Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(C)C.C[Li].C1(O[C:23]#[N:24])C=CC=CC=1.Cl>CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C.O1CCCC1>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]#[C:5][C:23]#[N:24])=[CH:8][CH:9]=1
Reactant: N#COc1ccccc1
Reactant: C[Si](C)(C)C#Cc1ccc(O)cc1
Agent: Cl
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC#Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A solution of 381 mg of p-[(trimethylsilyl)ethynyl]phenol in 5 ml of hexamethylphosphoric acid triamide was treated at -5° C. in a sulphonation flask under argon gasification with 2.5 ml of a 1.75M solution of methyl lithium in diethyl ether. 15 minutes after completion of the addition the mixture, which had become a red slurry, was diluted with 5 ml of absolute tetrahydrofuran and subsequently stirred at room temperature for 3 hours. The mixture was then cooled to -30° C. and 322 μl of phenyl cyanate were added. The new brown-orange clear solution was warmed to 0° C. within 60 minutes, then poured into 50 ml of 1N hydrochloric acid and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed a further three times with 50 ml of water each time (to which was added a small amount of sodium chloride solution), dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the orange residue (570 mg) on silica gel with 15% ethyl acetate/petroleum ether followed by 20% ethyl acetate/petroleum ether gave 160 mg (56%) of (p-hydroxyphenyl)propiolonitrile as light yellowish crystals; m.p. 134°-137° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[N:6][CH:7]=1.C([Li])(C)(C)C.[CH2:20]([N:23]1[C@@H:28]([CH3:29])[CH2:27][O:26][C:25](=[O:30])[CH2:24]1)[CH2:21][CH3:22].[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[CH3:14][C:9]1[N:8]([C:5]2[N:6]=[CH:7][C:2]([C:25]3([OH:30])[O:26][CH2:27][C@H:28]([CH3:29])[N:23]([CH2:20][CH2:21][CH3:22])[CH2:24]3)=[CH:3][CH:4]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: CCCN1CC(=O)OC[C@@H]1C
Reactant: Cc1ccc(C)n1-c1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCN1CC(O)(c2ccc(-n3c(C)ccc3C)nc2)OC[C@@H]1C

Procedure:
5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine (1.5 g 5.9 mmol) was azeotroped with toluene and dissolved in THF (20 ml). This mixture was cooled to −78 C. and t-butyllithium (1.7M in pentane, 7 ml, 11.9 mmol) was added maintaining the temperature below −70 C. The material from example 62 was dissolved in THF (20 ml) and added to the mixture immediately on completion of the t-butyllithium addition. The mixture was allowed to stir at −78° C. for 30 minutes at which time NH4Cl (10% aq, 150ml) was added and the mixture extracted into EtOAc (200 ml), dried with magnesium sulphate, filtered and evaporated. Flash chromatography on SiO2 eluting with a stepped gradient from 25% EtOAc/pentane to 50% EtOAc/pentane gave the title compound as mixture of diastereoisomers in approximately 3.5:1 ratio as a yellow oil (480 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](C(F)(F)F)[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13]CCO.Cl.[O-:18]C#N.[K+]>O>[N:12]1[C:13](=[O:18])[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=12
Reactant: N#C[O-]
Reactant: Nc1cc(C(F)(F)F)ccc1NCCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C1N=c2ccccc2=N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 21 parts of 3-{[2-amino-4-(trifluoromethyl)phenyl]amino}-1-propanol and 100 parts of water are added 14.4 parts of hydrochloric acid solution. The whole is stirred for 10 minutes at room temperature. After cooling to 0°-10° C., there is added dropwise a solution of 18 parts of potassium cyanate in 50 parts of water. Upon completion, stirring is continued for 2 hours. The precipitated product is filtered off and dried. Then it is melted and the melt is stirred for 10 minutes. After cooling, it is dissolved in trichloromethane while heating. The solution is filtered and the product is allowed to crystallize from the filtrate. It is filtered off and dried, yielding 8 parts (34%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-trifluoromethyl)-2H-benzimidazol-2-one.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH2:14])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[CH3:20][CH:21]([CH3:25])[C:22](Cl)=[O:23]>ClCCl.O>[CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH:14][C:22](=[O:23])[CH:21]([CH3:25])[CH3:20])[CH2:3][CH2:2]1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of 2-cyclopropyl-4-fluoro-5-nitrobenzenamine (as described in WO2011068898) (1.98 g, 10.09 mmol, 1 equiv) in dichloromethane (50 mL) at room temperature, was added NaHCO3 (7.65 g, 90.84 mmol, 9 equiv), followed by 2-methylpropanoyl chloride (6.34 mL, 60.56 mmol, 6 equiv). The reaction mixture was stirred overnight. The reaction mixture was taken in water, and the layers were separated. The organic layer was washed with ice-cold 1N NaOH 2×, brine 1×, dried over Na2SO4, and concentrated to dryness. The crude product was absorbed onto silica gel and purified by flash chromatography and eluted with hex:EtOAc=100:0 to 50%-70% EtOAc using 10% EtOAc increments to afford N-(2-cyclopropyl-4-fluoro-5-nitrophenyl)isobutyramide (2.04 g, 84%) as a light-brown solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[O:13][C:14]([CH3:17])=[N:15][N:16]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH3:17][C:14]1[O:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[N:16][N:15]=1
Reactant: CCOC(=O)C1CCN(c2nnc(C)o2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnc(N2CCC(C(=O)O)CC2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.9 %

Procedure:
To a solution of 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidine-4-carboxylic acid ethyl ester (1.41 g, 5.89 mmol) in ethanol (5 ml) was added a 1 M solution of sodium hydroxide (5.9 ml, 5.9 mmol). The solution was stirred for 18 h at RT, and then was acified by addition of a 1 M solution of hydrochloric acid (5.9 ml). The reaction mixture was concentrated in vacuo. After the addition of Na2SO4 the residue was suspended in THF (20 ml), filtered off and washed with THF and dried under vacuo. The title compound (0.72 g, 38%) was obtained as an off-white solid. MS m/e: 210.1 [M−H].
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:13][C:7]1([CH3:14])[C:6]2[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=2)[O:10][CH2:9][CH2:8]1
Reactant: COc1ccc2c(c1)OCCC2(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCOc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a methylene chloride (3 ml) solution of 7-methoxy-4,4-dimethylchromane (1.9 g, 9.7 mmol) was added methylene chloride solution of boron tribromide (1M, 19.4 mL, 19.4 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was then quenched with methanol and then the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=¼ to furnish 1.3 g (75% yield) of the title compound as a yellow solid.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]=[C:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14]([O:16][CH3:17])=[O:15].[I:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1>C(#N)C.O>[I:23][C:24]1[CH:25]=[N:26][N:27]([CH2:12][CH:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14]([O:16][CH3:17])=[O:15])[CH:28]=1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: Ic1cn[nH]c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COC(=O)CC(Cn1cc(I)cn1)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (753 mg, 3 mmol) was added to a stirred mixture of dimethyl 2-methylenesuccinate (158 mg, 1.00 mmol) and 4-iodo-1H-pyrazole (194 mg, 1.00 mmol) in acetonitrile (2 mL) and the mixture was stirred at room temperature under N2 for 12 hours. The mixture was diluted with water and extracted with EtOAc. The EtOAc layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC on silica gel (petroleum ether/EtOAc) to afford dimethyl 2-((4-iodo-1H-pyrazol-1-yl)methyl)succinate. MS ESI calcd. for C10H14IN2O4 [M+H]+ 353, found 353. 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.39 (s, 1H), 4.55-4.36 (m, 2H), 3.72 (s, 3H), 3.68 (s, 3H), 3.42-3.33 (m, 1H), 2.70-2.47 (m, 2H).
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19][OH:20])=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24]O>>[CH3:24][O:8][C:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2=[N+:10]([O-:22])[C:11]3[C:16]([N+:17]([O-:21])=[C:18]2[CH2:19][O:20]1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CO
Reactant: O=C(c1ccccc1)c1c(CO)[n+]([O-])c2ccccc2[n+]1[O-]
Agent: Cl
Product: COC1(c2ccccc2)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A stirred suspension of 0.25 g. (0.84 mmol.) of 2-benzoyl-3-hydroxymethylquinoxaline 1,4-dioxide, in 10 ml. of methanol, was saturated with dry hydrogen chloride. The reaction mixture was stirred at room temperature overnight and then the suspended solid was collected by filtration. This afforded 0.16 g. (60% yield) of 1-methoxy-1-phenyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide, m.p. 150°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.I[CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH3:22])[C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1
Reactant: CI
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NCC(=O)N2
Product: COc1ccc2c(c1)C(c1ccccc1)=NCC(=O)N2C
Yield: 55 %

Procedure:
By replacing 7,8-dimethoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (XXIIaa) in the example by 7-methoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIao), and ethylene-carbonate by iodomethane, and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. M: 10–112° C. 1H-NMR (CDCl3, 300 MHz): d 3.38 (s, 3H, NCH3), 3.75 (s, 3H, OCH3), 4.30 (AB system, ? d=1.00, JAB=10.6, 2H, —CH2), 6.77–6.78 (m, 1H Ar), 7.09–7.14 (m, 1H Ar), 7.31 (s, 1H Ar), 7.38–7.46 (m, 3H Ar), 7.44–7.67 (m, 2H Ar).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:22]=1)[C:7](=[O:21])[N:8]([OH:20])[C:9]3=[O:19].C1C(=O)N([Cl:30])C(=O)C1.O>C(O)(=O)C>[Br:1][C:2]1[CH:22]=[C:6]2[C:5]3=[C:10]([CH:11]=[C:12]([Cl:30])[C:13]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:4]3[CH:3]=1)[C:9](=[O:19])[N:8]([OH:20])[C:7]2=[O:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1c2ccc(N3CCCC3)c3cc(Br)cc(c23)C(=O)N1O
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cc(Br)cc3c(N4CCCC4)c(Cl)cc(c23)C(=O)N1O
Yield: 43.3 %

Procedure:
A mixture of 5-bromo-2-hydroxy-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.15 g, 0.42 mmol, from Example 59) and NCS (0.072 g, 0.54 mmol) in acetic acid (12 mL) was reacted at 100° C. for 3 hours. The reaction mixture was cooled and poured into water. The resulting precipitate was collected by filtration, washed with water, and dried to give 0.072 g of the title compound.
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](B(O)O)[CH:30]=2)[CH:25]=[CH:24]1>CN(C=O)C.C(N(CC)CC)C>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:2]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]4[C:3]=3/[C:4](=[CH:15]/[C:16]3[NH:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])/[C:5](=[O:14])[NH:6]4)[CH:30]=2)[CH:25]=[CH:24]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: OB(O)c1ccc2cc[nH]c2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc4cc[nH]c4c3)c21
Temperature: 90 °C
Yield: 57.1 %

Procedure:
A solution of (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl) methylene]-5-nitro-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 6) and 6-indoleboronic acid (48 mg, 0.30 mmol) (from Example 48, Step A) were dissolved in 2 mL DMF and 2 mL triethylamine. The solution was degassed for 30 minutes by bubbling argon through the solution. At this time dichlorobis(triphenylphosphine) palladium(II) (20 mg, 0.029) (Aldrich) was added, and the reaction was heated, under argon, at 90° C. for 2 days. Water (20 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with 5% MeOH/CHCl3 to yield 64 mg (57%) (Z)-1,3-dihydro-4-(6-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one as a red powder.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:27])[C:16](=[O:26])[CH2:17][O:18][C:19]2[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:29][NH:30][CH3:31]>>[ClH:25].[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:27])[C:16](=[O:26])[CH2:17][O:18][C:19]2[CH:24]=[N:23][CH:22]=[C:21]([N:30]([CH3:31])[CH3:29])[N:20]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C(=O)COc1cncc(Cl)n1)C1CCN(Cc2ccccc2)CC1
Reactant: CNC
Agent: Cl
Product: CN(C)c1cncc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)n1

Procedure:
The title compound was synthesized from Compound 129 and dimethylamine hydrochloride in the same manner as in Example 130.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2.CCOCC>COCCOCCOC>[NH:26]1[C:27]2[C:23](=[C:22]([O:21][C:2]3[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])[CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: COC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: COC(=O)c1ccc(F)cc1Oc1cccc2[nH]ccc12

Procedure:
Methyl 2,4-difluorobenzoate (1.53 g), K3PO4 (1.89 g) and 4-hydroxyindole (1.08 g) were stirred at 110° C. in diglyme (12 mL) for 24 hours. The reaction was cooled and poured into ether. The solution was washed three times with 1M aqueous NaOH solution, and brine, and dried over Na2SO4. The solution was then concentrated, and the crude product was chromatographed on silica gel with 20% ethyl acetate/hexanes.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].Cl[CH2:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]([CH:45]2[CH2:47][CH2:46]2)[C:37]1=[O:48].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:45]1([N:38]2[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[N:36]([CH2:35][CH2:34][CH2:33][N:9]3[CH2:8][CH2:7][C:6]4([N:5]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH2:4][N:3]([CH2:18][C:19]5[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=5[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[C:2]4=[O:1])[CH2:11][CH2:10]3)[C:37]2=[O:48])[CH2:47][CH2:46]1
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Reactant: O=c1n(CCCCl)c2ccccc2n1C1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)n(C4CC4)c4ccccc43)CC2)C1=O
Temperature: 81 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A mixture of tert-butyl 2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (200 mg, 0.475 mmol, 1 equiv), 1-(3-chloropropyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (118.75 mg, 0.475 mmol, 1 equiv), sodium iodide (28.5 mg, 0.19 mmol, 0.4 equiv) and potassium carbonate (131.3 mg, 0.95 mmol, 2 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using the Biotage flash chromatography system (SNAP 10 g cartridge, Rf=0.5, gradient—1%-10% methanol in dichloromethane) to afford the title compound (230 mg, 76%); 1H NMR (400 MHz, DMSO-d6): δ 0.85-0.89 (m, 2H); 0.95-1.04 (m, 2H); 1.57 (s, 9H); 1.67 (d, 2H, J=12.4 Hz); 1.81 (t, 2H, J=6.4 and 6.8 Hz); 2.32-2.35 (t, 2H, J=6.8 Hz); 2.54-2.72 (m, 6H); 2.86-2.89 (m, 1H); 3.84-3.88 (t, 2H, J=6.8 and 6.4 Hz); 4.62 (s, 2H); 4.84 (s, 2H); 6.76-6.79 (t, 1H, J=7.2 Hz); 6.84-6.86 (d, 2H, J=8.4 Hz); 7.03-7.06 (t, 2H, J=5.6 and 6.8 Hz); 7.19-7.27 (m, 5H); 7.39-7.43 (t, 1H, J=7.6 and 7.2 Hz); 7.56-7.59 (t, 1H, J=8 and 6.4 Hz); 7.82-7.84 (d, 1H, J=7.6 Hz); MS for C38H45N5O4 m/z 636.12 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][OH:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][O:13][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:5][C:4]=1[C:17]([F:19])([F:18])[F:20])#[N:2]
Reactant: CC(O)(CO)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(O)(COS(C)(=O)=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 46 g (0.16 mol) of N-[4-cyano-3-trifluoromethyl-phenyl]-2,3-dihydroxy-2-methyl-propionamide in 1 1 of dichloromethane and 46 ml (0.57 mol) of dry pyridine was cooled to 0° C. and 46 ml (0.59 mol) of methanesulfonyl chloride was added dropwise. The mixture was stirred at 0° C. for 5 h, then washed three times with 500 ml of saturated aqueous sodium hydrogen carbonate, 500 ml of 10% aqueous hydrochloric acid and 500 ml of brine. The organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was crystallized with 200 ml of petroleum ether, which has a boiling range of 40–70° C.
Reaction SMILES: COCCO[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1OCCOC)[N:12]=[CH:11][N:10]=[C:9]2Cl.OC1ON=C(C2C=CC=CC=2)C=1.C(N(CC)CC)C>C(O)(C)C>[N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:15][CH:14]=2)[CH:9]=[N:10][CH:11]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Agent: Oc1cc(-c2ccccc2)no1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: c1ccc2ncncc2c1

Procedure:
0.3 g (1 mmol) of (6,7-bis(2-methoxyethoxy))-4-chloro-quinazoline was dissolved in 5 mL dry isopropanol. Under stirring, a solution of 0.175 g (1 mmol) of 5-hydroxy3-phenyl-isoxazole in 5 mL of isopropanol was slowly added dropwise to the reaction system, followed by the addition 0.101 g (1 mmol) of freshly distilled triethylamine. After the system was stirred at room temperature for 30 min, the reaction was hold at 60. After the completion of the reaction monitored by TLC, the reaction solution was concentrated under vacuum. The residue was directly separated by column chromatography (Vpetroleum ether:Vethyl acetate=5:1-2:1) to give the target compound of (6,7-bis(2-methoxyethoxy))-4-((3-(4-methylphenyl)-isoxazol-5-yl))-methoxy-)-quinazoline (i.e. Q-15 in the following Table). The other compounds were synthesized according to the synthetic process of (6,7-bis(2-methoxyethoxy))-4-((3-(4-methylphenyl)-isoxazol-5-yl))-methoxy-)-quinazoline. The structures were characterized by analytic methods such as IR, 1H NMR, ESI-MS, etc. The physical constants and spectral data of preferred compounds were indicated in the form of table.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]1([CH2:30][CH2:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:30][CH2:31][C:32]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)CCc1ccccc1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCc1ccccc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-phenyl-propionic acid to yield (3aR,4S,7aR)-methyl 4-(3-phenylpropanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=7.957 min; LC-MS Method II
Reaction SMILES: CN(C=O)C.S(Cl)([Cl:8])=O.N1C=CC=CC=1.[CH2:16]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:33]=1)[CH2:29]O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>ClCCl>[CH2:16]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:33]=1)[CH2:29][Cl:8])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCOc1cc(CO)cc(OCCCCCCCCC)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCC)c1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
A 1 L RBF was prepared containing 5 mL dry dichloromethane, a stir bar, a septum, an out-vent line and a nitrogen gas line. DMF (3.3 ml, 40.3 mmol) was added and the reaction mixture was cooled in an ice bath. Thionyl chloride (2.7 ml, 40.3 mmol) was added and the reaction mixture was stirred for 10 minutes. The ice bath was then removed and the reaction mixture was allowed to stir for an additional 10 minutes. The RBF was placed in an ice bath and a mixture of pyridine (2.72 ml, 33.6 mmol) and 3,5-dinonoxybenzylalcohol (13.2 g, 33.6 mmol) were added and dissolved in about 50 mL dichloromethane, drop-wise through the septum. After 15 minutes, the RBF was removed from the ice bath and the reaction was stirred for 2 hours after which the reaction mixture was placed in the refrigerator overnight. The solvent was removed by rotary evaporation. To the remaining organic matter, 100 mL of 50% ether/hexanes was added to dissolve the desired compound. A solid orange precipitate formed, the remaining liquid was decanted off and the precipitate was washed with an additional 100 mL of 50% ether/hexanes. The combined organic layers were vacuum filtered through a silica gel into a RBF and the solvent was removed under reduced pressure. The trace solvent was removed by high vacuum overnight. There was a 10.0 g yield or a 72.2% yield of the derivative. The NMR characterization data for this derivative is as follows. 1H NMR (300 MHz, CDCl3): 0.88 (t, J=6.3, 6H, CH2CH3), 1.1-1.55 (m, 28H, CH2(CH2)6), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.93 (t, J=6.6, 4H,), 4.50 (d, J=5.8, 2H, CH2Cl), 6.39 (t, J=2.2, 1H, ArH), 6.51 (d, J=2.2, 2H, ArH).
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]([OH:9])=O)[C:3]([OH:5])=[O:4].[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([N:16]2[C:7](=[O:9])[CH2:6][CH:2]([C:3]([OH:5])=[O:4])[CH2:1]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: NC1CCCCC1
Product: O=C(O)C1CC(=O)N(C2CCCCC2)C1
Yield: 96.5 %

Procedure:
Place 2-methylene-succinic acid (12.0 g, 92.2 mmol) and cyclohexylamine (9.15 g, 92.2 mmol) and heat to 160° C. for hours. Cool to give 18.8 g (96%) of 1-cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid. Charge a flask with 1-cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid (16.2 g, 76.7 mmol), add methylene chloride (20 mL) and cool to 0° C. Slowly add borane in THF (1M, 115.1 mL, 115.1 mmol) and stir for two hours at 0° C. Quench the reaction with ice and extract with methylene chloride. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (1-5% methanol in methylene chloride) to yield 9.9 g (65%) of the title compound: Mass spectrum (apci) m/z=198.1 (M+H).