Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:19]=[C:20]1[C:25]2=[CH:26][NH:27][C:28]([CH:29]=O)=[C:24]2[CH2:23][CH2:22][NH:21]1.N1CCCCC1>C(O)C>[N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[C:12]3=[CH:29][C:28]2[NH:27][CH:26]=[C:25]3[C:24]=2[CH2:23][CH2:22][NH:21][C:20]3=[O:19])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2cc(C(=O)N3CCOCC3)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(C(=O)N3CCOCC3)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 5-(morpholine-4-carbonyl)-1,3-dihydro-indol-2-one (49.2 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 eq.) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10]1)=[O:8].S1C=CC=C1CC(N1CCC[C@H](C(OCC)=O)C1)=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1)=[O:8]
Reactant: O=C(O)C1CCCN(C(=O)Cc2cccs2)C1
Agent: CCOC(=O)[C@H]1CCCN(C(=O)Cc2cccs2)C1
Product: O=C(O)[C@H]1CCCN(C(=O)Cc2cccs2)C1

Procedure:
This reaction was run in the same manner as 1-(2-thiopheneacetyl)-3-piperidine carboxylic acid, starting with (S)-ethyl 1-(2-thiopheneacetyl)-3-piperidinecarboxylate (10 g; 35.6). This gave (S)-1-(2-thiopheneacetyl)-3-piperidine carboxylic acid (9.27 g) as a white solid without further purification. MS m/z (positive ion) 506 (dimer+; 25), 254 (MH+; 100).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[N:12]=[N:11]2)=[CH:6][CH:5]=1.Cl[C:19]1[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=1>C1COCC1>[CH3:28][O:27][C:25]([C:22]1[CH:21]=[N:20][C:19]([O:16][CH2:15][C:14]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[N:11]=[N:12][C:13]=2[CH3:17])=[CH:24][N:23]=1)=[O:26]
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCc2c(C)nnn2-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a suspension of NaH (55% in oil, 116 mg, 2.7 mmol) in THF (4 mL) was added a solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol (500 mg, 2.4 mmol) in THF (6 mL) dropwise at 0° C. and the reaction mixture was stirred at room temperature for 30 min. Then a solution of methyl 5-chloropyrazine-2-carboxylate (460 mg, 2.65 mmol) in THF (6 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The mixture was then poured into ice water and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane, then 0 to 5% methanol in dichloromethane) afforded the title compound (787 mg, 95%) as a white solid. MS: m/e=344.3 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=O)=[N:9][CH:10]=1)([CH3:3])[CH3:2].[C:13]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.CCOC(C)=O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:10][N:9]=1)#[CH:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1ccc(C=O)nc1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1ccc(OC(C)C)cn1
Temperature: 25 °C

Procedure:
To 1.00 g (6.05 mmol) 5-isopropoxypicolinaldehyde in 20 mL methanol are added 1.67 g (12.1 mmol) K2CO3 followed by 1.4 g (7.26 mmol) dimethyl 1-diazo-2-oxopropylphosphonate. After stirring at r.t. over the weekend the reaction mixture is diluted with EtOAc and washed consecutively with NaHCO3 solution and water. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23](OC)=[O:24])=[CH:22][C:12]=2[N:11]=1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([NH:37][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:38])([F:29])[F:39])=[CH:36][N:35]=3)=[O:24])=[CH:22][C:12]=2[N:11]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)n(C)c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)Nc3ccc(C(F)(F)F)cn3)c3c(c21)CC(C)(C)O3
Yield: 19 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 using methyl 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (step-7 of Intermediate-49, 0.100 g, 0.247 mmol) and 5-(trifluoromethyl)pyridin-2-amine (0.053 g, 0.371 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.025 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 3.49 (s, 2H), 3.57 (s, 3H), 7.17-7.31 (m, 4H), 8.22 (d, J=9 Hz, 1H), 8.44 (d, J=9 Hz, 1H), 8.75 (s, 1H), 8.79 (s, 1H), 10.39 (s, 1H), 10.55 (s, 1H); MS [M+H]+: 534.21.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12](=[O:21])[C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:48][C:49]1[CH:54]=[CH:53][C:52](I)=[CH:51][CH:50]=1.[F-].[Cs+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:13](=[C:14](\[C:52]3[CH:53]=[CH:54][C:49]([Cl:48])=[CH:50][CH:51]=3)/[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)/[C:12]2=[O:21])[CH:5]=1
Reactant: Clc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester (369.4 mg, 1 mmol) in THF (5 ml) were added palladium(II) acetate (11.2 mg, 0.05 mmol), triphenylphosphine (26.2 mg, 0.1 mmol), 1-chloro-4-iodobenzene (262.3 mg, 1.1 mmol) and cesium fluoride (456 mg, 3 mmol) at room temperature. The solution was stirred for 3 h at 110° C. under an argon atmosphere. After being quenched with water, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with (hexane/ethyl acetate=5/1) to give 3-{3-[1-(4-chloro-phenyl)-1-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester, yield 297 mg (62%); 1H NMR (CDCl3, 300 MHz) δ ppm 8.00 (s, 1H), 7.92 (d, 1H), 7.50 (d, 1H), 7.26-7.43 (m, 10H), 7.08 (dt, 1H), 6.71 (dt, 1H), 6.59 (d, 1H), 6.52 (d, 1H), 4.95 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.[Cl-].[NH4+]>CN(C)C=O>[F:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2cccc(F)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 89.7 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.16 g of 3-fluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.26 g of 4-(3-fluorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (36)).
Reaction SMILES: Cl.F[C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[CH3:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:14]([F:13])([F:23])[F:24])=[CH:17][CH:18]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1Nc1ccc(OC(F)(F)F)cc1

Procedure:
The product (1.92 g) is obtained as a hydrochloride according to the method of stage 1 of Example 4, by using 1 g of 2-fluoro-3-methyl-nitrobenzene and 1.3 mL of 4-trifluoromethoxy-aniline in the presence of 1.16 g of potassium tert-butanolate in 10 mL of DMSO.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([N:13]=[C:14]=[O:15])[CH3:12]>>[CH2:11]([NH:13][C:14]([N:10]=[C:3]([O:2][CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15])[CH3:12]
Reactant: COC(=N)c1ccccc1
Reactant: CCN=C=O
Product: CCNC(=O)N=C(OC)c1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A neat mixture of benzimidic acid methyl ester (750 mg, 5.56 mmol) and ethyl isocyanate (808 mg, 11.3 mmol) was stirred at 50° C. for 24 h. Excess isocyanate was removed under vacuum to provide the desired product as a colorless viscous oil (1.09 g, 95%). This material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.07 (t, J=7.3 Hz, 3 H), 3.25 (q, J=7.3 Hz, 2 H), 3.87 (s, 3H), 4.97 (br s, 1H), 7.26-7.40 (m, 2H), 7.45 (d, J=7.4 Hz, 1H), 7.69-7.71 (m, 2H). MS, m/z 207=M+1.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][C:17]=1[OH:32]>C1COCC1>[F:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[CH:21][NH:22]2)=[CH:18][C:17]=1[O:32][S:11]([C:5]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=1[F:3])(=[O:13])=[O:12]
Reactant: CN1CCC(c2c[nH]c3cc(F)c(O)cc23)CC1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3cc(F)c(OS(=O)(=O)c4c(F)cccc4F)cc23)CC1
Yield: 27.7 %

Procedure:
By a method similar to Example 31, using 0.2N sodium hydroxide (2.4 mmol, 12.2 mL), 2,6-difluorobenzenesulfonyl chloride (2.9 mmol, 0.625 g), 6-fluoro-3-(1-methylpiperidin-4-yl)-1H-indole-5-ol (2.4 mmol, 0.608 g) in THF (7.7 mL). The crude isolated product was subjected to normal phase silica gel radial chromatography, 4 mm plate eluting with 9:1 methylene chloride:2M ammonia in methanol at 10 mL/minute. Fractions containing product combined, concentrated in vacuo to a white solid. The title compound was crystallized from methylene chloride to afford 0.282 g (27%) of the title compound: mp=202° C.; Mass spectrum (ion spray): m/z=425 (M+1); 1H NMR (DMSOd6): 11.10 (s, 1H), 7.91 (m, 1H), 7.40 (m, 2H), 7.26-7.16 (m, 3H), 2.78 (m, 2H), 2.52 (m, 1H), 2.20 (s, 3H), 1.96 (m, 2H), 1.69 (m, 2H), 1.51 (m, 2H); Calculated for C20H19F3N2O3S: C, 56.12; H, 4.57; N, 6.54. Found: C, 56.13; H, 4.56; N, 6.48.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]1([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:28][C:29]2[CH:34]=[C:33]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[CH:32]=[N:31][CH:30]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: CC1(C)OB(c2cncc(NC3CCC3)c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(NC5CCC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and cyclobutyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 172.1.1) to give the title compound as a white solid. (HPLC: tR 2.29 min (Method A); M+H=440 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.07 (m, 2H), 7.93-7.84 (m, 3H), 7.58-7.55 (m, 1H), 6.80-6.76 (m, 1H), 6.34 (d, 1H), 3.94-3.85 (m, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 2.44-2.34 (m, 2H), 1.96 (s, 3H), 1.93-1.73 (m, 4H))
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[F:22][C:23]1[CH:28]=[CH:27]C([Mg]Br)=[CH:25][CH:24]=1.[Cl-].[NH4+]>C(OCC)C.O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CN(C)C(c1ccc(F)cc1)C1CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 3 (19.89 g, 88 mmol) in abs. THF (160 ml) was added dropwise, under argon and while cooling with ice, to a 1M solution of 4-fluorophenylmagnesium bromide in THF (220 ml, 220 mmol), and stirring was carried out for 20 h at RT. For working up the reaction mixture, saturated ammonium chloride solution (100 ml) and water (100 ml) were added, while cooling with ice, and extraction with diethyl ether (3×100 ml) was carried out. The organic phase was washed with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]([CH2:21][CH2:22][O:23][CH3:24])[CH3:20])[CH:16]=[CH:15][C:14]=1[O:25][CH3:26])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr>C(Cl)(Cl)Cl>[CH3:26][O:25][C:14]1[C:13]2[N:12]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:11][C:18]=2[C:17]([N:19]([CH2:21][CH2:22][O:23][CH3:24])[CH3:20])=[CH:16][CH:15]=1
Reactant: COCCN(C)c1ccc(OC)c(NC(=S)NC(=O)c2ccccc2)c1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccccc3)sc12
Temperature: 25 °C
Yield: 28.1 %

Procedure:
To a stirred solution of 430 mg (1.15 mmol) 1-benzoyl-3-{2-methoxy-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-thiourea in 8 ml chloroform was added dropwise 0.059 ml (1.15 mmol) bromine and the reaction mixture heated at reflux for 18 hours. The mixture was then cooled to room temperature, poured slowly onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/4 ethyl acetate/hexane) afforded 120 mg (28%) N-{4-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-benzothiazol-2-yl}-benzamide as a yellow solid. ES-MS m/e (%): 394 (M+Na+, 14), 372 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>>[C:24]([N:13]1[CH2:12][C:11]2[CH:23]=[C:7]([CH:8]=[CH:9][CH:10]=2)[NH:6][C:5]2=[N:21][C:20](=[C:2]([Cl:1])[CH:3]=[N:4]2)[NH:19][C:18]2=[CH:22][C:14]1=[CH:15][CH:16]=[CH:17]2)(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(=O)Cl
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Product: CCCC(=O)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Yield: 50 %

Procedure:
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene and butyryl chloride as the starting materials in 50% yield. LCMS for C21H21ClN5O (M+H)+: m/z=394.1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(-c2ncccc2C(F)(F)F)ccc1C(=O)O

Procedure:
Hydrogenate the solution of 2-nitro-4-(3-trifluoromethyl-pyridin-2-yl)-benzoic acid (3.84 mmol) in 95% EtOH (100 mL) with 10% Pd—C (150 mg) for over night. Filter through a celite pad and concentrate the filtrate to give 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)=[N:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:35][CH2:36][O:37][CH3:38].O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH2:35][CH2:36][O:37][CH3:38])[C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:24]=2)=[N:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cn2)cc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(Oc2ccc(N(CCOC)C(=O)OCc3ccccc3)cn2)cc1
Reaction time: 0.58 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-[4-(5-benzyloxycarbonylaminopyridin-2-yloxy)phenyl]propionate (1.7 g, 4.0 mmol) in DMF (50 mL) was added 60% sodium hydride (0.19 g, 4.9 mmol) under ice cooling, and the resulting solution was stirred for 35 minutes at the same temperature. 2-Bromoethylmethyl ether (0.4 mL, 4.2 mmol) was added dropwise to the solution. The reaction solution was stirred for 2 hours under ice cooling, and then stirred for 2 days at room temperature. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 1.6 g of the title compound.
Reaction SMILES: C.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([OH:15])=[C:13]([N+:16]([O-])=O)[CH:12]=[C:11]([C:19]#[N:20])[CH:10]=1.NN>CO.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[NH2:16][C:13]1[CH:12]=[C:11]([C:19]#[N:20])[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[C:14]=1[OH:15]
Reactant: N#Cc1cc(-c2ccccc2F)c(O)c([N+](=O)[O-])c1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: N#Cc1cc(N)c(O)c(-c2ccccc2F)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a suspension of charcoal (283 mg) in 25 ml of methanol was added iron (III) chloride hexahydrate (35 mg), and 2′-fluoro-6-hydroxy-5-nitrobiphenyl-3-carbonitrile (668 mg). The resultant green mixture was heated under nitrogen at 70° C. for 10 min. Hydrazine (403 μl) was added slowly, and the mixture was stirred for 2 h at 70° C. The mixture was then cooled to room temperature and filtered through a plug of Celite. The eluent was concentrated in vacuo to provide the title compound (543 mg, 92%). Mass spectrum (ESI) 229.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[CH:7]SC=2)NC(=O)[C:3]=1[C:12]#[N:13].C(O[C:17]([C:19]1[C:20](=[O:29])[NH:21][C:22]2[C:26]([C:27]=1[OH:28])=[CH:25][S:24][CH:23]=2)=[O:18])C.C1(N)CCCCC1>>[CH:12]1([NH:13][C:17]([C:19]2[C:20](=[O:29])[NH:21][C:22]3[C:26]([C:27]=2[OH:28])=[CH:25][S:24][CH:23]=3)=[O:18])[CH2:3][CH2:2][CH2:10][CH2:6][CH2:7]1
Reactant: N#Cc1c(Cl)c2cscc2[nH]c1=O
Reactant: CCOC(=O)c1c(O)c2cscc2[nH]c1=O
Solvent: NC1CCCCC1
Product: O=C(NC1CCCCC1)c1c(O)c2cscc2[nH]c1=O

Procedure:
To prepare compounds of structure (II) with R2 as carbonitrile, and R1 and R3 as defined above, 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (33), was used as a key intermediate. To prepare this intermediate, 7-hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester, depicted by formula (23), was reacted with cyclohexylamine to yield intermediate 7-hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid cyclohexylamide, depicted by formula (31). This intermediate was converted to 5,7-dichloro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (32), by reacting with phosphorous oxychloride, and was then converted into 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-6-carbonitrile, depicted by formula (33), as shown in Scheme 15.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:7]=[CH:8][CH:9]=1)=[O:4].[CH:18]([NH:22][CH:23]([CH2:25][CH3:26])[CH3:24])([CH2:20][CH3:21])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.CCOCC>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3](=[O:4])[CH2:2][N:22]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:18]([CH2:20][CH3:21])[CH3:19]
Reactant: CCC(C)NC(C)CC
Reactant: O=C(CCl)c1cccn1Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: CCC(C)N(CC(=O)c1cccn1Cc1ccccc1F)C(C)CC
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of 16.0 g of 2-chloroacetyl-1-(o-fluorobenzyl)pyrrole, Example 1a, 8.3 g of di-sec-butylamine and 20.0 g of potassium carbonate in 250 ml xylene is stirred at 120° C. for 72 hours. The mixture is cooled, washed with water, dried and filtered and the xylene is evaporated leaving a brown oil. The oil is dissolved in ether and extracted into a 2 N hydrogen chloride solution. The aqueous acidic solution is basified with a sodium carbonate solution and extracted with ether. The ether solution is washed, dried and filtered and the ether removed leaving a brown oil of 1-(o-fluorobenzyl)-2[(di-sec-butylamino)acetyl]-pyrrole. Infrared and nuclear magnetic resonance spectra confirm this structure.
Reaction SMILES: [CH2:1]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:16]([O:18][C:19](=[O:31])[CH2:20][O:21][C:22](OC1C=CC=CC=1)=[O:23])[CH3:17]>C1(C)C=CC=CC=1>[C:4]1(/[CH:3]=[CH:2]/[CH2:1][N:10]2[CH2:15][CH2:14][N:13]([C:22]([O:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:31])=[O:23])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: C(=C/c1ccccc1)\CN1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)N1CCN(C/C=C/c2ccccc2)CC1
Yield: 35.3 %

Procedure:
A solution of 1.40 g (6.93 mmol) of trans-1-cinnamylpiperazine and 1.74 g (7.76 mmol) of ethyl{[(phenoxy)carbonyl]oxy}acetate (J. Med. Chem., 1999, 42, 277-290) in 15 ml of toluene is heated at 80° C. overnight. It is evaporated to dryness and the residue is taken up in 50 ml of ethyl acetate. It is washed with 2 times 20 ml of water and 1 times 10 ml of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 50/50 mixture of cyclohexane and ethyl acetate, then with ethyl acetate, to give 0.814 g of product in the form of a pale yellow oil.