Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[I:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:31]2[CH:32]=[CH:33][C:28]([I:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(I)cc1
Yield: 92.2 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 4-iodobenzenesulfonyl chloride (Acros, 155 mg, 0.52 mmol) in THF. 254 mg (93%) of 101 was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([CH2:25][N:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[CH:10]=[C:11]([CH:24]=3)[CH2:12][CH2:13][O:14][C:15]3[CH:23]=[C:19]([NH:20][C:21]=1[N:22]=2)[CH:18]=[CH:17][CH:16]=3.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([CH2:25][N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:10]=[C:11]([CH:24]=3)[CH2:12][CH2:13][O:14][C:15]3[CH:23]=[C:19]([NH:20][C:21]=1[N:22]=2)[CH:18]=[CH:17][CH:16]=3
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc3cc(c2)Nc2ncc(Cl)c(n2)Nc2cccc(c2)OCC3)CC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cnc2nc1Nc1cccc(c1)OCCc1cc(CN3CCNCC3)cc(c1)N2
Yield: 32 %

Procedure:
A solution of tert-butyl 4-{[6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).1(9,13)]tricosa-1(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]methyl}piperazine-1-carboxylate in TFA (1.5 mL) was stirred at 20° C. for 15 min, concentrated, and purified by preparative LCMS to give the desired product (15 mg, 32% for 2 steps) as a white solid. LCMS for C23H26ClN6O (M+H)+: m/z=437.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)C[CH2:22]1.F[P-](F)(F)(F)(F)F>CCO.CN(C1C=CN=CC=1)C>[CH2:21]([O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[CH3:22]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-(4-iodo-phenyl)-propionic acid (3 g) in anh. EtOH (38 mL) was added DMAP (187 mg) and PyBOP (6 g). The reaction mixture was stirred on at RT and partitioned between EA and water. The org. phase was separated, washed with 10% aq. citric acid and sat. aq. NaHCO3, dried (Na2SO4) and evaporated off. The resulting crude material was purified by CC (Hept/EA 1/0 to 0/1) to afford the title compound as a white solid (3 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:14]=[CH:13]2.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14]2)=[CH:20][CH:21]=1
Reactant: C1CCNCC1
Reactant: Fc1ccc(-n2ccc3cc(OCCCCCCCBr)ccc32)cc1
Product: Fc1ccc(-n2ccc3cc(OCCCCCCCN4CCCCC4)ccc32)cc1

Procedure:
In analogy to example 2.2, 5-(7-Bromo-heptyloxy)-1-(4-fluoro-phenyl)-1H-indole and piperidine were converted to yield 1-(4-Fluoro-phenyl)-5-(7-piperidin-1-yl-heptyloxy)-1H-indole as colorless gum, MS: 408 (MH+).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[NH2:15])=[CH:10][C:9]=1[NH:17][C:18](=[O:36])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29](C=O)=[CH:28][C:27]=1[O:34][CH3:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:7])([CH3:6])[CH3:5]>N1C=CC=CC=1.O>[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[NH2:15])=[CH:10][C:9]=1[NH:17][C:18](=[O:36])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29](=[N:2][OH:3])[CH2:28][C:27]=1[O:34][CH3:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:5])([CH3:7])[CH3:6]
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)C1=C(OC)CC(=NO)C=C1
Reaction time: 0.33 h

Procedure:
137 mg (1.97 mmol) of hydroxylamine hydrochloride were added to a solution of 398 mg (0.879 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(4-formyl-2-methoxyphenyl)octanamide (prepared as described in Example 110) in 5 ml of pyridine, and the resulting mixture was stirred for 20 minutes. At the end of this time, the reaction mixture was diluted with water, and the diluted aqueous mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. In order to remove the pyridine remaining in the residue, it was dissolved in toluene and the solvent was azeotropically distilled off. Repetition of this procedure gave 414 mg (a quantitative yield) of the title compound as a foam-like substance.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O)[CH3:15].S([O-])(O)=O.[Na+].CN(C=O)C>O>[CH2:14]([S:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)[CH3:15]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: CCSc1ccccc1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 160 °C
Yield: 61.8 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (1.0 g), 2-ethylsulfanylbenzaldehyde (0.96 g), sodium hydrogen sulfite (1.80 g), sodium hydrogen sulfite (1.80 g) and DMF (10 ml) was stirred with heating at 160° C. for 5 hours. The reaction mixture was ice-cooled, and water was added thereto. The precipitated crystal was collected by filtration, and washed with water, then hexane. The obtained crystal was dried under reduced pressure to give 1.09 g of 2-(2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:17][C:16]1[N:18]=[C:19]([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[N:12]2[C:13]=1[CH:14]=[N:15][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N:11]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccsc3)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccsc4)n3n2)cc1
Yield: 49.4 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-3-thiophenecarboxamide (Intermediate 57) (95 mg, 0.27 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.20 mL, 2.14 mmol), to afford 5-methyl-N-[4-(methyloxy)phenyl]-7-(3-thienyl)imidazo[5,1-f][1,2,4]triazin-2-amine (45 mg) as a yellow solid. MS m/z 338 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1
Reactant: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCNC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCN(S(C)(=O)=O)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (50 mg, 0.124 mmol) and DIPEA (0.032 mL, 0.186 mmol) in DCM (1 mL) was added methanesulfonyl chloride (10.6 μL, 0.137 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr and concentrated via rotary evaporation. The resulting crude material was partitioned between EtOAc (2 mL) and water (1 mL). The organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated via rotary evaporation. The crude material was dissolved in EtOAc and MeOH, adsorbed on silica gel (0.75 g), and purified via medium pressure chromatography using a gradient eluant of 50% to 100% EtOAc in heptane on a 4 g silica gel column (Single Step™) to give the title compound (50.6 mg, 85%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12-1.19 (m, 6H), 2.53-2.61 (m, 4H), 2.74 (t, J=5.9 Hz, 2H), 2.97 (s, 3H), 3.00 (d, J=7.3 Hz, 4H), 3.44-3.48 (m, 1H), 3.59 (s, 2H), 4.02-4.10 (m, 1H), 4.16 (s, 2H), 5.41 (d, J=7.8 Hz, 1H), 7.08 (td, J=8.4, 2.2 Hz, 1H), 7.22 (td, J=9.9, 2.7 Hz, 1H), 7.44-7.54 (m, 1H); ESI-MS m/z [M+H]+ 480.9.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1.COS(OC)(=O)=O>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[C:12]([Cl:17])[C:11]=1[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: Clc1cc(Cl)cc(I)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: Cc1c(Cl)cc(I)cc1Cl
Yield: 93.2 %

Procedure:
To the mixture of LDA (5 mL, 8.6 mmol) in THF (20 mL) was added compound 1,3-dichloro-5-iodobenzene (2.35 g, 8.6 mmol) under −78° C. Then the mixture was added to the pre-cooled solution of (CH3)2SO4 (12 mL, 10.3 mmol) in THF (10 mL) under −78° C. The solution was concentrated under vacuum. The residue was diluted with EA, washed with 1N HCl, 1N NaOH, brine, dried over Na2SO4, concentrated under vacuum to give the desired product (2.3 g, 93% yield).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH:17]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:18]2[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][N:19]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)ccc3c(Cl)c2C)c1

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4-dichloro-7-fluoro-3-methylquinoline (0.109 g, 0.47 mmol), 4-methyl-2-(tributylstannyl)pyridine (0.199 g, 0.52 mmol), palladium tetrakistriphenylphosphine (0.055 g, 0.047 mmol) in toluene (2 mL) to give 4-chloro-7-fluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=287.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[N:21]1[C:30]2[C:29](=O)[CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:20])[C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][CH2:10][NH:11][CH:29]1[C:30]2[N:21]=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH2:27][CH2:28]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)OC(C)(C)C
Reactant: O=C1CCCc2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC1CCCc2cccnc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 53.6 %

Procedure:
To a solution of (2S)-5-amino-2-(tert-butoxycarbonylamino)-pentanoic acid tert-butyl ester (free base) (0.905 g, 3.11 mmol) in CH3OH (15 mL) was added 6,7-dihydro-5H-quinolin-8-one (0.504 g, 3.43 mmol) and the resultant solution was stirred at room temperature for 5 hours. Powdered NaBH4 (0.379 g, 9.98 mmol) was added, and the mixture was stirred at room temperature for 25 minutes then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL) and brine (20 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2—CH3OH) provided 0.700 g (54%) of (2S)-2-tert-butoxycarbonylamino-5-(5,6,7,8-tetrahydroquinolin-8-ylamino)-pentanoic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2
Reactant: [H][H]
Reactant: CCCCCC=Cc1cc2cc(Cl)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCc1cc2cc(Cl)ccc2[nH]1
Reaction time: 5 h

Procedure:
5-Chloro-2-hept-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred for 5 hours. Then the reaction mixture was filtered through Celite. The solvent was evaporated to give 5-chloro-2-heptyl-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[Cl:13][C:14]1[CH:15]=[C:16]([N:31]=[C:32]=[O:33])[CH:17]=[C:18]([Cl:30])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C>CC(C)=O>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[N:8][C:32]([NH:31][C:16]1[CH:17]=[C:18]([Cl:30])[C:19]([O:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[C:14]([Cl:13])[CH:15]=1)=[O:33])[O:5][CH2:6][CH3:7]
Reactant: CCOC(=N)c1ccccc1Cl
Reactant: O=C=Nc1cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=NC(=O)Nc1cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 2-chlorobenzimidate hydrofluoroborate (1.90 g., 7.00 mmol), 3,5-dichloro-4-(4-nitrophenoxy)phenylisocyanate (2.28 g., 7.00 mmol) and triethylamine (0.72 g., 7.20 mmol) in acetone (20 ml) is stirred at room temperature for four hours under an atmosphere of dry nitrogen. The reaction mixture is concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase is washed sequentially with dilute hydrochloric acid, dilute sodium bicarbonate, and brine. After drying over sodium sulfate, the ethyl acetate solution is concentrated under reduced pressure and the residue chromatographed over silica gel eluting with 20% ethyl acetate in hexane. The product fractions are combined and concentrated under reduced pressure to leave the title compound as an amorphous solid.
Reaction SMILES: [CH:1]1([N:4]2[CH2:16][C@@H:7]3[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]3[C:5]2=[O:17])[CH2:3][CH2:2]1.[C:18](N)(C)(C)C>>[C:1]([N:4]1[CH2:16][CH:7]2[CH:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:17])([CH3:2])([CH3:3])[CH3:18]
Reactant: CC(C)(C)N
Reactant: COC(=O)[C@@H]1NCCN2C(=O)N(C3CC3)C[C@H]12
Product: COC(=O)C1NCCN2C(=O)N(C(C)(C)C)CC12

Procedure:
Compound 86-C was prepared in analogy to compound 82-C by using tert-butylamine instead of cyclopropylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][NH2:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(CN)c[nH]c2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCc1c[nH]c2cc(C)ccc12
Reaction time: 0.33 h

Procedure:
To a solution of C-(6-methyl-1H-indol-3-yl)-methylamine (0.24 g) in dichloromethane (4 ml) was added acetic anhydride (0.14 ml) and pyridine (0.13 ml) and stirring was continued at 22° C. for 20 min. The mixture was washed with aqueous HCl (1N), the organic layer was dried and evaporated. The residue was chromatographed on silica using dichloromethane/methanol (70:1) to give the title compound as a colorless foam (0.15 g). MS: 203.1 ([M+H]+).
Reaction SMILES: [CH:1]1[C:16]2[C:17]3[C:4]([C:5](=O)[O:6][C:7](=[O:18])[C:8]=3[CH:9]=[C:10]3[C:15]=2[O:14][CH2:13][CH2:12][O:11]3)=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22].O>N1C=CC=CC=1>[OH:22][N:21]1[C:5](=[O:6])[C:4]2=[CH:3][CH:2]=[CH:1][C:16]3[C:17]2=[C:8]([CH:9]=[C:10]2[C:15]=3[O:14][CH2:13][CH2:12][O:11]2)[C:7]1=[O:18]
Reactant: O=C1OC(=O)c2cc3c(c4cccc1c24)OCCO3
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C1c2cccc3c4c(cc(c23)C(=O)N1O)OCCO4
Yield: 97 %

Procedure:
To a solution of 70 mg (0.27 mmol) of 9H,10H-5,8,11-trioxabenzo[de]anthracene-4,6-dione (from Example R3) in 4 mL pyridine was added 80 mg (1.16 mmol) of hydroxylamine hydrochloride and the reaction mixture refluxed for 1.5 hours and poured into 20 mL water while hot. The precipitate was isolated after 24 hours, washed with water, 1% HCl, water, and dried to yield 71 mg of the title compound, mp 344-347° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C@H:18]12[CH2:24][C@H:21]([NH:22][CH2:23]1)[CH2:20][N:19]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(O)CCC>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:22]2[CH2:23][C@@H:18]3[CH2:24][C@H:21]2[CH2:20][N:19]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Nc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(N)ncn1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.222 g, 1.71 mmol) and diisopropylethylamine (0.222 g, 1.71 mmol) were suspended in n-butanol. tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate 16-1 (0.34 g, 1.71 mmol) was then added. The reaction was stirred at 150° C. for 18 hours and then the product was purified on a silica column. 1H-NMR (DMSO): 7.91 ppm (s, 1H); 6.18 ppm (s, 2H); 5.33 ppm (s, 1H); 4.72 ppm (s, 1H); 4.41 ppm (d, 1H); 3.40 ppm (t, 1H); 3.27 ppm (m, 1H); 3.12 ppm (m, 2H); 1.86 ppm (m, 2H); 1.40 ppm (s, 4H); 1.36 ppm (s, 5H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH3:30])[C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:31]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH3:30])[C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:27])([CH3:28])[C:21]=3[CH:29]=2)=[O:31])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: OO
Reactant: CC(=O)Nc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-acetamido-phenylmercapto)-butoxy]-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[CH2:42][SH:43])[C:36]([OH:38])=[O:37].FC(F)(F)C(O)=O>C(Cl)Cl>[C:36]([C:35]1[CH:39]=[CH:40][C:41]([CH2:42][S:43][CH:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:3][C:4]([OH:6])=[O:5])=[C:33]([O:32][CH3:31])[CH:34]=1)([OH:38])=[O:37]
Reactant: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1CS
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)O)ccc1CSC(CC(=O)O)c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 4 h

Procedure:
A solution of 0.54 g (1.32 mmol) of tert-butyl 3-hydroxy-3-[2-(8-phenyloctyl)phenyl]propionate and 0.52 gm, (2.64 mmol) of 3-methoxy-4-mercaptomethylbenzoic acid in 10 ml of methylene chloride at 0° was treated dropwise with 20 ml of trifluoroacetic acid. Stirring was continued at 0° for 4 hours and 221 for 1 hour, and all the solvents were thoroughly evaporated. The residue was crystallized first from H2O/MECN (1:4), and then from Me2CO/hexane, and to yield the product, 0.26 gm. nmr (CDCl3 /Me2CO/DMSO): 7.05-7.72(m, 12H), 4.52 (d of d, 1H), 4.83(d, 1H), 4.82(s,3H), 4.68(d.1H), 2.88-3.24(m, 2H), 2.36-2.74 (m, 4H), 1.10-1.75(m,12H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:32])([F:31])[C:24]1[N:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:30][CH2:29][C:27]3[O:26][N:25]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:28]=3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NCc1nc(C(F)(F)F)no1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nc(C(F)(F)F)no1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b) was reacted with C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methyl amine hydrochloride (CAS 944905-93-5) in the presence of TBTU and DIEA to give the title compound as white solid; MS (EI): m/e=434.5 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:9]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:7]1[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccccc1O
Reactant: Nc1ccc(OC(F)(F)F)c(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(OC(F)(F)F)c(-c2nc3ccccc3o2)c1
Temperature: 250 °C
Reaction time: 3.5 h
Yield: 21.7 %

Procedure:
A mixture 750 mg of 5-amino-2-trifluoromethoxybenzoic acid (750 mg, 3.39 mmol) and 2-aminophenol (370 mg, 3.39 mmol) in 10 mL of polyphosphoric acid was heated and stirred at 250° C. for 3.5 hours. The mixture was poured into ice water under stirring, followed by addition of NaHCO3 until pH 8. The mixture was extracted with ethyl acetate. The organic phase was washed with water twice, brine, rinsed with activated charcoal, dried over MgSO4 and evaporated to give an oil, which contained two compounds, according to TLC. This mixture was dissolved in DMF and separated on semi preparative HPLC (Gilson 215 Liquid Handler), stationary phase: RP18, mobile phase: Water/MeCN gradient 95%/5%-5%/95% to afford 216 mg (22%) of 3-benzoxazol-2-yl-4-trifluoromethoxyphenylamine as crystals.