Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:17])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)C.[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.C[Al](C)C.C1(C)C=CC=CC=1>ClCCCl.C(OCC)C.CO>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:19]([NH:18][C:4](=[O:17])[C:5]#[C:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:11][CH:12]=2)[CH:20]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: CCOC(=O)C#Cc1ccc(C(C)(C)C)cc1
Agent: C[Al](C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(C#CC(=O)Nc2cnc3ccccc3c2)cc1

Procedure:
A solution of (4-tert-butyl-phenyl)-propynoic acid ethyl ester (0.23 g, 1.0 mmol) and 3-aminoquinoline (0.144 g, 1.0 mmol) in 1,2-dichloroethane (15 mL) was treated with a 2N solution of trimethylaluminum in toluene (0.75 mL, 1.5 mmol). The resultant solution was stirred at room temperature for 15 minutes, then heated at reflux for 18 h. The solution was cooled and treated with methanol (0.50 mL). The product was preabsorbed onto silica gel and purified by flash chromatography, using a gradient of methanol in dichloromethane as the eluant. The product was isolated, after trituration in diethyl ether, as a colorless solid, 0.17 g (52%). MS: m/z 329.2 (MH+). 1HNMR (DMSO-d6): δ 1.31 (s, 9 H), 7.54-7.72 (m, 6 H), 7.97 (d, 1 H), 8.72 (d, 1 H), 8.96 (d, 1 H) and 11.3 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[C:14](Cl)[C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:28]1C(CC)=C(C=C[C:36]=1O)C(O)=O.ClC1C(CC)=C(C=CC=1O)C=O>>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[C:14]([CH2:28][CH3:36])[C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(C(=O)O)ccc(O)c1Cl
Reactant: O=C(O)c1c(Cl)cc(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCc1c(C=O)ccc(O)c1Cl
Product: CCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)O

Procedure:
2,4-bisbenzyloxy-6-chlorobenzoic acid, m.p. 135-1360 (35%) and 3-chloro-2-ethyl-4-hydroxybenzoic acid from 3-chloro-2-ethyl-4-hydroxybenzaldehyde: yield 51%, m.p. 138-1390.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:14])=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]2[N:6]=[C:5]([NH2:14])[CH:4]=[N:3][C:2]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:9]=1
Reactant: Nc1cnc(Br)c(-c2cccnc2)n1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cnc(-c2ccncc2)c(-c2cccnc2)n1
Temperature: 150 °C
Yield: 93.4 %

Procedure:
A mixture of 5-bromo-6-pyridin-3-ylpyrazin-2-amine (Preparation 6, 0.4 g, 1.59 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.424 g, 2.07 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (1:1) (76 mg, 0.095 mmol) and cesium carbonate (1.55 g, 4.77 mmol) in dioxane (14 mL) and water (3.72 mL) was heated to 150° C. for 10 minutes in the microwave oven. The mixture was partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and evaporated. Silica gel flash chromatography (95:5 dichloromethane/methanol) gave the title compound (0.37 g, 74%) as a solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23]C)[CH2:6][CH2:7][N:8]([CH3:19])[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.B(Br)(Br)Br.ClCCl.CO>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[OH:23])[CH2:6][CH2:7][N:8]([CH3:19])[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(CCN(C)C(=O)/C=C/c2cccnc2)cc1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CN(CCc1ccc(O)c(O)c1)C(=O)/C=C/c1cccnc1
Reaction time: 14 h
Yield: 88.3 %

Procedure:
(E)-N-(3,4-dimethoxyphenethyl)-N-methyl-3-(3-pyridyl)-2-propenoic acid amide (2.65 g, 8.31 mmol) obtained in Example 84 was dissolved in dichloromethane (66 ml) and 1M boron tribromide-dichloromethane solution (33 ml) was dropwise added under argon at −30° C. and stirred for 14 hours. After methanol was added at the same temperature to stop the reaction, the solvent was distilled out under reduced pressure and hydrogen chloride/methanol solution was added to the residue and heated and refluxed for 1 hour. The solvent was distilled out under reduced pressure and potassium hydroxide/methanol solution was added to the residue to neutralize. The precipitated inorganic salts were filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1) and recrystallized to yield the titled compound (2.19 g, 90%).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([NH2:12])([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:26]([NH:12][C:4]12[CH2:10][CH:8]3[CH2:7][CH:6]([CH2:11][C:2]([OH:1])([CH2:9]3)[CH2:3]1)[CH2:5]2)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OC12CC3CC(C1)CC(NC(c1ccccc1)(c1ccccc1)c1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 3-hydroxytricyclo[3.3.1.13,7 ]decan- 1-amine (5 g; 0.03 mole) dissolved in dichloromethane (140 ml) with gentle heating is added triethylamine (6 g; 0.06 mole) and cooled in an ice bath. Triphenylmethyl chloride (8.30 g; 0.03 mole) in CH2Cl2 (10 ml) is added all at once. The reaction is stirred in an ice bath for 10 minutes, warmed to room temperature and then refluxed for 3 hours. The reaction is then filtered and the filtrate evaporated to dryness. The reaction products are separated on HPLC, using 15% ethyl acetate/hexane and the product is then recrystallized from ethyl acetate/pet. ether to give N-trityl-3-hydroxytricyclo-[3.3.1.13,7 ]decan-1-amine (m.p. 184°-186° C.) which is used directly in step C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4][CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>CN(C)C=O>[N+:15]([C:14]1[C:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:21](=[O:23])[CH3:22])[CH2:20][C:6]=2[C:7]2[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=2[CH:13]=1)([O-:17])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 9-amino-6-nitro-1,4,7,8,9,10-hexahydro-benzo[f]quinoxaline-2,3-dione (0.15 g, 0.5 mmol), acetic anhydride (0.1 g, 1 mmol) and triethylamine (0.2 g, 2 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 3 h. The solvent was removed by rotoevaporation, and the residue suspended in water and 2N HCl. The solid which formed was collected by filtration, washed with diethyl ether and dried to give the acetamide (0.14 g) in 88% yield. Anal. calc'd for C14H14N4O5.H2O: C, 50.00; H, 4.80; N, 16.66; found-C, 49.92; H, 4.77; N, 16.04.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C@H:8]2[CH2:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:3]1=[O:28].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35].C(N(C(C)C)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:25]([S:22]([CH2:21][C@H:8]1[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[C:31]([C:30]([F:29])([F:40])[F:41])[CH:32]=3)[C:3]2=[O:28])[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:9]1)(=[O:24])=[O:23])([CH3:26])[CH3:27]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A sample of tert-butyl (1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-(isopropylsulfonylmethyl)cyclohexylcarbamate (200 mg, 0.47 mmol) in DMF (10 mL) was charged with 3-(trifluoromethyl)benzoic acid (109 mg, 0.57 mmol), N,N-diethylisopropylamine (0.1 mL, 0.57 mmol), and HATU (216 mg, 0.57 mmol). The reaction was stirred for 48 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1×). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford tert-butyl (1R,3R,4S)-3-(isopropylsulfonylmethyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate. MS found: (M+H)+=590.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19](O)=[O:20])[C:14]=1[CH3:22].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C:60](=[O:72])[C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH2:68][CH2:69][CH2:70][NH2:71])=[N:63][CH:62]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C:60](=[O:72])[C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH2:68][CH2:69][CH2:70][NH:71][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:20])=[N:63][CH:62]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Reactant: NCCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.9 %

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (300 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(3-aminopropylamino)nicotinamide (299 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (465 mg, 82%) as a yellow solid. 1H NMR (DMSO-d6)δ1.79 (m, 2H, CH2), 2.42 (s, 3H, pyrrole-CH3), 2.44 (s, 3H, pyrrole-CH3), 3.30 (m, 2H, CH2), 3.38 (m, 2H, CH2), 4.85 (s, 2H, benzene-NH2), 6.51 (m, 1H), 6.58 (m, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.83 (t, J=8.0 Hz, 1H), 6.92 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 7.71˜7.77 (m, 3H), 7.91 (d, J=8.0 Hz, 1H), 8.64 (s, 1H), 9.37(s, 1H, benzene-NH), 10.90 (s, 1H, indolinone-NH), 13.68 (s, 1H, pyrrole-NH). LC-MS (m/z) 568 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:19]=[C:20]=[S:21])[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:20]([NH:19][CH2:13][C:14]1[O:18][CH:17]=[CH:16][CH:15]=1)=[S:21])(=[O:10])=[O:11]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: S=C=NCc1ccco1
Agent: Cl
Product: Nc1cc(Cl)sc1S(=O)(=O)NC(=S)NCc1ccco1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and furfuryl isothiocyanate by a procedure analogous to the procedure described in example 3-a (yield of crude product: 92%).
Reaction SMILES: CC1C=CC(Cl)=CC=1C=O.Cl[C:12]1[N:13]=[N:14][C:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[CH3:25])=[CH:16][CH:17]=1.[CH:26]([NH:28][NH2:29])=O>C(O)CCC>[CH3:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:26]=[N:28][N:29]=2)[N:14]=1
Reactant: NNC=O
Reactant: Cc1ccc(Cl)cc1-c1ccc(Cl)nn1
Agent: Cc1ccc(Cl)cc1C=O
Solvent: CCCCO
Product: Cc1ccc(Cl)cc1-c1ccc2nncn2n1

Procedure:
As described in Example 35, 2-methyl-5-chlorobenzaldehyde is converted to 3-chloro-6-(2-methyl-5-chlorophenyl)pyridazine. A mixture of the preceding compound and formylhydrazine in n-butanol is refluxed for 24 hours to give the product of the example.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[C:2]#[C:3][CH2:4]C.C(=O)([O-])[O-].[K+].[K+].[OH:16][N:17]=[C:18](Br)[Br:19]>ClCCl>[CH2:8]([O:7][C:1]([C:2]1[C:18]([Br:19])=[N:17][O:16][C:3]=1[CH3:4])=[O:6])[CH3:9]
Reactant: CCC#CC(=O)OCC
Reactant: ON=C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1c(Br)noc1C
Temperature: 25 °C
Yield: 114 %

Procedure:
To a solution of ethyl 2-pentynoate (16.09 mL, 138 mmol) in dichloromethane (80 mL) was added potassium carbonate (20.65 g, 147.9 mmol) and then a solution of hydroxycarbonimidic dibromide (20.0 g, 98.6 mmol) in dichloromethane (100 mL) was added. The reaction mixture was stirred at room temperature over night. The solvent was then removed and purification by filtration (silica, dichloromethane then ethyl acetate) afforded the title compound (26.3 g, 88%) as a light yellow oil. MS: m/e=234.0 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])[C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.[NH2:34][OH:35]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[N:34][OH:35])[NH2:30])=[CH:25][C:24]=2[F:31])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CN([C@H](CCC(F)(F)F)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Reactant: NO
Solvent: O
Solvent: CO
Product: NC(=O)[C@@H](CCC(F)(F)F)N(Cc1ccc(C(N)=NO)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 47.5 °C
Yield: 96 %

Procedure:
(2R)-2-[[(4-Chlorophenyl)sulfonyl][(4-cyano-2-fluorophenyl)methyl]amino]-5,5,5-trifluoropentanamide (399 g) and methanol (1.6 L) were charged to a reactor followed by hydroxylamine (50% solution in water, 93 mL, 1.8 eq). The mixture was heated to 45-50° C. until complete reaction by HPLC (<0.15 relative Aβ starting material). Water (0.5 L) was charged slowly, keeping the batch temperature between 30-50° C. The batch was allowed to stand until crystallization started and then water (2.7 L) was charged. The batch was cooled to 15-20° C. and filtered. The cake was washed with 2:1 MeOH:water (2 L) and then dried under vacuum at 50° C. to give the title compound as white solid (415 g, 96% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.43-1.64 (m, 1H) 1.77-1.93 (m, 1H) 1.93-2.17 (m, 2H) 4.41 (dd, J=8.48, 6.03 Hz, 1H) 4.60 (d, J=17.14 Hz, 1H) 4.94 (d, J=16.77 Hz, 1H) 5.81-5.98 (m, 2H) 7.19-7.27 (m, 1H) 7.37-7.47 (m, 2H) 7.52 (d, J=4.14 Hz, 2H) 7.64 (d, J=8.67, Hz, 2H) 7.85 (d, J=8.85 Hz, 2H) 9.71-9.83 (m, 1H). IR (KBr): 3491, 3379, 1680, 1651, 1592, 1433, 1343.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:40]([C:37]1[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:45])=[CH:39][CH:38]=1)(=[O:42])=[O:41]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 4-(trifluoromethyl)benzene sulfonyl chloride (13 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 29 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-(trifluoromethyl)benzenesulfonamide (percentage yield: 97%), was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:20])[C:6](=[O:19])[NH:7]2.Cl[Sn]Cl.O>CCO>[NH2:12][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][C:10]=1[C:15]([F:17])([F:18])[F:16])[NH:7][C:6](=[O:19])[C:5](=[O:20])[NH:4]2
Reactant: O=c1[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1c(C(F)(F)F)cc2[nH]c(=O)c(=O)[nH]c2c1Cl
Yield: 73.6 %

Procedure:
A mixture of 5-chloro-6-nitro-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione (230 mg, 0.743 mmol), SnCl2.2 H2O (1.90 g, 7.43 mmol) and EtOH (300 mL) was refluxed for 24 h, then rota-evaporated to dryness. The residual solid was washed on a Bursch funnel with water (6×15 mL), and dried to give 153 mg (74%) of the title compound as a yellow powder. Mp >360° C. 1H NMR (DMSO-d6) 11.777 (s, IH), 11.360 (s, 1H), 7.140 (s, 1H), 5.499 (s, 2H).
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.C1(C)C(S(O)(=O)=O)=CC=CC=1.[Cl:22][C:23]1[CH:30]=[C:29]([F:31])[C:28]([C:32]2[C:36]([Cl:37])=[C:35]([O:38][CH:39]([F:41])[F:40])[N:34]([CH3:42])[N:33]=2)=[CH:27][C:24]=1C=O.C(N(CC)CC)C>O1CCCC1>[Cl:37][C:36]1[C:32]([C:28]2[CH:27]=[C:24]([CH:1]([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])[C:23]([Cl:22])=[CH:30][C:29]=2[F:31])=[N:33][N:34]([CH3:42])[C:35]=1[O:38][CH:39]([F:41])[F:40]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: CCOC(OCC)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl

Procedure:
20 ml of triethyl orthoformate and 0.1 g of toluenesulfonic acid were added to a solution of 3 g (8.8 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzaldehyde in 50 ml of tetrahydrofuran. After the mixture had been refluxed for 2 hours, it was treated with 3 ml of triethylamine. The mixture was subsequently concentrated. The residue was treated with 50 ml of water. The product was subsequently extracted from the aqueous phase using ethyl acetate. The organic phase was then washed using saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and finally concentrated. The crude product was purified by means of column chromatography on silica gel (eluent: hexane/ethyl acetate=9:1). Yield: 1 g.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:26]([Br:27])=[CH:25][C:10]2[C:11]([C:21]([O:23][CH3:24])=[O:22])=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1.N1C=CC=CC=1>ClCCl.O>[Br:27][C:26]1[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[C:11]([C:21]([O:23][CH3:24])=[O:22])[C:10]=2[CH:25]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(Br)cc12
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
MsCl (4.8 g, 41.2 mmol) was added to a solution of methyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (5.0 g, 13.4 mmol) and pyridine (5.4 g, 68.7 mL) in dry dichloromethane (50 mL) at 0° C. After stirred overnight at room temperature, the mixture was diluted with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography to provide methyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (5.3 g, yield: 83%). 1H-NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.99˜8.03 (m, 2H), 7.83 (s, 1H), 7.11˜7.16 (m, 2H), 6.82 (br s, 1H), 3.90 (s, 3H), 2.96 (s, 3H). MS (M+H)+: 442/444.
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.C(N(CC)CC)C.[Br:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][CH:24]([CH2:28][CH2:29][CH2:30][CH3:31])[C:25](O)=O)=[C:21](C=O)[CH:20]=1.CC1CCCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:28]([C:24]1[O:23][C:22]2[CH:21]=[CH:20][C:19]([Br:18])=[CH:33][C:32]=2[CH:25]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCC(Oc1ccc(Br)cc1C=O)C(=O)O
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCc1cc2cc(Br)ccc2o1
Temperature: 80 °C

Procedure:
25.8 ml of benzenesulfonyl chloride (0.202 mol; 1.4 equivalent) and 40 ml of toluene are placed in an equipped reactor and the mixture is stirred at 80° C. 65 ml of anhydrous triethylamine (0.47 mol) and then 45.2 g of 2-(4-bromo-2-formylphenoxy)-hexanoic acid (compound XI) (0.144 mol) in solution in 250 ml of toluene are slowly added at 80° C. The progress of the reaction is monitored by TLC (eluent: methylcyclohexane/ethyl acetate: 80/20; Rf of compound XI=0.08; Rf of the desired compound XII=0.80).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)=[CH:11][C:10]=1[CH2:21][C:22](OC)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:20])[O:16][CH2:17][CH2:18][O:19]2)=[CH:11][C:10]=1[CH2:21][CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cc(C2(C)OCCO2)ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1(c2ccc(OCc3ccccc3)c(CCO)c2)OCCO1
Yield: 108.9 %

Procedure:
Methyl 2-[2-benzyloxy-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]acetate (9.0 g) was dissolved in diethyl ether (130 ml), and lithium aluminum hydride (1.0 g) was added portionwise to the solution under ice-cooling with stirring. After reaction for an hour, water was added portionwise to the reaction mixture under ice-cooling with stirring, and the resulting precipitates were filtered off. Concentration of the filtrate in vacuo gave 2-[2-benzyloxy-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethanol (9.0 g) as an oil.