Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:8][CH:9]=1
Reactant: O=C1COC(c2ccc([N+](=O)[O-])cc2)=NN1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C2=NNC(=O)CO2)cc1

Procedure:
A solution of 2-p-nitrophenyl-4H,6H-1,3,4-oxadiazin-5-one (Example 17; 2.2 g.) in ethyl acetate (250 ml.) was hydrogenated in the prsence of a 5% palladium-on-charcoal catalyst at laboratory temperature and atmospheric pressure until 670 ml. of hydrogen had been absorbed. The mixture was filtered and the filtrate was evaporated to dryness. There was thus obtained as solid residue 2-p-aminophenyl-4H,6H-1,3,4-oxadiazin-5-one, m.p. 253°-255° C. (with decomposition).
Reaction SMILES: [C:1]1([CH:7]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14](O)[C:13]=2[C:23](=O)[CH3:24])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O-:29])(=[O:28])[CH3:27].[Na+].C(OC(=O)C)(=O)C>C(OCC)C>[C:26]([O:29][C:14]1[C:13]2[C:23]([CH3:24])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][C:12]=2[C:17]([Cl:18])=[CH:16][C:15]=1[CH2:19][CH2:20][CH3:21])(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: CCCc1cc(Cl)c(OC(C(=O)O)c2ccccc2)c(C(C)=O)c1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCCc1cc(Cl)c2oc(-c3ccccc3)c(C)c2c1OC(C)=O

Procedure:
A mixture of 2-phenyl-2-(2-acetyl-3-hydroxy-4-propyl-6-chlorophenoxy) acetic acid (Step b)(3.4 g, 9.3 mmol), anhydrous sodium acetate (6.8 g, 82 mmol) and acetic anhydride (50 mL) was refluxed for 1 hour. The mixture was cooled, diluted with diethyl ether and the salts filtered off. The filtrate was concentrated and the residue chromatographed on silica gel with 10% ethyl acetate in hexane to obtain the title compound, m.p. 86°-87° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]([CH3:43])=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[CH:17]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH:26]=O)=[CH:24][CH:25]=2)[CH:19]=1)=[O:13].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:13])[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH2:26][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:24][CH:25]=2)[CH:17]=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:15]=1[CH3:43]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)nc3)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.78 %

Procedure:
To a stirred solution of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-formylpyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (1 equiv.) and morpholine (5 equiv.) in methanol (5 mL for 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 4 h. Then reducing agent NaBH3CN (1 equiv.) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and residue purified by column chromatography over silica gel affording desired tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-5-(6-(morpholinomethyl)pyridin-3-yl)phenyl)(methyl)amino)piperidine-1-carboxylate. This compound was then dissolved in DCM (5 mL) and cooled to 0° C. TFA (2 mL) was added to it. Reaction mixture was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was purified by solvent washings to afford the title compound (0.1 g, 65.78%). LCMS: 559.35 (M+1)+; HPLC: 95.60% (@254 nm) (Rt; 3.906; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.96 (s, 1H), 8.67 (m, 1H), 8.22 (d, 2H, J=8 Hz), 8.17 (t, 1H), 7.61 (d, 1H, J=8 Hz), 7.48 (s, 1H), 7.32 (s, 1H), 5.87 (s, 1H), 4.52 (s, 2H), 4.29 (d, 2H, J=4.4 Hz), 3.84 (bs, 4H), 3.26 (bs, 6H), 3.16 (t, 1H), 2.89-2.91 (m, 2H), 2.64 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.81 (bs, 4H).
Reaction SMILES: C[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[Si](I)(C)(C)C.C(#N)C.Cl>C(Cl)Cl>[OH:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COCC1CCC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: OCC1CCC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A mixture of 4'-(4-methoxymethylcyclohexyl)-4-trifluoromethoxybiphenyl (100 mmol), TMSI (144 mmol), 15 ml of acetonitrile, and 10 ml of methylene chloride was stirred at room temperature for 4 hr. Ice and 6 M HCl were added to the reaction mixture, and the mixture was stirred. The organic phase was washed twice with a saturated aqueous solution of sodium thiosulfate. It was then dried over magnesium sulfate anhydride, and the solvent was distilled off under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (eluting solution: toluene--(1:1) mixture of toluene and ethyl acetate) to give 4'-(4-hydroxymethylcyclohexyl)-4-trifluoromethoxybiphenyl (68 mmol, yield 68%).
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH2:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@@H:2]([C:15]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
43.2 g of Z-D-Lys(Boc)-OH, prepared analogously to the L-compound, are dissolved in 400 ml of dimethylformamide. 24.5 g of H-Phe-OMe.HCl, 15.33 g of HOBt, 14.53 ml of NEM and, with stirring, 25 g of DCC are added, and the mixture is left to stand overnight at room temperature. After the urea has been filtered off, the solvent is distilled off in vacuo and the oily residue is recrystallized from 200 ml of 80% strength ethanol.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([C:12]([OH:14])=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[N+:15]([C:13]1[C:4]2[N:5]([N:1]=[N:2][N:3]=2)[C:6]2[C:11]([C:12]=1[OH:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc2nnnn2c2ccccc12
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)c2ccccc2n2nnnc12
Temperature: 52.5 °C
Yield: 76.3 %

Procedure:
Tetrazolo[1,5-a]quinolin-5-ol (63.25 g, 0.34 mol) was added to glacial acetic acid (630 ml) to form a thick off white suspension. The mixture was vigorously stirred while nitric acid (23.6 ml, 0.37 mol, 70% solution) was slowly added. The reaction was then heated from 25 to 80° C. over a period of 15 minutes. A yellow precipitate formed and the reaction was maintained at 80° C. for 5 minutes. The mixture was slowly cooled to 0° C. The solid was collected by filtration and then dried in vacuo to yield 60.0 g of 4-nitro-tetrazolo[1,5-a]quinolin-5-ol as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2I)=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1>>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2[C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1
Reactant: OB(O)c1cccnc1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2cccnc2)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 7, [4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-methanone (example 46) was reacted with pyridin-3-yl-boronic acid to give the title compound as off-white foam. MS: 530.3 (MH+).
Reaction SMILES: [O:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[CH2:12])=[CH:6][CH:5]=1)[C:2]#[N:3].[CH3:13][O:14][SiH:15]([O:18][CH3:19])[O:16][CH3:17]>C1(C)C(C)=CC=CC=1>[O:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Si:15]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:13])=[CH:6][CH:5]=1)[C:2]#[N:3]
Reactant: CO[SiH](OC)OC
Reactant: C=CCc1ccc(OC#N)cc1
Solvent: Cc1ccccc1C
Product: CO[Si](CCCc1ccc(OC#N)cc1)(OC)OC
Yield: 42 %

Procedure:
To 3.94 g (24.75 mmol) of purified 1-cyanato-4-(2-propenyl)benzene, prepared as described above, at 65° C. was added 10 μL of a 3% solution of Karstedt's™ catalyst (platinum-divinyltetramethyldisiloxane complex) in xylene (United Chemical Technologies, Bristol, Penn.). Trimethoxysilane (Aldrich) was added in 500 μL increments followed by 10 μL increments of the catalyst solution until NMR showed that the reaction was more than 80% complete. The product was distilled twice to yield 2.94 g (42%) of 3-(4-cyanatophenyl)propyltrimethoxysilane. The structure of the product was verified by IR and NMR.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[CH2:20]([NH:27][C:8]1[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6](=[O:19])(=[O:18])[C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 51.3 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.500 mmol) and benzylamine (0.110 ml, 1.001 mmol) in DMF (2 ml) was heated in the microwave reactor at 120° C. for 15 mins. EtOAc was added, the mixture was washed with brine and evaporated to dryness. The residue was purified by silica gel column chromatography (Horizons Biotage) using 15-20% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.095 g, 51%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.50-7.38 (m, 5H), 7.34-7.25 (m, 3H), 7.06-6.98 (m, 2H), 5.55 (bs, 1H), 4.02 (d, 2H), 1.77 (9H, s); 13C NMR (125 MHz, CDCl3): δ 159.8, 136.8, 133.0, 131.9, 129.8, 129.0, 128.7, 128.2, 127.6, 124.8, 108.2, 61.6, 48.4, 27.9; Mass Spectrum M+H+ 371.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[C:5](=[CH:12]/[C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)/[CH2:6][C:7]([O:9][CH2:10][CH3:11])=O)[CH3:2].C([O-])(=[O:23])C.[Na+]>C(OC(=O)C)(=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([O:9][C:10](=[O:23])[CH3:11])[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH:12]=1)=[O:20])[CH3:2]
Reactant: CCOC(=O)C/C(=C\c1cccc(C)c1)C(=O)OCC
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(OC(C)=O)c2ccc(C)cc2c1
Temperature: 25 °C

Procedure:
To a solution of 2 g of 2-[1-m-Tolyl-meth-(E)-ylidene]-succinic acid diethyl ester in 10 ml of acetic acid anhydride, 594 mg sodium acetate was added and the reaction mixture was heated to reflux for 5 h. After cooling to RT the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed three times with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 860 mg.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:26]=[CH:25][C:11]([NH:12][CH:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]>C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:25][CH:26]=1)[N:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]2[OH:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(OCCOC(C)=O)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2ccc(OCCOC(C)=O)cc2c1O
Temperature: 250 °C
Yield: 8.7 %

Procedure:
Sodium hydroxide (6.22 g) is added to a solution of p-nitrophenol (21.45 g) in DMF (300 mL) and stirred until the reagents are fully dissolved. After a dropwise addition of 2-chloroethanol (10.66 ml), the reaction mixture is heated to 100° C. for 72 hours. After filtering and evaporating the solvent under reduced pressure, the resulting oil is recrystallized in a methanol/water mixture and filtered to afford 21.62 g (92%) of 2-(4-nitrophenoxy)-1-ethanol. A mixture of 2-(4-nitrophenoxy)-1-ethanol (6.17 g) and palladium on carbon (0.08 g) in EtOH (120 mL) is hydrogenated in a 500 mL Parr jar at 33 psi for 18 hrs. Vacuum filtration through celite and evaporation under reduced pressure affords 5.00 g (96%) of 2-(4-aminophenoxy)-1-ethanol. This material is combined with diethyl ethoxymethylenemalonate (7 mL) and heated to 130° C. for 1 hr in a round bottom flask under a gentle stream of nitrogen. The mixture is cooled, diluted with 1:1 cyclohexane/toluene (20 mL), and filtered to afford 9.1 g (86%) of diethyl 2-{[4-(2-hydroxyethoxy)anilinorlmethylene}-malonate. A solution the resulting malonate (8.59 g) in acetic acid (15 mL) and acetic anhydride (4 mL) is heated to 60° C. for 36 hrs. The reaction mixture is diluted with water, extracted with ethyl acetate and washed with saturated sodium bicarbonate. Evaporation under reduced pressure leaves a brown oil which is recrystallized from 1:1 methanol/water and filtered to afford 7.09 g (73%) diethyl 2-({4-[2-(acetyloxy)ethoxy]anilino}methylene)malonate. Diethyl 2-({4-[2-(acetyloxy)ethoxy]anilino}methylene)malonate (6.55 g) is dissolved in diphenyl ether (75 mL) and refluxed at 250° C. for 1 hr. After the mixture is cooled and diluted with 250 mL toluene, the resulting precipitate is collected by filtration, washed with toluene and recrystallized from aqueous acetic acid. This procedure yielded 0.50 g (9%) of ethyl 6-[2-(acetyloxy)ethoxy]-4-hydroxy-3-quinolinecarboxylate. The resulting carboxylate ester (0.49 g) and 4-chlorobenzylamine (0.90 mL) are heated to 175° C. for 2 hrs. After the reaction mixture is cooled and diluted with xylenes, the dark solid is filtered. Recrystallization from acetic acid and water affords 0.150 g (26%) of the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:24]2)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[S:24])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Nc1ccc(N2CCCCC2=O)cc1
Solvent: Cc1ccccc1
Product: Nc1ccc(N2CCCCC2=S)cc1
Reaction time: 0.75 h

Procedure:
15 g (78.8 mmol) of 1-(4-aminophenyl)piperidin-2-one are heated to the boil together with 16.0 g (39.5 mmol) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) in 100 ml of anhydrous toluene. After 45 minutes, the solvent is evaporated, and the residue is taken up in dichloromethane and 2 N HCl. The aqueous phase is extracted three times with dichloromethane and adjusted to a pH of 12 using conc. NaOH. Extraction with dichloromethane, drying over sodium sulfate and evaporation of the solvent give 1-(4-aminophenyl)piperidine-2-thione as a colourless solid, ESI 207.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[N:20]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:17]3[S:18][C:11]4[C:12](=[N:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]4[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=4[F:1])[CH:16]=3)=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: OB(O)c1ccc(Cn2cccn2)cc1
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(Cn5cccn5)cc4)sc23)c(F)c1
Yield: 64.9 %

Procedure:
Prepared from 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 0.300 g, 0.777 mmol) and 4-((1H-pyrazol-1-yl)methyl)phenylboronic acid (0.196 g, 0.971 mmol) using the procedure described for Example 94, Step A, to provide the product (210 mg, 36%) as a brown solid. LRMS (esi+) m/e 417 (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.[I:16]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)(=O)C>[I:16][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(I)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 193.8 %

Procedure:
A mixture of 2-amino-3-nitropyridine (5.0 g, 35.9 mmol), acetic acid (22 mL), water (5 mL), sulfuric acid (0.650 mL), and HIO4×2H2O (1.7 g, 7.5 mmol) was allowed to stir at 90° C. for 10 min. Iodine crystals (3.7 g, 14.6 mmol) were added in portions. After stirring for 1 h, the reaction was poured into saturated sodium thiosulfate and extracted with ethyl acetate. The organic layers were washed with 0.1 M NaOH and saturated brine, dried with sodium sulfate, then evaporated to give orange solid (7.5 g, 79% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[CH:14]1([C@H:17]2[CH2:22][NH:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:18]2[OH:31])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[CH:14]1([C@H:17]2[CH2:22][N:21]([C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]4[CH2:11][CH2:12][CH2:13][C:3]=34)[CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C@@H:18]2[OH:31])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C2CC2)[C@H]1O
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@H](C2CC2)[C@H]1O
Temperature: 90 °C
Yield: 40.7 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.094 g, 0.47 mmol), tert-butyl [(3R,4R,5S)-5-cyclopropyl-4-hydroxypiperidin-3-yl]carbamate (0.13 g, 0.51 mmol), and triethylamine (0.26 mL, 1.9 mmol) in isopropyl alcohol (2 mL) was heated at 90° C. for 2 days. The desired product partially precipitated from the reaction mixture and was collected by filtration, washed with hexanes and dried under reduced pressure to afford pure sub-title compound (0.080 g). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (20 g silica gel column, eluting with 0-15% MeOH/DCM) to afford further sub-title compound (0.034 g, total 0.114 g, 58%). LCMS (ESI) m/z calc. for C21H31N4O5 419.2 [M+H]+. found 419.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:14]([O-])=O)[C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:14][C:5]1[C:6]([CH3:13])=[C:7]([CH:12]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(OC)cc(N)c1C
Temperature: 80 °C
Yield: 80.9 %

Procedure:
To a stirred solution of methyl 5-methoxy-2-methyl-3-nitrobenzoate (1.7 g, 7.6 mmol) in ethanol (20 mL) was added ammonium chloride (1.7 g, 32 mmol) dissolved in water (20 mL) and iron powder (3.38 g, 60.44 mmol). The mixture was heated at 80° C. for 3 h, filtered and the residue washed well with hot ethanol. The filtrate was concentrated and the residue was basified with aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, dried, and concentrated under reduced pressure to give the crude title compound (1.2 g) which was used directly in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]([O:34][CH:35]4[CH2:38][CH2:37][CH2:36]4)=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]([O:31][CH3:32])=[O:30])[C@@H:24]([CH3:33])[CH2:23][CH2:22]4)[CH:16]=[N:15]2)[CH:10]([O:39][CH3:40])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:35]1([O:34][C:20]2[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]4[O:39][CH3:40])[CH:18]=3)=[CH:28][CH:27]=[C:26]3[C:21]=2[CH2:22][CH2:23][C@H:24]([CH3:33])[N:25]3[C:29]([O:31][CH3:32])=[O:30])[CH2:36][CH2:37][CH2:38]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4OC)c3)c(OC3CCC3)c2CC[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1c2ccc(-c3cnn(C4CCNCC4OC)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A 25-mL round-bottom flask was charged with (2S)-methyl 6-(1-(1-(tert-butoxycarbonyl)-3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (40 mg, 0.07 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1 mL). The resulting solution stirred for 1 h at room temperature. The reaction mixture was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: Xbridge RP C18, 19×150 mm, 5 um; Mobile Phase water (0.05% trifluoroacetic acid), acetonitrile (15% to 43% acetonitrile in 9 min, flow rate: 20 mL/min); Detector, 254/220 nm. The fractions were combined and concentrated under vacuum and the residue was further purified via reverse phase chromatography (acetonitrile/water (0.05% ammonium bicarbonate)=5/95-95/5). The fractions were combined, concentrated and lyophilized to afford methyl (2S)-5-cyclobutoxy-6-[1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (14 mg, 43%) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.10-1.20 (m, 3H), 1.25-1.50 (m, 2H), 1.50-1.70 (m, 1H), 1.95-2.52 (m, 8H), 2.80-3.10 (m, 2H), 3.10-3.35 (m, 4H), 3.55-3.90 (m, 6H), 4.05-3.15 (m, 1H), 4.40-4.65 (m, 2H), 7.18-7.35 (m, 2H), 7.93 (s, 1H), 8.01-8.12 (m, 2H). MS (ESI, pos. ion) m/z 455 [M+H]+.