Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.OC(C(F)(F)F)=O.[NH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:30][CH:29]([NH:31][C:32]([CH2:34][NH:35][C:36](=[O:47])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)=[O:33])[CH2:28]2)[CH2:23][CH2:22]1>C(Cl)Cl>[F:46][C:43]([F:44])([F:45])[C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[C:36]([NH:35][CH2:34][C:32]([NH:31][CH:29]1[CH2:28][N:27]([CH:24]2[CH2:23][CH2:22][CH:21]([NH:20][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[O:11])[CH2:26][CH2:25]2)[CH2:30]1)=[O:33])=[O:47]
Reactant: NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(NC(=O)c3ccc4c(c3)OCO4)CC2)C1
Reaction time: 2 h

Procedure:
Benzo[1,3]dioxole-5-carbonyl chloride (Aldrich, 74 mg, 0.404 mmol) was added into a solution of N-{[1-(4-amino-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide TFA salt (as prepared in the previous step 200 mg, 0.404 mmol) and TEA (170 μL, 1.21 mmol) in DCM (5 mL) at 0° C. The reaction was stirred for an additional 2 hours and quenched with saturated sodium bicarbonate. The reaction was then partitioned between DCM and water. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:30]([CH3:31])[C@H:29]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:28])=[CH:20]2)=[N:14]4)=[C:9]([CH3:38])[C:8]=3[CH:39]=[CH2:40])[C:4]=1[CH3:41].Cl.CO.ClCCl>O1CCCC1>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:30]([CH3:31])[C@H:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:28])=[CH:20]2)=[N:14]4)=[C:9]([CH3:38])[C:8]=3[CH:39]=[CH2:40])[C:4]=1[CH3:41]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)O)[C@@H]3C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl pyropheophorbide-a (2, 250 mg) was dissolved in distilled tetrahydrofuran (50 ml) and 4N HCl (125 ml) was added in one lot. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 4 hours. The reaction was monitored by analytical tlc (silica plates), using 10% methanol/dichloromethane as a mobile phase. The reaction mixture was then poured in ice water, extracted with dichloromethane. The dichloromethane layer was washed several times with water (3×200 ml). The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation of the solvent gave a residue, which was crystallized from dichloromethane/hexane. Yield, 225 mg. The purity of the compound was ascertained by tlc and the structure was confirmed by NMR spectroscopy. The NMR data were similar as described for 2 except the resonances for the --OCH3 protons of the propionic ester (--CH2CH2CO2CH3) were missing.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:12][O:10][C:9]([C:7]1[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C(C)=O)s1
Yield: 60.3 %

Procedure:
A solution of 5-acetyl-thiophene-2-carboxylic acid (1 g, 5.88 mmol) in DMF (24 mL) is treated with potassium carbonate (813 mg, 5.88 mmol), then iodomethane (0.368 mL, 5.88 mmol), and stirred for 60 h at rt. The reaction mixture is acidified and extracted into ethyl acetate twice. The combined organic layers are washed with brine, dried, filtered, and concentrated, then taken up in ethyl acetate, washed with saturated aqueous potassium carbonate, dried, filtered and concentrated to give 5-acetyl-thiophene-2-carboxylic acid methyl ester (653 mg).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:12]2[N:11]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:9]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:8]=2[C:7](=[O:33])[N:6]([CH3:34])[C:5]1=[O:35].Cl.[CH3:37][NH:38][CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:9]2[C:8]3[C:7](=[O:33])[N:6]([CH3:34])[C:5](=[O:35])[N:4]([CH2:3][CH2:2][N:38]([CH3:39])[CH3:37])[C:12]=3[N:11]=[C:10]2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[CH:27][CH:28]=1
Reactant: Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(CCBr)c1=O
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCn1c(=O)n(C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 14.5 %

Procedure:
To a solution of 3-(2-bromoethyl)-7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (110 mg, 0.192 mmol) in DMF (3 mL) was added dimethylamine hydrochloride (150 mg, 1.84 mmol), followed by potassium carbonate (100 mg, 0.725 mmol). The mixture was stirred at 40° C. for 16 h; then it was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give 7-(4-chlorobenzyl)-3-(2-(dimethylamino)ethyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (15 mg, 13.3% yield) as white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Br.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-:24].[K+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl>[O:23]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:24][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: [OH-]
Reactant: BrCc1ccccc1-c1ccccc1CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc(OCc2ccccc2-c2ccccc2COc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A mixture of 25.0 g (73.5 mmol) of 2,2'-bis(bromomethyl)biphenyl, 14.2 g (151 mmol) of phenol, 14.7 g (261 mmol) of pulverized potassium hydroxide and 3.41 g (15 mmol) of triethylbenzylammonium chloride is admixed with 120 ml of dichloromethane and stirred for 5 hours at 40° C.
Reaction SMILES: [Na+].[C:2]1([C:12]([O:14][CH2:15][C:16]([F:22])([F:21])[S:17]([O-:20])(=[O:19])=[O:18])=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)S([O-])(=O)=O.[C:31]1([CH:37]([SH+:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:38]1([CH:37]([SH+:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1.[F:22][C:16]([F:21])([S:17]([OH:20])(=[O:19])=[O:18])[CH2:15][O:14][C:12]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(OCC(F)(F)S(=O)(=O)[O-])c1cccc2ccccc12
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: c1ccc([SH+]C(c2ccccc2)c2ccccc2)cc1
Product: O=C(OCC(F)(F)S(=O)(=O)O)c1cccc2ccccc12
Yield: 94.45 %

Procedure:
<2> The reaction described in <3> of Synthesis Example 1 was performed under the same conditions, except that the 1-naphthoyloxymethyl difluoromethanesulfonic acid sodium salt (2.61 g) produced in <1> of Synthesis Example 7 above was used instead of the benzoyloxymethyldifluorosulfonic acid sodium salt in the reaction with diphenylmethylphenylsulfonium trifluoromethanesulfonate salt, and thus 3.92 g (yield 94.45%) of 1-naphthoic acid 2,2-difluoro-2-sulfoethyl ester diphenylmethylphenylsulfonium salt as shown in the following reaction scheme 15 was obtained. The structure of the product was confirmed by 1H-NMR (see FIG. 14).
Reaction SMILES: O[CH:2]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl.C1(C)C=CC=CC=1>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(O)c2nccs2)cc1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cc2nccs2)cc1
Yield: 83.6 %

Procedure:
The product of Step 1 (4.00 g, 16.05 mmol) was taken up in DCE (80 ml) with triethylsilane (25.6 ml, 160 mmol), and trifluoroacetic acid (24.72 ml, 321 mmol) was added. The reaction was stirred at reflux overnight. The reaction was diluted with toluene and evaporated to dryness. The residue was taken back up in EtOAc, washed with aqueous saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated. Flash chromatography (0-50% EtOAc/hexanes) afforded methyl 4-(1,3-thiazol-2-ylmethyl)benzoate (3.13 g, 13.42 mmol, 84% yield) as a pale yellow gum that crystallized upon standing. MS ESI: [M+H]+ m/z 234.1.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[N:22]([CH3:23])[C:21]5[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=5[N:19]=4)[CH:13]=3)[CH2:8][CH2:7]2)=O)[CH2:3][CH2:2]1.S(C)C>C1COCC1>[CH:1]1([CH2:4][N:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:13]=[C:14]([C:18]4[N:22]([CH3:23])[C:21]5[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=5[N:19]=4)[CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)[CH2:3][CH2:2]1
Reactant: Cn1c(-c2cccc(N3CCN(C(=O)C4CC4)CC3)c2)nc2ccccc21
Solvent: C1CCOC1
Solvent: CSC
Product: Cn1c(-c2cccc(N3CCN(CC4CC4)CC3)c2)nc2ccccc21
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a solution of cyclopropyl-{4-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazin-1-yl}-methanone (0.17 g, 0.47 mmol) in dry THF (3.50 mL) was added (CH3)2S.BH3 in THF (0.11 mL, 1.18 mmol) and the resulting suspension was heated at 65° C. overnight. The reaction solution was then cooled to room temperature, solvent was removed under reduced pressure and 1N HCl (3 mL) was added to the residue before heating at 100° C. for 6 h. The reaction was cooled to room temperature, then made basic by the dropwise addition of 15% NaOH and extracted with EtOAc (3×10 mL) The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford a residue that was purified by Preparative HPLC, to obtain 0.05 g (32%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:24])([CH3:23])[CH:9]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:24])([CH3:23])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC1(C)C=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1

Procedure:
10% Palladium-carbon (water-content ca. 50%, 20 mg) was added to a solution of N-[4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-7-yl]methanesulfonamide (a compound obtained in Example 5, 20 mg) in ethanol (4 mL), and the mixture was stirred under atmospheric pressure of hydrogen at room temperature for 20 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=95/5 to 70/30) to give the titled compound (20 mg) as a colorless powder.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-:20].[Na+]>CO>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH:1]=[C:14]2[CH2:15][CH2:16][CH2:17][C:18](=[CH:1][C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:20])=[CH:5][CH:4]=3)[C:13]2=[O:19])=[CH:4][CH:5]=1)=[O:8]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C1CCCCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C=C2CCCC(=Cc3ccc(C(=O)OC)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 289.9 %

Procedure:
To a solution of methyl p formylbenzoate (186.0 g, 1.13 mol) and cyclohexanone (50.4 g, 0.514 mol) in 1 L of methanol, prepared and maintained under an inert atmosphere in a 2 L, 3-necked, round bottom flask equipped with a mechanical stirrer, is added 20 mL of an aqueous solution containing sodium hydroxide (4.0 g, 0.1 mol). The mixture is stirred at ambient temperature for 4.5 hours and the reaction mixture is then filtered and the product dried to give 113.2 g of 2,6-bis(4'-methoxycarbonylbenzylidene)cyclohexanone. The filtrate is heated on a steam bath for 45 minutes, cooled and filtered to give an additional 27.9 g of product for a total yield of 141.1 g (70% of theory) of 2,6-bis(4'-methoxycarbonylbenzylidene)-cyclohexanone. The results from analyses of a sample recrystallized from acetic acid are:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.C(Cl)Cl>[CH3:17][O:16][C:14]([C:11]1[CH:12]=[CH:13][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1)=[O:15]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)sc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2cc(C(=O)O)sc2c1
Reaction time: 5 h

Procedure:
To a solution of benzo[b]thiophene-2,6-dicarboxylic acid dimethyl ester (139 mg, 0.56 mmol) in THF/MeOH (2/2 mL) was added 1 N NaOH (555 μL). After 5 h, the solution was diluted with CH2Cl2 and acidified with 5% citric acid. The combined organic fractions were dried, filtered, and concentrated to yield the desired acid, which was used without further purification. MS (EI): cal'd (MH+) 237.01, exp (MH+), 237.13.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:19][C:18]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:17]=2[F:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc(F)cc2F)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 2,4-difluorobenzyl bromide
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([NH2:16])[CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>C(#N)C>[Br:24][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([NH2:16])=[N:5][C:6]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Solvent: CC#N
Product: Nc1cc(Cl)c(Br)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-chloro-6-(2-phenylethynyl)pyridin-2-amine B3a (1.0 g, 4.37 mmol), NBS (778 mg, 4.37 mmol) and ACN (20 ml) is stirred for 3 h at RT in the dark. The mixture is concentrated in vacuo and the product purified NP chromatography. Yield: 1.0 g (74%). HPLC-MS: M+H=307/309.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[CH:45][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)=[N:47][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([F:24])[CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:43]4[CH:44]=[CH:45][C:46]([N:49]5[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]5)=[N:47][CH:48]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 101.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (STEP 1 example 71) (1 g, 1.515 mmol) was coupled with tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (intermediate 69C) (581 mg, 1.818 mmol) using sodium carbonate (481 mg, 4.545 mmol) and Pd(PPh3)2Cl2 (53 mg, 0.075 mmol) in toluene/ethanol/water (10/15/2 ml). This afforded 1.12 g (100% yield) of the titled compound after purification by column (Silica gel 60/120) using 40% ethyl acetate in hexane as eluent. MS: m/z=726.3 (M+1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].[OH-].[Na+]>ClCCl>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) in dichloromethane (1 ml) was added at room temperature triethylamine (89 mg, 123 μl, 880 μmol) and methanesulfonyl chloride (27.5 mg, 18.7 μl, 240 μmol). The mixture was allowed to stir at room temperature for 18 h, poured into ice/water (5 ml) and 1N sodium hydroxide solution (5 ml) and extracted with dichloromethane (2×15 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO4) and evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1) and trituration with dichloromethane (1 ml) and heptane (5 mL) for 30 min to yield the title compound as an off-white solid (43 mg, 66%), MS (ISP) m/z=409.4 [(M+H)+], mp 220° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:20]=1[C:21](OCC)=[O:22].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:30][C:27]1[CH:26]=[C:20]2[C:19]([CH2:18][N:1]([C:2]3[CH:3]=[CH:4][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=3)[C:21]2=[O:22])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cc(Cl)ccc1CBr
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C(=O)OC(C)(C)C)c1ccc(N2Cc3ccc(Cl)cc3C2=O)cc1
Temperature: 100 °C
Yield: 53.7 %

Procedure:
A mixture of tert-butyl 2-(4-aminophenyl)propanoate (0.24 g, 1.08 mmol), ethyl 2-(bromomethyl)-5-chlorobenzoate (0.25 g, 0.901 mmol) and N,N-diisopropylethylamine (0.14 g, 1.08 mmol) in ethanol (5 mL) was heated in a sealed tube at 100° C. overnight. After this time, the mixture was cooled with an ice bath and the solids collected by filtration to afford tert-butyl 2-(4-(6-chloro-1-oxoisoindolin-2-yl)phenyl)propanoate (0.18 g, 55%) as a white solid: mp 169-171° C.; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.56 (dd, J=8.0, 2.0 Hz, 1H), 7.45 (d, J =8.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 4.84 (s, 2H), 3.63 (m, 1H), 1.45 (d, J=7.5 Hz, 3H), 1.41 (s, 9H); ESI MS m/z 404 [M+H+CH3OH]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.C[N:22]([CH:30]1CCNC[CH2:31]1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C([N:39]([CH2:43][CH3:44])[CH:40]([CH3:42])C)(C)C>>[Br:1][C:2]1[C:10]2[C:9]([N:39]3[CH2:40][CH2:42][CH:31]([CH2:30][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:44][CH2:43]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1

Procedure:
A mixture of 5-bromo-4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine D5 (1.5 g), 1,1-dimethylethyl methyl(4-piperidinyl)carbamate (1.294 g, 6.04 mmol, commercially available from e.g Fluorochem, Apollo, or Astatech) and N,N-diisopropylethylamine (1.758 mL, 10.06 mmol) was heated at 150° C. for 20 min. Crude product needs to be purified by silica chromatography eluting with 10-50% EtOAc in isohexane. The fractions have been collected and the solvent has been evaporated to give the product D24 in 0.763 g. LC/MS [M+H]+549.71/551.79@1.50 min (2 min run)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8](CC3C=CC(OC)=CC=3)[C:9]2=[O:12])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.S(O)(C(F)(F)F)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][NH:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2Cc3ccc(OC)cc3C2=O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1)C(=O)NC2
Temperature: 40 °C
Yield: 42 %

Procedure:
Alternatively, a mixture of 6-methoxy-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (98.5 mg, 0.35 mmol) in dichlormethane (10 mL) containing TFA (1.6 mL, 20.8 mmol) and TfOH (0.6 mL, 7.0 mmol) was heated overnight at 40° C. Then the mixture was poured into sodium hydrogen carbonate and water and the product extracted with dichloromethane. The combined organic layers were then dried over sodium sulphate, filtered and evaporated. The residue was then purified by chromatography (SiO2, dichloromethane:MeOH 20:1) to afford the title product (24 mg, 42%) as a light yellow solid. MS m/e=164.2 (M).