Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26]([C:2]2[S:6][C:5]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[N:4][CH:3]=2)[CH:27]=1
Reactant: Brc1cnc(N2CCOCC2)s1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncc(-c2cnc(N3CCOCC3)s2)cc1-c1nc2ccccc2s1
Temperature: 100 °C

Procedure:
A solution of 4-(5-bromothiazol-2-yl)-morpholine (0.0600 g, 0.241 mmol), 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (0.110 g, 0.313 mmol), potassium carbonate (0.106 g, 0.771 mmol), and Pd(PPh3)4 (0.02 g, 0.02 mmol) in previously degassed DME/Water (4:1) (2.7 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor at 100° C. for 45 min. The reaction mixture was partitioned between CHCl3 and H2O and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×), and the combined organic extracts were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was submitted for MDP for purification. The pure fractions were combined and the organic was concentrated in vacuo then diluted with CHCl3 and neutralized with sat. NaHCO3. The layers were separated, and the aqueous layer was re-extracted with CHCl3 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, giving the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=3.44 (d, J=5.1 Hz, 4H), 3.73 (d, J=5.1 Hz, 4H), 7.49 (t, J=7.7 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.61 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 8.03 (br. s., 2H), 8.10 (d, J=7.7 Hz, 1H), 8.15 (d, J=7.3 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H). MS (ES+): m/z=396.07 (100) [MH+]. HPLC: tR=3.57 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([BH3-])#[N:16].[Na+].CN(C)P([N:26]([CH3:28])[CH3:27])(N(C)C)=O>>[CH:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:12]=[CH:11][C:10]([CH:7]([N:26]3[CH:27]=[N:16][CH:15]=[CH:28]3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][CH:8]=2)=[CH:6][CH:5]=1
Reactant: Br[Mg]c1ccc(-c2ccccc2)cc1
Reactant: [BH3-]C#N
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Na+]
Product: c1ccc(-c2ccc(C(c3ccccc3)n3ccnc3)cc2)cc1
Yield: 68.2 %

Procedure:
Bifonazole has also been prepared by benzoylation of imidazole with PhCOCl, yielding 74.7% of 1-benzoylimidazole which is subject to react with Gringnard's reactant 4-PhC6H4MgBr followed by a tosylation and subsequent reduction with sodium cyanoborohydride in hexamethylphosphoramide, to yield 68.2% Bifonazole (Es. Patent 539,345).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:15][O:14][N:13]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:32][OH:33]>C1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:15][O:14][N:13]=2)=[N:32][OH:33])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccccc1
Product: ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-4-(3-morpholin-4-ylpropyl)-1,2,5-oxadiazole-3-carboxamide (10.0 mg, 27 μmol) was suspended in benzene (0.4 mL) under an atmosphere of nitrogen and phosphorus pentachloride (6.2 mg, 29.8 μmol) was added. The solution was heated at reflux for 2.5 h. The volatiles were evaporated in vacuo. The reaction was dissolved in EtOH (0.3 mL) and hydroxylamine (40 μL, 0.7 mmol) (50% solution in water) was added to the reaction. After stirring for 1 h, the reaction solution was diluted with MeOH and purified by preparative LCMS to give the desired product (5.2 mg, 50%). LCMS for C16H20ClFN5O3 (M+H)+: m/z=384.1.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]1[NH:15][C:14](=[O:16])[CH2:13][O:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:18]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)C=O>[CH2:3]([CH:10]1[N:15]([CH:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:14](=[O:16])[CH2:13][O:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClC(CCN1CCOCC1)c1ccccc1
Reactant: O=C1COCC(Cc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1COCC(Cc2ccccc2)N1C(CCN1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% NaH (80 mg, 2 mmol) in dry dimethylformamide (8 ml) was added 5-benzyl-3-morpholinone (880 mg, 2 mmol). The mixture was stirred at room temperature for 1 hour. To this were added 4-(3-chloro-3-phenylpropyl)morpholine (480 mg, 2 mmol) and dry dimethylforamide (1 ml). The mixture was then stirred overnight at 60° C. The stirred mixture was placed under reduced pressure to evaporate the solvent. Water was added to the residue, and extraction with ethyl acetate was performed. The extract was washed with a saturated aqueous brine and dried over anhydrous sodium sulfate. The dried extract was placed under reduced pressure to remove the solvent. The oily residue was placed on silica gel column and eluated with ethyl acetate/methanol (20/1) to yield the desired diastereomer A (168 mg, 21.3%) and diastereomer B (156 mg, 19.8%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:8]=1[CH2:9][OH:10].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH3:5][O:4][C:2]([NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:8]=1[CH2:9][OH:10])=[O:3]
Reactant: Cc1cccc(N)c1CO
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cccc(C)c1CO
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A solution of methyl chloroformate (0.416 g) in methylene chloride (1 ml) was added dropwise to a solution of 2-amino-6-methylbenzyl alcohol (0.549 g) and pyridine (0.364 g) in methylene chloride (10 ml) with ice cooling. After being stirred for 1 hour, the mixture was poured into 1N hydrochloric acid and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was washed with n-hexane and dried to give 2-methoxycarbonylamino-6-methylbenzyl alcohol (0.64 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[CH:19][C:20]4[CH:25]=[C:24]([CH:26]=[O:27])[N:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:21]=4[N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1(C)C=CC(S([N+:42]#[C-:43])(=O)=O)=CC=1.[C:45]([O-])([O-])=O.[K+].[K+]>CO>[CH2:31]([CH:28]([N:23]1[C:21]2[N:22]=[C:17]([NH:16][C:13]3[CH:14]=[CH:15][C:10]([N:7]4[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:11][CH:12]=3)[N:18]=[CH:19][C:20]=2[CH:25]=[C:24]1[C:26]1[O:27][CH:43]=[N:42][CH:45]=1)[CH2:29][CH3:30])[CH3:32]
Reactant: CCC(CC)n1c(C=O)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Reactant: [C-]#[N+]S(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(CC)n1c(-c2cnco2)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Yield: 63.3 %

Procedure:
To a solution of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (30 mg, 0.07 mmol) in MeOH (1 mL) are added p-toluenesulfonyl isocyanide (16 mg, 0.08 mmol) and K2CO3 (29 mg, 0.21 mmol). The reaction mixture is heated at reflux for 1.5 h and concentrated in vacuo. The residue is purified by preparative HPLC to give 21 mg of 1-(4-{4-[7-(1-ethyl-propyl)-6-oxazol-5-yl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone as a pale brown solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33](=[O:36])[NH:34][CH3:35])[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][NH:34][C:33]([C:31]1[N:32]=[C:20]2[N:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][N:21]2[N:30]=1)=[O:36]
Reactant: CNC(=O)c1nc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1nc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 8-7 (50 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 8-8.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([N:15]=[C:16]=[O:17])[CH:12]=[CH:13][CH:14]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([S:25]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[O:36][C:37]2[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=2)[C:31]#[N:32])(=[O:27])=[O:26])[CH2:21][CH2:20]1>C(Cl)Cl>[NH2:18][CH:19]1[CH2:20][CH2:21][N:22]([S:25]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[O:36][C:37]2[CH:38]=[C:39]([Cl:44])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:31]#[N:32])(=[O:27])=[O:26])[CH2:23][CH2:24]1.[C:31]([C:30]1[CH:33]=[CH:34][C:35]([O:36][C:37]2[CH:38]=[C:39]([Cl:44])[CH:40]=[C:41]([Cl:43])[CH:42]=2)=[C:28]([S:25]([N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:16]([NH:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[CH:10]=3)=[O:17])[CH2:20][CH2:21]2)(=[O:27])=[O:26])[CH:29]=1)#[N:32]
Reactant: O=C=Nc1cccc(F)c1
Agent: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(N)CC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(NC(=O)Nc3cccc(F)c3)CC2)c1
Reaction time: 3 h

Procedure:
3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile was prepared following the procedure of Example 1. The final product was prepared by the addition of triethyl amine (0.42 mL) followed by 3-fluorophenyl isocyanate to a solution of 3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile (102 mg) in methylene chloride (4.0 mL). After stirring for 3 hours, the starting material was consumed, as confirmed by TLC (50% EtOAc/hexanes). 4 mL of hexanes was added and the product collected by vacuum filtration and washed with 1N HCl. The desired product was obtained as a white powder (99 mg, 73.3%). 1H NMR (500 MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.28 (d, J=2 Hz, 1H), 8.13 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.55 (t, J=2 Hz, 2H), 7.42 (m, 1H), 7.37 (d, J=2 Hz, 2H), 7.34 (d, J=9 Hz, 1H), 7.22 (m, 1H), 6.99 (m, 1H), 6.68 (m, 1H), 6.33 (d, J=8 Hz, 1H), 3.61 (m, 3H), 2.96 (m, 2H), 1.88 (m, 2H), 1.40 (m, 2H). MS (ESI+ ion, m/z): 564.
Reaction SMILES: C(Cl)CCl.C(N(CC)CC)C.[C:12]12([CH2:22][OH:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.[C:24]([NH:31][C@H:32]([C:40](O)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C1C=CN=CC=1)C.ClCCl>[C:12]12([CH2:22][O:23][C:40](=[O:41])[C@H:32]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH:31][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
1192 mg (6.2 mmol) of EDC, 578 μl (4.1 mmol) of triethylamine, 345 mg (2.8 mmol) of DMAP, and 345 mg (2.1 mmol) of 1-adamantylmethanol were added at RT to a solution of 500 mg (1.89 mmol) of N-Boc-L-phenylalanine in 25 ml dichlormethane. The reaction composition was stirred overnight, then diluted with 50 ml dichlormethane and successively washed in a solution of 10% of aqueous citric acid, water, and saturated saline. The organic phase was dried over magnesium sulphate and then evaporated, and the residue purified with preparative HPLC. The yield was 769 mg (90% o. th.) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[CH:20]=O.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:26][O:25][C:23]1[CH:22]=[C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:18]=[C:17]([O:16][CH3:15])[CH:24]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Yield: 46 %

Procedure:
2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3,5-dimethoxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (120 mg, 46%) was isolated as a yellow solid. Selected data: MS (m/z): 343.05; MP 270-272° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH:17]1([CH2:21][C:22](O)=[O:23])[CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:21][C:22]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:23])[CH2:20][CH2:19][CH2:18]1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(O)CC1CCC1
Product: O=C(CC1CCC1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-cyclobutylacetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO) δ 11.61-11.40 (m, 1H), 8.46-8.38 (m, 1H), 8.17-8.09 (m, 1H), 8.09-7.98 (m, 2H), 2.73-2.61 (m, 1H), 2.46 (d, J=7.5, 2H), 2.15-2.01 (m, 2H), 1.93-1.70 (m, 4H); MS (ESI) m/z 326 (M+H)+.
Reaction SMILES: [Cl-].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:39]=[CH:38][C:17]([CH2:18][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:16][CH:15]=1.[H-].[Na+].[OH:42][C:43]1[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=1>CN(C=O)C>[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:47][C:46]2[CH:49]=[CH:50][C:43]([OH:42])=[CH:44][CH:45]=2)=[CH:38][CH:39]=1
Reactant: c1ccc([P+](Cc2ccc(OCc3ccc4ccccc4n3)cc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of (13.29 mmol) of 4-(2-quinolinylmethyloxy)benzyl triphenylphosphonium chloride in 100 ml of dry DMF under positive nitrogen atmosphere is cooled to 0° C. and 0.50 g (20.77 mmol), of an 80% NaH in oil dispersion is added in small portions. The suspension is aged for 15 minutes at 0° C. followed by 45 minutes at room temperature to assure complete anion formation. The flask is cooled back to 0° C. and (13.29 mmol) of 4-hydroxybenzaldehyde in 20 ml of DMF is dropped in over a period of 15 minutes. The reaction is allowed to equilibrate to room temperature and stirred for 2 hours. The resultant mixture is poured into ice water and filtered. The precipitate is dissolved in CH2Cl2, dried, and concentrated in vacuo. The crude product is recrystallized from ether to give 4-(4-(2-quinolinylmethyloxy)styryl)phenol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH3:20].C(OC(=O)C)(=O)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=1>O.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:34][C:32]1[N:33]=[C:29]([CH3:28])[S:30][CH:31]=1
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Br
Reactant: Cc1nc(C=O)cs1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2Br)cs1
Temperature: 25 °C
Yield: 52 %

Procedure:
Anhydrous zinc chloride (0.150 g, 1.1 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (5 mL) was then added. To this mixture was added 3-(2-bromo-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.182 g, 0.55 mmol), acetic anhydride (0.156 mL, 1.65 mmol), and 2-methylthiazole-4-carboxaldehyde (0.209 g, 1.65 mmol in 3 mL of dioxane). The reaction was refluxed 3 hours, and was then cooled to ambient temperature. Once the reaction had cooled to ambient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The combined chloroform layers were washed with water and brine, then dried over magnesium sulfate and then concentrated to yield a dark residue. This residue was triturated with ether, filtered and dried to afford 0.116 g (52% of 3-(2-bromo-phenyl)-6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].[F:20][C:21]([F:38])([F:37])[CH:22]1[CH2:24][N:23]1[S:25]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=1[CH3:36])(=[O:27])=[O:26].N1CC1>CN(C=O)C>[CH3:36][C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[C:33]([CH3:34])[C:28]=1[S:25]([NH:23][CH:22]([CH2:24][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8]1)[C:21]([F:38])([F:20])[F:37])(=[O:26])=[O:27]
Reactant: [H][H]
Reactant: c1ccc(-c2c[nH]c3ccccc23)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC2C(F)(F)F)c(C)c1
Agent: C1CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)NC(Cn2cc(-c3ccccc3)c3ccccc32)C(F)(F)F)c(C)c1
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of 48 mg (0.25 mmol) of 3-phenyl-1H-indole in 3 mL of DMF was added 28 mg (0.7 mmol) of 60% sodium hydride in mineral oil. The mixture stirred until hydrogen evolution ceased and then 73 mg (0.25 mmol) of 2-trifluoromethyl-1-(2,4,6-trimethylbenzenesulfonyl)aziridine was added. The reaction was monitored by TLC (20% EtOAc-hexanes and 50% hexanes-CH2Cl2) indicating starting aziridine was consumed. After 30 minutes, the mixture was quenched with 7 mL of saturated aqueous ammonium chloride solution and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with three 7 mL portions of saturated aqueous ammonium chloride solution and three 7 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ether to afford 88 mg (72%) of the title compound. MS: m/z 487.59 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14](Cl)=[O:15].COC1C=[C:27]2C(C(=O)C=[CH:25][NH:26]2)=CC=1C(O)=O.C(N(C(C)C)CC)(C)C.O1CCCC1.CNC>O1CCCC1.O>[CH3:25][N:26]([CH3:27])[C:14]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[N:10]=[CH:9][CH:8]=[C:7]2[Cl:13])=[O:15]
Reactant: COc1cc2[nH]ccc(=O)c2cc1C(=O)O
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)Cl
Agent: CNC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2nccc(Cl)c2cc1C(=O)N(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
After dissolving 7-methoxy-4-chloro-quinoline-6-carbonyl chloride synthesized by the method of Production Example 152-2 from 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (1.0 g) in tetrahydrofuran (60 ml), the solution was cooled to 0° C. Diisopropylethylamine (1.6 ml) and a 2.0 M dimethylamine tetrahydrofuran solution (3 ml) were added and the mixture was stirred overnight at room temperature. Water was added, extraction was performed 3 times with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over sodium sulfate and then dried under reduced pressure to obtain the title compound (933 mg).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:19]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:10]([C:7]2[CH2:8][CH:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[CH2:5][CH:6]=2)=[CH:11]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), benzoyl chloride (13 μL, 0.12 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:17])=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CNc1ccc(CCO)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)CN(C)c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 67.1 %

Procedure:
To a solution of ethyl N-[4-(2-hydroxyethyl)phenyl]-aminoacetate (1.15 g) in N,N-dimethylformamide (10 ml) were added potassium carbonate (1.17 g) and methyl iodide (420 μl), and the mixture was stirred for 9 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by flash column chromatography on silica gel (eluent: dichloromethane/diethyl ether=10/1) gave ethyl N-[4-(2-hydroxyethyl)phenyl]-N-methylaminoacetate (820 mg).