Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH2:19]([O:21][C:22]([C:24]1[C:29](=[O:30])[N:28]2[CH:31]([CH3:35])[CH2:32][CH2:33][CH2:34][C:27]2=[N:26][CH:25]=1)=[O:23])[CH3:20]>O>[CH2:19]([O:21][C:22]([C:24]1[C:29](=[O:30])[N:28]2[CH:31]([CH3:35])[CH2:32][CH2:33][C:34](=[N:10][NH:6][C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:27]2=[N:26][CH:25]=1)=[O:23])[CH3:20]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2=NNc1ccc(Cl)cc1
Yield: 56 %

Procedure:
To a mixture of 2.5 g. (0.02 mole) of p-chloroaniline and 10 ml. of a 1:1 diluted aqueous hydrochloric acid a solution of 1.4 g. (0.01 mole) of sodium nitrite and 10 ml. of water is slowly added dropwise at 0°-5° C. under stirring. To the reaction mixture 12.0 g. of solid sodium acetate are added in portions, whereupon a solution of 4.7 g. (0.02 mole) of ethyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate and 10 ml. of water is slowly added dropwise under vigorous stirring. The reaction mixture is stirred at 0°-5° C. for 2-3 hours, whereupon it is allowed to stand in a refrigerator overnight. The precipitated crystals are filtered off and washed with a small amount of water. After recrystallization from ethanol 4.2 g. (56.0%) of ethyl-9-(p-chloro-phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-(1,2-a)pyrimidine-3-carboxylate are obtained. Mp.: 177°-178° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1)([OH:3])=[O:2].[CH3:25]O.OS(O)(=O)=O>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1)([O:3][CH3:25])=[O:2]
Reactant: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1ccnc2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)c1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Yield: 90 %

Procedure:
A solution of 5-carboxy-3-(quinol-4-ylmethylene)-2-oxindole (3.163 g, 10 mmol), methanol (3.2 g, 100 mmol) and H2SO4 95% (1 g) in benzene (100 ml) was heated in a Soxhlet apparatus for 10 h. To dry the distillate continuously, the cap of the Soxhlet contained anhydrous MgSO4. After cooling, water was added, the organic phase repeatedly washed with water and then evaporated under vacuum. Thus almost pure title compound was obtained in about 90% yield.
Reaction SMILES: [C:1](O)([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([S:31]([N:34]([CH3:45])[CH:35]([C:37]2[O:41][CH:40]=[C:39]([C:42](O)=[O:43])[CH:38]=2)[CH3:36])(=[O:33])=[O:32])=[C:26]([CH3:46])[CH:25]=1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O>CN(C=O)C>[F:4][C:3]([F:6])([F:5])[C:1]([NH2:8])=[O:2].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][C:42]([C:39]2[CH:38]=[C:37]([CH:35]([N:34]([S:31]([C:27]3[C:26]([CH3:46])=[CH:25][C:24]([O:23][CH3:22])=[CH:29][C:28]=3[CH3:30])(=[O:33])=[O:32])[CH3:45])[CH3:36])[O:41][CH:40]=2)=[O:43])=[CH:17][CH:18]=1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)C(C)c2cc(C(=O)O)co2)c(C)c1
Reactant: O=C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(C)C(C)c2cc(C(=O)NCCc3ccc(C4=NCCN4)cc3)co2)c(C)c1
Product: NC(=O)C(F)(F)F

Procedure:
The title compound was prepared according to general procedure AH using the bis TFA salt of 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethanamine, (40 mg, 0.1 mmol), TEA (0.05 mL, 0.32 mmol), DMF (1 mL), 5-(1-{[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}ethyl)furan-3-carboxylic acid (39 mg, 0.11 mmol), EDCI (24 mg, 0.13 mmol) and HOBt monohydrate (17 mg, 0.13 mmol). The crude product was purified using MP-TsOH resin, washing with MeOH (5 mL) and eluting with 7N NH3 in MeOH (7 mL). A portion of the resulting partially purified product was purified using prep method C to afford the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH2:34])[CH2:32][CH3:33]>>[N:25]1([C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:10]4[O:9][C:8]([CH2:7][CH2:6][NH:34][CH2:31][CH2:32][CH3:33])=[CH:12][C:11]=4[CH:13]=3)=[N:18][CH:19]=2)=[O:24])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: CCCN
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CCCNCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and propylamine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.25-3.8 (m, 12H), 3.05 (t, J=7.5 Hz, 2H), 1.74 (m, 2H), 1.05 (t, J=7.5 Hz, 3H); MS (DCI) m/z 394 (M+H)+;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH2:25]([Mg]Br)[CH2:26][CH3:27].[NH4+].[Cl-]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH2:25][CH2:26][CH3:27])[CH2:6][C:5]2=[O:12]
Reactant: CCC[Mg]Br
Reactant: O=c1ccoc2ccc(Br)cc12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCC1CC(=O)c2cc(Br)ccc2O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of 6-bromo-4H-chromen-4-one (12 g, 53 mmol) in CH2Cl2 (24 mL) was added TMSOTf (12.5 mL, 69.18 mmol) at ambient temperature. After stirring for 1 hour, THF (210 mL) was added to the mixture at ambient temperature and cooled to −78° C. To the mixture was added n-propylmagnesium bromide (1.05M solution in THF, 66 mL, 69 mmol). After stirring for 1 hour at −78° C., 1M aqueous NH4Cl was added to the mixture. The mixture was warmed to ambient temperature and stirred overnight. The organic and the aqueous layers were separated, and the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 10%) to afford 6-bromo-2-propyl-2,3-dihydro-4H-chromen-4-one (11.42 g).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.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>[CH3:11][O:10][C:8]1[C:7]([O:12][CH3:13])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH:9]=1
Reactant: COc1cc(Br)c(C=O)cc1OC
Reactant: OB(O)c1cccnc1
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: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C=O)c(-c2cccnc2)cc1OC
Temperature: 140 °C

Procedure:
A mixture of 2-bromo-4,5-dimethoxybenzaldehyde (0.368 g, 1.5 mmol), pyridin-3-ylboronic acid (0.246 g, 2.0 mmol), Pd(PPh3)4 (0.173 g, 0.150 mmol), and cesium carbonate (0.977 g, 3 mmol) were suspended in dioxane (4 mL) and water (1 mL). The mixture was heated to 140° C. in a microwave for 1 h. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate (˜25 mL), filtered through a bed of Celite, and conc. in vacuo to afford the aldehyde which was purified via SiO2 chromatography (40 g) using ethyl acetate/hexanes (5:1) as eluent to afford the title compound as a white solid (0.340 g, 93%); m/z 244.
Reaction SMILES: S1C=CC(C2C=C(C=CC=2)OCCOCCN)=C1.CC(C)(C)C#C/C=C/CBr.[S:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=2)[O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[CH:30]1.[CH3:47][O:48][C:49]([CH3:57])([CH3:56])[C:50]#[C:51]/[CH:52]=[CH:53]/[CH2:54]Br>>[CH3:47][O:48][C:49]([CH3:57])([CH3:56])[C:50]#[C:51]/[CH:52]=[CH:53]/[CH2:54][NH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][O:37][C:36]1[CH:44]=[CH:45][CH:46]=[C:34]([C:31]2[CH:32]=[CH:33][S:29][CH:30]=2)[CH:35]=1
Reactant: NCCCCCOc1cccc(-c2ccsc2)c1
Reactant: COC(C)(C)C#C/C=C/CBr
Agent: CC(C)(C)C#C/C=C/CBr
Agent: NCCOCCOc1cccc(-c2ccsc2)c1
Product: COC(C)(C)C#C/C=C/CNCCCCCOc1cccc(-c2ccsc2)c1

Procedure:
Compound of Example 53 was obtained by performing the same reaction as in Example 52 except that 2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine and (E)-6,6-dimethyl-2-hepten-4-ynyl bromide were used instead of the starting compounds, 5-[3-(3-thienyl)phenoxy]pentylamine and (E)-6-methoxy-6-methyl-2-hepten-4-ynyl bromide, which were used in the above-mentioned reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:14])=[O:13])[C:9]([O:23]C)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:13])=[O:14])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COc1c(S(=O)(=O)Nc2ccc(Cl)cc2)cc(Cl)c2cccnc12
Agent: BrB(Br)Br
Product: O=S(=O)(Nc1ccc(Cl)cc1)c1cc(Cl)c2cccnc2c1O

Procedure:
The title compound is prepared from 5-chloro-N-(4-chlorophenyl)-8-methoxy-7-quinolinesulfonamide, which is the fist title compound of Preparation 9, and 6 equivalents of BBr3 according to the procedure described in Example 18. Crystallization from Et2O/hexane/CH2Cl2 affords 0.015 g of the title compound as a red-brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24](I)=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([Si:29]([CH3:32])([CH3:31])[CH3:30])#[CH:28]>CN(C=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:28]#[C:27][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(I)ccc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C#Cc1ccc2[nH]c([C@@H]3CCCCN3C(=O)OCc3ccccc3)nc2c1
Product: C[Si](C)(C)C#Cc1ccc2[nH]c([C@@H]3CCCCN3C(=O)OCc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 138.8 %

Procedure:
To a stirring solution of (S)-2-(5-iodo-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (524 mg, 1.135 mmol), CuI (22 mg, 0.114 mmol) and bis(triphenylphosphine)palladium(II)dichloride (40 mg, 0.056 mmol) in DMF (4 mL) is added TEA (0.47 mL, 3.4 mmol) followed by ethynyl-trimethylsilane (0.17 mL, 1.25 mmol). The reaction mixture is stirred at room temperature overnight and concentrated in vacuum to dryness. The residue is purified by flash column chromatography on silica gel (EtOAc/hexanes 5% to 100%) to give a yellow residue which is triturated twice with DCM to afford the title compound (S)-2-(5-trimethylsilanylethynyl-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (340 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[C:16](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:16])[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1C
Temperature: 50 °C
Yield: 30.1 %

Procedure:
In dimethylformamide (5 mL), combine ethyl 5-bromo-1H-indole-2-carboxylate (1.00 g, 13.7 mmole), potassium carbonate (1.4 g, 10 mmole), and methyl iodide (280 μL, 4.50 mmole). Heat the mixture to 50° C. for 18 hours. Cool to room temperature and partition between EtOAc and water. Extract with EtOAc (3×), wash with brine (3×), dry (MgSO4) and concentrate to provide crude material. The crude material is purified on 120 g silica gel with 0 to 50% EtOAc in heptane to give 850 mg (81%) of the title compound. ES/MS m/e (81Br) 284.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCBr
Reactant: Oc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1ccccc1F
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 2-fluorophenol (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 50 mL of water. The solution was cooled to room temperature and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted 3 times with EtOAc to yield 2.5 g of less pure compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:20]=[CH:19]2.[CH:33]1[CH:38]=[CH:37][C:36]([O:39][C:40](OC2C=CC=CC=2)=[N:41][C:42]#[N:43])=[CH:35][CH:34]=1>CC(O)C.C1COCC1>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:8]3[C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:4]#[C:3][CH2:2][NH:1][C:40](=[N:41][C:42]#[N:43])[O:39][C:36]5[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=5)[CH:6]=4)[N:11]=[CH:10][N:9]=3)=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: N#CN=C(NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1)Oc1ccccc1
Reaction time: 8 h
Yield: 49.6 %

Procedure:
[6-(3-Amino-prop-1-ynyl)-quinazolin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (280 mg, 0.663 mmol) is treated with diphenyl cyanocarbonimidate (163 mg, 1.031 equiv.) in a mixture of i-PrOH (12 ml) and THF (4 ml). Stir mixture overnight, then concentrate to dryness and chromatograph on silica (EtOAc/hexanes) to obtain 186.3 mg (49.6%) of pure desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=[O:11]>C(OCC)(=O)C>[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[C:10]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Temperature: 115 °C

Procedure:
To a solution of 4-chloroaniline (3.13 g, 24.5 mmol) in N,N-dimethylformide (20 mL) was added isatoic anhydride (4.00 g, 24.5 mmol), and the reaction mixture was heated at 115° C. for 14 h, cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with 1 N NaOH (200 mL), water (100 mL), then brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; EtOAc/hexane=1:9) to give 2-amino-N-(4-chloro-phenyl)-benzamide as white solid. Yield: 1.67 g (28%).
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].O.[CH3:15][CH2:16][O:17][C:18]([CH3:20])=O.[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>>[O:17]1[C:18]2[CH:20]=[CH:23][CH:22]=[CH:21][C:25]=2[CH:15]([CH2:5][CH2:6][NH2:7])[CH2:16]1
Reactant: CCOC(C)=O
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: NCCC1COc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a stirred suspension of sodium hydride (247 mg, 6.16 mmol) in dry THF (6 ml) at 0° C. under nitrogen was added a solution of diethylcyanomethyl phosphonate (0.98 ml, 6.16 mmol) in 2 ml THF and the whole stirred at 0° C. for 1 h. 5-Acetyl-2,3-dihydro[b]benzofuran (Aldrich) (1 g, 6.16 mmol) in THF (2 ml) was added dropwise and the whole stirred at room temperature for 16 h. Water (20 ml) and EtOAc (20 ml) were added, the organic layer separated, and the aqueous layer extracted with EtOAc (2×20 ml). The combined organics were dried over MgSO4, filtered and evaporated to afford a pale brown oil which solidified on standing. This solid was purified by column chromatography using 20-30% EtOAc in pentane as eluant to give the title product (789 mg, 69%); 1HNMR (400 MHz, CDCl3) δ: 2.4 (s, 3H), 3.2 (t, 2H), 4.6 (t, 2H), 5.5 (s, 1H), 6.7 (d, 1H), 7.2 (d, 1H), 7.3 (s, 1H); LRMS: M+NH4 203 (ES+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(F)ccc1Cl
Reactant: CN1Cc2occc2C(O)C1
Product: CN1Cc2occc2C(Oc2ccc(Cl)c([N+](=O)[O-])c2)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-chloro-5-fluoronitrobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [N+]([C:4]1[C:15]([CH3:16])=[C:14]([CH3:17])[CH:13]=[C:12]([N+]([O-])=O)[C:5]=1[NH:6][CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])([O-])=O.[N+](C1C(C)=C(C)C=C([N+]([O-])=O)C=1N(N=O)C(CC)CC)([O-])=O.S(=O)(=O)(O)N.Cl>O.C(Cl)CCl>[CH2:8]([CH:7]([NH:6][C:5]1[CH:12]=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[CH:4]=1)[CH2:10][CH3:11])[CH3:9]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Agent: CCC(CC)N(N=O)c1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Agent: Cl
Agent: NS(=O)(=O)O
Solvent: O
Solvent: ClCCCl
Product: CCC(CC)Nc1ccc(C)c(C)c1
Temperature: 80 °C

Procedure:
To a crude nitration solution comprising 1550 g. of 2,6-dinitro-N-(1-ethylpropyl)-3,4-dimethylaniline and 340 g. of 2,6-dinitro-N-nitroso-N-(1-ethylpropyl)-3,4-dimethylaniline in 3700 mls. of ethylene dichloride was added 212 g. of sulfamic acid and 2850 mls. of 37.7% hydrochloric acid. The mixture was refluxed at 80° C. for six hours, 2-liters of water was added thereto and the aqueous phase was separated. The aqueous phase was extracted with 500 ml. of ethylene dichloride and the organic phases were combined. The combined organic phase was washed with 3-liters of water, the aqueous phase separated and the ethylene dichloride was removed under vacuum at 68° C. to recover 1915 g. of product containing 1820 g. of 2,6-dinitro-N-(1-ethylpropyl)-3,4-dimethylaniline and less than 0.1% of 2,6-dinitro-N-nitroso-N-(1-ethylpropyl)-3,4-dimethylaniline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:30]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)(=[O:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:38][C:37]5[CH:36]=[CH:35][C:34]([O:33][C:30](=[O:32])[CH3:31])=[CH:41][CH:40]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: CC(=O)Oc1ccc(CBr)cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(OC(C)=O)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-acetoxy-benzyl bromide following a procedure analogous to that described for Intermediate 7. LC (method 8): tR=1.27 min; Mass spectrum (ESI+): m/z=541 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[N:6]=[C:7]2Cl.N[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:22]#[N:23].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]2[C:8](=[C:7]([NH:6][C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:22]#[N:23])[CH:28]=[C:5]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:4]3=2)[CH:9]=[CH:10][N:11]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Fc1ccc2nc(Cl)c3ccnc(Cl)c3c2c1
Reactant: Cc1ccc(C#N)cc1N
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C#N)cc1Nc1cc2ccc(F)cc2c2c(Cl)nccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,5-dichloro-9-fluorobenzo[c]-2,6-naphthyridine (Example 1, Step 5) (250 mg, 0.94 mmol) and 3-amino-4-methylbenzonitrile (136mg, 1.03 mmol) in THF (9.3 mL) at 0° C. was added NaHMDS (1.8 mL, 1 M in THF, 1.80 mmol). The reaction stirred at 0° C. for 15 minutes and then quenched by the addition of sat. aq. NaHCO3 solution. The precipitated solid was collected by filtration, washed with EtOAc and dried under vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1cncc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dibromopyridine (1.00 g) in toluene (10 mL) and ethanol (5 mL) was added phenylboronic acid (515 mg), sodium carbonate (1.34 g) and tetrakis (triphenylphosphine)palladium(0) (24 mg) and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted into ethylacetate (2×30 mL). The organic layers were washed with brine (40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-bromo-5-phenyl-pyridine as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[CH:16])[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C[Si](C)(C)[C:22]#[C:23][CH:24]=[C:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CC(NC1C=CC=C(Br)C=1)=[O:35].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[C:16][C:27]3[CH:26]=[C:25]([CH2:30][C:29]([NH2:28])=[O:35])[CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CC=C1CCNCC1
Reactant: CC(=O)Nc1cccc(Br)c1
Reactant: C#CC=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(=CC#Cc3cccc(CC(N)=O)c3)CC2)n1
Yield: 54 %

Procedure:
The title Compound was prepared from Compound 274c following the procedure described for the compound of Example 274 using 3-bromoacetanilide instead of 1-bromo-3,5-difluorobenzene and adding 1 molar equivalent of tetrabutylammonium fluoride monohydrate to the starting reaction mixture. After the work-up, the residue was purified by automated flash liquid chromatography (SP1™-Biotage) eluting with PE-EtOAc gradient from 7:3 to 4:6 affording the title product. Orange oil. Yield: 54%.