Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[C:10]3[S:15][C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:17][C:9]2=3)=[CH:4][CH:3]=1.CN(C=O)C.[Br:29]N1C(=O)CCC1=O>>[Br:29][C:17]1[C:9]2[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:13][NH:12][C:11](=[O:14])[C:10]=2[S:15][C:16]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1NCC(c2ccc(Cl)cc2)c2cc(N3CCOCC3)sc21
Solvent: CN(C)C=O
Product: O=C1NCC(c2ccc(Cl)cc2)c2c1sc(N1CCOCC1)c2Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-chlorophenyl)-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (0.478 g, 1.37 mmol, single enantiomer of unknown absolute configuration) in DMF (8.9 mL, 110 mmol) was added N-bromosuccinimide (0.2561 g, 1.439 mmol), and the mixture was stirred at room temperature for 2 hours. Reaction was quenched via addition of 10% aqueous sodium thiosulfate solution (30 mL), and then diluted with EtOAc (100 mL) and water (10 mL) with sonication to encourage complete dissolution of solids. The layers were separated, and aqueous layer was extracted 1×EtOAc (50 mL). The combined organic layers were washed 1× brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was adsorbed to Celite (15 mL) and dryloaded onto a silica gel column. Column chromatography (eluent: 0-100% EtOAc:hexanes) then afforded 3-bromo-4-(4-chlorophenyl)-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (526 mg, 90%). LCMS: (FA) ES+ 427, 429, 431. 1H NMR (400 MHz, CDCl3) δ: 7.26 (d, J=8.3 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 5.41 (d, J=4.1 Hz, 1H), 4.20-4.06 (m, 2H), 3.87 (dd, J=4.6, 4.6 Hz, 4H), 3.52 (dt, J=14.4, 3.9 Hz, 1H), 3.35-3.24 (m, 2H), 3.24-3.10 (m, 2H).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:6][NH:5][CH2:4]1.Cl.Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[C:19](=[O:20])[C:18]([N:21]3[CH:25]=[CH:24][N:23]=[N:22]3)=[CH:17][NH:16]2)[CH:10]=1.C(N(C(C)C)C(C)C)C>O1CCCC1>[CH3:2][CH:3]1[CH2:6][N:5]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([N:15]3[C:19](=[O:20])[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)=[CH:17][NH:16]3)[CH:10]=2)[CH2:4]1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Reactant: CC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1CN(c2cc(-n3[nH]cc(-n4ccnn4)c3=O)ncn2)C1

Procedure:
43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 12A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 25 mg (25% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:35])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29]OS(C)(=O)=O)=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:37]=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:35])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][N:42]4[C:41](=[O:43])[C:40]5=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]5[C:38]4=[O:48])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:37]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-methanesulfonyloxyethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.75 g) in dimethylformamide (10 ml) is added potassium phthalimide (0.26 g), and the mixture is stirred at 110° C. for one hour. The mixture is poured into ice-water, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is purified by silica gel column chromatography to give 7-chloro-1-[6-(6,7-benzo-1-oxo-4-azepin-5-on-4-yl)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g, Compound A) and 7-chloro-1-{6-[2-(2-phthalimidoethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g, Compound B), separately.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: [NH4+]
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCCCC1CC(N)=O
Yield: 46.2 %

Procedure:
The title compound (0.92 g) was prepared from 2-(RS)-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and ammonium chloride (0.86 g) according to the method of Example 97.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15]>N1C=CC=CC=1.O>[C:12]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=1)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: CCCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCC(=O)Oc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
N-(3-Hydroxyphenyl)acetamide (300 g) was stirred in pyridine (990 mL) followed by the addition of butyryl chloride (246 mL). This reaction was stirred at room temperature for 30 min. The resulting crystalline suspension was left for 18 hrs. to ensure completion. The mixture was dissolved in water and ethyl acetate (1:1, 1000 mL), the organic layer was separated and washed with brine (3×1000 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo at 70° C. to remove pyridine. Upon cooling the oil become a very low melting solid. This solid was carefully added to a coarse 500 mL frit and dried. Minimal washing with ice cold hexane was used to cake the solid. The final compound was collected to provide the title compound in 75% yield (440 g) as a light-yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C1C=CC2N(O)[N:20]=[N:19]C=2C=1.CCN=C=NCCCN(C)C.Cl.NN.C1CCCCC=1>C(#N)C>[OH:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([NH:19][NH2:20])=[O:9])=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CC#N
Solvent: C1=CCCCC1
Product: NNC(=O)/C=C/c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a stirred solution of 4-hydroxycinnamic acid (3.28 g, 20 mmol) in acetonitrile (40 ml) was added HOBt (3.24 g, 24 mmol) and EDC.HCl (4.6 g, 24 mmol). The mixture was stirred at room temperature for 2 h, and the resulting yellow suspension was cooled to 0° C. by an ice bath. A ice-cold solution of hydrazine (1.25 ml, 40 mmol) and cyclohexene (0.61 ml, 6 mmol) in acetonitrile (30 ml) was added into the suspension in one portion, and the mixture was stirred at 0° C. for 20 min, then all owed to warm to ambient temperature, with the stirring continued for additional 1 h. The yellow suspension was filtered off via suction, washed the solid successively with MeOH (3×30 ml), H2O (2×30 ml), saturated NaHCO3 (2×30 ml), H2O (2×20 ml) and EtOAc (2×20 ml), and air-dried to afford 133 (1.3 g, 36% yield) as yellow solid. 1H NMR (300 MHz, DMSO-d6): δ4.40 (brs, 3H), 6.32 (d, J=15.9 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H), 7.33 (d, J=16.2 Hz, 1H), 7.36 (d, J=8.1 Hz, 2H), 9.21 (br s, 1H); 13C NMR (75 MHz, DMSO-d6): δ116.49, 117.21, 126.44, 129.83, 139.08, 159.72, 165.86; MS (ESI): m/z 179 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[C:17]([Si:21]([CH3:36])([CH3:35])[O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH2:33]O)=[CH:28][CH:27]=[CH:26]2)([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:33][C:29]2[C:30]3[C:25](=[CH:24][C:23]([O:22][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:36])[CH3:35])=[CH:32][CH:31]=3)[CH:26]=[CH:27][CH:28]=2)[C:7]1=[O:15]
Reactant: COC(=O)CCn1c(=O)[nH]c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(CO)cccc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCn1c(=O)n(Cc2cccc3cc(O[Si](C)(C)C(C)(C)C)ccc23)c2ccccc21
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a stirred solution of 3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (180 mg, 0.82 mmol) in THF (12 ml) was added [6-(tert-butyl-dimethyl-silanyloxy)-naphthalen-1-yl]-methanol (283 mg, 0.98 mmol) and triphenylphosphine (257 mg, 0.98 mmol). The DIAD (0.20 ml, 0.98 mmol) was then introduced in a dropwise manner and the resulting mixture was stirred at ambient temperature over night. Silica gel was added and the reaction mixture was concentrated to dryness. The resulting solid was purified via column chromatography (silica gel, 40% ethyl acetate/hexanes) to give 240 mg (60%) of the desired product as an oil which solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[OH-:16].[K+]>C(O)C.O>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[OH:16]
Reactant: [OH-]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=c1c(Cl)c(O)cnn1-c1ccccc1

Procedure:
4,5-Dichloro-2-phenylpyridazin-3-one (2.4 g, 0.01 moles) was suspended in ethanol (50 ml) and potassium hydroxide (2.0 g, 0.03 moles) was added in water (20 ml). Refluxed for 4 hours. Evaporated to dryness and added water. Acidified to pH2 with c. hydrochloric acid. Filtered off the product as a buff solid and dried in a desiccator. (2.1 g) Took 0.5 g and dissolved in methanol, filtered and evaporated. Triturated with ether to give the product as a cream solid. (0.4 g, 76%)
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:9]=2)[N:5]=[C:4]([C:21]#[N:22])[N:3]=1.Cl.[NH2:24][OH:25].CCN(C(C)C)C(C)C>CCO>[OH:25][NH:24][C:21]([C:4]1[N:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:9]=2)[N:5]=1)=[NH:22]
Reactant: Cc1nc(C#N)nn1Cc1cccc(N2CCN(C)CC2)c1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc(C(=N)NO)nn1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methyl-1-(3-(4-methylpiperazin-1-yl)benzyl)-1H-1,2,4-triazole-3-carbonitrile (120 mg, 0.40 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (31 mg, 0.44 mmol) and DIPEA (141 μL, 0.81 mmol). The reaction was stirred at 80° C. for 2 h before the solvent was removed under reduced pressure. The crude product was used without further purification. MS (ES+) C16H23N7O requires: 329 found: 330 [M+H]+.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH:34](O)[C:35]4([CH3:40])[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.S(Cl)([Cl:44])=O>C1COCC1>[Cl:44][CH:34]([C:35]1([CH3:40])[CH2:39][CH2:38][CH2:37][CH2:36]1)[C:21]1[CH:20]=[C:19]([O:18][CH2:17][C:13]2[CH:12]=[C:11]([CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:16]=[CH:15][CH:14]=2)[CH:24]=[CH:23][C:22]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)C3(C)CCCC3)c2)c1)C1CC1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(C(Cl)C3(C)CCCC3)c2)c1)C1CC1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-2-(hydroxy(1-methylcyclopentyl)methyl)-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)propanoate (99 mg) in THF (3 mL) was added thionyl chloride (64 μL) and the mixture was stirred at 50° C. for 15 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (95 mg) as a colorless oil.
Reaction SMILES: [CH:1]1([S:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:29]=[CH:28][C:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)=[CH:26][C:24]=4[CH:25]=3)=[O:18])=[CH:12][CH:11]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:45])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:1]1([S:7]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]3[CH2:20][CH2:21][O:22][C:23]4[CH:29]=[CH:28][C:27]([C:30]5[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=5)=[CH:26][C:24]=4[CH:25]=3)=[O:18])=[CH:14][CH:15]=2)(=[O:45])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)C4CCCCC4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)(=O)C4CCCCC4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of N-(4—(cyclohexylsulfinylmethyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.13 g) in chloroform (45 ml) was added 70% m-chloroperbenzoic acid (mCPBA) (0.097 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added sodium thiosulfate solution, and the mixture was washed with sodium hydrogen carbonate solution and water, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethanol-hexane to give N-(4—(cyclohexylsulfonylmethyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 107) (0.11 g) as colorless crystals.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([OH:10])=O)=[O:4].[CH3:37][C:38]([NH2:41])([CH3:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:38]([NH:41][C:8](=[O:10])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:36])([F:34])[F:35])[O:19][N:18]=2)=[CH:15][CH:16]=1)([CH3:40])([CH3:39])[CH3:37]
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 36.4 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), 2-methylpropan-2-amine (4.80 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.9) to provide (R/S)-N-tert-butyl-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanamide (10 mg, 0.016 mmol, 37.1% yield): LCMS=558.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.36 Hz), 7.53-7.74 (7 H, m), 5.11 (1 H, s), 3.41-3.53 (2 H, m), 2.27-2.41 (2 H, m), 1.30 (9 H, s); HPLC peak RT=9.4 min (Method A).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])(=O)=O>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OCc1ccccc1CBr
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1CBr
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 88.1 %

Procedure:
To a solution of the title compound of step (A) (10 g, 50 mmol) in CH2Cl2 (80 ml) cooled at 0° C. was added 2,6-lutidine (7.57 mL, 65 mmol), followed by dropwise addition of tert-butyldimethylsilyl trifluoromethanesulfonate (14.92 mL, 65 mmol). The reaction mixture was stirred at 0° C. for 45 minutes, then quenched with H2O (20 mL) and partitioned between EtOAc (450 mL) and H2O (150 mL). The organic layer was separated and washed with 10% NaHCO3 solution, brine (2×), dried (MgSO4) and concentrated in vacuo to give a yellow syrup, which was chromatographed eluting with 10-50% EtOAc/hexane to afford 13.89 g (88%) of the title compound of this step as a light yellow oil.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:12](=[O:27])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O>>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][N:17]([CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[C:29]([I:28])[CH:30]=4)[CH2:16][CH2:15]3)[N:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:12](=[O:27])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCNCC2
Reactant: O=Cc1cccc(I)c1
Agent: Cl
Product: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1cccc(I)c1)CC2

Procedure:
Reductive amination using methyl 4-[4-(cyclohexylamino)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-1-yl]butanoate dihydrochloride and 3-iodo-benzaldehyde using a similar procedure as described in the preparation of intermediate I.1.d.1. LRMS (M+1)=567.3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH: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)=[CH:7][CH: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]([CH:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH: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)c1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Reactant: CC(C)C(=N)NO
Product: CC(C)c1noc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 5): tR=1.15 min; Mass spectrum (ESI+): m/z=469 [M+H]+.
Reaction SMILES: O=[C:2]([CH:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)[CH2:3][C:4]([O:6]CC)=O.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>CCO>[O:13]1[C:12]2([CH2:11][CH2:10][CH:9]([C:2]3[CH:3]=[C:4]([OH:6])[N:21]4[N:22]=[CH:23][CH:24]=[C:20]4[N:19]=3)[CH2:18][CH2:17]2)[O:16][CH2:15][CH2:14]1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)C1CCC2(CC1)OCCO2
Solvent: CCO
Product: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Temperature: 100 °C

Procedure:
To a 20 mL scintillation vial containing ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-8-yl)propanoate (11.7 mmol, 3.00 g) is added 3-amino-1H-pyrazole (11.7 mmol, 973 mg). The two oils were mixed and heated neat at 100° C. for 3 hours. The resulting off-white solid was dissolved up in EtOH (100 mL) and reduced in vacuo to remove water formed during cyclization. This solid was used in the next step without further purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH2:30]>C(#N)C>[CH3:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH:30][CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC(C)(C)CN
Solvent: CC#N
Product: CC(C)(C)CNC[C@H]1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.196 g, 0.5 mmol), 2,2-dimethylpropan-1-amine (1 ml, 8.5 mmol) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and by flash chromatography (EtOAc) gave the title compound. Yield: 0.1 g. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 242° C. MS m/z (rel. intensity, 70 eV) 313 (M+, 6), 298 (32), 257 (14), 256 (bp), 207 (12), 100 (92). [α]=−53° (MeOH).
Reaction SMILES: [C:1]1([CH2:6][NH:7][C:8]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:9]=2[CH:10](O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:5][CH:4]=[CH:3][CH:2]=1.[C:25](=O)([O:27]CC)[NH2:26]>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[C:1]1([CH2:6][N:7]2[C:8]3[C:9](=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:26][C:25]2=[O:27])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(NCc2cccs2)c(C(O)c2ccccc2)c1
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: O=C1NC(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1Cc1cccs1
Temperature: 180 °C

Procedure:
A mixture of 3.42 g of 2-(2-thenylamino)-5-nitrobenzhydrol, 6 g of ethyl carbamate and 0.5 g of zinc chloride was heated at 180° C. (bath temperature) for 2 hours. After cooling, the reaction mixture was dissolved in chloroform and the chloroform solution was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1-(2-thenyl)-4-phenyl-6-nitro-3,4-dihydro-2(1H)-quinazolinone.
Reaction SMILES: O1C2C=CC=CC=2C=C1C1CCCOC1[N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])=[CH:22][CH:23]=2)[CH:18]=[N:17]1.Cl.O1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[O:35]1[C:36]2[CH:37]=[CH:18][CH:19]=[CH:20][C:21]=2[CH:33]=[C:34]1[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([C:25]([NH:27][CH:28]([CH3:29])[CH3:30])=[O:26])[CH:20]=2)[NH:16][N:17]=1
Reactant: CC(C)NC(=O)c1ccc2c(cnn2C2OCCCC2c2cc3ccccc3o2)c1
Reactant: C1COCCO1
Agent: Cl
Product: CC(C)NC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Reaction time: 8 h
Yield: 7 %

Procedure:
(3-Benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl(1H-indazol-5-yl))-N -(methylethyl)carboxamide (170 mg, 0.41 mmol) was taken up in a solution of 4 N HCl in dioxane and allowed to stir overnight. The reaction was neutralized to pH 7 and extracted with ethyl acetate. The organic layer was dried, filtered, and concentrated to yield the crude material which was purified by semi-preprative HPLC to yield the title compound (9 mg, 7% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.7 (s, 1H), 8.4 (d, 1H), 8.0 (d, 1H), 7.6–7.8 (m, 4H), 7.4 (m, 2H), 4.2 (m, 1H), 3.2 (d, 1H), 1.2 (d, 6H)