Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:15][C:16](=[O:36])[N:17]([CH2:26][C:27]1[C:28]([O:34][CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1)[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][N:19]=1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[C:11]([O:15][C:16](=[O:36])[N:17]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][CH:9]=2)[OH:25])=[CH:20][N:19]=1)[CH2:26][C:27]1[C:28]([O:34][CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ccc(C=O)cn1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ccc(C(O)c2c[nH]c3ncnc(Cl)c23)cn1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 0.121 g, 0.790 mmol), (5-fluoro-2-methoxy-pyridin-3-ylmethyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (77), 2.5 mL of N,N-dimethylformamide and cesium carbonate (0.751 g, 2.30 mmol) were combined in a round bottom flask. The reaction was stirred at room temperature for 6 days, then neutralized with 0.1 N aqueous hydrochloric acid, then extracted 3× with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated. The resulting material was purified by silica gel column chromatography, eluting with methanol and dichloromethane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (78, 0.023 g). MS (ESI) [M−H+]−=513.2, 515.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[N:5]([C:7]2[C:12]([Br:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:17][C:18]1[C:26]([Br:27])=[CH:25][C:24]([Br:28])=[CH:23][C:19]=1[C:20](O)=[O:21].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:28][C:24]1[CH:25]=[C:26]([Br:27])[C:18]2[N:17]=[C:14]([C:4]3[N:5]([C:7]4[C:12]([Br:13])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH:6]=[C:2]([Br:1])[CH:3]=3)[O:16][C:20](=[O:21])[C:19]=2[CH:23]=1
Reactant: O=C(O)c1cc(Br)cn1-c1ncccc1Br
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Br)cn2-c2ncccc2Br)nc2c(Br)cc(Br)cc12

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4-bromo-1-(3-bromo-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 6,8-dibromo-2-[4-bromo-1-(3-bromo-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][NH:21][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:11]=1
Reactant: NCCO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Product: COc1ccc(C(=O)NCCO)cc1/C=C/c1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-7 and 2-aminoethanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [C:1]([O:5][C@@H:6]([CH3:18])[C@H:7]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[N:12]=1)[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl.CC1C=CC=C(C)N=1.CCOC(C)=O.CCCCCCC>C(Cl)Cl.O>[C:1]([O:5][C@H:6]([C@H:7]1[CH2:8][O:9][C:20](=[O:22])[N:10]1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[N:12]=1)[CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](OC(C)(C)C)[C@@H](CO)Nc1ccnc(Cl)n1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: Cc1cccc(C)n1
Product: C[C@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 132.6 %

Procedure:
To a round bottom flask containing (2R,3S)-3-(tert-butoxy)-2-((2-chloropyrimidin-4-yl)amino)butan-1-ol (1.8 g, 6.58 mmol) and a stir bar under nitrogen was added DCM (66 ml). The resulting reaction mixture cooled to −70° C. in a dry ice/acetone bath. To this cold solution was added triphosgene (1.07 g, 3.62 mmol) followed by the addition of 2,6-dimethylpyridine (3.6 mL, 30.9 mmol). Resulting reaction mixture allowed to gradually warm to room temperature and stirred for 30 min at room temperature. Reaction mixture diluted with DCM and water and allowed to stir 1 hr at room temperature. The phases were then partioned and aqueous extracted with DCM. Organics phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (1.44 g, 4.80 mmol, 73% yield) as a white crystalline. LCMS m/z 300.1 (M+H)+, Rt 0.91 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:29])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Product: CC1(C)CN(Cc2cccnc2)c2ccc(OC(=O)NCc3ccccc3)cc21

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with benzylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (12.8 mg, 40%) having the following characteristics.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([CH3:20])=[C:18]([S:21][CH3:22])[C:17]([C:23]#[N:24])=[N:16]1.O>CO.CC(O)C.OS(O)(=O)=O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([CH3:20])=[C:18]([S:21]([CH3:22])=[O:1])[C:17]([C:23]#[N:24])=[N:16]1
Reactant: OO
Reactant: CSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: Cc1c(S(C)=O)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C

Procedure:
30% Hydrogen peroxide (1.82 ml) was added to a stirred solution of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylthio-1H-pyrazole-3-carbonitrile (6.2 g) in methanol, containing i-PrOH/H2SO4 catalyst (5.31 ml) described by Drabowicz, et al (above) at 0-5° C. The mixture was allowed to warm to 20° C. over 17 hours. Additional hydrogen peroxide (5.46 ml) was added in three portions over the next 24 hours, along with the catalyst (5 ml). After stirring for a further 60 hours water was added to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (6.72 g) as a yellow oil (91.7% area purity by HPLC) having a retention time of 3.61 minutes on a 25.0 centimeter by 4.6 millimeter SUPELCOSIL LC-18 column, eluting with CH3CN/H2O (3:1) solvent at 1 ml/minute.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[C:7]1([S:13]([NH:16][C:17]2[C:22](I)=[CH:21][C:20]([S:24][CH3:25])=[CH:19][N:18]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O1CCOCC1>C(OCC)(=O)C.O>[C:7]1([S:13]([N:16]2[C:17]3=[N:18][CH:19]=[C:20]([S:24][CH3:25])[CH:21]=[C:22]3[CH:6]=[C:5]2[Si:2]([CH3:4])([CH3:3])[CH3:1])(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: C#C[Si](C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1cnc2c(c1)cc([Si](C)(C)C)n2S(=O)(=O)c1ccccc1
Yield: 80.3 %

Procedure:
A mixture of trimethylsilylacetylene (0.41 g), 2-benzenesulfonylamino-3-iodo-5-methylthiopyridine (0.82 g), triethylamine (0.42 g), cuprous iodide (30 mg), dichlorobis (triphenylphosphine) palladium. (75 mg) and dioxane (2 ml) was stirred at 70° C. for 16 hours under nitrogen atmosphere. To the reaction solution were then added water and ethyl acetate. The insolubles were filtered off. To the filtrate was added a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 0.61 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[Cl:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:44]3[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc(Cl)cc3)c2)c1CCC(=O)OCC
Yield: 72.3 %

Procedure:
A similar procedure as described in Example 44, step 3 was used, starting from 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), 4-chloro-phenylboronic acid (165 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) to obtain 4-[3-[6-(4′-chloro-5-ethoxy-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (231 mg, 72%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C37H47ClO7 (M+Na)+ 661.2902. found 661.2905.
Reaction SMILES: [C:1]([CH:5]1[CH2:12][CH2:11][CH2:10][NH:9][C:8](=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[CH3:19][O+](C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]([O:13][CH3:19])=[N:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCCNC(=O)CC1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCCCC(C(C)(C)C)CC1
Temperature: 25 °C

Procedure:
5-tert-Butylazocan-2-one (30 mg) was dissolved in 2 mL methylene chloride and stirred at room temperature under nitrogen. 31.3 g Trimethyloxonium tetrafluoroborate was added and the reaction stirred overnight. The mixture was added to saturated aqueous sodium bicarbonate and extracted with methylene chloride (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent evaporated to provide crude 5-tert-butyl-8-methoxy-2,3,4,5,6,7-hexahydroazocine.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:22][C:23]1[C:24]2[C:29]([CH:30]=[C:31]3[C:36]=1[CH:35]=[CH:34][CH:33]=[CH:32]3)=[CH:28][CH:27]=[CH:26][CH:25]=2>>[CH:25]1[C:24]2[C:29](=[CH:30][C:31]3[C:36]([C:23]=2[CH2:22][N:7]2[C:8]([C:9](=[O:18])[C:10]4[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=4)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2c3ccccc3cc3ccccc23)c(=O)[nH]c1=O
Yield: 46.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 9-chloromethyl anthracene were reacted by the same way with the example 1 to obtain the titled compound (216 mg, yield: 46.7%).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H](C#N)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#C[C@H]1CC[C@H](C(=O)O)CC1
Reaction time: 8 h

Procedure:
To a solution of methyl trans-4-cyanocyclohexanecarboxylate (996 mg, 5.96 mmol) in THF (37 mL) was added a solution of 0.5 M lithium hydroxide in water (20 mL). The mixture was stirred overnight then the THF was removed in vacuo and the residual aqueous solution acidified to pH 4. The resulting mixture was extracted with ether (2×30 mL), EtOAc (2×30 mL) and CHCl3 (2×30 mL) then the combined extracts, dried over anhydrous sodium sulfate and concentrated in vacuo. This material was taken to the next step without any purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.73 (4 H, m), 2.05-2.22 (4 H, m) and 2.36-2.59 (2 H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][N:45]=[N+]=[N-])=[CH:26][CH:25]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:48])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][NH2:45])=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCN=[N+]=[N-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCN)cc1
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, to a suspension of palladium hydroxide (20% by weight; 18 mg) in methanol (1 ml), a solution of Compound 27 (190 mg, 0.323 mmol) in methanol (1.5 ml) was added; after the nitrogen atmosphere was replaced with a hydrogen atmosphere, stirring was conducted at room temperature for 1 hour. After a nitrogen atmosphere was restored, insoluble matter was separated by filtration on Celite and washed with methanol. Concentration under reduced pressure was conducted to yield a crude product of Compound 28.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=4)(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)cc1OC
Agent: Cl
Product: COc1ccc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4[nH]cnc34)c2F)cc1OC
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-3,4-dimethoxybenzenesulfonamide (20 mg, 0.032 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 16 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-3,4-dimethoxybenzenesulfonamide (percentage yield: 16 mg), was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([CH2:9]CC3CCN(CC4C=CC=CC=4)CC3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:26]([O:29][CH2:30][CH2:31]Br)[CH2:27]Br.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:9][C:6]1[C:5]2[CH:24]=[CH:25][C:2]([N:1]3[CH2:31][CH2:30][O:29][CH2:26][CH2:27]3)=[CH:3][C:4]=2[O:8][N:7]=1
Reactant: Nc1ccc2c(CCC3CCN(Cc4ccccc4)CC3)noc2c1
Reactant: BrCCOCCBr
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc2cc(N3CCOCC3)ccc12
Temperature: 120 °C
Yield: 147.5 %

Procedure:
A mixture of 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole (0.230 g, 1.55 mmol), β,β'-dibromodiethyl ether (0.397 g, 1.71 mmol), and diisopropylethyl amine (Hunig's base, 0.648 mL, 3.72 mmol) in toluene (2.5 mL) was heated at 120° C. for 15 hours. The cooled reaction mixture was diluted with EtOAc and washed with water and brine and dried (MgSO4), filtered, and concentrated. Two additional separate reactions using 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole (0.050 g, 0.34 mmol, and 0.150 g, 1.01 mmol) were carried out in the same manner. Crude product from the three reactions was combined and purified by silica gel flash chromatography (1% MeOH/CH2Cl2) to give the title compound (0.499 g, 79% combined yield) as a pale yellow solid. A small sample was further purified by recrystallization (EtOAc/hexanes) to give a white solid.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18]>C1COCC1>[CH3:12][NH:11][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[C:4]([CH:9]=1)[C:3]([OH:21])=[O:2])(=[O:13])=[O:14]
Reactant: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)OC)c1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Temperature: 50 °C

Procedure:
To 2.3 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NAOH and the mixture was heated at 50° C. for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m/e): 312.0 ([M−H]−, 100%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[C:33]3[C:28](=[C:29]([N+:35]([O-])=O)[C:30]([CH3:34])=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[CH:19][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1>[Fe].C(O)C.O>[NH2:35][C:29]1[C:30]([CH3:34])=[CH:31][CH:32]=[C:33]2[C:28]=1[CH:27]=[CH:26][N:25]=[C:24]2[NH:23][C:20]1[CH:21]=[CH:22][C:3]([Cl:2])=[C:4]([CH:19]=1)[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1
Reactant: Cc1ccc2c(Nc3ccc(Cl)c(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)nccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(Nc3ccc(Cl)c(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)nccc2c1N
Yield: 71.6 %

Procedure:
Iron (257 mg, 4.145 mmol) and concentrated hydrochloric acid (0.03 mL) were added to ethanol/water (10 mL/10 mL), and refluxed for 1 hour. The mixed reaction solution was added with tert-butyl 4-(2-chloro-5-((6-methyl-5-nitroisoquinolin-1-yl)amino)benzyl)piperazine-1-carboxylate (424.5 mg, 0.829 mmol) obtained in <Step 3> above, and refluxed for 3 hours. The reaction mixture was filtered a Celite pad under reduced pressure, and washed with ethanol and chloroform/2-propanol=3/1 (v/v). The filtrate obtained was distilled under reduced pressure, and dissolved in chloroform/2-propanol=3/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (ethyl acetate:hexane=1:3→1:2 (v/v)) to obtain the title compound (286 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[N:10]([CH2:18][CH2:19][C:20]2[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28]CC)=[O:27])=[CH:22][CH:21]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[N:10]([CH2:18][CH2:19][C:20]2[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:31])([CH3:32])[C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCCCCCCN(CCc1ccc(OC(C)(C)C(=O)OCC)cc1)C(=O)Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCN(CCc1ccc(OC(C)(C)C(=O)O)cc1)C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
2.4 g of ethyl 2-(4-[2-(3-[4-fluorophenyl]-1-heptylureido)ethyl]phenoxy)-2-methylpropionate was dissolved in 50 mL of ethanol and 30 mL of 1N aqueous sodium hydroxide was added. The resulting solution was heated at reflux for 30 minutes, cooled to room temperature, acidified with 100 ml of 2N aqueous HCl and extracted with CH2Cl2. The organic extract was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The resulting solid was recrystalized from diethyl ether/hexane to yield 1.1 g of the title compound as a white powder; m.p. 162-4° C.; 1H NMR (CD3OD, δ, 300 MHz): 7.35-6.7 (7H, m, aromatic), 3.48 (2H, t, NCH2), 3.24 (2H, t, NCH2), 2.76 (2H, t, ArCH2), 1.5-1.1 (10H, m, (CH2)5CH3), 1.45 (6H, s, (CH3)2C), 0.83 (3H, t, (CH2)5CH3).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.BrC1C=CC(I)=CC=1C(Cl)=O.[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[O:6]
Reactant: CCOP(OCC)OCC
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: O=C(Cl)c1cc(I)ccc1Br
Product: CCOP(=O)(OCC)C(=O)c1cc(I)ccc1Br

Procedure:
2-Bromo-5-iodobenzoic acid was converted to 2-bromo-5-iodobenzoyl chloride following procedures similar to those in Example 82A. The 2-bromo-5-iodobenzoyl chloride was reacted with triethyl phosphite following procedures similar to those in Example 82 to give diethyl (2-bromo-5-iodophenyl)oxomethylphosphonate. The diethyl (2-bromo-5-iodophenyl)oxomethylphosphonate was converted to diethyl (2-bromo-5-iodophenyl)difluoromethylphosphonate following procedures similar to those in Example 80C. Compound 94 was synthesized according to procedures similar to those of Example 40 from this corresponding diethyl phosphonate. MS (ES−): m/z 411.0, 413.0 (M−H). 1H NMR: (DMSO-d6, 400 MHz) δ 7.93 (s, 1H), 7.67-7.69 (m, 1H), 7.45 (d, J=8.2, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[C:5]([N:7]1[CH2:12][CH2:11][C:10]([F:15])([CH2:13][OH:14])[CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[C:5]([N:7]1[CH2:12][CH2:11][C:10]([F:15])([CH:13]=[O:14])[CH2:9][CH2:8]1)=[O:6]
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC(F)(CO)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1(F)CCN(C(=O)c2ccc(F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
2.48 g of pyridine-SO3 complex (15.5 mmol) are added in a single portion to a solution of 1.5 g of 1-(3-Chloro-4-fluorobenzoyl)-4-fluoro-4-piperidine-methanol (5.18 mmol), 2.16 ml of triethylamine (15.5 mmol) and 15 ml of anhydrous DMSO. After stirring for 3 hours at room temperature, the yellow solution obtained is poured into an ice-water mixture and extracted twice with ethyl acetate. The organic phases are washed with aqueous 5% citric acid solution and then with salt water, dried over MgSO4 and filtered and the solvent is removed under vacuum. 1.49 g (quantitative yield) of a yellow oil are obtained, this product being used without further purification in the following step.