Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([NH:35]O)=[NH:34])=[CH:31][N:30]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:26][N:35]=[C:33]([C:32]5[CH:37]=[CH:38][C:29]([NH2:28])=[N:30][CH:31]=5)[N:34]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3-fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.18) (197 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (95 mg, 37%). MS (ISP) 510.3 [(M+H)+]; mp 233° C.
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=2[I:15])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=2[I:15])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc(C2CCC2)c(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2CCC2)c(I)c1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A solution of methyl 4-cyclobutyl-3-iodobenzoate (compound 9.2, 11.0 g, 34.8 mmol) and sodium hydroxide (4.00 g, 100 mmol) in methanol (100 mL) and water (50 mL) was stirred at 50° C. overnight. After cooling to ambient temperature, the volatile solvent was removed under reduced pressure. The residual aqueous material was washed with ethyl acetate (20 mL). The pH of the aqueous was then adjusted to 3-4 with aqueous hydrogen chloride (6 M). The resulting precipitate was collected by filtration and dried to yield the title compound as a white solid (8.60 g, 82%).
Reaction SMILES: [O:1]1[C:6](=[O:7])[CH2:5][C:4]2([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:3][C:2]1=O.[CH3:22][NH2:23].Cl>>[CH3:22][N:23]1[C:2](=[O:1])[CH2:3][C:4]2([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][C:6]1=[O:7]
Reactant: O=C1CC2(CC(=O)O1)c1ccccc1Oc1ccccc12
Reactant: CN
Agent: Cl
Product: CN1C(=O)CC2(CC1=O)c1ccccc1Oc1ccccc12

Procedure:
This anhydride is treated with excess aqueous methylamine at room temperature. After ten minutes, the solution is acidified with dilute hydrochloric acid and the monoacid-monoamide is filtered and dried. Without further purification it is treated with excess acetic anhydride at reflux for 0.5 hours, and the reaction mixture then poured into cold aqueous sodium bicarbonate. The product, extracted with ethyl acetate, is chromatographed on silica gel and eluted with 2% ethyl acetate-petroleum ether (b.p. 60°-80° C.), giving 1'-methylxanthene-9-spiro-4'-piperidin-2',6'-dione which is recrystallised from ethyl acetate-petroleum ether (b.p. 60°-80° C.), m.p. 148°-149° C.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[C:20]=1[C:26]([F:29])([F:28])[F:27]>>[Br:18][C:19]1[C:20]([C:26]([F:27])([F:28])[F:29])=[C:21]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Fc1cccc(Br)c1C(F)(F)F
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Oc1ccc2ncn(-c3cccc(Br)c3C(F)(F)F)c2n1

Procedure:
From 5-(Benzyloxy)-3H-imidazo[4,5-b]pyridine and 1-bromo-3-fluoro-2-(trifluoromethyl)benzene, prepared in a similar manner as the one described in Example 1.96, the title compound was obtained. LCMS m/z=358.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13](C(OC(C)(C)C)=O)[CH3:14])=[CH:9][C:8]=1[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH3:2]
Reactant: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1CCCOC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc(NC)cc1CCCOC

Procedure:
1.55 g (4.06 mmol) of the above prepared [4-(tert-butoxycarbonyl-methyl-amino)-2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester was dissolved in 41 ml of CH2Cl2 and treated dropwise with 10 ml of TFA. After additional 30 Min. at RT, the bulk of the solvents was removed i. V. and the residue distributed between cold NaHCO3-solution and AcOEt. Washing with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents left 1.15 g of the title compound as brownish oil which was used as such for the next step.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:25][CH2:26][Cl:27]>O1CCCC1>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:25][CH2:26][Cl:27])[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: ClCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCN(CCCl)CC1)c1ccc(F)cc1

Procedure:
A mixture of 4-(4-fluorobenzamido)piperidine (2 g; preparation 2), triethylamine (3.75 ml) and 1-bromo-2-chloroethane (1.11 ml) in 150 ml of dry tetrahydrofuran was refluxed overnight, then further triethylamine (3.75 ml) and 1-bromo-2-chloroethane (1.11 ml) were added. The mixture was refluxed for an additional 5 hours, treated again with 3.75 ml of triethylamine and 1.11 ml of 1-bromo-2-chloroethane and refluxed overnight. The reaction mixture was concentrated to a small volume, treated with ethyl acetate (200 ml) and the mixture washed with an aqueous saturated potassium carbonate solution. The organic phase was dried over sodium sulfate and concentrated to dryness. The residue (1.3 g) was crystallized from 10 ml of diethyl ether and dried under vacuum at 50° C., to give 1.06 g of the product, m.p. 220-225° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:16][CH:15]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 49 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5.0 g, 30 mmol), 4-chlorobenzaldehyde (4.6 g, 1 equiv.) and TFA (4.6 mL, 2 equiv.) to give the title compound (4.16 g, 49%) as a white powder.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([N:13]([CH2:15][CH:16]=C)[CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClCCl.[O:21]=[O+][O-]>CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:16]([OH:21])[CH2:15][N:13]([CH3:14])[C:11]2=[O:12])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CN1CC(O)N(c2cc(C(C)(C)C)on2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.96 g. portion of 1-(5-t-butylisoxazol-3-yl)-3-allyl-3-methylurea was dissolved in 25 ml. of 1:1 by volume dichloromethane:methanol, and the solution was cooled to -78°. Ozone diluted in dry air was bubbled into the solution with good stirring for 30 minutes, after which tlc analysis indicated that the starting material was gone. Nitrogen was bubbled through the mixture for 10 minutes to remove residual dissolved ozone, and then 1 ml. of dimethyl sulfide was added and the mixture was allowed to warm to ambient temperature with continual stirring. The reaction mixture was then diluted with water, the layers were separated, and the product was isolated from the organic layer substantially as shown in Example 2 above to obtain 2.6 g. of the desired product, m.p. 168°-174°. The nuclear magnetic resonance analysis of the product indicated that it was substantially identical to that of Example 1 above.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([CH:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31](=[O:50])[N:32]4[CH2:37][CH2:36][N:35]([C:38]5[CH:43]=[CH:42][C:41]([C:44]6[N:49]=[CH:48][CH:47]=[CH:46][N:45]=6)=[CH:40][CH:39]=5)[CH2:34][CH2:33]4)[CH2:26]3)=[O:24])[CH:20]=2)[NH:15][N:14]=1>C(O)C.O.NN>[NH2:3][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([CH:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31](=[O:50])[N:32]4[CH2:33][CH2:34][N:35]([C:38]5[CH:43]=[CH:42][C:41]([C:44]6[N:49]=[CH:48][CH:47]=[CH:46][N:45]=6)=[CH:40][CH:39]=5)[CH2:36][CH2:37]4)[CH2:26]3)=[O:24])[CH:20]=2)[NH:15][N:14]=1
Reactant: O=C(Nc1ccc2[nH]nc(CN3C(=O)c4ccccc4C3=O)c2c1)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)cc12
Yield: 29.3 %

Procedure:
1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1H-indazol-5-yl]-amide (compound 50 from Example 78, 424 mg, 0.633 mmol) was dissolved in ethanol and 0.31 ml of hydrazine hydrate. The mixture was heated at 80 C for 20 hrs and then evaporated to dryness. The mixture was chromatographed on silica gel to obtain 100 mg of title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][N:26]=[CH:25][C:24]=2[CH:28]=1.C([O-])(O)=O.[Na+]>ClCCl>[O:27]1[C:23]2[CH:22]=[CH:21][C:20]([NH:19][S:9]([C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])=[CH:28][C:24]=2[CH:25]=[N:26]1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc2oncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc2oncc2c1)c1cc(Cl)ccc1Cl
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a solution of 2,5-dichlorobenzenesulphonyl chloride (192 mg, 0.783 mmol), in dichloromethane (4 mL) was added pyridine (150 μL, 1.86 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-1,2-benzisoxazole (100 mg, 0.746 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (174 mg, 68%), single spot at Rf 0.68 (1:1 hexane:ethyl acetate). mp 172.9-173.6° C., HPLC purity 99+% (tR 2.41 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.64 (1H, s), 7.89 (1H, d, J=2.2 Hz), 7.56-7.28 (5H, m). LCMS: 341.07 (M−). FAB-MS (MH+, C13H8Cl2N2O3S): calcd 342.9711, found 342.9710.
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[F:42][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][N:33]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:34][CH2:35]3)[CH:21]3[CH2:22][CH2:23][N:24]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCNCC2)C2CCNCC2)n1
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCN(S(C)(=O)=O)CC2)C2CCN(S(C)(=O)=O)CC2)n1
Yield: 36 %

Procedure:
Reaction of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(1-piperazinyl)propyl]-N-(4-piperidinyl)-1,3,5-triazin-2-amine with methanesulfonyl chloride in CH2Cl2 gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-{3-[4-(methylsulfonyl)-1-piperazinyl]propyl}-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine in 36% yield; mp (CH2Cl2/MeOH) 246-250° C.; 1H NMR (DMSO-d6) (rotamers) δ 7.94 and 7.89 (2d, J=8.3 Hz, 1H), 7.73 and 7.70 (2t, JHF=53.0, 52.9 Hz, 1H), 7.44 and 7.40 (2t, J=8.4, 8.2 Hz, 1H), 6.97 (dd, J=8.0, 3.3 Hz, 1H), 4.68-4.51 (m, 1H), 3.98 (s, 3H), 3.81-3.69 (m, 10H), 3.59-3.48 (m, 2H), 3.12-3.10 (m, 2H), 3.06-3.02 (m, 2H), 2.94 and 2.92 (2s, 3H), 2.90-2.78 (m, 2H), 2.87 and 2.83 (2s, 3H), 2.55-2.39 (m, 6H), 1.92-1.75 (m, 6H); Anal. Calcd. for C30H44F2N10O6S2.0.25H2O: C, 48.2; H, 6.0; N, 18.7. Found: C, 48.1; H, 6.0; N, 18.7%.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=C(C#N)[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[C:21]([OH:24])(=[O:23])[CH3:22].O.S(=O)(=O)(O)O>C(OCC)(=O)C>[S:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:22]([C:21]([OH:24])=[O:23])[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: CC(=O)O
Reactant: N#Cc1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To 288 mg of 3-benzo[b]thiophen-2-yl-1H-5-indazolecarbonitrile were added 3 ml of glacial acetic acid, 1 ml of water and 0.8 ml of concentrated sulfuric acid, and the mixture was stirred at 110° C. for 4 hours. After standing to cool, the mixture was added with 120 ml of ethyl acetate, sequentially washed with water and brine, dried over anhydrous magnesium sulfate. After filtering the organic layer through a silica gel pat, the solvent was evaporated, to give 307 mg of the title compound as ocher yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]#[N:13])[C:9]([NH2:11])=[O:10])=[C:4]([N+:14]([O-])=O)[CH:3]=1>C(O)(=O)C.C1(C)C=CC=CC=1.[Zn]>[NH2:13][C:12]1[NH:14][C:4]2[C:5]([C:8]=1[C:9]([NH2:11])=[O:10])=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2
Reactant: N#CC(C(N)=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: NC(=O)c1c(N)[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 31.9 %

Procedure:
2-(4-Bromo-2-nitrophenyl)-2-cyanoacetamide (Reference compound 1-1, 0.60 g, 2.1 mmol) was dissolved in acetic acid (7.0 mL) and toluene (3.5 mL), and the whole was stirred at 90° C. Zinc powder (0.97 g, 15 mmol) was added portionwise to the solution while keeping at 90° C., and then the reaction mixture was stirred at room temperature for 45 minutes. Ice-water (30 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (30 mL). The organic layer was washed with brine (30 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the mixture of the title reference compound (0.17 g) as a brown solid (yield 32%).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:31]=[CH:30][C:21]2[C:22]3[CH:23]=[CH:24][O:25][C:26]=3[CH2:27][CH2:28][O:29][C:20]=2[C:19]=1[C:32]([O:34]C)=[O:33])(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+]>O.O1CCOCC1>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:31]=[CH:30][C:21]2[C:22]3[CH:23]=[CH:24][O:25][C:26]=3[CH2:27][CH2:28][O:29][C:20]=2[C:19]=1[C:32]([OH:34])=[O:33])(=[O:15])=[O:16])[CH3:37]
Reactant: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCCc1occc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCCc1occc1-2
Yield: 27.6 %

Procedure:
A mixture of methyl 8-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-4,5-dihydro-3,6-dioxabenzo[e]azulene-7-carboxylate (Intermediate 50, 0.134 g) and lithium hydroxide monohydrate (0.159 g) in water (3.8 mL) and dioxane (3.8 mL) was sealed in a microwave vial and irradiated in the microwave at 130° C. for 30 minutes. The mixture was concentrated in vacuo, water was added and it was acidified to pH3 with formic acid. This was extracted into ethyl acetate, dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 2.5-10%. The resultant product was recrystallised from a mixture of DCM and ethyl acetate to give 8-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-4,5-dihydro-3,6-dioxabenzo[e]azulene-7-carboxylic acid (0.036 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.CO[CH:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Br:24])[CH:22]=2)[C:17](=[O:25])[NH:16][C:15]1=[O:26]>CN(C)C=O>[Br:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:25])[NH:16][C:15](=[O:26])[C:14]2=[CH:13][NH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1
Reactant: NCc1cc(=O)c(O)co1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNCc1cc(=O)c(O)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-aminomethyl-5-hydroxy-pyran-4-one (106 mg, 0.75 mmole), 4 mL of N,N-dimethylformamide and 4-methoxymethylene-6-bromo-4H-isoquinoline-1,3-dione (212 mg, 0.75 mmole) is stirred for one hour at ambient temperature. The reaction mixture is evaporated to dryness, dissolved in 7.5% methanol in chloroform passed through Florisil eluting with 7.5% methanol in chloroform. The eluate is evaporated, treated with acetonitrile, the resulting solid filtered and dried to give an off white solid, 220 mg, (75%), mp 293-7° C. dec; MS (ES+): m/z 391 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[N:25]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[N:29][C:24]2=[N:23][CH:22]=1)CCC>>[F:32][C:30]([F:31])([F:33])[C:28]1[CH:27]=[CH:26][N:25]2[C:21]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[C:10]#[N:11])[CH:3]=3)=[CH:22][N:23]=[C:24]2[N:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: N#Cc1ccccc1-c1cc(Cl)ccn1
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccn1
Yield: 13.7 %

Procedure:
2-(4-Chloropyridin-2-yl)benzonitrile (65 mg, 0.3 mmol) was coupled with 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.6 mmol) as described in Example 1 to give 2-[4-(7-trifluoromethyl-imidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrile (15 mg) as a white solid: δH (400 MHz, DMSO) 7.62 (1H, d, J 7.0), 7.69 (1H, m), 7.88 (1H, m), 7.93 (1H, dd, J 5 and 2), 8.04 (2H, m), 8.27 (1H, d, J 1), 8.60 (1H, s), 8.92 (1H, dd, J 5 and 1), 9.60 (1H, d, J 8); m/z (ES+) 366 (M++H).
Reaction SMILES: [Na+].[Cl-].[CH3:3][C:4]([CH3:28])=[CH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:14]2O[C:23]3[CH:22]=[C:21]([OH:25])[CH:20]=[C:19](O)[C:18]=3[C:16](=O)[C:15]=2O)[CH:10]=[CH:11][C:12]=1[OH:13].C[OH:30]>>[OH:30][C:8]1[C:7]([CH2:6][CH:5]=[C:4]([CH3:28])[CH3:3])=[C:12]([OH:13])[CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=1
Reactant: CC(C)=CCc1cc(-c2oc3cc(O)cc(O)c3c(=O)c2O)ccc1O
Reactant: CO
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)=CCc1c(O)ccc(CCCc2ccc(O)cc2)c1O

Procedure:
Brown powder; mp 115-116° C.; UV (MeOH) λmax (log ε) 279 (3.28), 232 (3.55) nm; IR (NaCl) γmax 3421, 2909, 1652, 1515 cm−1; 1H and 13C NMR data, see Table 3; HMBC correlations: H-1/C-1′, C-21, C-61; H-2/C-1′, C-1″; H-3/C-1″, C-2″; H-5′/C-1′, C-3′, C-4′; H-6′/C-1, C-2′, C-4′; H-2″/C-3, C-1″, C-4″; H-3″/C-1″, C-4″; H-1′″/C-2′, C-41; H-4′″ and H-5′″/C-2′″, C-3′″; EIMS m/z 312 (M+, 67), 257 (12), 191 (100), 135 (74); HREIMS m/z 312.1725, calcd for C20H24O3, 312.1725.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:22])[CH3:21]
Reactant: COC(=O)c1cc(N=Cc2ccccc2)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(N=Cc2ccccc2)ccc1OC(C)=O
Reaction time: 48 h
Yield: 49 %

Procedure:
Methyl 2-hydroxy-5-benzylideneaminobenzoate (23.5 g, 92.2 mmole) was dissolved in pyridine (50 ml) and acetic anhydride (11 ml) was added after which the reaction mixture was left at room temperature for 48 hours and evaporated to dryness, in vacuo. The remaining material was recrystallized from hexane to give the title compound (13.4 g, 49%), m.p. 101°-103° C. Found (Calc. for C17H15NO4) C 68.57 (68.69), H 4.98 (5.05) N 4.80 (4.71).
Reaction SMILES: [Cl:1][O-].[Na+].[NH:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]1>CC(O)=O>[CH2:12]([O:11][C:9]([C:8]1[C:7]([Cl:1])=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:5][N:4]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
Sodium hypochlorite (2.79 mL, 5.89 mmol) was added to a solution of diethyl 3,5-pyrazoledicarboxylate (0.5 g, 2.36 mmol) in AcOH (10 mL) and the mixture was stirred at room temperature for 16 hours. Then, the solvent was evaporated in vacuo and the mixture was acidified with a 1N solution of HCl and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 05/95). The desired fractions were collected and the solvents evaporated in vacuo to yield 4-chloro-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (450 mg, 66% yield) as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Reactant: Cc1cccnc1Br
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ncccc4C)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 2-bromo-3-methylpyridine