Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[CH:17]=[CH:16][N:15]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31](OCC)=[O:32])=[CH:29][N:30]=[C:24]2[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:21][C:22]1[CH:27]=[CH:26][N:25]2[C:28]([C:31]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:12][C:13]3[CH:17]=[CH:16][N:15]([CH:18]([CH3:20])[CH3:19])[N:14]=3)=[O:32])=[CH:29][N:30]=[C:24]2[CH:23]=1
Reactant: Cc1nn(Cc2ccn(C(C)C)n2)c2cccc(N)c12
Reactant: CCOC(=O)c1cnc2cc(Cl)ccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(Cc2ccn(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Temperature: 0 °C
Yield: 52 %

Procedure:
3-Methyl-1-((1-isopropylpyrazole-3-yl)methyl)-4-amino-1H-indazole (1 equivalent) and ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate (Example 7 step D; 1 equivalent) were dissolved in dry THF (0.2 M) and the resulting solution was cooled to 0° C. Lithium bis(trimethylsilyl)amide (2.3 equivalents) was slowly added and the resulting mixture was allowed to warm to ambient temperature overnight. THF was removed under vacuum and the remaining material was partitioned between water and ethyl acetate. The bottom aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were combined, dried over sodium sulfate, filtered and \ concentrated to give desired compound (52% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[N:22]3)=[CH:19][CH:20]=2)[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>CC#N>[CH3:1][N:2]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[N:22]3)=[CH:19][CH:20]=2)[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1
Reactant: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)N(C)CCC(=O)OC(C)(C)C)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)N(C)CCC(=O)O)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Step C of Example 1, using (+/−)-tert-butyl 3-(N-methyl-4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoate. Column: Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95% H20/5% MeCN linear to 5% H20/95% MeCN over 4.0 min, Hold at 5% H20/95% MeCN to 5.0 min. Flow: 2.0 mL/min. Retention time: 3.27 min. MS (M+1): 498.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:7]=1[CH2:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[O:5])[CH3:2].[H-].[Na+].I[CH3:31]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH3:31])[C:7]=1[CH2:17][C:18]12[CH2:27][CH:22]3[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]3)[CH2:25]1)[CH2:19]2)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1CC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccccc2)n(C)c1CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of 2-adamantan-1-ylmethyl-5-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (Example 1, step b) (726 mg, 2.00 mmol) in DMF (3 ml) was added sodium hydride (60% dispersion in oil) (100 mg, 2.50 mmol) in small portions at 0° C. The mixture was stirred at room temperature for 30 min, then iodomethane (1.00 ml, 16.0 mmol) was added and the stirring was continued for 1 h. The reaction mixture was partitioned between ethyl acetate and 1M hydrochloric acid, the organic layer was washed with water, dried, and the solvent was evaporated to afford the product as a white solid (620 mg, 82%). 1H NMR (300 MHz, CDCl3) 7.35 (5H, m), 6.64 (1H, s), 4.27 (2H, q), 3.51 (3H, s), 2.80 (2H, br s), 1.96 (3H, br s), 1.64 (12H, m), 1.35 (3H, t).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of 1.35 g (5.233 mmol) of the product of Example 50 dissolved in 20 mL of chloroform and 1.5 mL of pyridine was added 1.02 g (5.233 mmol) of 4-fluorobenzenesulfonyl chloride and the resulting mixture was stirred overnight at room temperature. The chloroform was removed in vacuo and the residue was diluted with ether and washed with water, 5% HCl solution and saturated sodium bicarbonate solution and then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether/hexanes (1:1) and the solid was collected by filtration and dried in vacuo to provide 1.50 g (69%) of the sulfonamide as a white solid. Electrospray Mass Spec: 416.9 (M+H)+
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40]Br)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][S:19][CH2:20][CH2:21][OH:22])[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cccc(-c2ccccc2CBr)c1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2ccccc2CSCCO)c1

Procedure:
2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester was synthesized as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester (10.3 g, 32.27 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol (3.03 g, 38.72 mmol, 1.2 eq.) and potassium carbonate (13.38 g, 96.81 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a yellow/orange oil.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1.N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:19][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cnc(OCC2CC2)c(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
Ethylsulfonyl chloride (170 uL, 1.8 mmol) was added to a stirred solution of 5-bromo-6-(cyclopropylmethoxy)pyridin-3-amine (440 mg, 1.8 mmol) and pyridine (725 uL) in DCM (4.5 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with 1N HCl (15 mL) and extracted with DCM (3×15 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100%) in DCM to afford the title compound (181 mg, 88%) as a tan solid. LCMS (M+H)+=336.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][CH2:8][CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCN1CCCC1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
Pyrrolidine (50 g, 700 mmol), 3-chloropropanol (58.5 ml, 700 mmol) and potassium carbonate (145 g, 1.05 mol) were refluxed in acetonitrile (1 l) for 20 hours. Upon cooling to ambient temperature the precipitate was filtered off and rinsed with acetonitrile. The solvent was evaporated off and the residual oil purified by distillation under vacuum to give 3-(pyrrolidin-1-yl)propan-1-ol (62.1 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]3[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 70 μmol), (4-chloro-phenyl)-acetic acid (13 mg, 79 μmol) and DIPEA (31 μL, 237 μmol) in THF (3 mL), T3P (151 μL, 237 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (74%, 35 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C@H:9]([C:16]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[CH2:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([NH:38][O:39]C(OCC(C)C)C)=[O:37])=[CH:30][CH:29]=1)=O>ClCCCl>[C:12]([O:11][CH2:10][C@@H:9]([C:16]([O:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:17])[NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:26][C:28]2[CH:29]=[CH:30][C:31](/[CH:34]=[CH:35]/[C:36]([NH:38][OH:39])=[O:37])=[CH:32][CH:33]=2)=[CH:25][CH:24]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)COC(C)ONC(=O)/C=C/c1ccc(C=O)cc1
Reactant: CC(C)(C)OC[C@H](NCc1ccc(CN)cc1)C(=O)OC1CCCC1
Solvent: ClCCCl
Product: CC(C)(C)OC[C@H](NCc1ccc(CNCc2ccc(/C=C/C(=O)NO)cc2)cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.4 %

Procedure:
To a suspension of cyclopentyl N-[4-(aminomethyl)benzyl]-O-tert-butyl-L-serinate (prepared as described in Example 73-0.282 g, 0.67 mmol) and (2E)-3-(4-formylphenyl)-N-(1-isobutoxyethoxy)acrylamide (prepared as described in Example 12-0.230 g, 0.79 mmol) in DCE (25 mL) was added STAB (0.700 g, 3.3 mmol). The mixture was stirred at RT for 3 h, and then quenched with sat. NaHCO3 solution (75 mL). The product was then extracted with DCM (3×100 mL) and the combined organic extracts were dried (MgSO4), concentrated and purified by preparative HPLC to yield the desired product (5 mg, 2%). LCMS purity 98%, m/z=524.25 [M+H]+, 1H NMR (300 MHz, CD3OD) δ: 7.41 (2H, d, J=7.9 Hz), 7.24 (2H, d, J=7.7 Hz), 7.20 (3H, br s), 6.37 (1H, d, J=15.6 Hz), 5.09 (1H, t, J=5.7 Hz), 3.44-3.75 (8H, m), 3.25 (1H, t, J=3 Hz), 1.45-1.90 (8H, m), 1.04 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[CH:3]=1.[C:31]([O:36][CH3:37])(=[O:35])[CH:32]([CH3:34])O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:10])=[O:11])[C@H:32]([C:31]([O:36][CH3:37])=[O:35])[CH3:34])=[C:4]([CH2:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reactant: COC(=O)C(C)O
Product: COC(=O)[C@H](C)N(c1ccc(Cl)cc1Cc1c(F)cccc1F)S(=O)(=O)c1ccc(OC)c(OC)c1

Procedure:
By reaction of 2 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxybenzenesulfonamide with methyl lactate according to process 35, 1.393 g of the expected product are obtained.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:27])=[N:24][C:25]=1[CH3:26].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[CH3:15])[C:8]([C:4]1[C:3](=[O:18])[C:22]2[C:23](=[N:24][C:25]([CH3:26])=[C:20]([CH3:19])[CH:21]=2)[NH:27][CH:5]=1)=[O:17]
Reactant: Cc1ccc(N)nc1C
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc(C(=O)c2c[nH]c3nc(C)c(C)cc3c2=O)cc1C
Yield: 11.2 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.50 g (2.01 mmol) 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester, 0.25 g (2.01 mmol) of 5,6-Dimethyl-pyridin-2-ylamine, and 15 mL of diphenyl ether to yield 68.7 mg of 3-(3,4-Dimethyl-benzoyl)-6,7-dimethyl-1H-[1,8]naphthyridin-4-one as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1[N:26]=[CH:27][N:28]([CH2:30][CH2:31][CH2:32][OH:33])[CH:29]=1.CC([O-])(C)C.[K+]>COCCOC.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:33][CH2:32][CH2:31][CH2:30][N:28]4[CH:27]=[N:26][N:25]=[CH:29]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: OCCCn1cnnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCn4cnnc4)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidin-1-carboxylic acid tert-butyl ester (31.6 mg, 95.5 μmol), as prepared in Example 12b, 3-[1,2,4]-triazol-4-yl-propan-1-ol (ChemPacific) (12.0 mg, 94.5 μmol), and KOtBu (11.7 mg, 104 μmol) in DME (100 μL) and DMSO (50 μL) was stirred at rt for 1 hr. The resulting homogeneous amber solution was partitioned with DCM (2 mL) and 0.5M sodium phosphate/pH 7 (2 mL). The organic layer was concentrated to provide the crude title compound. LC/MS (ESI): calcd mass 438.2, found 439.1 (MH)+.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Reactant: OCc1ccc(B(O)O)cc1
Product: CSc1ccc(C2=C(c3ccc(CO)cc3)CCC2)cc1
Yield: 92.5 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 250 mg (0.93 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio) benzene (Example 1, Step 2) was reacted with 290 mg (1.9 mmol) of 4-hydroxymethylphenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (1:4) gave 255 mg (92%) of 1-[2-(4-hydroxymethylphenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a solid: mp 82°-85° C.; NMR (CDCl3) δ2.04 (m, J=7 Hz, 2H), 2.45 (s, 3H), 2.88 (t, J=7 Hz, 4H), 4.64 (s, 2H), 7.08 (s, 4H), (m, 2H), 7.15-7.25 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[CH2:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:24][C:25]#[CH:26]>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]([C:26]#[C:25][CH2:24][CH2:23][CH2:22][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Reactant: C#CCCCc1ccccc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cn1nc(C#CCCCc2ccccc2)cc1C(F)(F)F

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (86 mg, 60%); 1H NMR δ (CDCl3): 7.31-7.25 (m, 2H), 7.22-7.16 (m, 3H), 6.64 (s, 1H), 3.98 (s, 3H), 2.78 (t, J=7.44 Hz, 2H), 2.42 (t, J=7.04 Hz, 2H), 1.95 (p, J=7.33 Hz, 2H); LCMS m/z: 292.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C@@H:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[O:9][C:8]([CH3:14])([CH3:13])[C@H:7]2[OH:15])=[CH:19][CH:18]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Sc1ccc(Cl)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Sc2ccc(Cl)cc2)[C@@H]1O

Procedure:
A mixture of 2 g of 6-cyano-2,2-dimethyl-3,4-epoxychroman and 1.8 g of parachlorothiophenol in 15 ml of dioxane and 0.3 ml of a 35% methanolic solution of benzyltrimethylammonium hydroxide is refluxed for 5 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[N:9]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:8]=1)=[O:6]
Reactant: BrCc1cccnc1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OCO4)cc1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccnc3)c3cc4c(cc3c2=O)OCO4)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 71 mg (0.22 mmol) of 7-(3,4-dimethyl-benzoyl)-5H-[1,3]dioxolo[4,5-g]quinolin-8-one, 23 mg of 60% sodium hydride, 72 mg of 3-bromomethylpyridine hydrobromide and 1.3 mL of N,N-dimethylformamide. Yield: 45 mg of a white solid: LC-MSD, m/z for C25H20N2O4 [M+H]+=413.5; HPLC retention time: 1.5 min.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH3:24])[C:21](O)=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:21](=[O:22])[C@@H:20]([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH3:24])[C:3]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(Br)ccn1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 60.5 %

Procedure:
The title compound was prepared following the experimental procedure described in preparation 20a from 6.1 g (18.38 mmol) of methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate and 3.5 g (28.50 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich). The crude product was purified by flash chromatography in hexane/ethyl acetate (0 to 25%) to afford 4.34 g (61% yield) of the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:10]1([C:16]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:24]3[C@H:20]([CH2:21][NH:22][CH2:23]3)[C:19](=[O:25])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([N:22]1[CH2:21][C@H:20]2[C@H:24]([C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][CH2:18][C:19]2=[O:25])[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
7.9 cm3 of benzyl bromide are added to a solution, cooled to 0° C., of 21.7 g of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride in 300 cm3 of dichloromethane and 18.5 cm3 of triethylamine. After stirring for 1 hour at 0° C. and 2 hours at 20° C., the reaction mixture is washed with 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.06 mm, diameter 5 cm, height 40 cm), eluting under a nitrogen pressure of 0.6 bar with an ethyl acetate and cyclohexane mixture (75/25 by volume) and collecting fractions of 250 cm3. Fractions 3 to 6 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 22.1 g of (3aR, 7aR)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone are obtained in the form of a white solid; melting point 124° C. [α]20 =-279° C.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:3][O:4][C:5]([NH:7][C@@H:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:11])=O)=[O:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:54][N:55]([CH3:81])[C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][C:65]([C@@:68]3([O:77][CH3:78])[CH2:72][NH:71][C@H:70]([C:73]([O:75][CH3:76])=[O:74])[CH2:69]3)=[CH:64][CH:63]=2)=[C:58]([CH:79]=[CH2:80])[CH:57]=1>C(Cl)Cl>[CH3:81][N:55]([CH3:54])[C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:63]=[CH:64][C:65]([C@@:68]3([O:77][CH3:78])[CH2:72][N:71]([C:9](=[O:11])[C@@H:8]([NH:7][C:5]([O:4][CH2:3][C:2]([CH3:1])([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[O:6])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:70]([C:73]([O:75][CH3:76])=[O:74])[CH2:69]3)=[CH:66][CH:67]=2)=[C:58]([CH:79]=[CH2:80])[CH:57]=1
Reactant: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1cc(N(C)C)ccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccc(N(C)C)cc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
(S)-2-((2,2-dimethylhex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (62 mg, 0.217 mmol), DIEA (0.076 mL, 0.434 mmol) and HATU (61 mg, 0.159 mmol) were added to a solution of (2S,4R)-methyl 4-(4′-(dimethylamino)-2′-vinylbiphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (55 mg, 0.145 mmol) in DCM (3 mL). The reaction was stirred at r.t. for 2 hrs. The reaction was evaporated and purified on the Biotage (10-45% EtOAc:Hex) to give (2S,4R)-methyl 4-(4′-(dimethylamino)-2′-vinylbiphenyl-4-yl)-1-((S)-2-((2,2-dimethylhex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxypyrrolidine-2-carboxylate (61 mg, 0.094 mmol, 65% yield) as a yellow oil. LCMS: rt=2.00 min. [M-OMe]+=616 and [M+H]+=648; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.