Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]([F:17])[C:12]([CH:15]=O)=[N:13][CH:14]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([F:17])[C:12](/[CH:15]=[N:7]/[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[N:13][CH:14]=1
Reactant: O=Cc1ncc(Br)cc1F
Reactant: CC(C)(C)[S@](N)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-(+)-2-methyl-2-propanesulfinamide (9.898 g, 81.67 mmol) in CH2Cl2 (160 mL) was added 5-bromo-3-fluoropyridine-2-carbaldehyde (16.66 g, 81.67 mmol), pyridinium p-toluenesulfonate (1.026 g, 4.08 mmol), and magnesium sulfate (49.15 g, 408.3 mmol). The reaction was stirred at room temperature overnight, then filtered through celite and concentrated in vacuo. The residue was subjected to silica gel chromatography eluted with 0 to 10% ethyl acetate in hexanes to provide N-[(1E)-(5-bromo-3-fluoropyridin-2-yl)methylidene]-2-methylpropane-2-sulfinamide that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 307.0 for M+H+ (81Br).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]2[N:14]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=[C:16]([CH3:17])[C:3]=12.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.O>CN1C(=O)CCC1>[CH3:17][C:16]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]=2[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:15]=1
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3ccccc3)c(Cl)c12
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Temperature: 200 °C
Yield: 100 %

Procedure:
4-Chloro-3-methyl-5-phenyl-1-(phenyl sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.300 g, 0.784 mmol) and piperazine (0.675 g, 7.84 mmol) were placed in NMP (1 mL) and heated to 200° C. in a microwave for 1 hour. The reaction was then poured into water and extracted with MTBE. The combined organic fractions were dried, filtered, and concentrated to give the crude product 3-methyl-5-phenyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.339 g, 100% yield), which was used without further purification.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][SH:15]>O1CCCC1>[CH3:18][O:17][C:13]([CH2:14][S:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:16]
Reactant: COC(=O)CS
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CSc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
First, 0.8 g of sodium hydride was added to a mixture of 3.17 g of 2-chloro-3-nitropyridine, 2.12 g of methyl thioglycolate, and 20 ml of tetrahydrofuran at 0° C. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was washed with diisopropyl ether and hexane to give 3.1 g of 2-(methoxycarbonyl)methylthio-3 -nitropyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27](=[O:29])[CH3:28])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[BrH:30].BrBr>C(O)(=O)C>[BrH:30].[BrH:30].[Br:30][CH2:28][C:27](=[O:29])[CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:20][CH2:21]1
Reactant: CC(=O)CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A stirred solution of 47.5 parts of 4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-butanone and 500 parts of acetic acid was acidified with a hydrobromic acid solution in glacial acetic acid. Then there were added dropwise 11.8 parts of bromine dissolved in acetic acid. Upon completion, stirring was continued overnight at room temperature. The precipitated product was filtered off and suspended in 2-propanone. The product was filtered off and dried, yielding 23 parts (48.3%) of 1-bromo-4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-butanone dihydrobromide (intermediate 92).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][C:3]1([CH3:14])[CH3:13].[NH:15]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]=[CH:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>C1COCC1>[CH3:23][O:22][C:20]([C:18]1[N:17]([CH:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[CH2:4][C:3]2([CH3:14])[CH3:13])[CH:16]=[N:15][CH:19]=1)=[O:21]
Reactant: CC1(C)CC(=O)c2ccccc2C1O
Reactant: COC(=O)c1c[nH]cn1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)CC1(C)C
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a solution of 4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-naphthalen-1-one (2.87 g, 13.88 mmol) and methyl 4-imidazolecarboxylate (CAS#17325-26-7, 1.25 g, 9.72 mmol) in THF (80 mL) at 0° C. is added triphenylphosphine (3.68 g, 13.88 mmol) and dimethyl azodicarboxylate (40% in toluene, 5.14 mL, 13.88 mmol) and the cooling bath is removed. After 15 hours, the mixture is concentrated and the resulting residue is dissolved in ethyl acetate (250 mL) and is extracted five times with 1M aqueous HCl (40 mL portions). The acidic aqueous phases are cooled to 0° C. and the pH is adjusted to ca. 12 with 4M aqueous NaOH at 0° C. The aqueous phase is then extracted three times with dichloromethane. The combined organic layers are dried over MgSO4 and filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (dichloromethane-methanol, 49:1) to give 3-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 299.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (s, 3 H), 1.15 (s, 3 H), 2.63 (d, J=16.8 Hz, 1 H), 2.74 (d, J=16.8 Hz, 1 H), 3.93 (s, 3 H), 6.79 (s, 1 H), 7.02 (d, J=7.6 Hz, 1 H), 7.35 (s, 1 H), 7.47 (t, J=7.6 Hz, 1 H), 7.55 (td, J=7.6, 1.5 Hz, 1 H), 7.86 (s, 1 H), 8.13 (dd, J=7.6, 1.5 Hz, 1 H);
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[CH2:15](C1CCC(C2CCC(=O)CC2)CC1)C>>[CH2:5]([CH:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]1)[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:15]
Reactant: CC1CCC(C2CCC(=O)CC2)CC1
Reactant: CCC1CCC(C2CCC(=O)CC2)CC1
Product: CCCCCCCC1CCC(=O)CC1

Procedure:
4-(4-methylcyclohexyl)cyclohexanone [151772-66-6]; 4-(4-ethylcyclohexyl)cyclohexanone [150763-46-5];
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=O)(C)(C)C.[C:18]1([C:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH2:26]O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[C:18]1([C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:25][CH2:26][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH2:8])=[CH:16][CH:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Product: NCCc1ccc(OCCC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
N-(t-butoxycarbonyl)-2-(4-hydroxyphenyl)ethylamine (1.3 g) and 3,3,3-triphenylpropanol (1.4 g) were coupled by the method of example 5. The product (1.4 g) was dissolved in 15 mL isopropanol containing 1.0 g HCl, and stirred 3 hr at room temperature. A precipitate formed, which was collected and recrystallized from ethanol-ether to provide the hydrochloride salt of the title compound as a white solid, mp 163°-165° C., in 66% yield. Anal. calcd. for C29H29NO·HCl·0.75 H2O: C, 76.13; H, 6.94; N, 3.06. Found: C, 75.99; H, 6.81; N, 3.02.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)=[C:11]([O:40][CH3:41])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[O:42]1[CH:46]=[N:45][N:44]=[C:43]1[NH2:47].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25]([NH:47][C:43]5[O:42][CH:46]=[N:45][N:44]=5)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)=[C:11]([O:40][CH3:41])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1nnco1
Reactant: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Nc3nnco3)ccc12
Reaction time: 3 h
Yield: 46.4 %

Procedure:
A vial was charged with perfluorophenyl 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE KKKKK; 50.05 mg, 0.084 mmol), 1,3,4-oxadiazol-2-amine (7.89 mg, 0.093 mmol), cesium carbonate (82 mg, 0.253 mmol), and acetonitrile (0.42 mL). After 3 h or stirring, the mixture was diluted with 0.5 N aq. HCl, then extracted with EtOAc (3×), 20% MeOH/EtOAc (2×), and DCM (1×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7% MeOH/DCM) to give 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,3,4-oxadiazol-2-yl)isoquinoline-6-sulfonamide (19.1 mg, 0.039 mmol, 45.8% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ=12.24 (br. s., 1H), 8.82 (d, J=2.0 Hz, 1H), 8.78 (d, J=5.7 Hz, 1H), 8.23 (d, J=5.3 Hz, 1H), 8.17 (s, 1H), 8.00-7.94 (m, 1H), 7.92-7.84 (m, 1H), 7.68-7.60 (m, 2H), 7.58-7.49 (m, 2H), 7.47-7.41 (m, 1H), 7.30 (tt, J=2.3, 9.3 Hz, 1H), 3.78 (s, 3H). m/z (ESI) 495.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[F:17][C:18]([F:32])([F:31])[C:19](=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[NH2:20].C(N(C(C)C)CC)(C)C>ClCCl.O1CCOCC1.CN(C)C=O>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([N:22]2[C:6]([C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=3)=[N:20][C:19]([C:18]([F:17])([F:31])[F:32])=[N:21]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(NN=C(N)C(F)(F)F)cc1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(C)nc2)cc1
Reaction time: 1 h
Yield: 15.3 %

Procedure:
To a suspension of 6-methylnicotinoic acid (329 mg, 2.4 mmol) in dichloromethane (3 mL), was added oxalyl chloride (0.209 mL, 2.4 mmol). And then 10 micro-L of dimethylformamide was added to the mixture. The mixture was stirred for 1 hour and the solvent was removed under reduced pressure. The residue was azeotroped with dichloromethane. To the residue, was added 3 mL of dioxane. Then a solution of 2,2,2-trifluoro-N′-(4-methoxyphenyl)ethanehydrazonamide (466 mg, 2 mmol) and diisopropylethylamine (0.418 mL, 2.4 mmol) in 4.5 mL of dioxane was added to the mixture and the mixture was refluxed with stirring for 3.5 hours. The solvent was removed under reduced pressure, and dichloromethane and 0.1 N hydrochloric acid were added to the residue. The organic layer was separated, washed with 0.1 N hydrochloric acid, water, and brine, dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (8:1 toluene-ethyl acetate). The desired product was rinsed with hexane and dried in vacuo to give 5-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]2-methylpyridine (102 mg, 14.8% yield).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:16])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].C(O)CO.[F-:21].[K+]>CCOCC>[F:21][CH2:2][CH:3]=[C:4]([CH3:16])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: CC(C)=CCCC(C)CC=CC(C)=CCBr
Reactant: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: OCCO
Product: CC(C)=CCCC(C)CC=CC(C)=CCF

Procedure:
A mixture of 33 g. of 1-bromo-3,7,11-trimethyldodeca-2,4,10-triene and 100 ml. of dry ethylene glycol is slowly added with stirring, to a suspension of 11.5 g. of potassium fluoride in 30 ml. of dry ethylene glycol and heated to about 120°, under an inert atmosphere. When addition is completed, the reaction mixture is stirred for about an additional 16 hours while maintaining the temperature at 120°. Then the mixture is cooled and 200 ml. of ether added. The mixture is washed thoroughly with water and the ether phase dried over sodium sulfate and solvent evaporated under reduced pressure to yield 1-fluoro-3,7,11-trimethyldodeca-2,4,10-triene.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[N+](C1C=CC(S(NC2C=CC=CC=2C)(=O)=O)=CC=1)([O-])=O.[CH3:42][O:43]C1C=CC=C(N)C=1>>[CH3:42][O:43][C:4]1[CH:3]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: COc1cccc(N)c1
Reactant: COc1cccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 73 %

Procedure:
N-(3-methoxy-phenyl)-4-nitro-benzenesulfonamide (RK1-1-27D) I This compound was prepared according to the procedure described for compound 11a except using m-anisidine. Recrystallization from DCM/Hexanes obtained the required product as brown-yellow needles (202 mg, 73%). Mp=96-98° C.; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=9.0 Hz, 2H), 7.94 (d, J=9.0 Hz, 2H), 7.16 (t, J=8.0 Hz, 1H), 6.73-6.70 (m, 2H), 6.60-6.58 (m, 2H), 3.76 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[NH:8][N:7]=1.P(Cl)(Cl)([Cl:19])=O>ClC(Cl)C>[Cl:19][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(-c2ccco2)c2ccccc12
Solvent: CC(Cl)Cl
Product: Clc1nnc(-c2ccco2)c2ccccc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1.0 g of 4-(2-furyl)-1-phthalazinone and 5 ml of phosphorus oxychloride were dissolved in 5 ml of dichloroethane, and the solution was stirred at 100° C. for 3 hours. The reaction solution was distilled off, and a 1-N aqueous NaOH solution was added thereto under cooling with ice. The solution was extracted with chloroform, dried and concentrated to obtain 910 mg of 1-chloro-4-(2-furyl)phthalazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21]C(=O)OC(C)(C)C)[CH:9]([OH:20])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[NH2:21][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)[OH:20]
Reactant: CC(C)(C)OC(=O)NC(c1ccc(F)cc1)C(O)c1cccc2cccnc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(c1ccc(F)cc1)C(O)c1cccc2cccnc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 134 %

Procedure:
2.78 g (7.27 mmol) of tert-butyl [1-(4-fluorophenyl)-2-hydroxy-2-quinolin-8-ylethyl]carbamate were dissolved in 75 ml of methylene chloride and cooled to 0° C. 18 ml of an HCl solution (4N) in dioxane were added, and the mixture was stirred at 0° C. for 20 minutes and allowed to reach room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was treated with diisopropyl ether. Filtration was followed by washing with diisopropyl ether and pentane and drying in vacuo. 2.75 g of 2-amino-2-(4-fluorophenyl)-1-quinolin-8-ylethanol were obtained as hydrochloride (diastereoisomer mixture: 85/15) as a pale yellow very hygroscopic powder (yield: quantitative). The substance was used without further purification for the next stage.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.[Cl:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18]Br>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[CH2:18][C:17]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:16]=1[Cl:15]
Reactant: Fc1ccc(Cl)c(CBr)c1
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Product: CC1(C)C(=O)N(C2CC3CCC2C3)N1Cc1cc(F)ccc1Cl

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-5-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[S:10][C:11]2[N:12]=[C:13]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]3[CH2:33][CH3:34])[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:16]=2[N:17]=1.[C:36](O)(=[O:40])[C@H:37]([CH3:39])[OH:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([C:25]1[N:24]([C:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:16]3[N:17]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][N:6]([C:36](=[O:40])[C@@H:37]([OH:38])[CH3:39])[CH2:7][C:2]4([CH3:35])[CH3:1])[S:10][C:11]=3[N:12]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: C[C@H](O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3(C)C)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)[C@H](C)O)CC3(C)C)sc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(2,2-dimethylpiperazin-1-ylmethyl)-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (200 mg, 0.41 mmol), L-lactic acid (34 μL, 85% solution in H2O), HATU (170 mg, 0.45 mmol) and DIPEA (80 μL, 0.46 mmol) in DCM (4 mL) was allowed to stir at r.t. for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-2%) then (C18, MeOH:H2O, 10-20%). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 829 (41 mg, 18%). LCMS (method I): RT 3.79 min, [M+H]+ 565.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.98 (1 H, m), 7.76-7.75 (1 H, m), 7.32-7.22 (2 H,m), 4.41-4.38 (5 H, m), 4.08-4.01 (1 H, m), 3.89-3.88 (5 H, m), 3.79-3.77 (1 H, m), 3.59-3.44 (2 H, m), 3.34 (2 H, q, J=7.47 Hz), 3.27-3.25 (1 H, m), 2.75 (2 H, s), 1.44 (3 H, t, J=7.47 Hz), 1.37-1.35 (3 H, m), 1.27-1.11 (6 H, m)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]O)[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:40]I>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][I:40])[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: O=C1CC(CO)CN1Cc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1CC(CI)CN1Cc1ccccc1
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
To alcohol lactam 74 (11.18 g, 0.056 mol) in 210 mL toluene was added in turn, triphenylphosphine (20.0 g, 0.076 mol), imidazole (10.8 g, 0.159 mol), and iodine (19.0 g, 0.075 mol). After stirring the suspension for 1.5 hours, the supernatant was poured into another flask. The sticky yellow residue was washed twice with ether and the solutions were combined. The solvent was evaporated and the residue was chromatographed on silica, eluting with 1:1 acetone/hexane to give 7.92 g, 46% of the iodolactam 75 as yellow oil. 1H NMR (CDCl3) δ 7.25 (m, 5H), 4.38 (d, 1H, J=14.6), 4.46 (d, 1H, J=14.6), 3.38 (dd, 1H, J=7.8 and 2.2), 3.20 (dd, 1H, J=5.6 and 4.4), 3.12 (dd, 1H, J=7.3 and 2.4), 2.96 (dd, 1H, J=5.8 and 4.4), 2.60 (m, 2H), 2.22 (dd, 1H, J=10.5 and 9.7). MS, m/z (relative intensity): 224 [M−H−Bn, 94%], 317 [M+2H, 64%]. IR 3027, 2917, 1688, 1438, 1267, and 701 cm−1.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C(OC(=O)C)(=O)C.[H][H]>C(O)(=O)C.[Pd]>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: OC1CCOc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCCO2
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a stirred solution of 4-hydroxychroman (10.14 g, 67.5 mmol) in acetic acid (150 mL) under Ar was added acetic anhydride (12.7 mL, 135 mmol) and the mixture was heated at reflux for 3 h, then allowed to cool to ambient temperature. Palladium on carbon (10 wt %; 1.8 g, 2.5 mol %) was added and the mixture was shaken in a Parr hydrogenator under a 42 psi atmosphere of hydrogen overnight. The reaction mixture was filtered, the solvent was removed in vacuo and the residue was taken-up in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate solution, brine, dried (magnesium sulfate) and concentrated in vacuo to afford the product (7.73 g, 85%) as a pale yellow liquid: IR νmax (film)/cm−1 2937, 2863, 1737, 1609, 1582, 1490, 1456, 1304, 1267, 1228, 1189, 1116, 1065, 1008 and 754; NMR (400 MHz, CDCl3) δH 2.00 (2H, m), 2.78 (2H, t, J 6.5 Hz), 4.17 (2H, t, J 7 Hz), 6.81 (2H, m) and 7.05 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:26]([CH3:27])=[CH:25][C:23]([NH2:24])=[C:22]([CH3:28])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[N:39]=[C:40]=[O:41]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:26]([CH3:27])=[CH:25][C:23]([NH:24][C:40]([NH:39][C:33]4[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=4[F:31])=[O:41])=[C:22]([CH3:28])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(Oc3cc(C)c(N)cc3C)ccnc2cc1OCc1ccccc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Oc3cc(C)c(NC(=O)Nc4ccc(F)cc4F)cc3C)ccnc2cc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylaniline (300 mg) was dissolved in chloroform (5 ml). 2,4-Difluorophenyl isocyanate (200 μl) was then added to the solution, and the mixture was stirred at 70° C. overnight. The reaction solution was purified by chromatography on silica gel by development with chloroform/acetone (75/25) to give 368 mg (yield 88%) of the title compound.