Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:48][NH:49][CH2:50][C:51]1[CH:62]=[CH:61][C:54]([CH2:55][N:56]2[CH2:59][CH:58]([OH:60])[CH2:57]2)=[CH:53][CH:52]=1>C(Cl)Cl>[OH:60][CH:58]1[CH2:57][N:56]([CH2:55][C:54]2[CH:61]=[CH:62][C:51]([CH2:50][N:49]([CH3:48])[C:21]([C:19]3[N:20]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:12])=[O:11])[CH3:14])[O:17][CH:18]=3)=[O:22])=[CH:52][CH:53]=2)[CH2:59]1
Reactant: CNCc1ccc(CN2CC(O)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N(C)Cc3ccc(CN4CC(O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3-oxazole-4-carboxylic acid (40 mg, 0.11 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol) DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}azetidin-3-ol dihydrochloride (35 mg, 0.13 mmol) and DCM (5 mL).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](=[S:5])[NH2:4].Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>CCO>[F:1][CH:2]([F:6])[C:3]1[S:5][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1
Reactant: NC(=S)C(F)F
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(C(F)F)n1
Temperature: 50 °C

Procedure:
A mixture of 2,2-difluoroethanethioamide (1.023 g, 9.21 mmol) and ethyl bromopyruvate (1.150 mL, 9.21 mmol) in EtOH (20 mL) was heated to 50° C. for 2 h.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([O:17][CH:18]([CH3:20])[CH3:19])[N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([O:17][CH:18]([CH3:20])[CH3:19])[N:12]=3)[CH:9]=2)[N:4]([S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH:3]=1
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(I)c3c2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cncc(OC(C)C)n4)ccc32)cc1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a solution of 3-iodo-5-(6-isopropoxy-pyrazin-2-yl)-1H-indole (20 g, 0.053 mol) in DMF (200 mL) was added NaH (6.5 g, 0.158 mol) slowly at 0° C., and then stirred for 15 min. p-Toluenesulfonyl chloride (15.10 g, 0.079 mol) was added slowly to the reaction mixture and stirred for 1 h. The resulting mixture was poured into ice with stirring and the precipitate was formed. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give the crude product. The crude product was purified by column chromatography eluting with EtOAc and n-hexane to afford the desire 3-iodo-5-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indole (15.5 g, 55%) as pale brown solid. MS (ESI, m/z): 533.6 (M+1).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14]CC)=[O:13])(OCC)=O)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.[OH-].[Na+]>O.C(O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:27]=[CH:28][C:29](/[CH:32]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:30][CH:31]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(Oc2ccc(C=O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2ccc(/C=C/C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.36 g) was added to an ethanol (30 ml) solution of ethyl diethylphosphonoacetate (1.4 g) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, to which was added 4-[(4-methoxyphenyl)oxy]benzenecarboaldehyde (1.2 g). The reaction mixture was stirred at room temperature for 2 hours, which was further stirred at 50° C. for 30 minutes. The reaction mixture was cooled, to which were added water (20 ml) and sodium hydroxide (0.5 g). The reaction mixture was stirred at room temperature for 2 hours, and concentrated. 2N Hydrochloric acid was added to the residue to become acidic, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (1.2 g).
Reaction SMILES: O.NN.[F:4][C:5]1[CH:6]=[CH:7][C:8]([N+:23]([O-:25])=[O:24])=[C:9]([CH2:11][N:12]2C(=O)C3=CC=CC=C3C2=O)[CH:10]=1.Cl>C(O)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([N+:23]([O-:25])=[O:24])=[C:9]([CH:10]=1)[CH2:11][NH2:12]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cc(F)ccc1[N+](=O)[O-]
Temperature: 40 °C

Procedure:
85% Hydrazine hydrate (1.67 ml) was added to a suspension of N-(5-fluoro-2-nitrophenyl)methyl-phthalimide (7.1 g) in ethanol (90 ml). The reaction mixture was heated to reflux for 3 hours, then cooled to 40° C. Hydrochloric acid was added and stirring was continued at that temperature for a further hour; then the solvent was removed under vacuum. The residue was taken up in water and the solid which separated was discarded. The mother liquors were treated with 10% sodium hydroxide and extracted with diethyl ether. After evaporation of the solvent 3.5 g of title compound were obtained as a reddish oil.
Reaction SMILES: C([OH:5])CCC.[CH3:6][C:7]1[CH:12]2[C:13]([CH3:15])([CH3:14])[CH:10]([CH2:11]2)[CH2:9][CH:8]=1.N1C=CC=CC=1.OO>>[CH3:14][C:13]1([CH3:15])[CH:12]2[C:7]3([CH3:6])[O:5][CH:8]3[CH2:9][CH:10]1[CH2:11]2
Reactant: CC1=CCC2CC1C2(C)C
Reactant: CCCCO
Agent: OO
Solvent: c1ccncc1
Product: CC1(C)C2CC3OC3(C)C1C2
Temperature: 49.85000000000002 °C
Reaction time: 0.65 h

Procedure:
48 ml of n-butanol (525 millimols), 152 ml of alpha-pinene (975 millimols), 1.15 ml of pyridine (14 millimols) and 807 mg of SeO2 (7.3 millimols) are introduced successively into a reactor similar to that of Example 1. The Florentine receiver itself contains 25 ml of n-butanol (273 millimols). After the reaction mixture has been heated to a temperature of 323 K., 10 ml of 84% strength H2O2 (340 millimols) are introduced over a period of 25 minutes. After the reaction has been left to continue for a further 39 minutes, the alpha-pinene oxide formed is determined by gas chromatography: 292 millimols.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[C:20](Cl)(=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.O>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[C:20](=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)CCCN1CCCc2cc([N+](=O)[O-])ccc21
Solvent: ClCCl
Solvent: O
Product: CN(CCCN1CCCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a stirred solution of N,N-dimethyl-3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine (1 g, 3.80 mmol) in dichloromethane (20 ml) was added phenyl carbonochloridate (0.715 ml, 5.70 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 50-100% ethyl acetate in hexanes, giving the desired phenyl methyl(3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)carbamate (1.02 g, 2.76 mmol, 72.7% yield). 1H NMR (DMSO-d6) δ 7.88 (t, J=7 Hz, 1H), 7.78 (s, 1H), 7.37 (t, J=7 Hz, 2H), 7.20 (t, J=7 Hz, 1H), 7.12-7.06 (m, 2H), 6.70 (d, J=9 Hz, 1H), 3.50-3.33 (m, 6H), 3.06, 2.93 (2s, 3H), 2.76-2.71 (m, 2H), 1.92-1.81 (m, 4H). ESI-MS (m/z, %) 370 (MH+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][CH:5]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:11]([C:3]1[C:2]([N:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[N:7][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:5][N:4]=1)#[N:12]
Reactant: CC(C)c1cnc(C#N)c(N)n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)c1cnc(C#N)c(N=CN(C)C)n1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A mixture of the product from Example 244B (0.37 g, 2.28 mmol) and dimethylformamide dimethylacetal (0.30 g, 2.5 mmol, 1.1 eq) in toluene (25 mL) was heated under reflux for 1.75 h. The reaction mixture was then cooled to room temperature and the solvent evaporated under reduced pressure to provide the title compound (0.50 g, 100%) as a thick red/brown oil that was used in subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]=O)[CH2:2][CH3:3].C([N:14]1C=CC=C1C=O)(C)C>ClCCl>[CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]#[N:14])[CH2:2][CH3:3]
Reactant: CC(C)n1cccc1C=O
Reactant: CCCn1cccc1C=O
Solvent: ClCCl
Product: CCCn1cccc1C#N
Yield: 45 %

Procedure:
In the same manner as described in Reference Example 2 (1) except that 1-n-propylpyrrole-2-carbaldehyde (prepared in the same manner as described in Can. J. Chem., 55, 4112, 1977, b.p. 72°-75°C./5 mmHg) (8.2 g, 60 mmole) is used instead of 1-isopropylpyrrole-2-carbaldehyde and further the product is isolated by silica gel column chromatography (solvent: dichloromethane) instead of distillation under reducted pressure, there is obtained 1-n-propylpyrrole-2-carbonitrile (3.6 g, yield: 45%).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([N+:23]([O-:25])=[O:24])=[C:12]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[N:28]([Sn](CCCC)(CCCC)CCCC)=[N+:29]=[N-:30]>C1(C)C=CC=CC=1>[CH3:22][N:14]([C:12]1[CH:13]=[C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]3[NH:30][N:29]=[N:28][N:2]=3)=[CH:27][CH:26]=2)[CH:9]=[CH:10][C:11]=1[N+:23]([O-:25])=[O:24])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C#N)cc2)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3nnn[nH]3)cc2)ccc1[N+](=O)[O-]
Yield: 97.2 %

Procedure:
A mixture of t-butyl N-[5-(4-cyanophenoxy)-2-nitrophenyl]-N-methylcarbamate (2.95 g), azidotributyltin (7.97 g) and anhydrous toluene (30 ml) was heated at reflux for 23 hours. The reaction mixture was concentrated and then partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reversed-phase liquid chromatography using water/acetonitrile=1/1 as the eluant to give the title compound (3.20 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[CH:11]1[C:20]([CH3:21])=[C:19]2[C:14](=[CH:15][C:16](OC(=O)C)([OH:22])[CH:17]=[CH:18]2)[O:13][C:12]1=[O:27].Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:27])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=2
Reactant: COc1ccc(C2C(=O)OC3=CC(O)(OC(C)=O)C=CC3=C2C)c(OC)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(-c2ccc(O)cc2O)c(=O)oc2cc(O)ccc12
Temperature: 210 °C

Procedure:
A mixture of acetic acid 3-(2,4-dimethoxyphenyl)-7-hydroxy-4-methyl-2-oxo-2H-chromen-7-yl ester, prepared as in Example 1 (0.177 g, 0.5 mmol, 1 eq) and dry pyridine hydrochloride (0.9 g, 8.8 mmol, 16 eq) was stirred and heated in an oil bath to a melt, at 210° C. under a closed nitrogen atmosphere in a loosely stoppered round bottom flask for 1 hour. After cooling to room temperature the reaction mixture was triturated with water and the aqueous solution was extracted several times with ethyl acetate until the latter was colorless. Combined organic extracts were washed with brine, dried (anhydrous sodium sulphate), filtered and evaporated to yield the title compound as a pinkish crystalline solid.
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:23]([CH2:26][CH2:27][C:28]1[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=1[CH3:33])([OH:25])=[O:24].N1CCCCC1>C(O)C>[CH:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[C:13](=[CH:34][C:30]2[NH:31][C:32]([CH3:33])=[C:28]([CH2:27][CH2:26][C:23]([OH:25])=[O:24])[C:29]=2[CH3:36])[C:14](=[O:20])[NH:15]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(OCCc2cccc3c2CC(=O)N3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(CCOc4ccc(C(C)C)cc4)c32)c(C)c1CCC(=O)O
Temperature: 90 °C
Yield: 58.2 %

Procedure:
A mixture of 4-[2-(4-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one (118 mg, 0.4 mmol), 4-carboxyethyl-3,5-dimethyl-2-formylpyrrole (78 mg, 0.4 mmol) and piperidine (0.3 mL) in 1.0 mL of ethanol was heated in a sealed tube at 90° C. for 18 hours and cooled to room temperature. The reaction mixture was concentrated and the residue was dissolved in methylene chloride followed by the addition of diethyl ether. The precipitate was filtered and washed with ethyl acetate to give 110 mg (58%) of 3-(5-{4-[2-(4-isopropyl-phenoxy)-ethyl]-2-oxo-1,2-dihydro-indol-3-ylidenemethyl}-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (piperidine salt).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][O:29][C:30]2[CH:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:33]1[N:32]=[CH:31][C:30]([O:29][CH2:28][CH:25]3[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH2:26]3)=[CH:35][CH:34]=1)[CH:9]=[CH:8]2)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Reactant: CN(C)C(=O)c1ccc2[nH]ccc2c1
Product: CN(C)C(=O)c1ccc2c(ccn2-c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using N,N-dimethyl-1H-indole-5-carboxamide (intermediate-12) and tert-butyl-4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Intermediate 29).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1C(O)=O)=[CH:9][C:8]([I:15])=[CH:7][CH:6]=2.[N+](C1C=CC=CC=1)([O-])=O.CCN(C(C)C)C(C)C>>[I:15][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][C:2]([OH:1])=[CH:11]2
Reactant: O=C(O)c1c(O)cnc2ccc(I)cc12
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Oc1cnc2ccc(I)cc2c1
Temperature: 210 °C
Reaction time: 3 h

Procedure:
3-hydroxy-6-iodoquinoline-4-carboxylic acid (22 g, 70 mmol) was suspended in 1-nitrobenzene (143 ml, 1397 mmol) followed by adding Hunig's base (25 mL)—the suspension was completely dissolved. The resulting mixture was heated to reflux (210° C.) under N2. After 3 h, LC/MS showed no sign of starting material mass. The reaction mixture was cooled to rt; solvent was removed as much as possible in vacuo. The crude product was redissolved in DCM/MeOH and the solid was collected by filtration. The solid was rinsed with hexane and either and dried as brownish solid. The filtrate was removed excess solvent and purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-058, 330 g SiO2, solvent system: hexanes:acetone=80%:20%, Flow=100 mL/min) to afford the desired product as brown solid. MS m/z: 272.3 (M+H). Calc'd. for C9H6INO—271.05.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:4]=1.[F:15][C:16]1[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([F:25])[C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[C:3]([CH2:2][O:24][C:23]3[C:16]([F:15])=[C:17]([C:20]([F:25])=[CH:21][CH:22]=3)[C:18]#[N:19])[S:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2nsc(CBr)n2)cc1
Reactant: N#Cc1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3)ns2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.4 %

Procedure:
To a solution of 5-bromomethyl-3-(4-chlorophenyl)-[1,2,4]thiadiazole (0.24 g, 0.82 mmol) in DMF (7 ml) was added 2,6-difluoro-3-hydroxybenzonitrile (0.12 g, 0.74 mmol) and potassium carbonate (0.39 g, 2.90 mmol). The reaction mixture was stirred at 25° C. for 2 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 50 ml water and extracted with ethyl acetate (3×40 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 15% EtOAc-Hexane) to get the desired product (0.30 g, 73%).
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.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>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]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(S(C)(=O)=O)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 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) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (18 uL, 0.24 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to give 5-Chloro-N2-(2-fluoro-5-methyl-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid: ESMS m/z 494.2 (M+H+).
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: CCO
Solvent: O
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: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:12]1[C:16]2[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH2:22]>C1COCC1>[NH2:22][C:13]1[S:12][C:16]2[CH:17]=[C:18]([NH:21][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])[CH:19]=[CH:20][C:15]=2[N:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccc2nc(N)sc2c1
Solvent: C1CCOC1
Product: Nc1nc2ccc(NC(=S)NC(=O)c3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.3 %

Procedure:
Benzoylisothiocyanate (0.12 mL, 0.91 mmol) was added dropwise to a solution of benzothiazole-2,6-diamine (Example 1, 150 mg, 0.91 mmol) in 10 mL of THF at room temperature. The mixture was stirred at room temperature for 7 hours and then concentrated. The residue was washed with a 1:1 mixture of Et2O and hexanes. Yield: 97.3%, 1H-NMR (DMSO-d6): δ 12.65 (s, 1H); 11.55 (s, 1H); 8.00 (m, 3H); 7.60 (m, 5H); 7.38 (m, 2H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[N:14][CH:15]=2)[CH:12]=1.[I:16]I>O.CCO>[F:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[N:14][C:15]=2[I:16])[CH:12]=1
Reactant: Fc1ccc2cncn2c1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccc2c(I)ncn2c1

Procedure:
To a solution of sodium bicarbonate (1.3 g, 15.4 mmol) in water (3.66 mL) was added 6-fluoroimidazo[1,5-a]pyridine (see Example 32, 560 mg, 4.11 mmol) in EtOH (7.31 mL) followed by iodine (1.46 g, 5.76 mmol) at room temperature. After 16 h another 800 mg of iodine was added. After a further 16 h the reaction mixture was quenched with sodium thiosulfate and diluted with ethyl acetate. The organic phase was washed with water and brine then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, ethyl acetate/hexane gradient). The product contained minor impurities and was used without further purification. MS (M+H)+=262.9; 1H NMR (CDCl3) δ: 8.14 (s, 1H), 7.90 (m, 1H), 7.35 (m, 1H), 6.77 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:28]=[C:27]([CH:34]=O)[CH:26]=2)=[CH:21][CH:20]=1>>[C:30]([N:29]1[C:25]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=2)=[CH:26][C:27]([CH2:34][NH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[N:28]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Product: Cc1ccc(N2CCN(CCNCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)c(C)c1
Yield: 60.3 %

Procedure:
Compound 33 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butyl pyrazole-3-carbaldehyde were used.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[O:20]1[CH:24]=[C:23]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:22]=[N:21]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cnoc2)C1
Temperature: 85 °C
Reaction time: 12 h
Yield: 62.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), 4-isooxazolylboronic acid pinacol ester (119 mg, 0.609 mmol), tripotassium phosphate (194 mg, 0.914 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (24.9 mg, 0.0305 mmol) in dioxane (2 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (120 mg, 62.2%) as an oil.