Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.N.[CH2:4]([N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([CH:17]([C:19]#[N:20])[OH:18])[N:10]=[C:9]1[N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)[C:5]#[C:6][CH3:7].S([O-])(O)=[O:35].[Na+]>CO>[CH2:4]([N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([CH:17]([C:19](=[O:35])[NH2:20])[OH:18])[N:10]=[C:9]1[N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)[C:5]#[C:6][CH3:7]
Reactant: O=S([O-])O
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(O)C#N)c1C(=O)OC
Agent: N
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(O)C(N)=O)c1C(=O)OC
Reaction time: 15 h

Procedure:
3.2 ml of 30% aqueous hydrogen peroxide and 3.2 ml of 28% aqueous ammonia solution were added to an 8 ml methanol solution of 0.274 g of t-butyl 4-[1-(2-butynyl)-4-(cyano-hydroxymethyl)-5-methoxycarbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate at 5° C., and the mixture was stirred for 15 hours. 100 ml of a saturated sodium hydrogen sulfite solution was added to the solution, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic layers were combined together. The combined organic layers were dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.039 g of the title compound was obtained from the fraction eluted with methanol-ethyl acetate (1:9).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]#[N:21]>O1CCCC1>[C:10]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH:8]=[O:9])[CH2:19][C:20]#[N:21])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CCBr
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(C=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of diphenylacetoaldehyde (1 g) in tetrahydrofuran (10 ml) was added a suspension of 60% sodium hydride (0.25 g) in tetrahydrofuran (5 ml) carefully dropwise under ice-cooling and stirring. After completion of dropwise addition, the mixture was further stirred for 20 minutes. Then, bromoacetonitrile (0.41 ml) was added and the mixture was further stirred for 30 minutes. The reaction mixture was poured in ice-water and the oil that had separated out was extracted into ethyl acetate. The organic layer was taken, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The group was purified by silica gel column chromatography to provide the title compound (0.85 g) as colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].O1CCOCC1.[Br:16]N1C(=O)CCC1=O>O>[Br:16][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH2:9])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccnc1N
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(Br)cnc1N
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a solution prepared by dissolving 360 mg of 3-ethylpyridine-2-amine (synthesized according to the method disclosed in International Publication WO2006/025567, page 142) in a mixed solvent of 12 mL of 1,4-dioxane and 4 mL of water, 553 mg of N-bromosuccinimide was added at 0° C., and the mixture was stirred for 1.5 hours at the same temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer thus obtained was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. Thereafter, the insolubles were filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=75/25), to obtain 394 mg of 5-bromo-3-ethylpyridine-2-amine [33-1] (hereinafter, referred to as the compound [33-1]).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:26]=C)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:26]([C:3]1[C:2]([CH3:1])=[C:11]([CH3:12])[C:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:18][CH:19]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:30]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-vinylbenzoate (0.96 g) in a mixed solvent of acetone (10.0 mL)-acetonitrile (10.0 mL)-water (10.0 mL) were added osmium oxide (fixed catalyst I) (0.34 g) and sodium periodate (2.86 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water. The insoluble substance was removed by filtration, and the filtrate was washed with saturated aqueous sodium bicarbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.17 g).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.S(Cl)([Cl:16])(=O)=O.C(=O)([O-])O.[Na+]>C1COCC1>[Cl:16][C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C1CCCNC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cl)CCCNC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of ethyl 2-oxopiperidine-3-carboxylate (30 g) in THF (300 mL) was added dropwise sulfuryl chloride (14.2 mL) at 0° C.-5° C., and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (300 mL) at 0° C., and the mixture was stirred at room temperature for 30 min and extracted with ethyl acetate (300 mL×3). The extract was washed with saturated brine (300 mL), and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane/ethyl acetate (5/1, 60 mL×2) to give the title compound (32.7 g). MS (ESI+): [M+H]+ 206.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH:12]=[CH:11][CH2:10]2)[CH2:8][C:7]1=[O:17].CC[O:20]C(C)=O.CCCCCC>>[OH:20][CH:11]1[CH2:12][CH2:13][C:9]2([CH2:8][C:7](=[O:17])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:15](=[O:16])[CH2:14]2)[CH2:10]1
Reactant: O=C1CC2(CC=CC2)CC(=O)N1CCCCBr
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1CC2(CCC(O)C2)CC(=O)N1CCCCBr
Yield: 75 %

Procedure:
This compound was prepared from 8-(4-bromobutyl)-8-azaspiro[4.5]dec-2-ene-7,9-dione according to the procedure as a viscous liquid. Flash chromatography in EtOAc/hexane (3:2) afforded the title compound in 75% yield as a clear oil; IR (neat) 3450, 2956, 1725, 1670, 1436, 1394, 1355, 1267, 1137 cm-1 ; 1H NMR (CDCl3) 6 5.32 (s, IH), 4.24 (b s, lH), 3.81 (t, J=7.1 Hz, 2H), 3.42 (t, J=7.1 Hz, 2H), 2.82 (s, 2H), 2.61 (s, 2H), 2.09-1.53 (m, 10H); mass spectrum, m/z (relative intensity) 320 (M.H+2, 61), 318 (M+H, 68), 302 (25), 300 (25), 260 (28), 258 (28), 137 (28), 135 (30), 95 (100).
Reaction SMILES: [C:1]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([OH:34])[C:28]([CH3:36])([CH3:35])[CH2:27]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([OH:21])[C:15]([CH3:23])([CH3:22])[CH2:14]1)=[O:11].[C:37]1([C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([CH3:45])[CH3:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:1]([O:25][CH:26]1[CH2:27][C:28]([CH3:36])([CH3:35])[N:29]([O:34][CH2:45][C:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH3:44])[C:30]([CH3:33])([CH3:32])[CH2:31]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:14][C:15]([CH3:22])([CH3:23])[N:16]([O:21][CH2:44][C:43]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:45])[C:17]([CH3:19])([CH3:20])[CH2:18]1)=[O:11]
Reactant: CC(C)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Product: CC(CON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCC(C)(c3ccccc3)c3ccccc3)C(C)(C)C2)CC1(C)C)(c1ccccc1)c1ccccc1

Procedure:
Bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-y) sebacate and 2,2-diphenylpropane are reacted following a procedure similar to that of Example 6.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:43])[CH2:14][N:15]1[CH2:34][C@@H:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=2)[C@:17]2([N:21]([CH3:22])[C:20](=[O:23])[N:19]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:18]2=[O:32])[CH2:16]1)(C)(C)C>C(Cl)Cl>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([C@H:33]2[C@:17]3([N:21]([CH3:22])[C:20](=[O:23])[N:19]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:18]3=[O:32])[CH2:16][N:15]([CH2:14][C:13]([OH:43])=[O:12])[CH2:34]2)=[CH:40][CH:39]=1)#[N:42]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(=O)OC(C)(C)C)C[C@H]2c1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(CC(=O)O)C[C@H]2c1ccc(C#N)cc1

Procedure:
Trifluoroacetic acid (4.8 ml, 59 mmol) was added to a solution of Example 63 (1.56 g, 2.95 mmol) in DCM (40 ml). The solution was refluxed for 3 h. It was then concentrated in vacuo and partitioned between EtOAc/aqueous NH4OH. The aqueous layer was acidified to pH=2 with SO2. The white precipitate was separated by filtration. The aqueous layer was extracted with DCM and concentrated to give white crystals which where combined with the precipitated solid to give, after drying, the above-titled compound (1.04 g), mp=220° C.
Reaction SMILES: Cl[C:2]1[CH:7]([Cl:8])[CH2:6][CH2:5][CH2:4][CH:3]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K].[I-].[K+].C(OCC)C>CN(C)C=O>[Cl:8][C:7]1[CH:2]([N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])[CH2:3][CH2:4][CH2:5][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC1=CCCCC1Cl
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C1CCCC=C1Cl
Yield: 73.5 %

Procedure:
A solution of 11.0 g (72.8 mmol) 1,6-dichlorocyclohexene, 20.0 g (108 mmol) potassium phthalimide and 1.0 g (6.0 mmol) potassium iodide in 50 ml dry dimethylformamide was stirred 24 hours at 110° C. under an atmosphere of nitrogen. The reaction mixture was allowed to cool then poured into 30 ml diethyl ether. The dark mixture was filtered, then the ether and DMF removed in vacuo. The dark crystalline residue was dissolved in ethyl acetate then chromatographed on 500 g flash silica eluting with 10% to 20% ethyl acetate/hexane. Concentration of appropriate fractions followed by recrystallization from ethyl acetate/hexane gave 14.0 g (73.5%) of the desired phthalimide, mp 99°-103° C.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:18])([CH3:17])[CH2:9]1.C(N(CC)CC)C>C1COCC1>[CH3:17][C:10]1([CH3:18])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:9]1
Reactant: CC1(C)CC(N)c2ccccc21
Reactant: CCS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC1CC(C)(C)c2ccccc21
Reaction time: 2 h
Yield: 79.9 %

Procedure:
With ice-cooling, 4.44 g (34.7 mmol) of ethanesulfonyl chloride were added dropwise to a solution of 5.1 g (31.6 mmol) of 1-amino-3,3-dimethylindan (Example 1a) and 12.8 g (126 mmol) of triethylamine in 100 ml of THF. After 2 h at RT, the reaction mixture was concentrated under reduced pressure and the residue was taken up in water and EA. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, giving 6.4 g of 3,3-dimethyl-1-ethylsulfonylaminoindan.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[N:14]=1>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:29][CH2:28]3)=[CH:25][CH:26]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (A7) (60 mg, 0.11 mmol) in anhydrous DMF (10 mL) was added a slurry of 10% Pd/C (30 mg) in DMF (2 mL). The resulting mixture was stirred at room temperature under an atmosphere of hydrogen for 72 hours then diluted with EtOAc (30 mL) and filtered through a plug of Celite, washing with EtOAc (50 mL). The filtrate was evaporated to dryness to give the title compound A8 as a brown oily residue (44 mg, 73%); 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.52 (dt, J=8.0, 2.5 Hz, 2H), 7.25-7.17 (m, 4H), 6.92 (dd, J=7.2, 5.1 Hz, 2H), 6.88 (s, 1H), 3.72 (s, 2H), 3.68 (d, J=3.0 Hz, 3H), 3.61-3.56 (m, 4H), 3.07 (dd, J=9.3, 5.1 Hz, 6H), 2.06 (s, 3H), 1.48 (s, 9H). LC-MS-A: rt 6.260 min; m/z 546.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2([C:21]([O:23]CC)=[O:22])[O:15][N:14]=[C:13]([C:16]([O:18]CC)=[O:17])[CH2:12]2)=[CH:2]1.O.[OH-].[Li+]>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2([C:21]([OH:23])=[O:22])[O:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[CH2:12]2)=[CH:2]1
Reactant: CCOC(=O)C1=NOC(Cc2c[nH]c3ccccc23)(C(=O)OCC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1=NOC(Cc2c[nH]c3ccccc23)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.03 g (3.0 mmols) of diethyl 5-(RS)-(3-indolylmethyl)-4,5-dihydroisoxazole-3,5-dicarboxylate was dissolved in a mixed solvent of 16 ml of ethanol and 4 ml of water. 290 mg (6.9 mmols) of lithium hydroxide monohydrate was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to a volume of ⅓ or so under reduced pressure, and 15 ml of water and 1N hydrochloric acid were added to adjust the reaction solution to a pH of from 1 to 2. The resulting solution was extracted three times with 20 ml of ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 5-(RS)-(3-indolylmethyl)-4,5-dihydroisoxazole-3,5-dicarboxylic acid as a light yellow powder.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24]O)=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2].C(N(CC)CC)C.CS([Cl:40])(=O)=O.[Cl-].[Li+]>ClCCl>[CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][Cl:40])=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Oc1cccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)Oc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a stirred solution of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-methanol (2.7 g, 7.08 mmol) in dichloromethane (14 mL) was added triethylamine (3.0 mL, 21.2 mmol) and methanesulphonyl chloride (1.24 mL, 15.6 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and lithium chloride (1.4 g, 33 mmol) was added at this temperature. The reaction mixture was stirred at room temperature for 15 hrs and diluted with dichloromethane (150 mL). The reaction mixture was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 1-(3-sec-butoxy-benzyl)-4-chloromethyl-6,7-dimethoxy-isoquinoline (2.1 g, 74% yield) as a brown oil. The crude product was used without further purification.
Reaction SMILES: [Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1.[CH2:29]([Sn:33](Cl)([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32].[Li]>C1COCC1>[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25]([Sn:33]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:29][CH2:30][CH2:31][CH3:32])[N:24]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
To a solution of nBuLi, 1.6 m in hexane (21.49 mL, 34.4 mmol) in THF (80 mL) at −50° C. was added 2,2,6,6-tetramethylpiperidine (5.80 mL, 34.4 mmol). The mixture was warmed to 0° C. and stirred for 20 min. The mixture was then cooled to −78° C. In another flask, 2-chloropyrazine (0.974 mL, 10.91 mmol) and tributyltin chloride (2.96 mL, 10.91 mmol) were dissolved in THF (50 mL) and cooled to −78° C. The cooled solution was transferred to lithium solution through cannula and the resulting orange mixture was slowly warmed up to −40° C. in 3 h, and was quenched with sat. HCl:EtOH:THF (1:4:5, 50 mL) and warmed to RT. The mixture was neutralized with sat. NaHCO3 and the volatiles were removed. The residue was diluted in H2O and extracted with DCM. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0-30% DCM in Hex) to give 2-chloro-6-(tributylstannyl)pyrazine (3.15 g, 7.81 mmol, 71.5%) as a clear oil. MS (ESI, pos. ion) m/z: 405 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.42 (1H, s), 8.38 (1H, s), 1.50-1.62 (6H, m), 1.27-1.41 (6H, m), 1.14-1.22 (6H, m), 0.89 (9H, t, J=7.3 Hz)
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:30]([NH2:32])=[S:31])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[N:26][C:25]([CH3:28])=[N:24]1>C(O)C.CCOC(C)=O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:30]2[S:31][C:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:3]=3[N:32]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[N:26][C:25]([CH3:28])=[N:24]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)n1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-n1cnc(C)n1
Yield: 39 %

Procedure:
A mixture of 2-bromo-6-phenylcyclohexanone (84 mg, 0.332 mmol, from preparation AAA) and 1-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (87 mg, 0.332 mmol, from step 4 of preparation F) was heated in ethanol (0.55 mL) at 80° C. for 3 h. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (60% acetone/hexanes) to give 54 mg (39% yield) of the titled compound as a white solid. LC-MS (M+H)+ 418.0. 1H NMR (400 MHz, chloroform-d) δ ppm 8.44 (s, 1 H) 7.49 (dd, J=5.41, 3.15 Hz, 2 H) 7.23-7.35 (m, 2 H) 7.12-7.21 (m, 3 H) 6.60 (dd, J=8.56, 2.27 Hz, 1H) 3.98-4.08 (m, 1 H) 3.49 (s, 3 H) 2.66-2.85 (m, 2 H) 2.46 (s, 3 H) 2.17-2.26 (m, 1 H) 1.92-2.05 (m, 1 H) 1.78-1.91 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](SC)=[N:7][C:8]([C:12]([F:21])([F:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:35][C:36]1[NH:40][N:39]=[C:38]([NH2:41])[CH:37]=1>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:41][C:38]3[CH:37]=[C:36]([CH3:35])[NH:40][N:39]=3)=[N:7][C:8]([C:12]([F:21])([F:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(Br)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 1.33 h
Yield: 3.9 %

Procedure:
To 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline (100 mg, 0.25 mmol) in DCM (3 mL) at 0° C. was added 70% meta-chloroperoxybenzoic acid (74 mg, 0.30 mmol) and the mixture was stirred at 0° C. for 80 min. Then additional 70% meta-chloroperoxybenzoic acid (70%, 15 mg, 0.086 mmol) was added and the mixture was stirred at 0° C. for 10 min. The mixture was diluted with DCM (10 mL), washed with saturated aq NaHCO3 (20 mL) and saturated aq sodium thiosulfate (20 mL), dried over Na2SO4 and concentrated under reduced pressure. To the residue (133 mg) at rt was added 5-methyl-1H-pyrazol-3-amine (92 mg, 0.96 mmol) in THF (3 mL). The mixture was stirred for 40 min and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex C-18 reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=5% ACN/0.05% AcOH/H2O) to afford 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (4.42 mg, 3.1%). 1H NMR (300 MHz, DMSO-d6) δ 12.09-12.33 (m, 1H), 10.73-10.99 (m, 1H), 8.66 (s, 2H), 8.00 (d, J=5.5 Hz, 3H), 7.74-7.87 (m, 1H), 5.95 (br s, 1H), 2.16 (s, 3H); LC-MS (ESI) m/z 449/451 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6](C)[C:7](C1C=CC(OCCCCl)=CC=1)=[O:8])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]=[O:8])[CH3:2]
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)CCC=O
Temperature: 80 °C
Yield: 293 %

Procedure:
A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-3-methyl-4-oxo-butyric acid ethyl ester (7 g, 22 mmol), K2CO3 (9.3 g, 67 mmol), Nat (330 mg, 2.2 mmol), and (R)-methyl-pyrrolidinium benzenesulfonate (11 g, 47 mmol) in CH3CN (160 mL) was heated under argon at 80° C. for 36 h. The reaction mixture was concentrated at reduced pressure and partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude material. The crude material was purified by ISCO (80 g siliga gel column) chromatography using 2% to 9% methanol in methylene chloride to 10% methanol containing 2.5 mL ammonium hydroxide in methylene chloride to afford a pure product. The pure product was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated to give 3-methyl-4-{4-R-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-oxo-butyric acid ethyl ester (8.39 g, quantitative yield), MS m/z 362 (M+H).