Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].Br.Br[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CC(C)=O>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][O:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=3[CH:11]=2)[CH:17]=1
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: BrCc1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCc3cccnc3)cc2s1
Yield: 61 %

Procedure:
To a solution of 2-cyano-6-hydroxybenzothiazole (0.39 g, 2.2 mmol) in acetone (50 mL) was added 3-(bromomethyl)pyridine hydrobromide (0.7 g, 2.76 mmol), cesium carbonate (2.15 g, 6.6 mmol), and a catalytic amount of sodium iodide. After adding 3 A molecular sieves, the yellow suspension was refluxed for 40 h under nitrogen. After cooling down the mixture and filtering the solids, the filtrate was concentrated and the residue was purified by silica gel chromatography using 50%-100% ethyl acetate in heptane. A yellowish solid was obtained in 61% yield. MS (ESI+): m/z 267.64 (M+H)+; calc'd: 268.05.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][O:6][C:5]([CH3:18])([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:4][CH2:3]1>CO.[Pd]>[F:19][C:2]1([F:1])[CH2:7][O:6][C:5]([CH3:18])([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CC1(C(=O)OCc2ccccc2)CCC(F)(F)CO1
Agent: [Pd]
Solvent: CO
Product: CC1(C(=O)O)CCC(F)(F)CO1
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a suspension of benzyl 5,5-difluoro-2-methyltetrahydro-2H-pyran-2-carboxylate (0.22 g, 0.814 mmol) in MeOH (5 mL) was added 10% Pd/C (0.12 g). The reaction mixture was stirred under H2 for 1 h. The reaction was filtered and concentrated to dryness to yield 5,5-difluoro-2-methyltetrahydro-2H-pyran-2-carboxylic acid (100 mg). 1H NMR (400 MHz, CDCl3) δ ppm 3.79-3.91 (2H, m), 2.29-2.42 (1H, m), 2.12-2.26 (1H, m), 1.85-2.08 (2H, m), 1.54 (3H, s).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCCC1>[CH2:9]([O:11][C:12](=[O:19])[CH:13]([CH2:27][C:26]1[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: -62 °C

Procedure:
21.4 g of lithium diisopropyl amide was added to 210 ml anhydrous tetrahydrofuran in a stream of nitrogen in a dry 3-necked flask with a drying tube and dropping funnel with pressure compensation. Next, 58.0 g of malonic acid diethyl ester in 100 ml anhydrous tetrahydrofuran was added dropwise at room temperature in 40 minutes. After 30 minutes the reaction solution was cooled to -62° C. and 39.1 g of 4-nitrobenzyl bromide in tetrahydrofuran was slowly added dropwise with vigorous agitation, followed by agitation for a further hour at -62° C., after which the precipitate was filtered cold. The filtrate was concentrated in a rotary evaporator, and the residue was dissolved in 300 ml ethanol at 65° C. and separated from the insoluble residue. 34.7 g of faintly yellowish crystals were obtained after cooling.
Reaction SMILES: COC(=O)C[O:5][C:6]1[CH:11]=[C:10](OC)[C:9]([S:14][C:15]#[N:16])=[CH:8][C:7]=1[CH3:17].[CH3:19]OC(=O)COC1C=C(C)C(S)=CC=1C>>[CH3:17][C:7]1[CH:8]=[C:9]([S:14][C:15]#[N:16])[C:10]([CH3:19])=[CH:11][C:6]=1[OH:5]
Reactant: COC(=O)COc1cc(OC)c(SC#N)cc1C
Reactant: COC(=O)COc1cc(C)c(S)cc1C
Product: Cc1cc(SC#N)c(C)cc1O

Procedure:
The title compound was prepared from compound WWA in a manner analogous to compound 1C. 400 MHz 1H NMR (DMSO-d6) δ 7.07 (s, 1H), 6.50 (s, 1H), 4.56 (s, 2H), 3.76 (s, 3H), (s, 1H), 2.26 (s, 3H), 2.17 (s, 3H); MS m/z 252 (m+1). Preparation of (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid methyl ester (Compound WW)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][O:26][CH3:27].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][CH2:25][O:26][CH3:27])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC(c2cn(CCOC)c3ncccc23)CC1
Temperature: 25 °C

Procedure:
1.0 g (3.66 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid ethyl ester were dissolved in 10 ml of DMF and, at room temperature, 0.19 g (4.76 mmol) of 60% sodium hydride were carefully added. This mixture was stirred for half an hour. 0.45 ml (5.12 mmol) of 1-bromo-2-methoxyethane were added dropwise and the mixture was further stirred for 24 hours at 60° C. The reaction mixture was cooled to room temperature and poured over cold water. The aqueous phase was extracted twice with dichloromethane and the organic phase was washed with water and brine, dried with magnesium sulphate, filtered and evaporated to dryness. This resulted in 0.86 g (71% of yield) of product.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[N:14]=[C:13]([O:28][CH3:29])[N:12]=2)[CH:8]=[CH:7][C:6]1=[O:30].O.[NH2:33][NH2:34]>CO.C(Cl)Cl>[Cl:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=1[CH2:19][CH2:18][NH:17][C:15]1[N:14]=[C:13]([O:28][CH3:29])[N:12]=[C:11]([C:9]2[CH:8]=[CH:7][C:6](=[O:30])[N:5]([CH2:4][C:3]([NH:33][NH2:34])=[O:2])[CH:10]=2)[CH:16]=1
Reactant: COC(=O)Cn1cc(-c2cc(NCCc3c(F)cccc3Cl)nc(OC)n2)ccc1=O
Reactant: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2ccc(=O)n(CC(=O)NN)c2)n1
Reaction time: 15 h

Procedure:
A solution of (5-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-2-oxo-2H-pyridin-1-yl)-acetic acid methyl ester [220 mg, 0.49 mmol, Example 22(d)] in a mixture of MeOH (5 mL) and DCM (2 mL) is treated with hydrazine hydrate (0.18 mL, 5.8 mmol). After 15 hours at 20° C., the mixture is concentrated to give (5-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-2-oxo-2H-pyridin-1-yl)-acetic acid hydrazide. MS: 447 (M+H). This material is used without further purification.
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH2:13][C:14](C)(C)[CH3:15])[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[N:25][CH:26]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:6][NH:8][C@H:9]([C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:26][N:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CCC[C@H](NC)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norvaline for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 262 Step B for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.67-8.57 (m, 1H), 8.30 (d, J=7.4, 1H), 7.68 (dd, J=8.9, 2.4, 1H), 6.40 (d, J=8.9, 1H), 4.48-4.37 (m, 1H), 3.87-3.78 (m, 1H), 3.67 (dd, J=11.1, 7.4, 1H), 3.59 (dd, J=10.7, 8.1, 1H), 3.37-3.29 (m, 1H), 3.20 (dd, J=6.9, 6.2, 1H), 2.82-2.67 (m, 2H), 2.43 (s, 3H), 2.16 (dtd, J=12.4, 7.2, 4.9, 1H), 2.00-1.90 (m, 1H), 1.83 (ddt, J=12.8, 9.5, 6.3, 1H), 1.76-1.64 (m, 2H), 1.60-1.35 (m, 4H), 0.86 (t, J=7.3, 3H); MS (ESI+) m/z 385 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:33])[N:12]([CH2:14]/[CH:15]=[CH:16]/[C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4C(OC(C)(C)C)=O)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.CCOC(C)=O>[C:1]1([CH:7]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:33])[N:12]([CH2:14]/[CH:15]=[CH:16]/[C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)n1ccc2c(/C=C/Cn3cc(C(c4ccccc4)c4ccccc4)ccc3=O)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1C/C=C/c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl 4-{(1E)-3-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]-1-propen-1-yl}-1H-indole-1-carboxylate (247 mg) in MeOH (5 mL) was added 1M NaOH aqueous solution (1.5 mL) at ambient temperature. The reaction mixture was stirred for 17 hours at ambient temperature. The resulting mixture was diluted with EtOAc (15 mL) and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20-50:50) to give 5-(diphenylmethyl)-1-[(2E)-3-(1H-indol-4-yl)-2-propen-1-yl]-2(1H)-pyridinone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([NH2:24])=[CH:19][CH:18]=2)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([NH:24][C:2]1[N:7]=[C:6]([NH:24][C:20]3[CH:21]=[C:22]4[C:17](=[CH:18][CH:19]=3)[NH:16][C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])=[CH:23]4)[C:5]([F:9])=[CH:4][N:3]=1)=[CH:19][CH:18]=2)=[O:14])[CH3:11]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5[nH]c(C(=O)OCC)cc5c4)n3)ccc2[nH]1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-ethoxycarbonyl-5-indoleamine were reacted to yield N2,N4-bis(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 11.83 (s, 1H), 11.63 (s, 1H), 9.21 (s, 1H), 8.99 (s, 1H), 8.08 (s, 1H), 8.01 (m, 2H), 7.49-7.22 (m, 4H), 6.92 (s, 1H), 6.63 (s, 1H), 4.29 (q, 4H, J=7.2 Hz), 1.32 (m, 6H); LCMS: ret. time: 24.74 min.; purity: 99%; MS (m/e): 503 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([NH:23][C:24]([O:26][CH2:27][CH2:28]Cl)=[O:25])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].C[O-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][C:24]2=[O:25])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(=O)OCCCl)cc3Cl)c2n1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(N4CCOC4=O)cc3Cl)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Methyl 3-(2-chloro-4-((2-chloroethoxycarbonyl)amino)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (240 mg) was dissolved in methanol (3 ml) and a 28% solution (159 mg) of sodium methylate in methanol was added at room temperature, which was followed by stirring at 60° C. for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid under ice-cooling. A saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (5 ml) was added to the residue and the mixture was heated and allowed to cool. The precipitated crystals were collected by filtration and dried under reduced pressure with heating to give methyl 3-(2-chloro-4-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (121 mg) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:10]=3[NH:11]/[C:12](=[N:17]\[NH:18][C:19](=O)[CH3:20])/[C:13]([CH3:16])([CH3:15])[N:14]=2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:10]=3[N:11]3[C:19]([CH3:20])=[N:18][N:17]=[C:12]3[C:13]([CH3:16])([CH3:15])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N/N=C1\Nc2sc(C)c(C)c2C(c2ccc(Cl)cc2)=NC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(C)(C)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A disposable tube fitted with a septum was charged with (Z)—N′-(5-(4-chlorophenyl)-3,3,6,7-tetramethyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-ylidene)acetohydrazide (112 mg, 0.288 mmol) and tetrahydrofuran (10 mL). Tosic acid (75 mg, 0.394 mmol, 1.4 equiv) was added, and the solution as stirred at room temperature 30 min, at which point LC/MS analysis indicated complete consumption of the starting material. The solution was concentrated for purification by column chromatography (eluting with dichloromethane/methanol/ammonium hydroxide) to yield an off-white amorphous solid. This solid was further purified by semi-prep HPLC (water/acetonitrile/0.1% trifluoroacetic acid), free-based with a strong cation exchange solid phase extraction column (eluting with ammonia in methanol), and lyophilized to yield 4-(4-chlorophenyl)-2,3,6,6,9-pentamethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine as a yellow amorphous solid (m/z=371) (46 mg, 43%). 1H NMR (400 MHz; DMSO): δ 7.48 (s, 4H), 2.60 (s, 3H), 2.39 (s, 3H), 1.97 (s, 3H), 1.57 (s, 3H), 1.07 (s, 3H).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([C:16]1[C:20]([CH3:21])=[CH:19][NH:18][C:17]=1[CH3:22])=[O:15])[CH3:12].Cl>ClCCl>[CH2:11]([O:13][C:14]([C:16]1[C:20]([CH3:21])=[C:19]([CH:3]=[O:4])[NH:18][C:17]=1[CH3:22])=[O:15])[CH3:12]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(C)c[nH]c1C
Agent: Cl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring. Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes. The maximum temperature reached was 18° C. The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring. The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring. The temperature increased to 22° C. The mixture was allowed to stand for 30 minutes and the layers allowed to separate. The temperature reached a maximum of 40° C. The aqueous layer was adjusted to pH 12–13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition. After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour. The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100% yield) as a yellow solid. 1H-NMR (DMSO-d6) δ 1.25 (t, 3H, CH3), 2.44, 2.48 (2×s, 2×3H, 2×CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1].
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15]CC)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[O:15]
Reactant: CCOC(=O)c1c(C)nc2ccccc2c1O
Reactant: COc1ccc(N)cc1
Solvent: Cc1ccccc1C
Product: COc1ccc(NC(=O)c2c(C)nc3ccccc3c2O)cc1

Procedure:
Using the procedure of Example 11, ethyl 4-hydroxy-2-methyl-3-quinoline-carboxylate [described in J. Het. Chem., Vol. 16 (1979), p. 1605] and p-anisidine in xylene were refluxed for 24 hours to obtain 4-hydroxy-N-(4-methoxyphenyl)-2-methyl-3-quinoline-carboxamide melting at 222° C.
Reaction SMILES: CON(C)[C:4](=[O:17])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][CH2:7][CH3:8].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[O:17]=[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:6][CH2:7][CH3:8]
Reactant: Br[Mg]c1ccccc1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 50 mL round-bottomed flask was (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopentan-2-ylcarbamate (91d, 250 mg, 0.96 mmol) dissolved in THF (9.6 ml). Phenylmagnesium bromide (2.88 ml, 2.88 mmol) 1.0 M in THF was added. The reaction was stirred at r.t. for 5 h. The reaction was poured into a mixture of saturated ammonium chloride and ethyl acetate. The mixture was shaken and the layers separated. The water layer was washed twice with ethyl acetate. The combined organic layers were washed once with a small portion of water and dried over sodium sulphate. The solvent was evaporated and the crude product was purified by flash chromatography.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].FC(F)(F)C([O-])=O.[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]1)=[O:21].C(O)(=O)C>O.C(O)C.O>[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([N:1]=[O:3])[CH2:25][CH2:24]1)=[O:21]
Reactant: O=N[O-]
Reactant: Cc1[nH]c(C(=O)NC2CC[NH2+]CC2)c(Cl)c1Cl
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1[nH]c(C(=O)NC2CCN(N=O)CC2)c(Cl)c1Cl
Temperature: 90 °C

Procedure:
A solution of NaNO2 (1.7 g, 24.6 mmol) in 20 ml of water was added to a solution of 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidinium trifluoroacetate (Intermediate 86; 4 g, 10.3 mmol) and 400 μl acetic acid in 60 ml of 1:1 EtOH—H2O. The mixture was heated to 90° C. for 1 hour. After cooling to room temperature, 200 ml of water was added. White solids were collected by filtration and dried in vacuo (2.8 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH2:7][C:6]2=[O:14])#N.C(C1C=C2C(=CC=1)N=C(C)C=C2[OH:28])#N.C(=O)(O)[O-].[Na+]>[Ni].C(O)=O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH2:7][C:6]2=[O:14])=[O:28]
Reactant: CC1=Nc2ccc(C#N)cc2C(=O)C1
Reactant: Cc1cc(O)c2cc(C#N)ccc2n1
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CC1=Nc2ccc(C=O)cc2C(=O)C1

Procedure:
A mixture of 6-cyano-2methyl-4-quinolone (9.2 g, Chem. Abs., 51, 11347h; known therein as 6-cyano-4-hydroxyquinaldine), Raney nickel (10 g) and 75% formic acid (150 ml ) was heated at reflux for 3 hours. The mixture was cooled, neutralised with a saturated aqueous solution of sodium bicarbonate and filtered. The solid residue was washed with warm methanol (3×50 ml). The combined filtrates were extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (100 ml), dried over sodium sulphate and evaporated to give 6-formyl-2-methyl-4-quinolone as a fawn coloured solid (9.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])=[O:16])[CH2:7][CH2:6]2>CO.C1COCC1.[Pd]>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH2:7][CH:8]([C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])=[O:16])[CH2:9]2
Reactant: COc1cc2c(cc1OC)CCC(C(=O)Nc1ccccc1C(=O)O)=C2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1OC)CC(C(=O)Nc1ccccc1C(=O)O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A mixture of 2-(6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxamido)benzoic acid (350 mg, 1 mmol) and 10% Pd/C (35 mg) in MeOH (50 mL) and THF (50 mL) was stirred at room temperature under H2 overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 2-(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene-3-carboxamido)benzoic acid (250 mg, 71%). 1H-NMR (400 MHz, DMSO-d6) δ 1.70-1.85 (m, 1H), 2.10-2.21 (m, 1H), 2.64-2.82 (m, 3H), 2.82-3.00 (m, 2H), 3.71 (s, 6H), 6.66 (s, 1H), 6.68 (s, 1H), 7.16 (app t, J=7.6 Hz, 1H), 7.60 (app t, J=8.0 Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H), 11.32 (s, 1H); LC-MS (ES-API); rt 8.96 min; m/z calculated for C20H21NO5 [M+H]+ 356.1, found 356.1.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][CH:6]=1.[N+:8]([O-])([OH:10])=[O:9].S(=O)(=O)(O)O>>[Br:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][C:6]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: Brc1ccc(Br)s1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)sc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
2,5-dibromothiophene (10.0 g, 0.0413 mol) was added in portions to nitric acid (38 mL) and concentrated sulfuric acid (75 mL) cooled at 0° C. with an ice bath. On complete addition, the reaction was removed from the cold bath and was stirred for 30 minutes before the reaction mixture was poured onto ice water (400 mL) and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), concentrated under vacuum and the residue purified by silica gel chromatography to afford the title product as solid (1.6 g, 13.7% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[S:58][CH:59]=[CH:60][CH:61]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[S:58][CH:59]=[CH:60][CH:61]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: O=C=Nc1cccs1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccs1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 20 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-isocyanatothiophene as the starting materials in 20% yield. LCMS for C29H31ClN7O2S (M+H)+: m/z=576.0.