][CH2:50][C:6]1[C:11]2[CH2:12][C:13](=[CH:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][C:27]([C:31]4[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=4)([OH:30])[CH2:28][CH2:29]3)[C:14]3[C:15]([O:20][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:57])[NH2:53]
Reactant: O=C(O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: O=C(O)CCc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: NC(=O)CCc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2

Procedure:
The titled compound was prepared by following the procedure of example 181, but replacing the product of example 133 with the product of example 123.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:16][CH3:17])=[N:4][C:5]([CH:11]=[CH:12]N(C)C)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Cl.C(=O)([O-])[OH:20].[Na+].[BH4-].[Na+]>COCCOC.O>[Cl:1][C:2]1[C:3]([S:16][CH3:17])=[N:4][C:5]([CH2:11][CH2:12][OH:20])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CSc1nc(C=CN(C)C)c([N+](=O)[O-])cc1Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1nc(CCO)c([N+](=O)[O-])cc1Cl
Reaction time: 0.5 h
Yield: 44 %

Procedure:
3-Chloro-6-[2-(dimethylamino)ethenyl]-2-methylthio-5-nitropyridine (D10) (1.05 g, 3.84 mmol) was dissolved in DME (40 ml) and treated with 2.5M hydrochloric acid (8 ml). After 15h, the reaction mixture was treated with solid sodium hydrogen carbonate until pH7 was reached. Water (20 ml) was then added and the resultant mixture was cooled to 0° C. Sodium borohydride (0.581 g, 15.36 mmol) was added portionwise over 2-3 minutes with stirring. After 0.5 h, water (200 ml) was added, and the reaction mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were then dried (Na2SO4) and evaporated under reduced pressure to give a red/brown solid, which was purified by silica gel chromatography (3:1 petrol: EtOAc as eluant) to give the title compound as an orange solid (0.420 g, 44%).