Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C@H:8]([C:36](OCC)=[O:37])[CH2:7]1)=[O:5])[CH3:2].C(OC(N1CCC(N)CC1)=O)(C)(C)C.N(C(C)C)=C=O.[BH4-].[Li+]>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C@H:8]([CH2:36][OH:37])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OCC)CC[C@@H]1NS(=O)(=O)c1ccc(NC(=O)c2ccccc2C)c2ccccc12
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(C)N=C=O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CC[C@H](NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3ccccc23)[C@H](CO)C1

Procedure:
(±)-(cis)-4-[4-(2-Methyl-benzoylamino)-naphthalene-1-sulfonylamino]-piperidine-1,3-dicarboxylic acid diethyl ester was made following general procedure in Scheme 5, substituting (±)-4-amino-1-benzyl-piperidine-3-carboxylic acid ethyl ester (5) for 4-amino-piperidine-1-carboxylic acid tert-butyl ester, and substituting ethyl chloroformate for 2-isocyanato-propane. To the solution of (±)-(cis)-4-[4-(2-Methyl-benzoylamino)-naphthalene-1-sulfonylamino]-piperidine-1,3-dicarboxylic acid diethyl ester (57 mg, 0.1 mmol) in THF (5 mL), was added lithium borohydride in THF solution (0.5 mL, 0.25 mmol) and the resultant solution was stirred at 0° C. for 2 h. The solvent was removed in vacuo and the crude material was purified by HPLC to give the title compound. 1H NMR (300 MHz, MeOD) δ 8.81 (d, 1H), 8.33 (d, 1H), 8.24 (d, 1H), 7.94 (d, 1H), 7.72 (m, 3H), 7.40 (m, 3H), 4.06 (q, 2H), 3.55 (m, 2H), 3.32 (m, 5H), 2.56 (s, 3H), 1.75 (m, 1H), 1.30 (m, 2H), 1.20 (t, 3H); LC/MS m/z 526 (M+H)+
Reaction SMILES: Cl.O1CCCC1.C([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([C:23]1[C:24](=[O:35])[C:25]2[C:30]([C:31](=[O:34])[C:32]=1[CH3:33])=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C>C(OCC)(=O)C>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([C:23]1[C:24](=[O:35])[C:25]2[C:30]([C:31](=[O:34])[C:32]=1[CH3:33])=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)OCCCCCC(C1=C(C)C(=O)c2ccccc2C1=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=C(C(CCCCCO)c2ccccc2)C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 83.7 %

Procedure:
6N Hydrochloric acid (20 ml) was added to a tetrahydrofuran solution (20 ml) containing 1-acetoxy-6-(3-methyl-1,4-naphthoquinon -2-yl)-6-phenylhexane (2.8 g, 7.2 mmole), followed by stirring for 5 hours with heating at 70° C. After cooling, ethyl acetate was added to the reaction solution, and the organic layer was separated out, washed with water, dried and evaporated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl ether-ethyl acetate (1:1), followed by recrystallization of the object compound from isopropyl ether to give 1-hydroxy-6-(3-methyl-1,4-naphthoquinon -2-yl)-6-phenylhexane (2.1 g). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 75, 79 and 81 were prepared.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.P(Cl)(Cl)([Cl:14])=O.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:14][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:6]=2[N:7]=1
Reactant: Cc1ccc2oc(S)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc2oc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methyl-benzooxazole-2-thiol (5.0 g, 30.2 mmol), phosphorus oxychloride (25.0 mL, 269.4 mmol), and phosphorus pentachloride (7.56 g, 36.3 mmol) were combined in CH2Cl2 (30 mL), and the reaction was stirred at room temperature overnight. The mixture was concentrated several times from fresh CH2Cl2 to remove traces of phosphorus oxychloride, and the residue was treated with saturated aqueous Na2CO3 to adjust to pH 8. The aqueous layer was extracted twice with CH2Cl2, and the combined organic layers were washed with H2O and brine, and then dried over Na2SO4, decanted, and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40](=[O:48])[CH2:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[CH3:38][O:39][C:40](=[O:48])[CH2:41][CH:42]1[CH2:43][CH2:44][N:45]([C:32]([N:12]2[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:46][CH2:47]1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COC(=O)CC1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)OC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with piperidin-4-yl-acetic acid methyl ester (Astatech) to give the title compound. HR-MS (ES, m/z) calculated for C37H45Cl2N4O4 [(M+H)+] 679.2813, observed 679.2808.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH2:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(O)(=[O:23])C.ClC1C=CC=C(C(OO)=O)C=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH2:20])=[O:19])[C:11]3=[N+:12]([O-:23])[CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ccc[n+]([O-])c21
Temperature: 60 °C
Yield: 52 %

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide (1.84 g, 0.0064 mole), glacial acetic acid, and m-chloroperbenzoic acid (4.4 g, 0.0256 mole) was heated at 60° C. for a total of 4 hrs. The reaction mixture was diluted with water and the organic acid which precipitated was filtered. The aqueous filtrate was neutralized for peroxides with 10% sodium sulfite. The aqueous solution was evaporated to dryness and the residue was treated with methylene chloride/saturated sodium bicarbonate. The insoluble precipitate was filtered, washed with methylene chloride and water, and dried at 50° C. under high vacuum overnight to give 1.0 g (52%) of title compound, mp. 272°-75° C. with decomposition.
Reaction SMILES: [ClH:1].[F:2][CH:3]([F:21])[O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:9]=2[CH:20]=1.[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.ClCCCl>[ClH:1].[F:21][CH:3]([F:2])[O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([CH:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)[CH2:18][CH2:19]3)[C:9]=2[CH:20]=1
Reactant: O=c1[nH]c2ccc(OC(F)F)cc2n1C1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=c1[nH]c2ccc(OC(F)F)cc2n1C1CCN(C2CCOCC2)CC1
Yield: 68.6 %

Procedure:
6-[(Difluoromethyl)oxy]-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D54, 0.3 g) 1,2-dichloroethane (10 ml) and triethylamine (0.5 ml), tetrahydro-4H-pyran-4-one (0.6 g), sodium triacetoxyborohydride (0.6 g) was stirred at room temperature over 3 days. The mixture was poured into sodium bicarbonate solution and extracted with dichloromethane. The organic phase was separated, washed with brine and the solvent was removed and the residue was chromatographed on silica gel eluted with dichloromethane/2M ammonia in methanol 0-10%. The resulting product was dissolved in a mixture of methanol and dichloromethane, treated with 1M hydrogen chloride in ether and the solvent was removed. Recrystallisation from methanol gave the title compound as a white solid (0.26 g). Mass Spectrum 368 M+H+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:63])([F:62])[C:9]([O:18][CH2:19][C:20]([CH2:47][O:48][C:49]([C:58]([F:61])([F:60])[F:59])([C:54]([F:57])([F:56])[F:55])[C:50]([F:53])([F:52])[F:51])([CH2:32][O:33][C:34]([C:43]([F:46])([F:45])[F:44])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])[CH2:21][O:22][CH2:23][CH2:24][C:25](OC(C)(C)C)=[O:26])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11]>C1COCC1>[F:7][C:8]([F:62])([F:63])[C:9]([O:18][CH2:19][C:20]([CH2:32][O:33][C:34]([C:35]([F:36])([F:37])[F:38])([C:39]([F:40])([F:41])[F:42])[C:43]([F:44])([F:45])[F:46])([CH2:47][O:48][C:49]([C:50]([F:53])([F:52])[F:51])([C:54]([F:55])([F:56])[F:57])[C:58]([F:61])([F:60])[F:59])[CH2:21][O:22][CH2:23][CH2:24][CH2:25][OH:26])([C:10]([F:13])([F:12])[F:11])[C:14]([F:17])([F:16])[F:15]
Reactant: CC(C)(C)OC(=O)CCOCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCOCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
(—OH version of 19F-27): To a suspension of lithium aluminum hydride (4.1 g, 108 mmol) in THF solution (450 mL) at 0° C. was added dropwise compound 4 (40 g, 43.5 mmol) in THF (100 mL). Afterward, the solution was stirred overnight at room temperature and quenched with dilute HCl carefully, concentrated through rotary evaporation, and subjected to silica gel chromatography using hexane/EtOAc as the eluent to afford alcohol 5 (33.7 g, 39.7 mmol, 91% yield) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 4.02 (s, 6H), 3.69 (t, J=6.0 Hz, 2H), 3.51 (t, J=4.5 Hz, 2H), 3.37 (s, 2H), 1.82-1.77 (m, 2H), 1.47 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 120.4 (q, J=294.7 Hz), 80.1-79.4 (m), 69.3, 66.3, 66.7, 60.4, 46.4, 32.5; 19F NMR (470 MHz, CDCl3) δ—73.40 (s); MS (APCI) m/z 849 (M+H)+; HRMS (ESI) calcd for C20H16F27O5 849.0567 (M+H)+, 866.0832 [M+NH4]+. found 849.0577, 866.0811, respectively.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][OH:16])=[CH:12][CH:13]=1)([CH3:4])[CH3:3].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:4][C:2]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][O:16][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:12][CH:13]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(CCO)o1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CCOCc2ccccc2)o1
Yield: 82.4 %

Procedure:
The alcohol 255C (1.00 g, 3.7 mmol) in 12 mL of THF was treated with 60% NaH (177.8 mg, 4.44 mmol), benzyl bromide (0.53 mL, 4.44 mmol) and tetrabutylammonium iodide (50 mg, 5%) for 3 h at rt. Water was added and the mixture was extracted with EtOAc (3×). The combined extracts were washed with water (1×) and brine (1×) and dried over Na2SO4. Purification by flash chromatography on silica gel eluting with 20% hexane/80% CH2Cl2 gave 1.10 g (3.05 mmol, 82.6%) of compound 255D as a yellow oil. E. 2-(2-Hydroxyethyl)-5-[2-(phenylmethoxy)ethyl]furan (255E)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH2:8]([N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1)[CH2:9][CH3:10].Br[C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C(#N)C>[CH2:8]([N:11]1[CH:15]=[C:14]([C:26]2[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=2)[CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH:13]=[N:12]1)[CH2:9][CH3:10]
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Reactant: CCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)cn1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 105.6 %

Procedure:
Pd-118 (51.7 mg) was dissolved in acetonitrile (8 mL) and stirred for 5 min before addition of potassium carbonate (1.1 g), water (8 mL) and a solution of 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (750 mg) in MeCN (1 mL). The mixture was stirred for a further 5 min then a solution of tert-butyl 3-(3-bromophenethoxy)propanoate (870 mg, prepared as in Preparation 3, Step i)) was added and the reaction was heated at the heating block (80° C.) for 30 min. The mixture was cooled and extracted into DCM. Organic was separated using a phase separator cartridge, solvents evaporated to give a brown oil. The crude product was purified by flash silica chromatography using elution gradient 0 to 100% ethyl acetate in isohexane to afford the subtitled compound (1 g) as a gum. MS [M+H-C4H9]+=303 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.63 (s, 1H), 7.34-7.30 (m, 2H), 7.26 (t, J=8.0 Hz, 1H), 7.09-7.05 (m, 1H), 4.11 (t, J=7.2 Hz, 2H), 3.70 (t, J=6.5 Hz, 2H), 3.68 (t, J=7.2 Hz, 2H), 2.89 (t, J=7.2 Hz, 2H), 2.49 (t, J=6.4 Hz, 2H), 1.93 (sextet, J=7.2 Hz, 2H), 1.43 (s, 9H), 0.95 (t, J=7.3 Hz, 3H)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:32][CH2:31][CH2:30][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:32][CH2:31][CH2:30][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(COc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 83.8 %

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-(1-hydroxy-2-phenoxyethyl)pyrrolidine (393 mg) was subjected to DMSO-DCC oxidation in the same manner as in Example 1-D) to give 328 mg of (2S)-1-(N-benzyloxycarbonyl-L-prolyl)-2-(phenoxyacetyl)-pyrrolidine (See Table 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:15]([C:16]2[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]1)(=[O:10])=[O:9].C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH:12]=[C:13]([CH2:24][NH:25][CH3:26])[CH:14]=[C:15]1[C:16]1[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:10])=[O:9]
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
To a solution of tert-butyl {[1-[(2-fluorophenyl)sulfonyl]-5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (218 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 147 mg, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].[Br:25][CH2:26][CH2:27][CH2:28]Br>CC(CC)=O>[Br:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(c1ccccc1)c1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCCBr)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-hydroxy-3-nitrobenzophenone (2.5 g) and 7.1 g of potassium carbonate were suspended in 15 ml methylethylketone. The suspension was stirred under heating with reflux for 30 minutes, added with 1,3-dibromopropane and then heated with reflux for 6 hours. The reaction mixture was cooled down to room temperature, and insoluble substances were removed by filtration. The filtrate was then concentrated, and the resultant precipitate was subjected to silica gel column chromatograph (hexane/ethyl acetate=3.1 (v/v)) for purification; thereby 2.08 g of an oil, 4-(3-bromopropyloxy)-3-nitrobenzophenone, was obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](CC2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH:39]=O>>[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: COc1ccccc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccccc1CN1C[C@@H](C)[C@H](c2nc3c(cnn3C3CCOCC3)c(=O)[nH]2)C1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyano borohydride and 2-methoxybenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.29-7.22 (m, 2H), 6.92-6.88 (m, 2H), 4.83-4.75 (m, 1H), 4.14-4.08 (m, 2H), 3.93 (s, 3H), 3.76-3.69 (m, 2H), 3.62-3.54 (m, 2H), 3.34 (t, J=8.7 Hz, 1H), 3.01 (d, J=9.5 Hz, 1H), 2.78 (m, 1H), 2.56 (m, 1H), 2.41-2.27 (m, 3H), 1.92-1.82 (m, 3H), 1.18 (d, J=7.1 Hz, 3H). MS: (M+H m/z 424.1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH:15]=C)=[C:11]2[C:17]([O:19][CH3:20])=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:25]CC1.I([O-])(=O)(=O)=O.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.[Os](=O)(=O)(=O)=O.O>[CH:15]([C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:11]=1[C:17]([O:19][CH3:20])=[O:18])=[O:25]
Reactant: C=Cc1ccn(S(=O)(=O)c2ccccc2)c1C(=O)OC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C=O)ccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of methyl 1-(phenylsulfonyl)-3-vinyl-1H-pyrrole-2-carboxylate (1640 mg, 5.63 mmol) in 45 ml of tetrahydrofurane were added 4-methylmorpholine 4-oxide (1.36 g, 11.3 mmol) and 2,4 ml (0.39 mmol) of a 4% aqueous solution of osmium tetraoxide and the reaction was leaved with stirring at room temperature overnight. Afterwards, the starting material was completely consumed and the reaction mixture was filtered through a pad of Celite® using tetrahydrofurane. The filtrate was evaporated to dryness, taken up with ethyl acetate and washed with water and brine. The organic layer was dried (Na2SO4) and concentrated to give a brown residue that was immediately submitted to the next step. In this sense, this residue was dissolved in tetrahydrofurane (28 ml) and water (3,4 ml) and solid sodium periodate (1.8 g, 8.4 mmol) was added stirring the reaction vigorously at room temperature overnight. Next day, a suspension was formed and reaction was finished. The work-up was done by adding 4% aqueous solution of sodium bicarbonate (200 ml) and extracting with ethyl acetate (3×). The organic mixture was washed with water and brine, dried (Na2SO4) and concentrated to dryness to give a residue that was purified by flash chromatography silica (hexane/ethyl acetate) to give a 1.46 g (88% yield) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1.Cl>C(O)C.[Fe]>[F:13][CH:2]([F:1])[O:3][C:4]1[N:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OC(F)F)nc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(OC(F)F)nc1
Yield: 106.3 %

Procedure:
To a solution of 2-(difluoromethoxy)-5-nitropyridine (0.900 g, 2.35 mmol) in ethanol (5.0 mL), was added iron powder (0.400 g, 7.14 mmol) and conc. HCl (0.2 mL). The reaction mass was refluxed for ½ h. Ethanol was removed under vacuum. To the reaction mass, water was added, basified with NaHCO3 and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.400 g of the desired product. 1HNMR (DMSO-d6): δ 7.65 (s, 1H), 7.52-7.03 (t, J=72.0 Hz, 1H), 7.27 (s, 1H), 6.73 (d, J=8.4 Hz, 1H); MS [M−H]−: 159.14.
Reaction SMILES: ClC1SC2NC(C([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:22][C@@H:23]4COC(C)(C)O4)[C:13]3=[O:30])=O)=CC=2C=1.[CH3:32][S:33]CCCl>>[NH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:22][CH2:23][S:33][CH3:32])[C:13]1=[O:30]
Reactant: CC1(C)OC[C@@H](CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)O1
Reactant: CSCCCl
Product: CSCCN1C(=O)C(N)Cc2ccccc21

Procedure:
Prepared by an analogous method to 3-amino-1-(2-methoxyethyl)-3,4-dihydroquinolin-2(1H)-one (Method 12) using 2-chloroethyl methyl sulphide instead of 2-bromoethyl methyl ether to give the title product as a clear, brown gum.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[F:17])(=O)=O.B([C:23]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:24]=1[O:25][C@@H:26]([CH3:30])[C:27]([OH:29])=[O:28])(O)O>>[F:17][C:8]1[CH:9]=[C:10]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:11]=[CH:12][C:7]=1[C:31]1[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=[CH:23][C:24]=1[O:25][C@@H:26]([CH3:30])[C:27]([OH:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1-c1ccc(S(C)(=O)=O)cc1F)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from step (i) and the product from example 146 step (iv).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(C)CC3)s2)c(C)[nH]c1=O
Yield: 63.3 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-methylpiperazine as described in Steps 5 and 6, Example 24 to give the title compound as a solid (63.3% yield). LC/MS: RT 2.07 min; m/e 382 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 11.3 (1H, s), 7.7 (1H, d); 7.4 (1H, s); 7.32 (1H, d), 4.8 (2H, m), 3.5 (2H, d), 3.2 (2H, m), 2.9 (2H, t), 2.75 (3H, s), 2.4 (2H, q), 2.36 (3H, s), 1.1 (3H, t).