Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH:43]([F:45])[F:44])[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[F:44][CH:43]([F:45])[N:41]1[C:40](=[O:46])[CH:39]=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42]1
Reactant: O=c1ccc(Br)cn1C(F)F
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C(F)F)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 110 °C
Yield: 50.6 %

Procedure:
A microwave vial equipped with a flea stirbar was charged with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.047 mmol), 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one (25 mg, 0.113 mmol), Cs2CO3 (27 mg, 0.083 mmol), H2O (0.1 mL) and dry dioxane (1 mL). The mixture was sparged with N2 for 10 min and heated at 110° C. in the microwave for 0.5 h. The mixture was diluted with glacial HOAc (0.1 mL) and MeOH (0.5 mL) and filtered. The filtrate was directly purified by prep HPLC to afford (S)-3-((S)-1-(4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (11.8 mg, 57%) as an oil. LC-MS Method 1 tR=1.55 min, m/z=497, 248; 1H NMR (CDCl3) 1.13 (s, 3H), 1.19 (s, 3H), 1.56 (d, 3H), 2.15-2.35 (s, 4H), 2.42 (m, 2H), 2.88 (m, 1H), 5.71 (q, 1H), 6.64 (d, 1H), 7.04 (d, 2H), 7.18 (d, 2H), 7.30-7.40 (5H), 7.52 (1H), 7.60 (m, 1H), 7.75 (t, 1H).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12]([O:14]C2C=CC([N+]([O-])=O)=CC=2)=O)C=CC=CC=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37].C(N(CC)CC)C.CC1C(=O)C2N3[C@@](OC)([C@H](COC(N)=O)C=2C(=O)C=1OC)[C@H]1N[C@H]1C3>CO>[CH2:36]([N:38]([CH2:39][CH3:40])[C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:14])[CH3:37]
Reactant: CCNCC
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)SCCN
Yield: 60 %

Procedure:
2-diethylaminocarbonylthioethylamine (formate: 184 mg) was prepared by subjecting N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (500 mg) and diethylamine (316 μl) to the similar reactions to those described in References 2 and 4. The product was dissolved in anhydrous methanol (4 ml). To the solution were added triethylamine (174 μl) and mitomycin A (273 mg: 0.75 molar equivalent). The reaction solution was treated in a similar manner to that described in Example 1 to obtain Compound 4 (130 mg) in the form of grayish blue powders with a yield of 60%.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][C@H:40]([CH2:43][CH3:44])[CH2:41][OH:42]>>[OH:42][CH2:41][C@H:40]([NH:39][C:33](=[O:35])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH:31]=1)[CH2:43][CH3:44]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: CC[C@@H](N)CO
Product: CC[C@H](CO)NC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 64.8 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg, 0.50 mmol, 1.0M in DMF) were combined to give 39 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 602 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15](OC3C=CC=CC=3)[C:14]=2[N:13]=[C:12]1[CH2:29][CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:36].[OH-].[K+]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15]([NH2:36])[C:14]=2[N:13]=[C:12]1[CH2:29][CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOCc1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCOCc1ccccc1
Temperature: 156 °C
Yield: 29.9 %

Procedure:
1-[2-(Benzyloxy)ethyl]-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine (6.6 g, 15.8 mmol) and ammonium acetate (66 g) were combined in a dried glass pressure flask under nitrogen with stirring. The flask was sealed with a teflon screw cap and heated to 156° C. for 44 hours. The reaction was complete as determined by HPLC and LC/MS, and the resulting solution was cooled and basified to a pH of about 14 with 1 N potassium hydroxide. The basic solution was extracted with dichloromethane (5×), and the organic layers were combined, washed with 1 N potassium hydroxide (3×), water (1×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate/diethyl ether, and the resulting solids were filtered off and dried. NMR analysis of the solids indicated impurities. The solids were recrystallized from isopropyl alcohol and dried. Impurities were found in the resulting solids (3.2982 g), which were then recrystallized from ethyl acetate/hexane and again dried. The resulting solids (2.4076 g), still with impurities, were dissolved in ethanol, and the resulting solution was treated with 1 M hydrochloric acid in diethyl ether (10 mL). The resulting hydrochloride salt was filtered off, dissolved in water, and the aqueous solution was basified with 1N potassium hydroxide to a pH of about 14. The resulting aqueous mixture was extracted with dichloromethane (5×), and the combined organic layers were washed with water (3×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid was dried to provide 1.5999 g of 1-[2-(benzyloxy)ethyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 99.5-100.0° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[C:24]1([O:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:12])=[CH:19][CH:18]=2)(=[O:21])=[O:22])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1
Reactant: O=C1Nc2ccccc2C1=CO
Product: O=C1Nc2ccccc2C1=CNc1ccc(S(=O)(=O)Oc2ccccc2)cc1
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield from 3-hydroxymethylene-1,3-dihydro-indol-2-one and phenyl 4-aminobenzenesulfonate according to Procedure J: 1H NMR (DMSO-d6): δ 10.8 (d, 1H), 10.5 (s, 1H), 8.6 (d, 1H), 7.7 (d, 2H), 7.6 (m, 3H), 7.4 (m, 2H), 7.3 (m, 1H), 7.0 (m., 3H), 6.9 (t, 1H), 6.8 (d, 1H); APCI−MS m/z 391 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][C:7]1[S:8][CH2:9][C:10](=[O:12])[N:11]=1.C(O[Na])(C)=O.O=C1C(=[CH:28][C:29]2[N:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[CH:32]3)SC(NCC2SC=CC=2)=N1>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:28][C:29]2[N:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[CH:32]3)[C:10](=[O:12])[N:11]=1
Reactant: O=C1CSC(NCc2ccc(F)c(Cl)c2)=N1
Reactant: N#Cc1cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc2c1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(C=C3SC(NCc4ccc(F)c(Cl)c4)=NC3=O)nc2c1
Temperature: 120 °C
Yield: 45.1 %

Procedure:
To a mixture of 2-(3-chloro-4-fluoro-benzylamino)-thiazol-4-one (41.4 mg, 0.16 mmol) (prepared as described below) AcONa (160 mg, 1.95 mmol), and 6-formyl-[1,5]naphthyridine-3-carbonitrile (33.6 mg, 0.18 mmol) (see Example 11) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 120° C. (oil bath) for 3 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, AcOEt and ether to give 6-[2-(3-chloro-4-fluoro-benzylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-[1,5]naphthyridine-3-carbonitrile as a light brown solid (30.6 mg, 45.1%). HR-ES (+) m/e calcd for C20H11FClN5OS (M+H)+ 424.0430. found 424.0431.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C@@H:9]1([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([OH:22])[C:20]=3[N:19]=[CH:18]2)[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1>CN(C=O)C>[Si:5]([C@@:11]1([OH:12])[C@@H:13]([CH2:14][O:15][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[O:16][C@@H:9]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([OH:22])[C:20]=3[N:19]=[CH:18]2)[CH2:10]1)([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@]1(O)[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of TBSCl (1.91 g, 12.67 mmol) was added to a solution of 2′-deoxyinosine (1.00 g, 3.96 mmol) and imidiazole (1.73 g, 25.34 mmol) in anhydrous DMF (3 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was gradually warmed to room temperature and stirred for 12 hours. The mixture was then concentrated in vacuo, dissolved in CH2Cl2 (100 mL), washed twice with water (50 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to yield 3′,5′-O-bis-tert-butyldimethylsilyl-2′-deoxyinosine dA.n9 (1.58 g, 83%) as a white powder.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([F:24])([F:23])[CH2:6][C@H:7]([NH:11][C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])[C:8](O)=[O:9])[CH2:3][CH2:2]1.CN(C(ON1N=[N:40][C:35]2[CH:36]=[CH:37]C=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.C(C1CC1)#N>CN(C=O)C>[C:34]([C:35]1([NH:40][C:8](=[O:9])[C@@H:7]([NH:11][C@@H:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([F:15])([F:14])[F:16])[CH2:6][C:5]([F:23])([F:24])[CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:37][CH2:36]1)#[N:39]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)[C@H](CC(F)(F)CC1CC1)N[C@@H](c1ccccc1)C(F)(F)F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@H](CC(F)(F)CC2CC2)N[C@@H](c2ccccc2)C(F)(F)F)CC1
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
A stirred solution of (S)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanoic acid (150 mg, 0.4 mmol) in DMF (15 mL) was treated with HATU (253 mg, 0.5 mmol) and DIPEA (0.3 mL, 1.7 mL mmol). After 15 min, 1-cyanocyclopropane hydrochloride (61 mg, 0.5 mmol) was added and the reaction mixture was stirred under a nitrogen atmosphere for 2 h. Once the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate & washed with 1 HCl solution and brine, dried over Na2SO4, filtered and was concentrated. The crude compound was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane followed by re-crystallization from DCM and pentane to provide (S)—N-(1-cyanocyclopropyl)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanamide (65 mg, 37%) as white solid. 1H-NMR (500 MHz, DMSO-d6): 8.88 (1H, s, NH), 7.38 (5H, s, Ar—H), 4.23 (1H, m, CHCF3), 3.39 (1H, m, CH), 3.18 (1H, m, NH), 2.23 (2H, m, CH2), 1.94 (2H, m, CH2), 1.32 (2H, m, CH2), 0.82 (2H, m, CH2), 0.57 (1H, m, CH), 0.45 (2H, m, CH2), 0.12 (2H, m, CH2). 19F-NMR (500 MHz, CD3OD): −74.609 (CF2), −95.308, −95.507 (CF3). EIMS (m/z): 416 (M+H)1. HPLC: 97.37% (RT 16.39)Column used zorbax SB, C8, 250×4.6 mm, SuMobile Phase: ACN (B): 0.1% TFA in water (A) Flow rate: 1.0 mL/Min
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(F)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(F)ccc43)nc2c1
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of methyl 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (88 mg, 0.18 mmol) in methanol (25 mL) and water (1 mL) was added sodium hydroxide (24.5 mg, 0.61 mmol) with stifling overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (10 mL), adjusted to pH 4 with hydrochloric acid (3 N) to give the precipitation, which was collected by filtration to afford 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (63 mg, 79%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:15]Br.O>FC(F)(F)C(O)=O.C(O)(=O)C>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([Br:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc2c1CCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c2c1CCCC2
Reaction time: 0.25 h

Procedure:
To a mixture of 1-acetylamino-5,6,7,8-tetrahydronaphthalene (1.9 g, 10 mmol) in trifluoroacetic acid (20 ml) was added: bromine (0.55 ml, 10 mmol) solved in acetic acid (5 ml). The mixture was stirred for 15 min at room-temperature. Water (50 ml) was added and the crystals were filtered. Yield 2.6 g (97%). Mp=185.2-188.6° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[CH:9]=1.CS(O[CH2:26][C@@H:27]([NH:29]C(OC(C)(C)C)=O)[CH3:28])(=O)=O>CN(C)C=O.O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:26][C@@H:27]([NH2:29])[CH3:28])=[C:10]([CH:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])[CH:9]=1
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CC(c1cc(F)ccc1O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1cc(F)ccc1OC[C@H](C)N)C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Cesium carbonate (28.6 g, 87.8 mmol) was added to a solution of crude 4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenol (C44) (6.00 g, 28.8 mmol) in N,N-dimethylformamide (60 mL). After addition of (2S)-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate (P12) (7.5 g, 29.6 mmol), the reaction mixture was heated in a 60° C. oil bath for 30 minutes, then treated with additional P12 (7.5 g, 29.6 mmol) and heated for 18 hours. At this point, the reaction mixture was allowed to cool to room temperature, diluted with water (500 mL), and extracted with diethyl ether (3×150 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting material (11.23 g) was dissolved in dichloromethane (200 mL); trifluoroacetic acid (40 mL) was added, and the reaction mixture was stirred for 1 hour. After removal of solvents in vacuo, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Eluents: 75% ethyl acetate in heptane, then ethyl acetate, then 10% methanol in ethyl acetate) afforded the product as a roughly 1:1 mixture of two diastereomers, as assessed by 1H NMR. Yield: 5.44 g, 20.5 mmol, 71%. LCMS m/z 266.1 (M+1). 1H NMR (400 MHz, CDCl3) δ [1.31 (d, J=6.6 Hz) and 1.32 (d, J=6.6 Hz), total 3H], 1.41 (d, J=7.2 Hz, 3H), 3.50-3.59 (m, 1H), 3.82-4.22 (m, 3H), 6.79-6.84 (m, 1H), 6.92-6.98 (m, 1H), 7.05-7.11 (m, 1H). Also obtained was material enriched in the higher Rf diastereomer (1.10 g, 4.15 mmol, 14%) and material enriched in the lower Rf diastereomer (324 mg, 1.22 mmol, 4%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[C:19]([N:26]1[CH:30]=[CH:29]N=C1)(N1C=CN=C1)=[O:20].[CH3:31][N:32]1[C:40]2[C:35](=[CH:36]C(N)=C[CH:39]=2)[CH:34]=[N:33]1>C(Cl)Cl>[CH3:31][N:32]1[C:40]2[C:35](=[CH:36][C:30]([NH:26][C:19]([NH:18][C:14]3[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=3)[O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=3)=[O:20])=[CH:29][CH:39]=2)[CH:34]=[N:33]1
Reactant: Cn1ncc2cc(N)ccc21
Reactant: COC(=O)c1cc(Oc2cccc(N)c2)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2cccc(NC(=O)Nc3ccc4c(cnn4C)c3)c2)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.1 %

Procedure:
To a solution of 4-(3-amino-phenoxy)-pyridine-2-carboxylic acid methyl ester (0.79 g, 5.35 mmol) in CH2Cl2 (3 mL) was added 1,1′-carbonyldiimidazole (0.87 g, 5.35 mmol), and the reaction mixture was stirred at room temperature for 12 h. A solution of 1-methyl-5-aminoindazol (1.02 g, 6.96 mmol) in CH2Cl2 (4 mL) was added, and the mixture stirred at room temperature an additional 8 h. The mixture was concentrated in vacuo. Purification of the crude product by column chromatography eluted with CH2Cl2/MeOH (95:5) gave 850 mg (38%) of the title compound. 1H-NMR (CD3OD) δ 8.57 (dd, 1H), 7.95 (d, 1H), 7.87 (d, 1H), 7.54 (d, 1H), 7.53-7.51 (m, 2H), 7.47-7.32 (m, 2H), 7.32 (d, 1H), 7.21 (dd, 1H), 6.86 (dd, 1H). 4.07 (s, 3H), 3.96 (s, 3H); MS LC-MS [M+H]+=418.2, RT=2.91 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([C:17]([C:19]4[C:20]([C:25]5[N:29](C6CCCCO6)[N:28]=[CH:27][CH:26]=5)=[N:21][CH:22]=[CH:23][CH:24]=4)=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1.Cl.[OH-].[Na+]>C1COCC1.O>[NH:29]1[C:25]([C:20]2[C:19]([C:17]([N:15]3[CH2:16][CH:11]4[CH:12]([CH2:13][N:9]([C:4]5[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=5)[CH2:10]4)[CH2:14]3)=[O:18])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:26][CH:27]=[N:28]1
Reactant: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccnc4-c4ccnn4C4CCCCO4)CC3C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccnc4-c4ccn[nH]4)CC3C2)n1
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methanone (Example 236) (210 mg, 0.43 mmol) in THF (10 mL) and H2O (1 mL) was added 4 N aq. HCl (1 mL). The reaction was let stir for 2 hours, neutralized with 3 N aq. NaOH, and extracted with DCM (3×20 mL). The organics were combined, dried with Na2SO4, and concentrated. Purification (FCC) (MeOH(NH3)/DCM) gave the title compound (128 mg, 73%) (MS (ESI): mass calculated for C21H23N7O, 389.20; m/z found 390.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.68-8.59 (m, 1H), 7.63 (d, J=9.1, 2H), 7.32-7.20 (m, 1H), 6.80 (d, J=2.2, 1H), 6.33-6.19 (m, 1H), 3.92-3.55 (m, 5H), 3.54-2.78 (m, 5H), 2.37-2.24 (m, 6H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[OH:17].[O:18]=O>C(Cl)(Cl)Cl>[CH3:16][C:12]1[C:13](=[O:18])[C:14]([CH3:15])=[C:9]([CH3:8])[C:10](=[O:17])[CH:11]=1
Reactant: O=O
Reactant: Cc1cc(C)c(C)c(O)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1=CC(=O)C(C)=C(C)C1=O

Procedure:
3.96 g of cobalt di-(salcylal)-3,3'-diimino -di-n-propylamine (0.1 mole) and 1.01 g of triethylamine (0.01 mole) were dissolved in 100 ml of chloroform and oxygen gas (100 ml/min) was then bubbled into the resulting solution for 5 seconds at a temperature of 10°C to form an oxygen complex. To this was added a solution of 13.6 g of 2,3,5-trimethylphenol (0.1 mole) in 100 ml of chloroform in three portions and oxygen gas (250 ml/min) was again introduced into the solution for a period of 8 hours to complete the reaction. After completion of the reaction, chloroform was distilled off and the residue was steam distilled by introducing steam thereinto. The distillate was extracted with ether and the ether was then distilled off to give 15.0 g of pseudocumoquinone (0.1 mole) having a melting point of 32°C, that is, the yield was quantitative.
Reaction SMILES: [Br-:1].C1(C(C2C=CC=CC=2)(C)C(O[C@@H]2C3CC[N+](CC(=O)NC4C=CON=4)(CC3)C2)=O)C=CC=CC=1.[Br-].O[C@@H]1C2CC[N+](CC(=O)NC3C=CON=3)(CC2)C1.[Br-].[OH:56][C@@H:57]1[CH:62]2[CH2:63][CH2:64][N+:59]([CH2:65][C:66](=[O:74])[NH:67][C:68]3[CH:73]=[N:72][CH:71]=[CH:70][N:69]=3)([CH2:60][CH2:61]2)[CH2:58]1.[CH:75]1([C:80]([OH:90])([C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)[C:81](O)=[O:82])[CH2:79][CH2:78][CH2:77][CH2:76]1>>[Br-:1].[CH:75]1([C:80]([OH:90])([C:84]2[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=2)[C:81]([O:56][C@@H:57]2[CH:62]3[CH2:63][CH2:64][N+:59]([CH2:65][C:66](=[O:74])[NH:67][C:68]4[CH:73]=[N:72][CH:71]=[CH:70][N:69]=4)([CH2:60][CH2:61]3)[CH2:58]2)=[O:82])[CH2:79][CH2:78][CH2:77][CH2:76]1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1cnccn1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: CC(C(=O)O[C@H]1C[N+]2(CC(=O)Nc3ccon3)CCC1CC2)(c1ccccc1)c1ccccc1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCC1)C2)Nc1cnccn1

Procedure:
This compound is prepared analogously to (R)-3-(2,2-Diphenyl-propionyloxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Example 4), substituting (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) with (R)-3-Hydroxy-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate H) and by replacing 2,2′-diphenylpropionic acid with cyclopentyl-hydroxy-phenyl-acetic acid, yielding the titled compound as a diastereomeric mixture. (M+465.4)
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.92 min; [M+H]+=393.99.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][C:20]([SH:22])=[N:19][N:18]=3)=[CH:13][C:12]=12.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl>>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][S:22][C:20]1[O:21][C:17]([C:14]2[CH:15]=[CH:16][N:11]3[N:10]=[CH:9][N:8]=[C:12]3[CH:13]=2)=[N:18][N:19]=1
Reactant: Fc1cccc(CCl)c1
Reactant: Sc1nnc(-c2ccn3ncnc3c2)o1
Solvent: CCN(CC)CC
Product: Fc1cccc(CSc2nnc(-c3ccn4ncnc4c3)o2)c1
Yield: 27 %

Procedure:
In the same manner as in Example 1 and using 5-(1,2,4-triazolo[1,5-a]pyridin-7-yl)-1,3,4-oxadiazole-2-thiol triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 27%) was obtained as colorless crystals.