Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:12]=[C:11]([OH:13])[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:14])[N:4]=1.[C:16](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C>[CH3:15][N:2]([CH3:1])[C:3]1[CH:12]=[C:11]([O:13][CH3:16])[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:14])[N:4]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(O)cc(N(C)C)nc1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1c(OC)cc(N(C)C)nc1C
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a stirred solution containing 689 mg (3.27 mmol) of methyl 6-(Dimethylamino)-4-hydroxy-2-methylnicotinate in 10 mL of anhydrous DMF were added 1.91 g (18.0 mmol) of anhydrous sodium carbonate followed by 611 μL (9.81 mmol) of methyl iodide. The reaction mixture was stirred at 23° C. for 16 h. Then, the reaction mixture was poured into 80 mL of water and extracted with two 80-mL portions of ethyl acetate. The combined organic solution was washed with one 80-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (3×10 cm). Elution with 1:1 hexanes-diethyl ether afforded the expected product as a white solid: yield 340 mg (47%); mp: 65-66° C.; silica gel TLC Rf 0.15 (1:1 hexanes-diethyl ether); 1H NMR (CDCl3) δ 2.37 (s, 3H), 3.07 (s, 6H), 3.80 (s, 3H) and 5.72 (s, 1H), 3.82 (s, 3H); 13C NMR (CDCl3) δ 168.4, 165.2, 160.3, 156.7, 107.6, 84.5, 55.2, 51.7, 37.8, 37.8 and 23.5; mass spectrum (APCI), m/z 225.1246 (M+H)+ (C11H17N2O3 requires 225.1239).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:13])[C:5]2[CH:14]=[C:15]([C:18]([O:20]C)=[O:19])[CH:16]=[CH:17][C:4]=2[NH:3]1>O1CCCC1.[OH-].[Na+]>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:13])[C:5]2[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)S(=O)c1ccccc1C(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccccc1C(=O)N2

Procedure:
Stir at room temperature 1.11 gm of the ester of Example 24 in a mixture of 50 ml of tetrahydrofuran and 50 ml of 10% aqueous sodium hydroxide for 3 hours. Separate the phases and extract the organic phase with 10% aqueous sodium hydroxide. Wash the combined aqueous phases with tetrahydrofuran and evaporate partially to remove residual tetrahydrofuran. Acidify with acetic acid. Separate the precipitate, wash with water and dry to obtain the title product (mp 352° C. dec).
Reaction SMILES: [N:1]1[C:9]([S:10][CH2:11][C:12]2[O:13][C:14](=[O:28])[C:15]3[C:20]([C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.Br[CH2:30]C1OC(=O)C2C(C=1C1C=C(C)C=CC=1)=CC=CC=2.O.N1C(S)=C2C(NC=N2)=NC=1.C([O-])([O-])=O.[K+].[K+]>>[N:1]1[C:9]([S:10][CH2:11][C:12]2[O:13][C:14](=[O:28])[C:15]3[C:20]([C:21]=2[C:22]2[CH:23]=[C:24]([CH3:30])[CH:25]=[CH:26][CH:27]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: O=c1oc(CSc2ncnc3[nH]cnc23)c(-c2ccccc2)c2ccccc12
Reactant: Cc1cccc(-c2c(CBr)oc(=O)c3ccccc23)c1
Agent: O=C([O-])[O-]
Agent: Sc1ncnc2[nH]cnc12
Agent: [K+]
Solvent: O
Product: Cc1cccc(-c2c(CSc3ncnc4[nH]cnc34)oc(=O)c3ccccc23)c1
Yield: 82 %

Procedure:
The title compound was made in a similar way as that of the compound of example 10, 3-(bromomethyl)-4-m-tolyl-1H-isochromen-1-one (intermediate C3, 64 mg, 0.194 mmol), 9H-purine-6-thiol hydrate (33 mg, 0.194 mmol) and K2CO3 (27 mg, 0.111 mmol) to give the title compound (64 mg, 82%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:23][CH3:24])=[N:12][N:13]3[C:18](O)=[CH:17][C:16]([CH2:20][O:21][CH3:22])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:27]>CCN(C1C=CC=CC=1)CC>[C:1]1([S:7]([C:10]2[C:11]([S:23][CH3:24])=[N:12][N:13]3[C:18]([Cl:27])=[CH:17][C:16]([CH2:20][O:21][CH3:22])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCc1cc(O)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COCc1cc(Cl)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Yield: 79 %

Procedure:
A suspension of 2.5 g (6.8 mmol) of 3-benzenesulphonyl-5-methoxymethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 40 ml of POCl3 and 20 ml of diethylaniline was heated at reflux for 1 hr. The reaction solution was cooled to RT and evaporated. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with 100 ml of CH2Cl2,and the organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 20:1) yielded 2.1 g (79%) of 3-benzenesulphonyl-7-chloro-5-methoxymethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as a pale yellow powder, m.p. 194-197°.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([CH:11]=1)[CH:9]=[O:10]>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([CH:9]([OH:10])[CH3:1])[CH:11]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)ccc1Cl
Reaction time: 15 h
Yield: 89.3 %

Procedure:
Methyl lithium (11.6 mL, 16.3 mmol, 1.4M in ether) was added to a cooled −78° C. solution of 5-bromo-2-chloro-benzaldehyde (2.75 g, 12.5 mmol) dissolved in THF (40 mL). The reaction mixture was stirred for 15 hours and then quenched with saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with 1N HCl, brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a solid (2.63 g, 91%). 1H NMR (400 MHz, CDCl3): δ 6.32 (d, J=6.3 Hz, 3H), 2.00 (d, J=3.8 Hz, 1H), 5.24 (m, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.33 (dd, J=8.6, 2.5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.COCCOC>[N:10]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=[C:7]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccncc2)CC1
Yield: 104.5 %

Procedure:
1 g of tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate, 0.256 g of lithium chloride, 1.418 g of potassium carbonate, 1.05 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 0.209 g of tetrakis(triphenylphosphine)palladium are introduced into 15 ml of 1,2-dimethoxyethane in a 100 ml three-necked flask under nitrogen; the mixture is brought to reflux for 1 h 30. The mixture is allowed to return to ambient temperature, 100 ml of water are added and the aqueous phase is extracted with 3 times 80 ml of ethyl acetate. The organic phases are combined and dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane to dichloromethane/methanol/aqueous ammonia 90/10/1 elution gradient. 0.821 g of tert-butyl 3,6-dihydro-4,4′-bipyridine-1(2H)-carboxylate is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][CH2:20][CH:21]([OH:50])[CH2:22][NH:23][C:24](=[O:49])[C@H:25]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:26]C(OCC1C=CC=CC=1)=O)=[O:18].[H][H]>COCCOC.CN(C)C=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][CH2:20][CH:21]([OH:50])[CH2:22][NH:23][C:24](=[O:49])[C@H:25]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[NH2:26])=[O:18]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(O)CNC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)NCC(O)CNC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl

Procedure:
1.80 g (2.46 mmol) of Nα -benzyloxycarbonyl-Nε -tert.-butoxycarbonyl-L-lysine-3-{2-[2-(2,6-dichlorophenylamino)-phenyl]-acetylamino}-2-hydroxypropylamide are dissolved in 100 ml of 1,2-dimethoxyethane/dimethylformamide (9:1) and after the addition of 0.40 g of palladium-on-carbon (10%) the whole is treated for 11/4 hours with hydrogen. The catalyst is filtered off, the filtrate is concentrated by evaporation at 30° in a rotary evaporator and the residue is lyophilised after being taken up in 100 ml of dioxan/water (7:3). Nε -tert.-butoxycarbonyl-L-lysine-3-{2-[2-(2,6-dichlorophenylamino)-phenyl]-acetylamino}-2hydroxypropylamide is obtained in the form of a colourless powder which is immediately processed further; Rf =0.52 (acetonitrile:water=3:1), Rf =0.66 (ethyl acetate:n-butanol:pyridine:acetic acid:water=42:21:21:6:10).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:31](=O)[CH2:32][CH2:33][CH3:34].C([BH3-])#N.[Na+]>CO>[CH2:31]([N:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:32][CH2:33][CH3:34]
Reactant: CCCC=O
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCN(CCCC)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 159 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride, butyraldehyde and sodium cyanoborohydride in methanol.
Reaction SMILES: [CH3:1][N:2]1[C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[O:24][CH2:23]3)=[C:16]([O:25][CH3:26])[CH:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:27][CH3:28])=[CH:7][CH:8]=2)[C:3]1=[O:29].[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[CH3:1][N:2]1[C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:24])[CH2:23][NH:33][CH:30]([CH3:32])[CH3:31])=[C:16]([O:25][CH3:26])[CH:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:27][CH3:28])=[CH:7][CH:8]=2)[C:3]1=[O:29]
Reactant: CC(C)N
Reactant: COc1ccc2cc(CCc3ccc(OCC4CO4)c(OC)c3)n(C)c(=O)c2c1
Product: COc1ccc2cc(CCc3ccc(OCC(O)CNC(C)C)c(OC)c3)n(C)c(=O)c2c1
Yield: 80 %

Procedure:
2-Methyl-3-[3-methoxy-4-(2-hydroxy-3-isopropylamino-propoxy)-phenethyl]-7-methoxy-isoquinolin-1(2H)-one was prepared analogous to Example 1b from 2-methyl-3-[3-methoxy-4-(2,3-epoxypropoxy)-phenethyl]-7-methoxy-isoquinolin-1(2H)-one and isopropylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1.[CH2:36]([Sn](CCCC)(CCCC)C#CC)[CH2:37][CH2:38]C>O1CCOCC1.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:36]#[C:37][CH3:38])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 80 °C
Yield: 99.2 %

Procedure:
To a suspension of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.32 mmol) prepared in Example 190c in dioxane (10 mL) was added CuI (5 mg, 0.026 mmol) (Aldrich). The mixture was degassed under nitrogen for 5 min, then tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.026 mmol, Strem), tri-phenylphosphine (6.7 mg, 0.026 mmol), and tributyl(1-propynyl)tin (1.1 g, 3.2 mmol, Aldrich) were added sequentially. The reaction mixture was heated at 80° C. under nitrogen for 1 h. After cooled to room temperature, the reaction mixture was filtered through a short pad of celite. The filtrate was partitioned between saturated water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(1-propynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.17 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][NH:27][C:28]=1[Sn](CCCC)(CCCC)CCCC>>[Cl:1][C:2]1[C:21]([C:28]2[NH:27][N:26]=[CH:25][C:24]=2[F:23])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2[nH]ncc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 13.1 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 25.2) and 4-fluoro-5-(tributylstannyl)-1H-pyrazole to afford an off-white powder. HPLC (Condition 4) tR=5.69 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=415 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([O:14][C:15]1[CH:16]=[C:17]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:13])=[O:12].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([O:14][C:15]1[CH:16]=[C:17]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:18][CH2:19][CH2:20][CH:21]=[O:22])(=[O:13])=[O:12]
Reactant: COc1ccc(OC)c(S(=O)(=O)Oc2cc(C)cc(OCCCO)c2)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC)c(S(=O)(=O)Oc2cc(C)cc(OCCC=O)c2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
To a cooled (0° C.), stirred solution of 360 mg (0.941 mmol) of 3-[3-(2,5-dimethoxyphenylsulfonyloxy)-5-methylphenoxy]propanol, as prepared in the preceding step, 344 μL (1.98 mmol) of N,N-diisopropylethylamine and 200 μL (2.82 mmol) of anhydrous dimethyl sulfoxide in 6.0 mL of anhydrous dichloromethane was added 300 mg (1.88 mmol) of sulfur trioxide pyridine complex. The mixture was warmed to ambient temperature over 30 min and stirred for 16 h. The mixture was then poured into 15 mL of dichloromethane and washed with 5% (w/v) aqueous citric acid (2×25 mL). Each wash was extracted with 5 mL of dichloromethane and the combined extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated. The resulting material was chromatographed on 35 g of silica gel with dichloromethane followed by 2.5% ethyl acetate-dichloromethane to afford 268 mg (75%) of the.title compound as a colorless resin: 1H-NMR (300 MHz; CDCl3) δ 9.83 (t, 1 H, J=1.4 Hz), 7.34 (d, 1 H, J=3.1 Hz), 7.15 (dd, 1 H, J=9.1, 3.1 Hz), 7.03 (d, 1 H, J=9.1 Hz), 6.59 (m, 1 H), 6.56 (m, 1 H), 6.47 (t, 1 H, J=2.1 Hz), 4.20 (t, 2 H, J=6.1 Hz), 3.97 (s, 3 H), 3.76 (s, 3 H), 2.86 (td, 2 H, J=6.1, 1.4 Hz), and 2.25 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:20](=O)[CH3:21])C.O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=1)=[C:20]([CH3:21])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(=O)c12
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.54 g), 2-(4-methanesulfonylbenzyl)-3-oxobutyric acid ethyl ester (0.75 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated at 130° C. for 20 hours. The mixture was diluted with water and the pH of this solution this solution was adjusted to 3 by the addition of sodium acetate. The resulting precipitate was collected by filtration and dried to afford title compound as a white solid, 1.0 g.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[C:16]([NH2:29])[N:15]=2)[CH2:12][CH2:11][CH2:10]1.O>C(Cl)(Cl)Cl>[Br:1][C:19]1[N:20]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:21]2[C:17]([N:18]=1)=[C:16]([NH2:29])[N:15]=[C:14]([O:13][CH:9]1[CH2:12][CH2:11][CH2:10]1)[N:22]=2
Reactant: Nc1nc(OC2CCC2)nc2c1ncn2C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc(OC2CCC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 25 °C
Yield: 112.8 %

Procedure:
N-Bromosuccinimide (1.152 g, 6.47 mmol) was added to a stirred solution of 2-(cyclobutyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.248 g, 4.31 mmol) in chloroform (15 ml) at 0° C. The mixture was warmed to room temperature and left overnight when water (15 ml) was added and the phases separated. The aqueous layer was extracted with dichloromethane and the organic extracts were combined, washed with brine, dried over anhydrous magnesium sulphate and evaporated to give the title compound as an orange foam (1.79 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[N:7]=1.[Br:17]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:17][C:9]1[CH:10]=[CH:11][C:6]([NH:5][CH2:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[Cl:1])=[N:7][C:8]=1[F:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cccc(NCc2ccccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1nc(NCc2ccccc2Cl)ccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To (2-chloro-benzyl)-(6-fluoro-pyridin-2-yl)-amine (16, 4.70 g, 19.8 mmol) in 100.0 mL of acetonitrile, N-bromosuccinimide (3.53 g, 19.8 mmol) in 20.0 mL of acetonitrile was added slowly at room temperature. The reaction was stirred at room temperature for 4 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was washed with ethyl acetate in hexane to provide the desired compound (17, 5.0 g).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[N:8](COCC[Si](C)(C)C)[C:9]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][C:25]3[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[C:27]([Cl:33])[CH:26]=3)[C:18]=2[F:34])=[O:14])=[C:10]([Cl:12])[N:11]=1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:10]1[N:11]=[C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])[NH:8][C:9]=1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][C:25]2[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[C:27]([Cl:33])[CH:26]=2)[C:18]=1[F:34])=[O:14]
Reactant: C[Si](C)(C)CCOCn1c(N)nc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
Methyl chloroformate (0.020 mL, 0.26 mmol) was added to a solution of 2-amino-4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.050 g, 0.086 mmol) and DIEA (0.075 mL, 0.43 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred at RT overnight. TFA (0.5 mL) was added and the reaction mixture was stirred at RT for another 1 h. The reaction mixture was then evaporated and taken up in MeOH (1 mL). NaBH4 (0.030 g, 0.80 mmol) was added and the reaction mixture was stirred overnight. CH2Cl2 and sat'd NaHCO3 were added and the solution was extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered, concentrated and purified by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) to afford the title compound (0.008 g, 19%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.56 (s, 1H) 7.34-7.44 (m, 2H) 7.25-7.29 (m, 1H) 7.24 (s, 1H) 4.57-4.70 (m, 2H) 3.81 (s, 3H). ES-LCMS: m/z 512.01, 513.97 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N+:10]([O-])=O)=[CH:4][C:3]=1[O:13][CH3:14].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C=C[N+](=O)[O-])ccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CCN)ccc1Cl
Yield: 100.8 %

Procedure:
1-Chloro-2-methoxy-4-(2-nitrovinyl)benzene (I-86a: 800 mg, 3.74 mmol) in dry THF (10 mL) was reacted with LAH (278 mg, 7.48 mmol) in dry THF (10 mL) to afford 700 mg of the product (100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:19]1[C:20]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:21]=2[S:22](=[O:32])[C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:20]2[C:19]([O:1][C:2]3[CH:3]=[CH:4][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[S:22](=[O:32])[C:21]=2[CH:33]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(O)cc1
Reactant: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1ccc(OC2=C(c3ccc(OC)cc3)S(=O)c3cc(OC)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of (E)-ethyl 3-(4-hydroxyphenyl)-2-methylacrylate (92 mg, 0.445 mmol) in DMF (2.0 mL) was added sodium hydride (60% suspension in oil, 17.79 mg, 0.445 mmol), the resulting mixture was allowed to stir for 30 min at room temperature. To the solution was added 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (125 mg, 0.342 mmol) as a suspension in DMF (2.0 mL). The reaction was heated to 80° C. for 15 h. Upon completion the reaction was cooled to room temperature, quenched with water and extracted with EtOAc. The combined organic layers were then washed with water, sat. aq. NaHCO3, brine and then collected (phase separator) and concentrated in vacuo to afford the crude product. The crude material was purified by column chromatography (SiO2, 0-70% EtOAc/Heptane) to afford (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate (144 mg, 0.294 mmol, 86% yield). LC/MS (m/z, MH+): 491.3