Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](=[O:36])[NH:34][OH:35])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])(C)(C)C.C(Cl)[Cl:39]>>[ClH:39].[NH2:7][CH:8]([C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([NH:34][OH:35])=[O:36])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)NO)cc2)cc1)C(=O)N1CCOCC1
Reactant: ClCCl
Product: Cl
Product: NC(Cc1ccc(Oc2ccc(CCC(=O)NO)cc2)cc1)C(=O)N1CCOCC1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
The compound 16 (1.1 g) was dissolved in CH2Cl2 (30 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×25 mL), decanted, and dried to yield the desired compound 17 as a white amorphous solid (0.82 g, 85%). 1H NMR (400 MHz, DMSO-d6): 10.40 (s, 1H), 7.23 (overlapped d, J=8.8 Hz, 2H), 7.20 (overlapped d, J=8.8 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 4.62 (m, 1H), 3.35-3.54 (m, 8H), 2.91-3.07 (m, 2H), 2.80 (t, J=8.0 Hz, 2H), 2.25 (t, J=8.0 Hz, 2H); LCMS: Obsd.414, Calcd. 413.47.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Br:13])[CH:7]=1)[CH3:2].[H-].[Na+].IC.[CH3:19]COC(C)=O>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Br:13])[CH:7]=1)[CH3:19])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)Cc1cc(Cl)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)C(C)c1cc(Cl)cc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of (3-bromo-5-chloro-phenyl)-acetic acid ethyl ester (5.0 g, 18.0 mmol) in DMF (50 mL) at 0° C. under N2 was added sodium hydride (60% in mineral oil; 0.8 g, 19.8 mmol), and the mixture was warmed to room temperature over 15 minutes. Iodomethane (1.3 mL, 19.8 mmol) was added, and the reaction was monitored by analytical LCMS. Once the reaction was complete, the mixture was worked-up with EtOAc and H2O, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C(N[C:6](=[O:13])[C:7]([C:9]1([CH3:12])[CH2:11][CH2:10]1)=O)(C)(C)C.[NH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17].Cl.C(O)C>O>[NH2:14][N:15]1[C:6](=[O:13])[C:7]([C:9]2([CH3:12])[CH2:11][CH2:10]2)=[N:19][N:18]=[C:16]1[SH:17]
Reactant: CC(C)(C)NC(=O)C(=O)C1(C)CC1
Reactant: NNC(=S)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(c2nnc(S)n(N)c2=O)CC1

Procedure:
183 grams of (1-methyl-cyclopropyl)-glyoxalic acid-tert.-butylamide and 112 grams of thiocarbohydrazide were added to a mixture of 1 liter of 1 normal HCl and 1 liter of ethanol. The mixture was boiled under reflux for 8 hours, cooled, diluted with 2 liters of water and the crystals filtered off with suction. There were obtained white crystals with a yellow luster which were dried.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C@:15]12[CH2:24][O:23][C@@H:22]([CH2:25][O:26][CH:27]([CH3:29])[CH3:28])[CH2:21][C@H:20]1[CH2:19][S:18][C:17]([NH:30]C(=O)OC(C)(C)C)=[N:16]2>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C@:15]12[CH2:24][O:23][C@@H:22]([CH2:25][O:26][CH:27]([CH3:28])[CH3:29])[CH2:21][C@H:20]1[CH2:19][S:18][C:17]([NH2:30])=[N:16]2
Reactant: CC(C)OC[C@H]1C[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2ccccc2F)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2ccccc2F)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a 0° C. solution of tert-butyl {(4aR,6R,8aS)-8a-(2-fluorophenyl)-6-[(propan-2-yloxy)methyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}carbamate (C20) (11.2 mg, 0.0255 mmol) in dichloromethane (1.5 mL), and the reaction mixture was allowed to warm to room temperature and stir for 18 hours. After removal of solvents in vacuo, the residue was purified via reversed-phase HPLC (Column: Waters Sunfire C18, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 20% to 100% B) to afford the product as an oil. Yield: 11.8 mg, 0.026 mmol, quantitative. LCMS m/z 339.3 (M+1). 1H NMR (600 MHz, DMSO-d6) δ 1.09 (d, J=5.7 Hz, 3H), 1.09 (d, J=6.1 Hz, 3H), 1.52-1.60 (m, 1H), 1.70-1.75 (m, 1H), 2.84 (dd, J=12.7, 4.0 Hz, 1H), 3.04 (dd, J=13.2, 2.6 Hz, 1H), 3.17-3.23 (m, 1H), 3.42 (dd, half of ABX pattern, J=10.3, 4.2 Hz, 1H), 3.46 (dd, half of ABX pattern, J=10.5, 5.7 Hz, 1H), 3.58 (septet, J=6.1 Hz, 1H), 3.76-3.81 (m, 1H), 3.91 (AB quartet, JAB=12 Hz, ΔνAB=32 Hz, 2H), 7.23-7.28 (m, 1H), 7.29-7.36 (m, 2H), 7.46-7.51 (m, 1H)
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[SH:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[CH2:17][S:16][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: SCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=O)C(SCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.1 %

Procedure:
A solution of 2.78 g (10 mmol) of tert-butyl 3-bromo-4-oxo-piperidine-1-carboxylate and 2.09 g (12 mmol) of 2-mercaptomethylnaphthalene in 100 ml of absolute acetonitrile was treated with 13.8 g (100 mmol) of anhydrous potassium carbonate and thereafter the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, the filtrate was poured on to ice-water and adjusted to pH 2-3 with concentrated hydrochloric acid; the aqueous phase was extracted three times with 200 ml of ethyl acetate each time, the organic phase was washed once with 200 ml of water, dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The crude product (5.5 g) was chromatographed on silica gel with hexane and ethyl acetate as the eluent. The product was recrystallized from ethyl acetate and hexane. There were obtained 2.27 g (61% of theory) of tert-butyl (3RS)-3-(naphthalen-2-ylmethylthio)-4-oxo-piperidine-1-carboxylate as a colourless solid; MS: 371 (M)+.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.Cl.Cl[CH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1.O>CO>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:17][S:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[CH:7][N:6]=2)[CH:23]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: Sc1ncnc2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccnc(CSc2ncnc3ccccc23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.3 %

Procedure:
13 ml of 28% methanolic solution of sodium methoxide were added to a solution of 5.0 g of 4-mercaptoquinazoline and 5.5 g of 2-chloromethyl-4-methylpyridine hydrochloride in 50 ml of methanol and stirred at room temperature for 5 hours. A reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with an aqueous sodium carbonate solution, dried over sodium sulfate and distilled off under reduced pressure. The residue was purified by silica gel column chromatography. The fraction eluted with 10% ethyl acetate/chloroform was crystallized from isopropyl ether to obtain 1.84 g (22.3%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[C:20]([F:23])[C:21]=1[F:22].[CH3:28][O:29][C:30]1[CH:38]=[C:37]2[C:33]([CH2:34][CH2:35][CH:36]2[NH2:39])=[CH:32][CH:31]=1>>[F:15][C:16]1[CH:17]=[C:18]([S:24]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:39][CH:36]2[C:37]4[C:33](=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:38]=4)[CH2:34][CH2:35]2)=[N:9]3)(=[O:26])=[O:25])[CH:19]=[C:20]([F:23])[C:21]=1[F:22]
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1
Reactant: COc1ccc2c(c1)C(N)CC2
Product: COc1ccc2c(c1)C(Nc1ccc3c(NS(=O)(=O)c4cc(F)c(F)c(F)c4)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=500.4 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 3,4,5-trifluorobenzenesulfonyl chloride and 6-methoxyindan-1-ylamine (CAS 103028-81-5).
Reaction SMILES: C(OC([C:6]1[N:7]([CH:26]([CH3:36])[CH2:27][NH:28][C:29]([O:31]C(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1)=[C:10]([Br:25])[CH:9]=2)=O)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[Br:25][C:10]1[C:11]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:20][CH2:21]2)=[CH:12][C:13]2[CH:14]=[C:6]3[C:29](=[O:31])[NH:28][CH2:27][C@@H:26]([CH3:36])[N:7]3[C:8]=2[CH:9]=1
Reactant: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2n1C(C)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(Oc2cc3cc4n(c3cc2Br)[C@H](C)CNC4=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.5 %

Procedure:
The solution of 0.21 g (0.37 mmol) 6-bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid ethyl ester in 4 mL dichloromethane was cooled to 0° C. and 2 mL (2.98 g, 26.1 mmol) trifluoroacetic acid were added dropwise within 5 min. The cooling bath was removed and after 1 h the volatile components were removed at a rotary evaporator. The residue was dissolved in 4 mL methanol and 0.2 g (1.48 mmol) potassium carbonate was added under cooling. The suspension was stirred for 72 hours at room temperature and then diluted with water. The solution was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with a gradient of dichloromethane:methanol (100:0 to 50:50 v/v) to give 49 mg (31%) of the product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]=[O:9].C[C:11]([OH:13])=O>[OH-].[Na+]>[OH:1][C:2]1[C:3]([CH2:11][OH:13])=[N:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: CC(=O)O
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: OCc1ccc(O)c(CO)n1
Reaction time: 8 h

Procedure:
71.1 g (0.75 mol) of 3-hydroxypyridine are dissolved in 300 ml of a 10% aqueous NaOH solution. The combined mixture is brought to 90° C. and then 7×60 ml of a 30% formaldehyde solution are introduced portionwise (5.1 mol). The mixture is left at ambient temperature overnight and then neutralized with CH3COOH. It is concentrated and the residue is taken up in 600 ml of DMF. The insoluble light material is separated. The liquors are acidified with 75 ml 10N HCl. The mixture is concentrated. The residual oil is purified by chromatography on silanized silica with elution with water. Crystals are obtained. w=47 g.
Reaction SMILES: [CH2:1]1N2CCN(CC2)C1.[CH3:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][NH:31]4)=[CH:27][CH:26]=3)[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]>C(=O)(OC)OC.CN(C=O)C>[CH3:1][N:31]1[C:32]2[C:28](=[CH:27][CH:26]=[C:25]([C:22]3[N:21]=[C:20]([C:12]4[CH:13]=[N:14][C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:10]([CH3:9])[CH:11]=4)[O:24][N:23]=3)[CH:33]=2)[C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30]1
Reactant: Cc1cc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cnc1OC(C)C
Reactant: C1CN2CCN1CC2
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(-c3ccc4c(CCC(=O)O)cn(C)c4c3)no2)cnc1OC(C)C
Temperature: 90 °C
Yield: 53.2 %

Procedure:
DABCO (110 mg) was added to a solution of 3-[6-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E85) (100 mg) in dimethyl carbonate (3 mL) and DMF (2 mL). The resulting mixture was heated at reflux for 5 days. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was dissolved in iPrOH (3 mL) and water (3 mL). Sodium hydroxide (30 mg) was added to the mixture. The resulting mixture was heated at 90° C. for 1 hour. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[1-methyl-6-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E86) (55 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.24 (3H, s), 2.60 (2H, t), 2.95 (2H, t), 3.83 (3H, s), 5.41 (1H, m), 7.31 (1H, s), 7.74 (2H, m), 8.10 (1H, s), 8.29 (1H, d), 8.82 (1H, d), 12.10 (1H, br s). MS (ES): C23H24N4O4 requires 420; found 421.2 (M+H+).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[C:8]([CH:15]([CH3:17])[CH3:16])=[CH:7][C:6]=1[C:18]1[N:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=2)[C:20](=[O:23])[NH:21][N:22]=1.ClCCCl>CCCCCC>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([CH:15]([CH3:17])[CH3:16])=[CH:7][C:6]=1[C:18]1[N:19]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:20](=[O:23])[NH:21][N:22]=1
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1-c1ccc(OC)cc1
Solvent: ClCCCl
Solvent: CCCCCC
Product: CC(C)c1cc(-c2n[nH]c(=O)n2-c2ccc(O)cc2)c(O)cc1O
Temperature: 80 °C
Reaction time: 24 h
Yield: 14.7 %

Procedure:
Crystals (3.30 g, 7.68 mmol) of 5-(2,4-bis(methoxymethoxy)-5-isopropyl phenyl)-4-(4-methoxyphenyl)-4H-[1,2,4]triazol-3-one (F60-03: an intermediate of Example 2-7) was added to a suspension of tribromoborane dimethylsulfide complex (11.65 g, 37.26 mol) and 1,2-dichloroethane (250 mL) in 300 mL eggplant shaped flask and stirred at room temperature for 2 hours and further at an external temperature of 80° C. for 24 hours. After completing the reaction, the reaction mixture was returned to room temperature and mixed with n-hexane (250 mL). The precipitates were collected by filtration, washed with diethyl ether and then purified by DIAION HP-20 column chromatography (water-methanol gradient elution), followed by CHP-20 column chromatography (water-methanol gradient elution) to obtain the title compound (OH-all: 370 mg, 14.8%). The fractions which were not sufficiently separated and purified were purified by HPLC fractionation to obtain the title compound (OH-all: 300 mg, total 670 mg, 26.8%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[CH2:14](Br)[CH:15]1[O:19][CH2:18][CH2:17][CH2:16]1>>[O:19]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:14][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: BrCC1CCCO1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: N#Cc1ccnc(-c2cn(CC3CCCO3)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and tetrahydrofurfuryl bromide according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C14H14N4O, 255. Found, 255.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:28][C:29]1([CH3:36])[CH2:34][C:33](=[O:35])[O:32][C:30]1=[O:31]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([NH:21][C:33](=[O:35])[CH2:34][C:29]([C:30]([OH:32])=[O:31])([CH3:36])[CH3:28])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Reactant: CC1(C)CC(=O)OC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)Nc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 7-chloro-2-(5-aminobenzofuran-2-yl)-quinoline (0.28 g) and pyridine (0.12 ml) in a mixture of dichloromethane (10 ml) and N,N-dimethylformamide (20 ml), 2,2-dimethylsuccinic anhydride was added dropwise at ambient temperature- After being stirred at ambient temperature for 1 day, the resulting mixture was poured into ice-water. The appeared precipitates were collected by filtration, washed with water and recrystallized from ethanol to give 7-chloro-2-[5-(3-carboxy-3-methylbutyrylamino)benzofuran-2-yl]quinoline (0.13 g).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.C(OCC)C>O1CCCC1.O>[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[OH:24])=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: C#C[Si](C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(O)C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
Place lithium hexamethyldisilazane (12 mL of a 1M solution in tetrahydrofuran, 12 mmol) under an argon atmosphere and cool to 0° C. Add trimethylsilylacetylene (1.7 mL, 12 mmol) and stir for 1 hour at 0° C. Add 4-dimethylaminobenzaldehyde (1.49 g, 10 mmol) in tetrahydrofuran (25 mL). Allow to warm to room temperature and stir for 3 hours. Pour the mixture into ethyl ether and water, separate the organic phase and evaporate the solvent in vacuo. Filter the oil through silica gel (20% ethyl acetate/hexane) and evaporate the solvent in vacuo to yield 2.26 g of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:12]([CH3:18])[C:13]([NH:16][CH3:17])=[N:14][N:15]=2)[CH:8]=[CH:7][N:6]=1.CS(O[CH2:24][C:25]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[O:27][N:26]=1)(=O)=O>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:12]([CH3:18])[C:13]([N:16]([CH2:24][C:25]3[N:29]=[C:28]([C:30]4[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=4)[C:36]#[N:37])[O:27][N:26]=3)[CH3:17])=[N:14][N:15]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CNc1nnc(-c2ccnc(OC)c2)n1C
Reactant: CS(=O)(=O)OCc1noc(-c2cccc(C#N)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc(N(C)Cc3noc(-c4cccc(C#N)c4)n3)n2C)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
Sodium hydride (0.013 g, 0.53 mmol) was added portionwise to a stirred solution of 5-(2-methoxypyridin-4-yl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine (0.086 g; 0.39 mmol) in DMF (10 ml) at 0° C. The mixture was stirred for 30 minutes before [5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl]methyl methanesulfonate (0.1 g; 0.36 mmol) in DMF (1 ml) was added dropwise. The mixture was stirred at r.t. for 3 h before quenching with water (30 ml). The resulting mixture was extracted with EA (3×40 ml). The organics were combined, dried (Na2SO4) and evaporated to give a crude material, which was purified by prep. HPLC to give the title compound (0.061 g; 42.3%). 1H NMR: 8.49 (s, 1H), 8.33 (dd, 1H), 8.28 (d, 1H), 7.86 (dd, 1H), 7.67 (t, 1H), 7.24 (d, 1H), 7.02 (s, 1H), 4.60 (s, 2H), 3.97 (s, 3H), 3.70 (s, 3H), 3.08 (s, 3H).
Reaction SMILES: ClC1C=[C:4]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][C:14](=O)[CH2:13]3)[C:9]2=[O:19])C=CC=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO>[NH2:26][CH:14]1[CH2:15][CH2:16][CH2:17][C:10]2([C:9](=[O:19])[N:8]([CH3:4])[CH2:12][CH2:11]2)[CH2:13]1
Reactant: [BH3-]C#N
Reactant: O=C1CCCC2(CCN(c3cccc(Cl)c3)C2=O)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CN1CCC2(CCCC(N)C2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 142.2 %

Procedure:
To a round bottom flask was added 2-(3-chloro-phenyl)-2-aza-spiro[4.5]decane-1,7-dione of step 5 (0.38 g, 1.35 mmol), methanol (4.92 mL), and ammonium acetate (1.25 g, 16.2 mmol). The mixture was stirred at rt for 1 hr. Sodium cyanoborohydride (0.085 g, 1.35 mmol) was then added. After stirring at rt for 2 hrs, the reaction mixture was quenched with ice and diluted with ethyl acetate (60 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 0.35 g (94%) of the title compound, 7-amino-2-methyl-2-aza-spiro[4.5]decan-1-one, as a white solid. The title compound is a mixture of two diastereomers (trans/cis: 5/2; under LC-MS method C, the first peak with RT of 0.80 min was assigned as cis, and the second peak with RT of 0.83 min was assigned as trans.). ESI-MS m/z: 279 (M+H)+. It was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].CCN(C(C)C)C(C)C.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=1>O1CCOCC1.C(OCC)(=O)C>[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:32]2[C:27]3[S:26][CH:25]=[C:24]([C:22]([NH:21][C:3]4[CH:4]=[C:5]([C:8](=[O:20])[NH:9][C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=5)[CH:6]=[CH:7][C:2]=4[CH3:1])=[O:23])[C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:49][CH:48]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncnc3c(C(=O)Nc4cc(C(=O)Nc5cccc(C(F)(F)F)c5)ccc4C)csc23)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)-4-(methylsulfinyl)thieno[3,2-d]pyrimidine-7-carboxamide (30 mg, 0.060 mmol) was dissolved in dioxane (1 mL) and DIPEA (20 μL, 0.119 mmol) and 4-methoxybenzeneamine (37 mg, 0.298 mmol) were added thereto. The reaction mixture was stirred at 120° C. for 18 hours, cooled to room temperature, diluted with ethyl acetate and washed with a brine. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel chromatography to obtain the title compound (28 mg, 81% yield).