Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:38]=[CH:37][C:24]([CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:27]4)=[CH:23][CH:22]=3)[N:17]=2)=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[C:6]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:25][N:26]4[CH2:27][CH:28]([C:30]([OH:32])=[O:31])[CH2:29]4)=[CH:37][CH:38]=3)[N:17]=2)=[N:7][O:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1c(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)cc3)no2)noc1-c1ccccc1

Procedure:
The tert-butyl 1-(4-(5-(4-butyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)-azetidine-3-carboxylate intermediate (0.156 g) was stirred in trifluoroacetic acid (4.03 mL, 52.3 mmol) for 30 min. and concentrated under reduced pressure to give the desired product as a yellow, viscous oil. The oil was dissolved in dichloromethane and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer, which contained the product (presumably as the sodium salt) was concentrated under reduced pressure. The white, solid residue was dissolved in water (pH ˜9), and the pH was adjusted to ˜4.5 with concentrated hydrochloric acid. The resulting white precipitate was collected by vacuum filtration and dried (no additional product in aqueous layer by HPLC). The solid was diluted with methanol and sonicated for 5 min. The methanol was removed under reduced pressure. The resulting solid was once again diluted with methanol, sonicated, collected by vacuum filtration, and washed with methanol. The resulting solid was dried well to give 1-(4-(5-(4-butyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (0.102 g, 0.222 mmol, 42.5% yield) as a white, crystalline solid (There was some product remaining in the methanol filtrate). The compound had an HPLC with a ret. time=3.11 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=459.1. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.42 Hz, 3H), 1.37-1.46 (m, 2H), 1.62-1.70 (m, 2H), 3.00-3.06 (m, 2H), 3.23 (br. s., 3H), 3.43 (br. s., 2H), 3.65 (s, 2H), 7.52 (d, J=8.25 Hz, 2H), 7.59-7.68 (m, 3H), 7.83 (d, J=7.15 Hz, 2H), 8.06 (d, J=8.25 Hz, 2H), and 12.27 (s, 1H).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[F:8][C:9]([F:45])([F:44])[C:10]1[CH:11]=[C:12]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:36])[CH:16]([NH:27][C:28](=[O:35])C1C=CC=CC=1)[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1.CN=C=O>O1CCCC1>[F:43][C:40]([F:42])([F:41])[C:38]1[CH:37]=[C:12]([CH:11]=[C:10]([C:9]([F:8])([F:44])[F:45])[CH:39]=1)[CH2:13][NH:14][C:15](=[O:36])[CH:16]([NH:27][C:28]([NH:3][CH3:1])=[O:35])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1
Reactant: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: CCN(CC)CC
Agent: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
Triethylamine (0.3 ml) was added to a stirred solution of the compound of Example 26 (1 g) in tetrahydrofuran (15 ml), at room temperature under a nitrogen atmosphere. After 5 minutes methyl isocyanate (0.13 ml) was added and the solution was stirred for 3 hours. The solvent was removed and the residue was dissolved in ethyl acetate (50 ml). The solution was washed with dilute hydrochloric acid, water and sodium bicarbonate solution. After drying over Na2SO4 removal of the solvent gave the title compound (0.9 g) after recrystallisation from ethyl acetate/petroleum ethereum ether, m.p. 213°-215° C. Found: C, 54.62; H, 4.28; N, 11.41. C22H20N4O2F6 requires C, 54.32; H, 4.14; N, 11.51.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[C@H:49]([NH:55][C:56]([C:58]1[C:62]3[CH:63]=[CH:64][C:65]([Br:67])=[CH:66][C:61]=3S[N:59]=1)=[O:57])[CH2:48]2.C(=O)([O-])[O-:69].[Cs+].[Cs+].CNC(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[C@H:49]([NH:55][C:56]([C:58]1[C:62]3[CH:63]=[CH:64][C:65]([Br:67])=[CH:66][C:61]=3[O:69][N:59]=1)=[O:57])[CH2:48]2
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1nsc2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CNC(C)=O
Solvent: Cc1ccccc1
Product: O=C(N[C@@H]1CN2CCC1CC2)c1noc2cc(Br)ccc12
Yield: 50 %

Procedure:
Palladium (II) acetate (0.040 mmol) was added to a solution of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.050 mmol) in toluene (6 mL) and the reaction mixture was maintained until the contents completely dissolved. The resultant yellow solution was transferred to a mixture of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-carboxamide (0.30 mmol), cesium carbonate (0.50 mmol) and N-methylacetamide (0.500 mmol) under an atmosphere of nitrogen gas and the reaction mixture was subjected to microwave irradiation at 200° C. for 300 s. The reaction mixture was filtered through Celite and concentrated. The residue was purified by HPLC, thus providing the product in 50% yield.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][C:21](=[O:33])[CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:34][CH2:35][O:36]C)[CH:4]=[CH:5]2.[C:38](O)(=O)C>O>[C:35]([O:34][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][C:21](=[O:33])[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH2:11][CH2:10][C@@H:9]35)(=[O:36])[CH3:38]
Reactant: CC(=O)O
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)CCCc4ccc(OC)cc4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: O
Product: COc1ccc(CCCC(=O)O[C@H]2CC[C@H]3[C@H]4Cc5ccc(OC(C)=O)c6c5[C@@]3(CCN4C)[C@H]2O6)cc1

Procedure:
4,5α-Epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinane (0.85 g, 1.67 mmol) is dissolved in water (35 ml) and glacial acetic acid (35 ml) and then stirred for 4 hours at 100° C. The volatile components are eliminated using a Rotavapor. The residue thus obtained is purified by flash chromatography (100 g silica gel; mobile phase: methylene chloride/methanol=7:1). The product is dissolved in a mixture of water and glacial acetic acid and lyophilised.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:9][C:10]1[N:15]=[C:14](Cl)[N:13]=[C:12]([N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:19][C:18]2([CH3:30])[CH3:29])[N:11]=1>O.C1(C)C=CC=CC=1>[Cl:9][C:10]1[N:15]=[C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:13]=[C:12]([N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:19][C:18]2([CH3:30])[CH3:29])[N:11]=1
Reactant: C1COCCN1
Reactant: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(Cl)n1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(N3CCOCC3)n1)OCCO2
Reaction time: 1.5 h

Procedure:
3.8 g of morpholine and, 15 minutes later, a solution of 1.7 g of NaOH in 5 ml of water are added to a solution of 30 g of 2,4-dichloro-6-(4,4-ethylenedioxy-2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 17) in 100 ml of toluene. The mixture is then warmed to 6020 and after 45 minutes a further 3.8 g of morpholine and 1.7 g of NaOH in 5 ml of water are added. After a further 1.5 hours, the reaction has ended. After cooling and adding 200 ml of toluene, the phases are separated. The organic phase is dried over Na2SO4 and evaporated. Recrystallizing from acetonitrile leads to the compound of the above structure which melts at 154°-156° (white powder).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].[SiH:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17]>O1CCCC1>[CH2:16]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:17]
Reactant: CC[SiH](CC)CC
Reactant: CSc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)CSc1ccccc1
Yield: 67.9 %

Procedure:
The reaction was conducted according to the General Procedure by heating thioanisole (62 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 65 hours at 65° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica using hexanes (isochratic) to obtain 81 mg (68%) of the title compound as a colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.31-7.26 (m, 2H), 7.25-7.19 (m, 2H), 7.11-7.01 (m, 1H), 1.03 (t, J=7.9 Hz, 9H), 0.78-0.60 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 140.73, 128.31, 125.69, 124.19, 13.01, 6.62, 3.06. HRMS: [C13H21SSi] calculated 237.1140, measured 237.1133. The HSQC spectra of the thioanisole and its reaction product as provided in FIGS. 7A and 7B.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].O.O.[Na].[S:12]1([C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[NH:15]1)(=[O:14])=[O:13]>CN(C)C=O.O>[O:17]=[C:16]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[S:12](=[O:14])(=[O:13])[N:15]1[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)OC(=O)CCl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)CN1C(=O)c2ccccc2S1(=O)=O
Temperature: 120 °C
Yield: 86.4 %

Procedure:
23.3 kg (170.6 mol) of isopropyl chloroacetate are added to a solution at 50° C. of 40 kg (165.8 mol) of saccharin sodium dihydrate in 40 l of dimethylformamide. The mixture is heated to 120° C. and maintained for 3 hours at this temperature. The mixture is cooled and diluted with 240 l of water. Finally, the precipitate is centrifuged, washed with cold water and dried, 40.6 kg (86%) of a crystalline white solid, m.p. 112°-7° C. (118°-9° C. from isopropanol), being obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].Cl.[CH3:24][C:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][C:25]1([NH:29][C:20]([CH:17]2[CH2:18][CH2:19][N:14]([CH:9]3[CH2:10][CH:11]4[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]([CH2:13][CH2:12]4)[CH2:8]3)[CH2:15][CH2:16]2)=[O:22])[CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(C(=O)O)CC1)C2
Reactant: CC1(N)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1C2CCC1CC(N1CCC(C(=O)NC3(C)CCC3)CC1)C2
Temperature: 25 °C
Reaction time: 60 h
Yield: 34 %

Procedure:
1-[8-(Ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxylic acid (0.50 g assumed 1.62 mmol) was dissolved in DMF (8 mL) and (1-methylcyclobutyl)amine hydrochloride (0.295 g, 2.44 mmol), HATU (0.926 g, 2.44 mmol) and DIPEA (1.05 g, 1.41 mL, 8.12 mmol) were added. The reaction mixture was stirred at rt for 60 h and the solvents were removed in vacuo. The residue was partitioned between DCM and sat. NaHCO3 sol., the organic layer was washed with sat. NaCl sol. and passed through a phase separator cartridge. The solvents of the organic filtrate were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-6 3 μm, 60 A, 25 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl 3-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate isomer 1 (0.208 g, 34%) as a light yellow gum.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][CH:5]2[O:7][CH:8]([CH2:10][O:11]C(=O)C3C=CC=CC=3)[CH2:9][CH:4]2[O:3]1.C[O-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:20])[O:6][CH:5]2[O:7][CH:8]([CH2:10][OH:11])[CH2:9][CH:4]2[O:3]1
Reactant: CC1(C)OC2CC(COC(=O)c3ccccc3)OC2O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C)OC2CC(CO)OC2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
Compound 9.4 (11.0 g, 39.6 mmol) in MeOH (100 mL) at 0° C. was treated with NaOMe (4.3 M in MeOH, 3 mL, 20 mmol) and stirred for 30 min. The mixture was warmed to ambient temperature and stirred for 1 h. The mixture was cooled to 0° C. and treated with 1 N HCl (10 mL) then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and stirred for 30 minutes, dried over MgSO4, filtered, and concentrated in vacuo. The residue was subjected to a silica gel column chromatography (SiO2, 4×20 cm, 20-50% EtOAc-hexanes gradient) to afford compound 9.5 (4.1 g, 60% yield).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)[S:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([NH:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([O:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:18]3)[S:15][CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(NCc1csc(N2CC(O)C2)n1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(CNS(=O)(=O)c3ccccc3)cs2)C1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of 1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]-3-hydroxyazetidine (1.06 g, 3.26 mmol) (obtained as described in Reference Example 65(2)) in methylene chloride (50 ml) were added methanesulfonyl chloride (0.38 ml, 4.89 mmol) and triethylamine (0.68 ml, 4.89 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (1.16 mg, yield 91%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:15]2[C:26]2[CH:31]=[CH:30][N:29]=[C:28](F)[CH:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][NH2:34]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[C:15]2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:34][CH3:33])[CH:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Fc1ccc(-c2ccn(C3CCN(Cc4ccccc4)CC3)c2-c2ccnc(F)c2)cc1
Solvent: C1CCOC1
Product: CNc1cc(-c2c(-c3ccc(F)cc3)ccn2C2CCN(Cc3ccccc3)CC2)ccn1
Temperature: 150 °C
Reaction time: 28 h
Yield: 60 %

Procedure:
A mixture of a solution of 1.50 g (3.49 mmol) of 1-(1-benzylpiperidin-4-yl)-3-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)-1H-pyrrole [prepared as described in step 72(i) above] in 30 ml of tetrahydrofuran and 50 ml (100 mmol) of a 2M solution of methylamine in tetrahydrofuran was stirred at 150° C. in an autoclave for 28 hours. At the end of this time, the solvent was distilled off from the reaction mixture under reduced pressure. Ethyl acetate and water were added to the residue, and the organic layer was separated, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 20:1 by volume mixture of dichloromethane and methanol as the eluant to give 1.83 g (yield 60%) of the title compound as a pale brown amorphous solid.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[C:23]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[N:25][CH:26]=1>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:30])=[O:29])[CH:22]=2)[CH:11]=1)#[N:16]
Reactant: CN(c1cncc(Br)c1)S(C)(=O)=O
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: CN(c1cncc(C#Cc2cc(C#N)ccc2OCC(=O)O)c1)S(C)(=O)=O

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and N-(5-bromopyridin-3-yl)-N-methylmethanesulfonamide (Intermediate 33), the title compound was obtained as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:11][CH:12]=[CH:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[CH:13]=[CH:12][S:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc2sccc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3sccc23)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
To a vial containing 4-chloro-5-nitrothieno[2,3-b]pyridine (138.2 mg, 0.6439 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 325.5 mg, 1.625 mmol), 1-butanol (3.00 mL) was added, followed by DIPEA (201.4 mg, 1.558 mmol), then the mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a yellow solid (228.4 mg, 94%). LCMS calc. for C17H23N4O4S (M+H)+: m/z=379.1. found 379.2.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1.C(N(CC)CC)C.O>ClCCl>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]([N:14]2[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[CH2:11][CH:12]([NH:16][C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:24])[CH2:13]2)=[O:35])[CH2:30][CH2:29]1
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Reactant: CN1CCN(C(=O)Cl)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Temperature: 25 °C

Procedure:
At 0° C., 100 mg (0.27 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 1.5 ml of dichloromethane, and 89 mg (0.55 mmol) of 4-methylpiperazine-1-carbonyl chloride and 58 μl (0.412 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 104 mg (77% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:23]=[N:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]3[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:26]I>CN(C=O)C.O>[Br:1][C:2]1[CH:23]=[N:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]3[N:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:8]=3[N:9]([CH3:26])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CCN1c2nc(C(F)(F)F)ccc2NC(=O)c2cc(Br)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(C(F)(F)F)nc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
To a solution of the 8-bromo-5,11-dihydro-11-ethyl-2-(trifluoromethyl)-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (200 mg, 0.52 mmol) in DMF (2.6 mL) was added NaH (20 mg, 0.78 mmol), and the mixture was heated to 50° C. for 30 min. The reaction mixture was cooled to room temperature and treated with MeI (97 μL, 1.56 mmol). After 16 h, the reaction mixture was diluted with water. The resulting mixture was extracted with EtOAc (3×). The combined organic layer was successively washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 8.5:1.5) to give the title compound (110 mg 53% yield) as a white foam.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[Cl:22])[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:2]([CH3:4])([CH3:3])[CH3:1])[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[Cl:22])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2ccccc2c(Cl)c1[C@H](O)COC(=O)C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: Cc1cc2ccccc2c(Cl)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Yield: 179.2 %

Procedure:
A solution of (S)-2-(1-chloro-3-methylnaphthalen-2-yl)-2-hydroxyethyl pivalate (4F) (1.13 g, 3.52 mmol) and perchloric acid, (70%, 0.605 mL, 7.04 mmol) in tert-butyl acetate (35 mL) was stirred at room temperature for 1.5 h. The reaction mixture was quenched with solid sodium bicarbonate (1.5 g) for 1 h. Saturated sodium bicarbonate solution was added and the reaction was extracted with ethyl acetate (3×). The combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 4G as a colorless oil (1.1889 g, 90%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH:28][NH:29][C:30](=N)[CH:31]([CH3:33])[CH3:32]>>[CH:31]([C:30]1[N:27]=[C:26]([N:23]2[CH2:24][CH2:25][CH:20]([C@H:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)[O:28][N:29]=1)([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@H](C2CCN(C#N)CC2)C3)CC1
Reactant: CC(C)C(=N)NO
Product: CC(C)c1noc(N2CCC([C@@H]3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from (S)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine-2-yl]-piperidine-1-carbonitrile (Intermediate 46; the configuration of the stereocenter is arbitrarily assigned) and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 6): tR=1.40 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C@H](C2C=CC=CC=2)C)[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Reaction time: 8 h

Procedure:
(3R,4R)-3-Methyl-4-(1-(s)-phenyl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (810 mg, 2.55 mmol) was dissolved in methanol (15 mL). Palladium hydroxide (20%, 100 mg) was added and the mixture was shaken under a hydrogen atmosphere overnight at 55 psi. The reaction was filtered and concentrated in vacuo to give the title compound as a clear oil. Wt.: 500 mg (92%). NMR (300 MHz, CDCl3) δ 4.06 (m, 1H), 3.96 (m, 1H), 2.73 (m, 1H), 2.34 (m, 2H), 1.77 (m, 1H), 1.43 (s, 9H), 1.27 (m, 2H), 0.94 (d, 3H); LC/MS m/z 215 (M+H)+.