Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]([Cl:14])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.O>[Cl:15][C:2]([Cl:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([Cl:14])[C:9]([O:13][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:10]([Cl:12])[CH:11]=1
Reactant: CC(C)(C)OC(=O)CCl
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 70 °C
Reaction time: 18 h
Yield: 102.4 %

Procedure:
A mixture of 0.5 gram (0.0017 mole) of 4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenol (known compound), 0.26 gram (0.0019 mole) of potassium carbonate and 0.26 gram (0.0017 mole) of tert-butyl chloroacetate in 0.12 mL of DMF was heated to 70° C. where it stirred for about 18 hours. After this time the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with 30 mL of water then extracted with three 30 mL portions of ethyl acetate. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a yellow oil. The crude oil was purified with column chromatography on silica gel using a mixture of hexanes and ethyl acetate (93:7) as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.7 gram of the subject compound.
Reaction SMILES: C([O:8][C:9](=[O:24])[C@H:10]([CH3:23])[C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12](O)=O)C1C=CC=CC=1.CN1CCOCC1.ClC(OCC(C)C)=O.[C:40]([C:44]1[CH:45]=[C:46]([NH2:51])[C:47]([NH2:50])=[CH:48][CH:49]=1)([CH3:43])([CH3:42])[CH3:41]>O1CCCC1>[C:19]([O:18][C:16]([NH:15][C@H:11]([C:12]1[NH:50][C:47]2[CH:48]=[CH:49][C:44]([C:40]([CH3:43])([CH3:41])[CH3:42])=[CH:45][C:46]=2[N:51]=1)[C@@H:10]([CH3:23])[C:9]([OH:24])=[O:8])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: C[C@@H](C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a cooled solution (−78° C.) of (2S,3R)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-3-methyl-4-oxobutanoic acid (Preparation 66, 4.10 g, 12.2 mmol) in tetrahydrofuran (50 mL) was added N-methylmorpholine (2.0 mL, 18.23 mmol) followed by isobutyl chloroformate (1.67 mL, 12.8 mmol) and the resulting white suspension stirred at −78° C. for 30 minutes. A solution of 4-(tert-butyl)benzene-1,2-diamine (2.40 g, 14.6 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude product was dissolved in ethyl acetate (200 mL) and washed with aqueous saturated sodium bicarbonate (3×50 mL), water (2×50 mL). The organic layer was concentrated in vacuo and purified by silica gel column chromatography eluting with a gradient of dichloromethane: EtOAc. The residue was dissolved in methanol (50 mL) and palladium hydroxide was added (20% wt % on carbon, 0.43 g). The reaction mixture was stirred under a hydrogen atmosphere (2 atm) at room temperature for 1 hour. The reaction mixture was filtered through a small pad of Arbocel and concentrated in vacuo. The residue was dissolved in acetic acid (100 mL) and stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase column chromatography eluting with a gradient of water/MeCN to afford the title compound as off-white solid (3.54 g, 78%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:13][C@H:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:10](=[O:26])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.I[CH2:38][C:39]#[N:40]>O1CCCC1.O>[C:39]([CH2:38][N:13]1[C@H:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:10](=[O:26])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[C:4]1=[O:3])#[N:40]
Reactant: N#CCI
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC#N

Procedure:
Sodium hydride (60% in mineral oil, 11 mg, 0.28 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18A, 50 mg, 0.10 mmol) in tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 20 min 2-Iodoacetonitrile (7 μL, 0.10 mmol) is added, and the mixture is stirred over night. Another portion of 2-iodoaceto-nitrile (7 μL, 0.10 mmol) is added, and the mixture is stirred over night. Another portion of 2-iodoacetonitrile (14 μL, 0.20 mmol) is added, and the mixture is stirred for 2 h, diluted with water and purified by preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 6 mg; ESI mass spectrum [M+H]+=529; Retention time HPLC: 1.05 min (Z018_S04).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27]C)/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH3:23])[C:10]=2[N:9]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[OH:27])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH3:23])[C:10]=2[N:9]=1
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CC)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(O)c3)n2C)n(CC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
Compound 65 (2.00 g, 5.20 mmol) obtained in Example 8 was dissolved in 40 ml of methylene chloride. To the solution was added 26 ml (26 mmol) of boron tribromide (1.0M methylene chloride solution) under ice cooling in argon atmosphere, and the mixture was stirred overnight at room temperature. Methanol was added thereto and the mixture was separated with chloroform-an aqueous solution of sodium bicarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was recrystallized from ethanol to give 643 mg (yield 35%) of Compound 173 as pale yellow grains.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.[Li]CCCC>Cl>[C:7]1([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[B:13]([OH:18])[OH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccsc1-c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Product: OB(O)c1ccsc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.1 %

Procedure:
To a mixture of 3-bromo-2-phenylthiophene (1.99 g, 8.32 mmol) and B(Oi-Pr)3 (1.81 mL, 12.5 mmol) in TI-IF (20 mL) was added n-BuLi (1.65 M in hexane, 10.1 mL, 16.6 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min and at 0° C. for 30 min. The mixture was diluted with 1 M HCl aqueous solution at 0° C., extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=90/10 to 0/100) to yield the title compound (87.4 mg, 5% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 7.19 (1H, d, J=4.9 Hz), 7.27-7.44 (3H, m), 7.46-7.58 (3H, m), 8.06 (2H, s).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21]CS([O-])(=O)=O)=[CH:15][CH:14]=1.C1OCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:21][CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-]CCCN1CCCCC1
Reactant: O=S(=O)([O-])CCCCc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(CCCOCCCN2CCCCC2)cc1

Procedure:
Sodium 3-piperidinopropanolate (20 mmol), 7 mmol of 3-(4-chlorophenyl)propylmesylate, and 0.5 mmol of 15-crown-5 in 30 ml of dry toluene were refluxed for 4 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel (eluent: methylene chloride/methanol (90/10)). After removing the solvent under reduced pressure the residue was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cc1cc(C)nc(Sc2ccc(O)cc2)n1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: Cc1cc(C)nc(Sc2ccc(OC(=O)N(C)c3ccccc3)cc2)n1

Procedure:
The title product was prepared from 4-(4,6-dimethylpyrimidin-2-ylsulfanyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (59%, white solid). HPLC-MS: m/z=366.1 (M+1); Rt: 4.50 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15]C(=O)C(C)(C)C)[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.C(O)(=O)C>[OH-].[Na+]>[NH2:15][C:10]1[NH:9][C:8](=[O:22])[C:7]2[C:6]3[CH:23]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1
Temperature: 75 °C

Procedure:
A solution of N-(9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.15 g, 0.4 mmole) in 0.75 N NaOH (7 ml) was stirred and heated to 75° C. under a nitrogen atmosphere for 10.5 hours. The solution was cooled and made slightly acidic with acetic acid to cause precipitation of the product. The precipitate was collected, washed successively with water, methanol and ether, and dried to give 3-amino-9-bromobenzo[f]quinazolin 1(2H)-one as an off-white solid. (0.115 g, 99%) 1H NMR (DMSO-d6, 200 MHz) δ: 6.64 (br s, 2H, NH2); 7.31 (d, J=8.8 Hz, 1H, Ar); 7.57 (dd, J=8.5, 1.9 Hz, 1H, Ar); 7.83 (d, J=8.6 Hz, 1H, Ar); 8.02 (d, J=9.0 Hz, 1H, Ar); 9.83 (s, 1H, Ar); 11.28 (br 5, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([F:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([F:17])=[CH:11][C:10]=1[Br:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(OCc2ccccc2)ccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1nc(OCc2ccccc2)c(Br)cc1F
Reaction time: 2 h
Yield: 37.3 %

Procedure:
step 3—A solution 142 (1 g, 4.29 mmol) in DMF (10 mL) was cooled in ice-bath and NBS (0.763 g, 4.29 mmol) was added. The colorless mixture was stirred for 2 h and then quenched with H2O. The mixture was extracted with EtOAc (2×50 mL). The combined extracts were washed sequentially with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography to afford 0.5 g of 6-benzyloxy-5-bromo-3-fluoro-2-methoxy-pyridine (144).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([CH3:27])([C:21]3[NH:22][CH:23]=[C:24]([CH3:26])[N:25]=3)[CH3:20])[CH:17]=2)[NH:12][C:11]=1[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH3:35][C:30]1[CH:29]=[C:28]([C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][NH2:7])=[CH:17][C:16]([C:19]([CH3:27])([C:21]2[NH:22][CH:23]=[C:24]([CH3:26])[N:25]=2)[CH3:20])=[CH:15][CH:14]=3)[CH:33]=[C:32]([CH3:34])[CH:31]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)c4nc(C)c[nH]4)cc3c2CCNC(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)c4nc(C)c[nH]4)cc3c2CCN)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a solution of (2-{2-(3,5-dimethylphenyl)-5-[1-methyl-1-(4-methyl-1H-imidazol-2-yl)ethyl]-1H-indol-3-yl}ethyl)carbamic acid tert-butyl ester (353 mg in 8 mL methylene chloride) at 0° C. was added 0.56 mL anisole followed by 2.5 mL trifluoroacetic acid and the mixture stirred at room temperature. After 2 hours, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene. The residue was solvated in methylene chloride and washed sequentially with 0.5N sodium hydroxide and brine. Purification of the concentrate by preparative tlc on silica gel (methylene chloride:methanol:ammonium hydroxide, 80:20:0.25) to give the title compound (198 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][C:14]1[Se:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[CH:13][C:14]1[Se:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1nc2ccccc2[se]1
Product: O=[N+]([O-])c1ccc(Cl)c(C=Cc2nc3ccccc3[se]2)c1
Yield: 44 %

Procedure:
This compound was prepared in a similar manner in 44% yield from 2-chloro-5-nitrobenzaldehyde and 2-methylbenzoselenazole, mp 201°-203° C., UV λmaxEtOH nm (ε) 208(31164), 225(31164), 331(34291); 1H-NMR δTMSCDCl3 (ppm) 8.61 (d, J=2.7 Hz, 1H), 8.20-7.26 (complex pattern, 8H); 13C-NMR δTMSCDCl3 (ppm) 169.2, 146.9, 140.2, 135.1, 131.7, 131.1, 130.1, 128.8, 128.5, 126.7, 126.1, 125.1, 124.8, 124.0, 121.9; IR νmaxKBr (cm-1) 1643.4, 1604.3, 1565.8, 1517.9, 1481.0, 1460.6, 1384.3, 1342.7, 1282.2, 1243.8, 1130.7, 1115.4, 1090.0, 910.9, 829.2, 815.2. Anal. Calcd. for C15H9ClN2O2Se: C, 49.53, H, 2.50, N, 7.70. Found: C, 49.66, H, 2.55, N, 7.77.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([N:5]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:19])[C:8]=2[CH:7]=1)[C:21]([Cl:20])=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: C1CCOC1
Product: CCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Yield: 595.2 %

Procedure:
A solution of butyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (7) (143 mg, 0.55 mmole) in 20 mL of THF was treated with 57 mg of triphosgene (0.35 eq.), stirred at reflux for three hours and then poured onto 50 mL ice-water. The mixture was extracted with three portions of 50 mL of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, to provide 368 mg of butyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (9) which was used without purification.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6](C=O)[CH2:5][CH:4]1[CH2:11][O:12][CH2:13][CH:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[OH:15])=O.[ClH:26].C(O)C>CO>[ClH:26].[ClH:26].[C:16]1([CH:14]([OH:15])[CH2:13][O:12][CH2:11][CH:4]2[CH2:5][NH:6][CH2:7][CH2:8][NH:3]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=CN1CCN(C=O)C(COCC(O)c2cccc3ccccc23)C1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: OC(COCC1CNCCN1)c1cccc2ccccc12
Reaction time: 8 h

Procedure:
In 1.5 ml of methanol was dissolved 250 mg of 2-[(1,4-diformylpiperazin-2-yl)methoxy]-1-(1-naphthyl)ethanol. To the solution was added 1.5 ml of a 5N dry hydrogen chloride-ethanol solution. The mixture was allowed to stand at room temperature overnight. The resulting crystals were collected by filtration, washed with ethanol, and dried to obtain 180 mg of 1-(1-naphthyl)-2-[(piperazin-2-yl)methoxy]ethanol dihydrochloride (compound No. 274).
Reaction SMILES: O1CCOCC1.Br.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:31][CH2:30]3)=[C:25]([O:32]C)[N:24]=2)=[CH:16]\[C@@H:17]2[NH:21][C:20](=[O:22])[CH2:19][CH2:18]2)=[CH:11][CH:10]=1>O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:23]2[NH:24][C:25](=[O:32])[C:26]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[CH:16]\[C@H:17]2[CH2:18][CH2:19][C:20](=[O:22])[NH:21]2)=[CH:13][CH:14]=1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(Cl)cc2)ccc1C1CC1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC[C@H](/C=C(\c2ccc(Cl)cc2)c2ccc(C3CC3)c(=O)[nH]2)N1
Temperature: 65 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
1,4-Dioxane (4 mL) and 48% hydrobromic acid (2 mL) were added to (5R)-5-[(E)-2-(4-chlorophenyl)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (250 mg), and the mixture was stirred at 65° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→90:10) to give the title compound as a colorless powder (65 mg, 68% (two steps)).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)=S)[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:21]O>C(O)(=O)C>[F:1][C:2]1[C:3]([CH:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)=[O:21])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: CC(NC(=S)Nc1ccc(Br)cn1)c1ncccc1F
Solvent: CC(=O)O
Product: CC(NC(=O)Nc1ccc(Br)cn1)c1ncccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.6 %

Procedure:
A solution of 400 mg (1.13 mmole) of N-(3-fluoropyrid-2-yl)eth-2-yl-N'-(5-bromopyrid-2-yl)-thiourea (see Example 920 of W093/03022) in 11.5 ml of glacial acetic acid was treated with 0.8 ml (7.83 mmole) of 30% hydrogen peroxide. After stirring 1.5 hrs at room temperature, the solution was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate (1×). The organic layer was back washed with brine (1×) and dried over sodium sulfate. Purification by flash silica gel chromatography (50% ethyl acetate/hexanes) gave 75 mg (19.6%) of the titled compound as a white solid: mp 151°-154° C.; IR (KBr, cm-1) 3200, 3100, 3000, 1685, 1557, 1467, 1360, 1290, 1230, 839; 1H NMR (300 MHz, DMSO-d6) δ 9.30 (br. s., 1H), 8.40 (d, 1H), 8.22 (d, 1h), 7.85 (dd, 1H), 7.79 (br.t., 1H), 7.70 (dt, 1H), 7.45 (d, 1H), 7.30-7.40 (m, 1H), 3.58 (q, 2H), 3.00 (t, 2); MS (FD) m/e 340 (Mt). Anal. Calc'd. for C13H12BrFN4O: C, 46.04; H, 3.57; N, 16.52. Found: C, 46.25; H, 3.66; N, 16.54.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.Cl.[CH3:20][NH:21][O:22][CH3:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:23][O:22][N:21]([CH3:20])[C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]2)=[CH:17][CH:16]=1
Reactant: CNOC
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (10.05 g), N,O-dimethylhydroxylamine hydrochloride (4.35 g), WSC (9.32 g), HOBt (6.57 g), and TEA (6.21 ml) in DMF (80 ml) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) and crystallized from hexane to give the title compound (7.60 g).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([Sn](C)(C)C)=[CH:6]1)(=[O:4])=[O:3].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CN(C)C=O.C(Cl)Cl.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>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)n1cc([Sn](C)(C)C)c2ccccc21
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(-c3cn(S(C)(=O)=O)c4ccccc34)c2cc1OC
Temperature: 90 °C

Procedure:
A solution of 1.33 g (4.01 mmol) of N-methylsulfonyl-3-trimethylstannylindole, 750 mg (3.34 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 0.19 g (5 mol % 0.16 mmol) of Pd (PPh3)4 in 10 ml of dry dimethylformamide is flushed thoroughly with nitrogen and heated to 90° C. for 12 hours. The reaction mixture is diluted with methylene chloride washed with 10% ammonium hydroxide and stirred vigorously and then washed with water and the combined organics are washed with brine (75 mL), dried (MgSO4) and evaporated to dryness. Recrystallized from ethyl acetate yields 4-(1-methylsulphonylindol-3-yl)-6,7-dimethoxyquinazoline (m.p. >220° C.).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH2:26])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[C:10]([F:14])=[CH:11][C:12]=1[Cl:13]>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:1](=[O:4])[CH:2]=[CH2:3])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[C:10]([F:14])=[CH:11][C:12]=1[Cl:13]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1

Procedure:
Acryloyl chloride was reacted with 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline in THF, at 0° C. The final product was obtained in quantitative yield.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N+:10]([CH:13]=[C:14](SC)[S:15][CH3:16])([O-:12])=[O:11]>C(O)C>[N+:10]([CH:13]=[C:14]([S:15][CH3:16])[NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])([O-:12])=[O:11]
Reactant: CCOC(CN)OCC
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CCOC(CNC(=C[N+](=O)[O-])SC)OCC
Yield: 57.9 %

Procedure:
(a)(i) A solution of aminoacetaldehyde diethylacetal (8g, 0.06 mol) and 1-nitro-2,2-bis-methylthioethylene (10g, 0.06 mol) in ethanol (100 ml) was refluxed for 20 hours. The solvent was removed in vacuo. The residue was chromatographed on a silica gel column eluted with carbon tetrachloride/chloroform (7:3) and the product was crystallised from propan-2-ol to give 1-nitro-2-methylthio-2-(2,2-diethoxyethylamino)ethylene (8.7g, 58%) m.p. 73--73.5°.