Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH:4][N:5]([CH2:15][C:16]([O:18]C)=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH3:14])[CH:7]=1)=[O:3].C[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[CH2:15][C:16](=[O:18])[NH:1][C:2](=[O:3])[NH:4]2)=[CH:7][C:8]=1[CH3:14]
Reactant: COC(=O)CN(NC(N)=O)c1ccc(OC)c(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(N2CC(=O)NC(=O)N2)cc1C

Procedure:
To a solution of methyl [2-[aminocarbonyl]-1-[4-methoxy-3-methyl phenyl]hydrazino]acetate (Intermediate 98, 222 mg, 0.8 mmol) in methanol (5 ml) was added sodium methoxide (43 mg, 0.8 mmol) with stirring and under nitrogen. After 30 minutes further sodium methoxide (43 mg, 0.8 mmol) was added and the reaction stirred at room temperature for 14 hours. Three separate portions of sodium methoxide (43 mg, 0.8 mmol) were then added with 30 minutes between each before the reaction was poured into pH 6 buffer (30 ml) and extracted with ethyl acetate (2×25 ml). The organic extract was dried (MgSO4) and evaporated to give a white semi-solid which was triturated with ethylacetate-ether (~1:1) to give an off white solid. This was dissolved in ethyl acetate (10 ml), filtered and evaporated to give the title compound as an off white solid (18 mg, 10%) m.p. 220°-222° C. (decomp).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21](O)=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:16])[F:17])[CH:7]=1
Reactant: CC(C)NNC(=O)C1CCOCC1
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)C1CCOCC1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 61.8 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (280 mg, 0.85 mmol) and tetrahydro-pyran-4-carboxylic acid N′-isopropyl-hydrazide (1.2 eq. 190 mg, 1.02 mmol) in DMF (3 ml) was treated with diisopropyl amine (0.370 ml, 2.12 mmol) and PyBroP (595 mg, 1.275 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 50-100% ethyl acetate/hexanes gradient to afford the product as a white solid (262 mg, 62%). MS m/e 499.23 (M+H+)
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].C1CCN2C(=NCCC2)CC1.[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([CH3:41])[O:30][C@@H:28]([OH:29])[C@@H:27]1[O:42][C:43](=[O:49])[CH2:44][CH2:45][C:46]([CH3:48])=[O:47])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:1][C:2]([Cl:6])([Cl:5])[C:3](=[NH:4])[O:29][C@@H:28]1[O:30][C@@H:31]([CH3:41])[C@H:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:27]1[O:42][C:43](=[O:49])[CH2:44][CH2:45][C:46]([CH3:48])=[O:47]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)CCC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](C)O[C@H]1O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)CCC(=O)O[C@H]1[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 74.1 %

Procedure:
Trichloroacetonitrile (1.3 mL, 13 mmol) and DBU (51 μL, 0.3 mmol) were added to a solution of the residue 211 (1.0 g, 2.3 mmol) in anhydrous DCM (6 mL) at 0° C. After 2 h, the mixture was concentrated. The residue was eluted from a column of silica gel with 3:1 cyclohexane-EtOAc and 0.2% Et3N to give 212 as a white foam (1.0 g, 95%); 1H NMR: δ 8.67 (s, 1H, NH), 7.40-7.30 (m, 10H, Ph), 6.19 (d, 1H, J1,2=1.9 Hz, H-1), 5.48 (dd, 1H, J1,2=2.0, J2,3=3.3 Hz, H-2), 4.95 (d, 1H, CH2Ph), 4.73 (d, 1H, CH2Ph), 4.66 (d, 1H, CH2Ph), 4.58 (d, 1H, CH2Ph), 4.51 (d, 1H, CH2Ph), 4.00 (dd, 1H, J3,4=9.5 Hz, H-3), 3.95 (dq, 1H, J4,5=9.6, J5,6=6.3 Hz, H-5), 3.52 (pt, 1H, H-4), 2.80 (m, 4H, Lev), 2.20 (s, 3H, Ac), 1.36 (d, 3H, H-6). Anal. Calcd for C27H30Cl3NO7.0.5H2O: C, 54.42; H, 5.24; N, 2.35. Found: C, 54.06; H, 5.06; 2.05.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Br)=[O:33])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: COc1ccc(C(=O)Br)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(OC)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 310 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 4-methoxy benzoyl bromide. The compound of example 310 was used directly without isolation, for the preparation of compound of example 311.
Reaction SMILES: OS(O)(=O)=O.[C:6]1([C@@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:18]I>O.CC(O)=O>[I:18][C:9]1[CH:10]=[CH:11][C:6]([C@@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=[O:16])=[CH:7][CH:8]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
A solution of H2SO4 (0.1 mL) in water (1 mL) and AcOH (4 mL) in a 25 mL flask was added trans-2-phenylcyclopropanecarboxylic acid (200 mg, 1.23 mmol), iodine (173 mg, 0.68 mmol) and KIO3 (61 mg, 0.28 mmol). The reaction mixture was heated to reflux, and added AcOH (6 mL) in portions of 2 mL to rinse iodine down the condenser. After 4 hours, when no further color changes appeared, the reaction was cooled to room temperature, quenched with 1M Na2S2O4 and added water. The mixture was extracted with EtOAc (3×), and the combined extracts were washed with brine, dried over MgSO4 and concentrated under vacuum. The crude product containing minor impurities of starting material and the ortho-iodinated product, was recrystallized from PE to provide 157 mg (44%) trans-2-(4-iodophenyl)cyclopropanecarboxylic acid as a pure and white crystalline product: Rt=11.33 min (HPLC method I); 1H NMR (CDCl3) δ 7.62-7.58 (m, 2H), 6.87-6.84 (m, 2H), 2.56-2.51 (m, 1H), 1.89-1.84 (m, 1H), 1.69-1.64 (m, 1H), 1.39-1.34 (m, 1H); 13C NMR (CDCl3) δ 179.3, 139.2, 137.6, 128.3, 91.7, 26.5, 23.9, 17.4; ESI-MS m/z 311.0 (M+Na+).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][C@@H:19]2[CH2:21][C@H:16]1[CH2:17][N:18]2[S:22]([CH3:25])(=[O:24])=[O:23])=O)(C)(C)C>C(Cl)Cl>[CH3:25][S:22]([N:18]1[CH2:17][C@@H:16]2[CH2:21][C@H:19]1[CH2:20][NH:15]2)(=[O:23])=[O:24]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Methanesulfonyl chloride (120 μL, 1.55 mmol) and DIPEA (187 μL, 1.07 mmol) were added to a solution of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in DCM (20 mL) and the reaction mixture stirred at ambient temperature for 17 h, then partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo to give (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g); the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a white solid (170 mg, 96%). 1H NMR (CDCl3, 400 MHz) δ 4.37 (d, J=2.0 Hz, 1H); 3.83 (d, J=2.0 Hz, 1H); 3.41 (dd, J=9.2, 2.19 Hz, 1H); 3.25 (d, J=9.2 Hz, 1H); 3.20 (d, J=10.3 Hz, 1H); 3.01 (dd, J=10.3, 2.14 Hz, 1H); 2.89 (s, 3H); and 1.79 (bs, 2H)
Reaction SMILES: Cl.[C:2](=N)(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]CC.[Na+].[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:29]([NH:31][NH2:32])=[O:30]>C(O)C.O1CCOCC1>[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:29]1[O:30][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:32][N:31]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2)o1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of ethyl benzimidate hydrochloride (376 mg; 2.03 mmol) in ethanol (4 mL) was added at 0° C. sodium ethoxide (2.72 M in ethanol, 355 L, 0.99 mmol) and stirred for 15 min. The suspension was filtered off and 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was added and stirred for 90 h at 70° C. The reaction mixture was suspended in dioxane (4 mL) and heated in the microwave for 30 min at 180° C. Concentration and then purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (163 mg, 29%) as a white solid. MS: m/e=304.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:14]([NH:16][O:17][CH3:18])=[O:15])[C:3]=1[C:23]#[N:24].Cl.[CH3:26][NH:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>C1COCC1>[C:23]([C:3]1[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:14]([NH:16][O:17][CH3:18])=[O:15])=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=1[N:27]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:26])#[N:24]
Reactant: CNCC(C)(C)C
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(SC)nc(Cl)c2C#N)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CONC(=O)c1ccc(C)c(Nc2nc(SC)nc(N(C)CC(C)(C)C)c2C#N)c1
Yield: 44.4 %

Procedure:
3-(6-Chloro-5-cyano-2-methylsulfanyl-pyrimidin-4-ylamino)-N-methoxy-4-methyl-benzamide (3.33 g, 9.2 mmol), N-methyl-neopentylamine hydrochloride (2.05 g, 15 mmol) and DIEA (3.87 g, 30 mmol) in THF (10 mL) were heated to 60° C. for overnight. The solvent was removed in vacuo and the product (1.75 g) was obtained after purification by silica gel column chromatography.
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.CN(C)[CH:8]=[CH:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH:1]1([N:4]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=[N:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)C=CN(C)C
Reactant: NNC1CC1
Product: CCOC(=O)c1ccnn1C1CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using cyclopropylhydrazine (Step 17.2) and ethyl 4-(Dimethylamino)-2-oxobut-3-enoate at 125° C. for 8 hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 2.5-45%). tR: 4.40 min (HPLC 1); tR: 0.91 min (LC-MS 2); ESI-MS: 181 [M+H]+ (LC-MS 2); Rf=0.85 (hexane/EtOAc 1:1).
Reaction SMILES: [NH2:1][C@H:2]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:23][B:24]1OB(C)OB(C)O1>C1(C)C=CC=CC=1>[CH:17]1([C@@H:2]2[C:3]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:4][B:24]([CH3:23])[NH:1]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CB1OB(C)OB(C)O1
Reactant: N[C@H](C1CCCCC1)C(O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CB1N[C@H](C2CCCCC2)C(c2ccccc2)(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-2-amino-2-cyclohexyl-1,1-diphenylethanol (2.95 g, 10 mmole) and toluene (60 mL) were charged to a 100 mL single neck flask fitted with a Dean and Stark trap, which was then flushed with nitrogen. The mixture was concentrated by distillation at atmospheric pressure to a volume of 30 mL. Toluene (30 mL) was then added and the mixture was concentrated again by distillation to 30 mL. Toluene (30 mL) was again added and the mixture was concentrated again by distillation to 30 mL. The reaction mixture was cooled to room temperature, trimethylboroxine (0.94 mL, 6.7 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Toluene (20 mL) was added and 30 mL of solvent was distilled out. More toluene (30 mL) was added and 30 mL more of the solvent was distilled out. Once again, more toluene (30 mL) was added and then all the solvent was removed by distillation to give (R)-4-cyclohexyl-5,5-diphenyl-2-methyl- 1,3,2-oxazaborolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][NH:13][C:14]([CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1)=O.O=S(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:13]([CH3:12])[C:14]([CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: CNC(=O)C1CCOC1
Reactant: Nc1cc(Br)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cn1c(C2CCOC2)nc2cc(Br)ccc2c1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The mixture of 2-amino-4-bromobenzoic acid (349 mg, 1.62 mmol), N-methyltetrahydrofuran-3-carboxamide (190 mg, 1.47 mmol), SOCl2 (0.13 mL, 1.76 mmol) and toluene (10 mL) was stirred at 80° C. for 5 h, and Na2CO3 aqueous solution was added after the mixture was cooled to room temperature. The water layer was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over Na2SO4, filtered, and evaporated to give the desired product, which was directly used for the next step. MS (ESI): 309, 311 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:24][N:25]([CH3:32])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH3:32])[CH3:24])[CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Fc1ccc(Nc2ncnc3oc4c(c23)CCNC4)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C/C=C/C(=O)N1CCc2c(oc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A suspension of N-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 39A (100 mg, 0.314 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (73 mg, 0.44 mmol) in THF (2 mL) was treated with DIPEA (160 mg, 1.26 mmol) and TBTU (150 mg, 0.47 mmol). The mixture was stirred at rt overnight and then purified directly by preparative HPLC. The product crystallized upon trituration with diethyl ether to afford 76 mg (56%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>O1CCCC1>[CH3:26][O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:6]=2[N:7]=1
Reactant: COC(=O)CCBr
Reactant: Cc1nc2cc(Br)ccc2s1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CCCc1nc2cc(Br)ccc2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-methylbenzothiazole (1000 mg) was dissolved in tetrahydrofuran (25 mL) and the mixture was cooled to −78° C. using an isopropanol/dry ice bath. Lithium diisopropylamide (1.5M in cyclohexane, 4.40 mL) was added, and the solution stirred for 30 minutes at −78° C. Methyl 3-bromopropionate (1.20 mL, 1836 mg) was added and the solution stirred at −78° C. for two hours. The reaction was quenched with 1M aqueous hydrochloric acid, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash column chromatography on silica gel using 10% ethyl acetate hexanes.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:45]=[CH:46][CH:47]=1)[O:12][C:13]1[CH:44]=[CH:43][C:16]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:42])([CH3:41])[C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=4)=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1.CN(C)C=O.P(=O)(O)(O)O>[C:1]1(=[O:7])[N:40]([C:36]2[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=2)[O:33][C:30]2[CH:31]=[CH:32][C:27]([C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:17]([CH3:19])([CH3:18])[C:16]4[CH:15]=[CH:14][C:13]([O:12][C:11]5[CH:45]=[CH:46][CH:47]=[C:9]([N:8]6[C:1](=[O:7])[CH:2]=[CH:3][C:4]6=[O:5])[CH:10]=5)=[CH:44][CH:43]=4)=[CH:25][CH:24]=3)([CH3:42])[CH3:41])=[CH:28][CH:29]=2)[C:4](=[O:5])[CH:3]=[CH:2]1
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(c1ccc(Oc2cccc(N)c2)cc1)c1ccc(C(C)(C)c2ccc(Oc3cccc(N)c3)cc2)cc1
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CC(C)(c1ccc(Oc2cccc(N3C(=O)C=CC3=O)c2)cc1)c1ccc(C(C)(C)c2ccc(Oc3cccc(N4C(=O)C=CC4=O)c3)cc2)cc1
Yield: 97.4 %

Procedure:
In the same reactor used in Example 2D, there were placed 26.5 g (0.27 mole) of maleic anhydride, 0.7 g of phosphoric acid and 150 ml of mixed xylene. A solution was then added dropwise thereto, the solution having been prepared by thermally dissolving 52.8 g (0.1 mole) of 1,4-bis[4-(3-aminophenoxy)-α,α-dimethylbenzyl]benzene obtained in Example 1D in a mixture of 100 ml of mixed xylene and 50 ml of N,N-dimethylformamide. A dropping time of 5 hours and an aging time of 2 hours were used in order to carry out the reaction. The reaction solution was concentrated to about 1/2 the original amount and then cooled. When a temperature of 80° C. had been reached, 50 g of water was added thereto. Afterward, the solution was slowly cooled, so that crystals precipitated. The precipitated crystals were then cooled to room temperatures filtered; and washed with cold methanol. 67.1 g of desired crude 1,4-bis[4-(3 -maleimidophenoxy)-α,α-dimethylbenzyl]benzene was obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]2[C:24]([C:25]3[CH:39]=[CH:38][C:28]([O:29][C:30]4[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=4[CH:32]=O)=[CH:27][CH:26]=3)=[CH:23][N:22]([CH:40]3[CH2:44][CH2:43][O:42][CH2:41]3)[C:18]=2[N:19]=[CH:20][N:21]=1.[CH2:45]([NH:47][CH2:48][CH3:49])[CH3:46]>ClCCCl>[Cl:15][C:16]1[C:17]2[C:24]([C:25]3[CH:26]=[CH:27][C:28]([O:29][C:30]4[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=4[CH2:32][N:47]([CH2:48][CH3:49])[CH2:45][CH3:46])=[CH:38][CH:39]=3)=[CH:23][N:22]([CH:40]3[CH2:44][CH2:43][O:42][CH2:41]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: CCNCC
Reactant: O=Cc1ccccc1Oc1ccc(-c2cn(C3CCOC3)c3ncnc(Cl)c23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CC)Cc1ccccc1Oc1ccc(-c2cn(C3CCOC3)c3ncnc(Cl)c23)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium triacetoxyborohydride (264 mg) was added to a mixture of 2-[(4-(4-chloro-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]benzaldehyde (330 mg) and diethylamine (121 mg) in 1,2-dichloroethane in a vial (5 ml) and the vial septum sealed. The mixture was stirred at ambient temperature for 20 hours then quenched with saturated aqueous sodium bicarbonate solution (5 ml). The mixture was extracted with ethyl acetate to give 2-[4-(4-chloro-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d)pyrimidin-5-yl)phenoxy]-N,N-diethylbenzylamine.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12>>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=4[CH3:1])=[CH:16][CH:15]=3)=[O:14])[CH2:22][C:21]=12
Reactant: CC1=C(c2ccc(C(=O)O)cc2)CCCC1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)CCCC1
Yield: 91.9 %

Procedure:
4-(2-Methyl-cyclohex-1-en-1-yl)-benzoic acid of Step C (0.720 g, 3.33 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.674 g, 3.66 mmol) were reacted according to the procedure of Example 1, Step D. The title compound was purified by recrystallization from petroleum ether to afford white crystals (1.17 g), m.p. 119-120° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[CH:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[S:50](Cl)(=[O:52])=[O:51]>>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:50]([C:41]1[CH:42]=[CH:43][C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=1)(=[O:52])=[O:51])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccc4ccccc4c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 53 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 5, Example 1)was added 2-naphthalenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 53% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH:10]([CH2:15][CH3:16])[C:11]([O:13]C)=[O:12])[CH:6]=[N:7][CH:8]=1)#[N:2].[OH-].[Na+].O>CC(O)C>[C:1]([C:3]1[CH:4]=[C:5]([O:9][CH:10]([CH2:15][CH3:16])[C:11]([OH:13])=[O:12])[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: CCC(Oc1cncc(C#N)c1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCC(Oc1cncc(C#N)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product from Step 1 (0.29 g) was dissolved in propan-2-ol (5 ml) containing sodium hydroxide (0.053 g) and water (2 ml). The mixture was stirred at ambient temperature for 20 minutes, evaporated under reduced pressure to a small volume and diluted with water. The solution was acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate (three times). The extracts were combined, washed with water (three times), dried over magnesium sulphate and evaporated under reduced pressure to give the required product, 0.25 g, as a gum.