Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>C1COCC1>[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1c([N+](=O)[O-])cnc2ccccc12
Yield: 43 %

Procedure:
4-Chloro-3-nitroquinoline (J. Med. Chem. 1974, 17, 245) (2.08 g, 0.01 mol) and 2-methylaniline (2.14 g, 0.02 mol) were dissolved in THF (50 ml) and the mixture stirred at reflux for 16 hours, during which time a pale yellow solid was deposited. After cooling, the solvent was evaporated and the residue dissolved in 2M HCl (80 ml). The acidic solution was extracted with CHCl3 (×3) and the chloroform solution washed with aqueous NaHCO3 and water. Drying and evaporation of the chloroform gave an orange-yellow solid which was crystallised from absolute ethanol to give the title compound (1.2 g, 43%) as orange needles, m.p. 137°-138°.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)(=O)=O.O[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:32][C:33]3[CH:46]=[CH:45][C:36]4[C@H:37]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:38][O:39][C:35]=4[CH:34]=3)[CH:26]=2)=[C:20]([CH3:47])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:44][O:43][C:41](=[O:42])[CH2:40][C@H:37]1[C:36]2[CH:45]=[CH:46][C:33]([O:32][CH2:31][C:27]3[CH:26]=[C:25]([C:21]4[C:22]([CH3:24])=[CH:23][C:18]([O:5][CH:6]5[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]5)=[CH:19][C:20]=4[CH3:47])[CH:30]=[CH:29][CH:28]=3)=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)cc4C)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CN(C(=O)OC(C)(C)C)C5)cc4C)c3)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate 14a (100 mg, 0.40 mmol, prepared by a method disclosed in PCT patent application WO2011097958”), (S)-methyl 2-(6-((4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 h (80 mg, 0.19 mmol) and cesium carbonate (130 mg, 0.40 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The reaction solution was heated to 80° C. and stirred for 12 hours. The resulting solution was mixed with 10 mL of water, and extracted with ethyl acetate (30 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-tert-butyl 3-((3′-(((3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yl)oxy)methyl)-2,6-dimethylbiphenyl-4-yl)oxy)azetidine-1-carboxylate 14b (60 mg, yield 50.0%) as a colorless oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[Cl:5][C:6]1[CH:10]=[C:9]([C:11](Cl)=[O:12])[NH:8][C:7]=1[C:14]([O:16][CH3:17])=[O:15]>C1COCC1>[Cl:5][C:6]1[CH:10]=[C:9]([C:11]([NH:4][CH2:3][CH2:1][OH:2])=[O:12])[NH:8][C:7]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1[nH]c(C(=O)Cl)cc1Cl
Reactant: NCCO
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c(C(=O)NCCO)cc1Cl
Yield: 57.3 %

Procedure:
Ethanolamine (0.175 mL, 2.90 mmol) was added to a solution of methyl 3-chloro-5-(chlorocarbonyl)-1H-pyrrole-2-carboxylate (0.150 g, 0.580 mmol) in THF and the resulting solution stirred until no starting material was evident by TLC. Purification was accomplished by silica gel column chromatography (30-100% EtOAc/hexanes) to afford the title compound (0.082 g, 57%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (br. s., 1H), 8.42 (t, 1H), 6.80 (s, 1H), 4.75 (t, 1H), 3.78 (s, 3H), 3.46 (q, 2H), 3.27 (q, 2H). LCMS: m/z 245.4 (M−1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][C:13](=[O:15])[O:12][C:11]([CH3:17])([CH3:16])[C:10]=2[CH:18]=1.[CH:19]1([C:25]2[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([C:25]2[CH:26]=[CH:27][C:28]([S:31][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:7]=[CH:8][C:9]4[NH:14][C:13](=[O:15])[O:12][C:11]([CH3:17])([CH3:16])[C:10]=4[CH:18]=3)=[CH:29][CH:30]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Sc1ccc(C2CCCCC2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCSc3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(3-chloropropoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:32]([CH:31]=[CH2:30])(=[O:34])=[O:33])[CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (5.0 g) and triethylamine (6.792 g) in dichloromethane (80 ml) was added dropwise at 0° C. a solution of 2-chloroethanesulfonyl chloride (4.11 g) in dichloromethane (20 ml), and the mixture was stirred at 0 for 30 minutes. The reaction solution was diluted with dichloromethane, washed with water, citric acid solution, sodium bicarbonate solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless amorphous of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-vinylsulfonyl-2-piperazinone (3.99 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)c(F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)c(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (1.967 g, 4.90 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.290 mL, 4.90 mmol) in water (2.000 mL) was added and the mixture stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.300 mL, 4.90 mmol) was added and stirring continued at −40° C. for 3.5 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (25.3 mL, 151.92 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM (150 mL) and water (150 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (1.354 g, 74.6%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.84-2.10 (m, 4H), 2.48-2.54 (m, 1H), 2.69-2.76 (m, 1H), 2.96-3.03 (m, 1H), 3.10-3.18 (m, 1H), 3.64 (s, 3H), 3.94-4.01 (m, 1H), 4.18-4.25 (m, 1H), 5.73 (s, 1H), 6.69-6.75 (m, 2H). MS m/z 369 (M−H)−
Reaction SMILES: [C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[C:11](OCC)=[O:12])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:6](=[O:24])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].CO>CCO>[C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[CH2:11][OH:12])[N:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:6](=[O:24])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1C2C1N(Cc1ccc(F)cc1)C(=O)CN2C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C2C(CO)C21
Reaction time: 8 h

Procedure:
To a solution of the exo isomer of ethyl 5-acetyl-2-(4-fluorobenzyl)-3-oxo-2,5-diazabicyclo[4.1.0]heptane-7-carboxylate (3.3 g, 9.87 mmol) in 32 ml EtOH at room temperature was added sodium borohydride (398 mg, 10.5 mmol). After stirring overnight, the reaction mixture was treated with 200 mL MeOH, stirred for 1 h and then concentrated. The residue was dissolved in dichloromethane (100 mL), treated with 1N HCl (10 mL) and water (20 mL). The aqueous phase was back extracted with chloroform (2×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate and methanol as eluents to give title product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:5]1[N:4]=[N:3][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2)nn1
Yield: 74 %

Procedure:
A mixture of 3-chloro-6-methoxy-pyridazine (4.0 g, 27.7 mmol) and phenyl boronic acid (5.1 g, 41.6 mmol) in toluene (160 mL) was degassed and tetrakis(triphenylphosphine)palladium (960 mg, 0.83 mmol) and 2M sodium carbonate (29.3 mL, 58.7 mmol) were added. The mixture was heated to reflux under nitrogen for 6 h, then cooled and the organic phase washed with 2M NaOH (75 mL), dried over magnesium sulphate and solvent removed under reduced pressure to give a solid which was subjected to column chromatography (n-Hex/EtOAc 9:1 to 1:1) to afford the title compound (74% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]=2[CH:22]=1.[N+:23]([O-])([OH:25])=[O:24]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([N+:23]([O-:25])=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]=2[CH:22]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(Br)cc12
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of ethyl 5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (50 g, 137.6 mmol) in CHCl3 (500 mL), fuming HNO3 (50 mL) was added dropwise at −15° C. and the mixture was stirred for 0.5 hour. The reaction mixture was poured into ice water and extracted with CH2Cl2. The organic layer was washed with a.q. sat. NaHCO3 and brine, after removed the most of solvent, the resulting residue was crystallized with petroleum ether/dichloromethane=20/1 to provide product of ethyl 5-bromo-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (35 g, yield: 66%). 1H-NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.02˜8.04 (m, 3H), 7.13˜7.18 (m, 2H), 4.36˜4.41 (m, 2H), 1.37 (t, J=4.0 Hz, 3H). MS (M+H)+: 408/410.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[CH:31]([C:34]1[NH:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)([CH3:33])[CH3:32]>>[CH:31]([C:34]1[N:35]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:3]=2)[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN(C(C)(C)C(N)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C(N)=O)CC3)n(C)c2n1

Procedure:
2-(4-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropanamide (75 mg) was reacted with 2-isopropylbenzimidazole via General Procedure I for Buchwald coupling to give 24.9 mg 439 following reverse phase purification. MS (Q1) 561.7 (M)+
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:18][CH2:19][CH3:20])([CH3:17])[CH3:16])[C:5]([NH2:21])=[CH:4][CH:3]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[Br:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:18][CH2:19][CH3:20])([CH3:17])[CH3:16])[C:5]([NH:21][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:26][CH:27]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: CCOC(C)(C)c1ccccc1Oc1nc(Br)ccc1N
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: CCOC(C)(C)c1ccccc1Oc1nc(Br)ccc1NC(=O)Nc1ccc(OC(F)(F)F)cc1

Procedure:
Example 582 was prepared from 6-bromo-2-(2-(2-ethoxypropan-2-yl)phenoxy)pyridin-3-amine and p-trifluoromethoxyphenyl isocyanate according to the procedure described for Example 2. (M−EtO)=508, 510. 1H NMR (400 MHz, DMSO-d6) δppm 0.82 (t, J=7.0 Hz, 3H), 1.53 (s, 6H), 3.21 (q, J=7.0 Hz, 2H), 7.21 (dd, J=8.1, 1.3 Hz, 1H), 7.30 (m, 6H), 7.56 (m, 4H), 8.49 (d, J=8.4 Hz, 1H), 8.73 (s, 1H), 9.61 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([F:14])[F:13])[N:8]=[C:7](/[CH:23]=[N:24]/O)[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])([F:14])[F:13])[N:8]=[C:7]([C:23]#[N:24])[CH:6]=[CH:5]2
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(/C=N/O)ccc2cc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C#N)ccc2cc1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a stirred solution of diethyl [(6-bromo-2-[(E)-(hydroxyimino)methyl]quinolin-7-yl)(difluoro)methyl]phosphonate (520 mg, 1.189 mmol) in acetonitrile (30 mL) at room temperature were added triphenylphosphine (1.248 g, 4.76 mmol) and carbon tetrachloride (230 μL, 2.383 mmol). The reaction mixture was stirred at 100° C. for 1 hour. It was concentrated to dryness in vacuo, pre-adsorbed in silica gel for flash chromatography eluting with ethyl acetate in toluene (20% to 30%) to afford diethyl [(6-bromo-2-cyanoquinolin-7-yl)(difluoro)methyl]phosphonate.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]1([NH:18][C:19](=[O:47])[C:20]2[CH:25]=[C:24]([N:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@@H:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:34]([CH3:37])[CH:35]=O)[C:27]3=[O:44])[C:23]([CH3:45])=[C:22]([F:46])[CH:21]=2)[CH2:17][CH2:16]1.[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:15]1([NH:18][C:19](=[O:47])[C:20]2[CH:25]=[C:24]([N:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@@H:33]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C@@H:34]([CH3:37])[CH2:35][N:48]4[CH2:52][CH2:51][CH2:50][CH2:49]4)[C:27]3=[O:44])[C:23]([CH3:45])=[C:22]([F:46])[CH:21]=2)[CH2:17][CH2:16]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)C=O)c1=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)CN2CCCC2)c1=O
Temperature: 22 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (0.284 g) was added to N-cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2R)-2-methyl-3-oxo-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide (Example 328e, 0.3 g), pyrrolidine (0.221 mL) and Hunig's Base (0.467 mL) in DCM (15 mL). The resulting suspension was stirred at 22° C. for 2 h. The reaction mixture was basified with satd sodium bicarbonate solution before extracting with DCM. The combined organic phases were concentrated in vacuo and the residue purified by preparative HPLC (Phenominex column using a 75-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent). The fractions containing the desired compound were evaporated to dryness to afford the title compound as a solid (0.046 g).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:29])[N:27]=2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCCCC3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1csc(N2CC(O)C2)n1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (607 mg, 1.20 mmol) (obtained as described in Reference Example 27(1)) in anhydrous tetrahydrofuran (25 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (1.40 ml, 1.40 mmol) in an ice bath, and the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (9:1) as the eluant to afford 3-hydroxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (310 mg, yield 97%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.[Na+]>>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C)cc3)c(C)o2)cc1
Yield: 87.7 %

Procedure:
A mixture of chloride 2 (1.54 g, 5.8 mmol) and sodium 4-methylbenzenesulfinate (1.08 g, 6.1 mmol) gave benzoate 3 (1.96 g, 88%) as a white powder: mp (EtOAc) 177-178° C.; 1H NMR (CDCl3) δ 8.08 (ddd, J=8.7, 2.0, 1.6 Hz, 2H, H-2, H-6), 7.92 (ddd, J=8.7, 2.0, 1.6 Hz, 2H, H-3, H-5), 7.69 (ddd, J=8.3, 1.9, 1.7 Hz, 2H, H-2′, H-6′), 7.30 (br d, J=8.3 Hz, 2H, H-3′, H-5′), 4.29 (s, 2H, CH2SO2), 3.94 (s, 3H, OCH3), 2.43 (s, 3H, CH3), 2.31 (s, 3H, CH3); MS m/z 386.5 (MH+, 100%). Anal. calcd for C20H19NO5S: C, 62.32; H, 4.97; N, 3.63. Found: C, 62.59; H, 4.96; N, 3.71%.
Reaction SMILES: [I-].[C:2]([O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][N+:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[N+:22]([O-])=O)=[O:8])([CH3:5])([CH3:4])[CH3:3].[H][H]>CO>[NH2:22][C:10]1[CH:11]=[C:12]([CH:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH:13]=[CH:14][C:9]=1[C:7]([O:6][C:2]([CH3:3])([CH3:4])[CH3:5])=[O:8]
Reactant: [H][H]
Reactant: C[n+]1ccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1
Agent: [I-]
Solvent: CO
Product: CN1CCC(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Yield: 140.9 %

Procedure:
0.48 g of platine (IV) oxide (2.12 mmol) is added to a solution of 26.8 g of 4-(4-(tert-butoxycarbonyl)-3-nitrophenyl)-1-methylpyridinium iodide (60.6 mmol) in 200 mL of methanol placed in a reactor made in stainless steel. The reaction medium is brought under 5 bar of hydrogen for 24 h. The catalyst is filtered and the filtrate is concentrated under reduced pressure to yield 24.8 g (98%) of white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[S:12])[NH:10][NH2:11])[CH:2]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[S:12])[NH:10][N:11]=[CH:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH:2]=1
Reactant: O=Cc1ccccn1
Reactant: NNC(=S)NCc1cccnc1
Solvent: CC(=O)O
Product: S=C(NCc1cccnc1)NN=Cc1ccccn1

Procedure:
The title compound was prepared from a mixture of 4-(3-picolyl)-3-thiosemicarbazide (100 mg, 0.549 mmol), 2-pyridinecarboxaldehyde (52 μL, 0.549 mmol) and glacial acetic acid (62 μL) similar to Example 3 and isolated as a white solid (87 mg, 58%). 1H NMR (DMSO-d6): 11.76 (s, 1H), 9.18 (t, J=6.0 Hz, 1H), 8.45-8.43 (m, 2H), 8.33 (dd, J=1.7, 4.7 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.0 (s, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.28-7.22 (m, 2H), 4.74 (d, J=6.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([CH3:13])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([CH3:13])[CH2:11][CH2:10][N:9]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:6][CH:7]=1
Reactant: CC1CCNC1c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCC(C)C2c2ccc(F)cc2)cc1

Procedure:
The title compound, off-white solid, m.p. 112° C. and MS: m/e=354.2 (M+) was prepared in accordance with the general method of example 1e from (2RS,3RS)-2-(4-fluoro-phenyl)-3-methyl-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C@H:15]([C:17]3[O:21][NH:20][C:19](=[O:22])[CH:18]=3)[CH2:14][CH2:13][N:12]2C(OC)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C@H:15]([C:17]3[O:21][NH:20][C:19](=[O:22])[CH:18]=3)[CH2:14][CH2:13][NH:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(S(C)(=O)=O)cc1
Agent: Br
Product: CS(=O)(=O)c1ccc([C@H]2C[C@H](c3cc(=O)[nH]o3)CCN2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.7 %

Procedure:
Trans-methyl 2-(4-(methylsulfonyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (301 mg, 0.79 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 2 mL, 28.55 mmol) and stirred at room temperature for 20 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(4-(methylsulfonyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (119 mg, 47%), HRMS Calcd for [C15H18N2O4S+H]+: 323.1065. Found: 323.1054.