Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][C:13]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.CO.[NH3:34].CC(O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:34])[N:17]=3)=[CH:14][C:13]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(CN3CCOCC3)cc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1ccc(Nc2ncc(CN3CCOCC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 90 °C
Yield: 34 %

Procedure:
A stirred mixture of N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-5-(morpholinomethyl)pyridin-2-amine (19 mg, 0.043 mmol) in 2.0 M NH3/iPrOH (3.0 mL) was sealed and heated at 90° C. for 24 h. The reaction mixture was concentrated and the crude product was adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (DCM to 5% MeOH in DCM) to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (6.00 mg, 0.015 mmol, 34.0% yield) as a yellow solid. LCMS (API-ES) m/z 409 (M+H); 1H NMR (400 MHz, CDCl3, with one drop of d6-DMSO) δ 11.69 (br. s., 1H) 8.76 (br. s., 1H) 8.39 (br. s., 1H) 8.23 (br. s., 1H) 8.12 (br. s., 1H) 6.77 (d, J=9.00 Hz, 1H) 5.92 (br. s., 2H) 3.93 (br. s., 3H) 3.49 (br. s., 2H) 2.55 (br. s., 3H) 2.50 (br s., 4H) 2.23 (br. s., 4H).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][N:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=4)[CH3:21])=[N:16][C:15]=3[CH:31]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][N:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28](=[NH:29])[NH2:30])=[CH:24][CH:23]=4)[CH3:21])=[N:16][C:15]=3[CH:31]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CN(C)c3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(Cc1nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc2s1)c1ccc(C(=N)N)cc1
Yield: 96 %

Procedure:
Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 96% of theory, C26H25N5O3S (487.58); Rf value: 0.48 (Merck RP-8, methanol/5% NaCl solution=6:4); EKA mass spectrum: (M+H)+=488; (M+2Na)++=266.5.
Reaction SMILES: Cl[C:2]1[C:6]2[C:7]([O:11][CH:12]([F:14])[F:13])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:16])(=[O:15])[N:3]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>C1COCC1>[F:13][CH:12]([F:14])[O:11][C:7]1[C:6]2[C:2]([NH:20][CH:17]([CH3:19])[CH3:18])=[N:3][S:4](=[O:16])(=[O:15])[C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)N
Reactant: O=S1(=O)N=C(Cl)c2c(OC(F)F)cccc21
Solvent: C1CCOC1
Product: CC(C)NC1=NS(=O)(=O)c2cccc(OC(F)F)c21
Temperature: 0 °C
Reaction time: 14 h

Procedure:
400 mg (1.5 mmol) 3-Chloro-4-difluoromethoxy-benzo[d]isothiazole 1,1-dioxide were dissolved in 5 ml dry THF and cooled to 0° C. 883 mg (15.0 mmol) isopropylamine was dissolved in 5 ml dry THF and added slowly. Stirring was continued for 1 h at this temperature and for 14 h at room temperature. The mixture was concentrated in vacuum. The residue was purified on silica (eluent: cyclohexane/ethyl acetate 4:1) to afford 140 mg (0.48 mmol; 32% of theory) of the title compound (C.26).
Reaction SMILES: CN(C)CC.[CH:6]1([C:10]([N:12]2[CH2:18][CH2:17][CH:16]3[CH2:19][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:21][CH2:22][N:15]3[C:14]3[N:31]=[CH:32][CH:33]=[CH:34][C:13]2=3)=O)[CH2:9][CH2:8][CH2:7]1>O1CCCC1>[CH:6]1([CH2:10][N:12]2[CH2:18][CH2:17][CH:16]3[CH2:19][N:20]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[CH2:21][CH2:22][N:15]3[C:14]3[N:31]=[CH:32][CH:33]=[CH:34][C:13]2=3)[CH2:9][CH2:8][CH2:7]1
Reactant: O=C(C1CCC1)N1CCC2CN(Cc3ccc(F)cc3)CCN2c2ncccc21
Agent: CCN(C)C
Solvent: C1CCOC1
Product: Fc1ccc(CN2CCN3c4ncccc4N(CC4CCC4)CCC3C2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of alane-dimethylethylamine complex (0.5 M in toluene, 3.1 mL, 1.55 mmol) was added to a stirring solution of the product of Example 65A (122 mg, 0.31 mmol) in tetrahydrofuran (5.0 mL) at room temperature under nitrogen. The turbid solution was stirred at room temperature for 4 hours. The reaction was quenched by addition of methanol (1 mL), followed after 5 minutes by water (5 mL) and 25% NaOH (0.5 mL). The aqueous layer was separated and extracted with ethyl acetate (2×5 mL) and the combined organic phase was washed with brine (5 mL), dried (Na2SO4) and concentrated under vacuum to provide a residue that was purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column (30×75 mm), eluted with methanol: 10 mM (NH4)2CO3 in water (50:50-95:5) to provide the title compound 1H NMR (300 MHz, CDCl3) δ ppm 1.62-1.94 (m, 6H), 1.97-2.12 (m, 2H), 2.13-2.26 (m, 1H), 2.30-2.49 (m, 1H), 2.51-2.69 (m, 2H), 2.72-2.87 (m, 1H), 2.91-3.03 (m, 1H), 3.02-3.15 (m, 2H), 3.17-3.70 (m, 6H), 6.74 (dd, J=7.8, 4.7 Hz, 1H), 6.92 (dd, J=7.8, 1.4 Hz, 1H), 7.01 (t, J=8.6 Hz, 2H), 7.27-7.39 (m, 2H), 7.79 (dd, J=4.7, 1.7 Hz, 1H); MS (DCI) m/z 381 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:6]2.[S:22](Cl)([Cl:24])=[O:23].CCCCCC>CCOCC>[Cl:24][S:22]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[C:18]([O:20][CH3:21])=[O:19])=[O:23]
Reactant: COC(=O)c1cc2cc(OC)ccc2n1-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)c1c(S(=O)Cl)c2cc(OC)ccc2n1-c1ccccc1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A mixture of 4.0 g (0.014 mole) of 5-methoxy-1-phenyl-1H-indole-2-carboxylic acid, methyl ester in 7.0 ml (11.4 g; 0.096 mole) of thionyl chloride (under a nitrogen atmosphere) was stirred at ambient temperature for ten minutes. After the addition of 50 ml of 20% hexane in ether solution, the new mixture was cooled in ice for 30 minutes to precipitate the crude intermediate sulfinyl chloride. The solid was filtered and washed with hexane to yield 3.0 g (63% crude yield) of 3-(chlorosulfinyl)-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid, methyl ester.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:27]=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Si:40](Cl)([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42].[NH4+].[Cl-]>CN(C=O)C.CCOCC>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42])([C:22]([F:25])([F:23])[F:24])[C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:27]=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Reactant: CC[Si](Cl)(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)cc(C=O)n2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 0.33 g (0.82 mmol) of 1-benzyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-1H-indole-2-carbaldehyde (example 23) in 3 mL of DMF at 0° C. were added 0.15 mL (0.99 mmol) of DBU, followed by 0.17 mL (0.99 mmol) of TESCl. The mixture was stirred at RT overnight and then poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 0.389 g (92%) of 1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole-2-carbaldehyde, MS: 516 (MH+).
Reaction SMILES: [CH2:1]1[C:7](=[O:8])[CH2:6][S:3](=[O:5])(=[O:4])[CH2:2]1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O)([O-:11])=[O:10].[NH2:20]/[C:21](/[CH3:27])=[CH:22]\[C:23]([O:25][CH3:26])=[O:24]>C(O)C>[OH:8][C:7]12[CH2:1][CH2:2][S:3](=[O:5])(=[O:4])[CH:6]1[CH:14]([C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[N+:9]([O-:11])=[O:10])[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:27])[NH:20]2
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C1CCS(=O)(=O)C1
Solvent: CCO
Product: COC(=O)C1=C(C)NC2(O)CCS(=O)(=O)C2C1c1ccccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A solution fo tetrahydrothiophene-3-oxo-1,1-dioxide (1.3 g, 0.01 moles), 2-nitrobenzaldehyde (1.5 g, 0.01 moles) and methyl 3-aminocrotonate (1.1 g, 0.01 moles) in ethanol (20 mL) was stirred overnight. The resulting crystals were isolated by filtration and washed 2x with ethanol and 2x with diethyl ether. After drying under high vacuum for 24 hours 2.54 g of product was obtained, mp 175°-179° C. (dec).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[F:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][NH2:29])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][N:29]3[CH2:11][C:5]4[C:4](=[C:9]([I:10])[CH:8]=[CH:7][CH:6]=4)[C:3]3=[O:13])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCCCc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(I)cccc2CN1CCCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.245 g, 0.7 mmol), 3-[4-(4-fluoro-phenoxy)phenyl]-propylamine (0.193 g, 0.8 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-{3-[4-(4-fluoro-phenoxy)-phenyl]-propyl}-7-iodo-2,3-dihydro-isoindol-1-one (0.086 g, 25%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.01 (m, 2H), 2.65 (t, 2H), 3.67 (t, 2H), 4.26 (s, 2H), 6.84-7.42 (m, 10H), 7.90 (d, 1H). GC-MS: m/z 487 (M)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[N:31][C:30]2[CH:32]=[CH:33][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CC(=O)c1cccc(C(C)=Nc2ccccc2C(C)(C)C)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(C(C)(C)C)cc1)c1cccc(C(C)=Nc2ccccc2C(C)(C)C)n1
Reaction time: 60 h

Procedure:
Monoimine (9,1.06 g, 3.6 mmol) and 4-tert-butylaniline (0.56 g, 3.75 mmol) were dissolved in 25 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 60 hours the mixture was filtered. The solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 0.81 g (53%) of mixed diimine (10). 1H-NMR (CDCl3) δ 8.36 (d, 1H, Py-Hm), 8.34 (d, 1H, Py-Hm), 7.88 (t, 1H, Py-Hp), 7.4 (m, 3H, ArH), 7.18 (t, 1H, ArH), 7.07 (t, 1H, ArH), 6.78 (d, 2H, ArH), 6.54 (d, 1H, ArH), 2.42 (s, 3H, Me), 2.38 (s, 3H, Me), 1.35 (s, 9H, But),1.34 (s, 9H, But).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]([CH3:24])[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]2([CH3:23])[CH3:22])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:24])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2([CH3:23])[CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(CN(C)C2CCN(C(=O)OC(C)(C)C)CC2(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(C)C2CCNCC2(C)C)cc1
Reaction time: 2 h

Procedure:
tert-Butyl 4-((4-methoxybenzyl)(methyl)amino)-3,3-dimethylpiperidine-1-carboxylate (1.87 g, 5.17 mmol, 1 eq) was dissolved in dichloromethane (4 ml); TFA (4 ml) was added at 0° C., and stirring was carried out for 2 h at RT. The reaction solution was concentrated under reduced pressure, taken up in toluene and dried again. The crude product was used in the next stage without being purified further.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1O.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.CN(C=O)C>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]2[O:20][C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)=[N:21][C:22]=2[CH:27]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Reactant: Nc1cc(Cl)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2cc(-c3nc4cc(Cl)ccc4o3)ccc2n1C1CCOCC1
Yield: 15.3 %

Procedure:
2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (0.25 g, 0.96 mmol), 2-amino-4-chlorophenol (0.15 g, 1.05 mmol), anhydrous DMF (10 mL) and WSC (0.22 g, 1.14 mmol) were stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added, the precipitated crystals were filtered off, and the filter residue was extracted with water/chloroform. After the organic layer was dried over anhydrous sodium sulfate, filtration and concentration gave crystals that were dissolved in toluene (5 mL), to which p-toluenesulfonic acid hydrate (0.32 g, 1.68 mmol) was added and this was stirred at reflux for 2 hours. After the solvent was concentrated at reduced pressure, water (5 mL) was added and the solid obtained was filtered off, and after washing with water, drying at reduced pressure at 50° C. yielded the title compound (54 mg, 15.3% yield) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>>[ClH:1].[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:25][CH2:24][CH2:22][OH:23])=[CH:3][C:4]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(-c2cc(Cl)c3ccc(OC)cc3n2)cc1
Reactant: NCCO
Product: COc1ccc(-c2cc(NCCO)c3ccc(OC)cc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 244-245° C. and MS: m/e=325.3 (M+H+), was prepared from 4-chloro-7-methoxy-2-(4-methoxy-phenyl)-quinoline and ethanolamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>>[N:31]1([CH2:30][CH2:29][CH2:28][NH:27][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:14]=3)=[O:26])=[C:2]([Cl:1])[CH:3]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NCCCn1ccnc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1-(3-aminopropyl)imidazole via Procedure G. The product was purified on reverse phase HPLC to yield N4-(3-(1H-imidazol-1-yl)propyl)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 495 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([OH:10])=O)[N:3]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([C:8]([NH:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: Nc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1)c1cccc(Br)n1
Reaction time: 2 h
Yield: 72.5 %

Procedure:
2-Bromopyridine-6-carboxylic acid (5.00 g, 24.8 mmol) was dissolved in DCM (100 mL) and DMF (1 mL), and oxalyl chloride (7.54 g, 59.4 mmol) was added dropwise over 5 min. The reaction mixture was stirred for 2 h and the solvents were removed in vacuo. The reaction mixture was azeotroped twice with DCM and dissolved in DCM (100 mL). DIPEA (12.8 g, 99.0 mmol) and 4-aminopyridine (4.66 g, 49.5 mmol) were added dropwise and the reaction mixture was stirred for 2 h, washed with sat aq NaHCO3 (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from MeOH to give the title compound (5.00 g, 73%) as an off white solid. LCMS (ES+): 278.2 [MH]+.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[O:11])=[N:8][CH:9]=1.CS(C)=[O:15].BrN1C(=O)CCC1=O.C(=O)([O-])O.[Na+].[OH2:30]>>[OH:30][CH:3]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[O:11])=[N:8][CH:9]=1)[C:2]([OH:15])([CH3:12])[CH3:1]
Reactant: CC(C)=Cc1ccc(C=O)nc1
Reactant: CS(C)=O
Reactant: O
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Product: CC(C)(O)C(O)c1ccc(C=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 5-(2-methylprop-1-en-1-yl)pyridine-2-carbaldehyde (9.40 g) in a mixed solvent of dimethylsulfoxide (230 mL) and water (1.89 mL) was added N-bromosuccinimide (18.7 g) at 0° C. The reaction solution was warmed to room temperature and stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in tetrahydrofuran (200 mL) was added 4.5M aqueous sulfuric acid solution, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-100:0, volume ratio) to give the title compound (9.00 g, yield 79%) as a pale-yellow oil. MS: 196 (MH+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:21]1>>[CH:13]1([NH:19][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[N:21]3)[N:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: NC1CCCCC1
Reactant: c1ccc2[nH]ncc2c1
Product: c1ccc2c(c1)cnn2-c1nc(NC2CCCCC2)c2ccccc2n1

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, cyclohexylamine and indazole. Mp=278.1-281.4° C. LC-ESI-HRMS of [M+H]+ shows 344.1879 Da. Calc. 344.18752 Da, dev. 1.1 ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1.[C:29]12[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:34]C(=O)O[C:30]2=[O:31]>C(O)C>[NH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=1[C:30]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1)=[O:31]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
The subtitled compound was prepared substantially in accordance with the method detailed in Example 39A using 16.5 g (0.0449 mol) of 2-(3-aminopropyl)-1-tritylimidazole and 7.5 g (O.046 mol) of isatoic anhydride, with the exception that after reducing the organic layer to dryness under reduced pressure to provide a solid the solid was filtered through silica gel using 3000 ml of methylene chloride followed by 4000 ml of a 2% methanol in methylene chloride solution. The resulting filtrate was reduced to dryness under reduced pressure to provide a foamy oil. This oil was dissolved in 1000 ml of boiling ethanol. The resulting solution was then reduced under reduced pressure to approximately 200 ml in volume and then cooled to 0° C. while solids precipitated. These solids were recovered by filtration and washed with ethanol to provide 18.6 g of the desired subtitled intermediate (m.p. 198.5°-207° C.).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:11]OC(OC)N(C)C>>[N:1]12[CH:11]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9][CH2:10]1)[CH2:3][CH2:2]2
Reactant: C1CNCCNCCNC1
Reactant: COC(OC)N(C)C
Product: C1CN2CCN3CCN(C1)C23

Procedure:
In a manner similar to that of Example 2 (A), 4.80 g (33.5 mmol) of 1,4,7-triazacyclodecane and 4.00 g of dimethylformamide dimethyl acetal were reacted to give 4.67 g (91%) of clear, colorless liquid, bp 96°-97.5° (4.0 mm). Redistillation in a molecular still at 70° (3.4 mm) gave an analytical sample of 1,4,7-triazatricyclo[5.3.1.04,11 ]undecane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>O1CCCC1>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:19](=[O:22])[CH:20]=[CH2:21])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc2cccnc12

Procedure:
A solution of 8-aminoquinoline (14.4 g, 0.1 mole) and triethylamine (15 ml, 0.11 mole) in dry tetrahydrofuran (50 ml) was treated dropwise at 0° (under a nitrogen atmosphere) with a solution of acryloyl chloride (8.5 ml, 0.1 mole) in tetrahydrofuran (25 ml). The reaction was filtered and the filtrate was partitioned between methylene chloride and water. The organic phase was separated, dried over sodium sulphate and concentrated to an oil. The oil was dissolved in ethyl acetate, treated with charcoal, filtered and again concentrated by vacuum distillation to an oil. Seed crystals were added and the oil cooled to -18°. The solid mass was stirred with petroleum ether and filtered affording 15.7 g of crude product of sufficient purity for further synthetic steps. Recrystallization from acetone/pentane afforded N-(8-quinolyl)-2-propenamide of analytical purity (m.p. 76.5°-78.5°).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[C:9](Cl)=[O:10])[CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:27])[C:25]=1[CH3:26].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8](/[C:9](/[O:10][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:30]([O:29][CH3:28])[CH:31]=3)=[CH:26]/[C:25]3[C:24]([Cl:27])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:19])[CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1c(Cl)cncc1Cl
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC

Procedure:
The compound was obtained starting from 3-cyclopropylmethoxy-4-difluoromethoxy -benzoyl chloride, 3,5-dichloro-4-methylpyridine and 3,4-dimethoxy-benzoyl chloride, following the procedure of Example 24.