Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][C:6]([C:15]2[CH:16]=[CH:17][C:12]([OH:18])=[CH:13][CH:14]=2)([C:15]2[CH:16]=[CH:17][C:12]([OH:18])=[CH:13][CH:14]=2)[CH2:5][CH2:4]1
Reactant: Oc1ccccc1
Reactant: O=C1CCC(C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Oc1ccc(C2(c3ccc(O)cc3)CCC(C(F)(F)F)CC2)cc1

Procedure:
A solution of 4-(trifluoromethyl)cyclohexanone (1.13 g, 6.8 mmol) and phenol (2.01 g, 21.4 mmol) in 3 mL of concentrated HCl (aq) was stirred at 40° C. for 18 h. The reaction mixture was diluted with EtOAc and saturated aqueous NaHCO3 was slowly added. The organic layer was collected and the aqueous layer was extracted twice with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0% to 40% EtOAc/hexanes over 10 column volumes, then 40% to 100% EtOAc/hexanes over 5 column volumes, affording the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([OH:31])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4].Cl[CH2:33][C:34]1[N:35]=[C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:37][CH:38]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([O:31][CH2:33][C:34]2[N:35]=[C:36]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[S:37][CH:38]=2)[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4]
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCC)c2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (262 mg) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3-ethoxy-5-(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (601 mg, yield: 85%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([CH3:27])[N:21]=[CH:22]2.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15])[CH2:8][NH:9][C:10]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([CH3:27])[N:21]=[CH:22]2)=[O:11]
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(C(F)(F)F)c(F)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2cn1
Temperature: 25 °C

Procedure:
The product from Example 192A (4.4 mmol) in toluene (10 mL) was treated with 5-amino-3-methylisoquinoline (460 mg, 2.9 mmol) and DIEA (3 mL). The mixture was heated at 80° for 1.5 hours, cooled to room temperature, and filtered. The precipitate thus obtained was purified by silica gel chromatography (97:3 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.77 (s, 1H), 8.17 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.70-7.81 (m, 3H), 7.38-7.53 (m, 3H), 7.19 (t, 1H, 6.1 Hz), 4.47 (d, 2H, J=5.8 Hz), 2.65 (s, 3H); MS (ESI+) m/z 378 (M+H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[N+:22]([O-])=O)[C:13]3=[O:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.O1CCCC1>>[NH2:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[CH:21][N:12]([CH2:11][C:9]1[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=1)[C:13]2=[O:25]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccc2c(c1)OCCO2
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc2c(=O)n(Cc3ccc4c(c3)OCCO4)ccc12

Procedure:
2-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-5-nitro-2H-isoquinolin-1-one (0.9 g, 0.002 mol), tin dichloride dihydrate (2 g, 0.009 mol) were stirred in tetrahydrofuran (10 mL, 0.1 mol) at room temperature for 20 hours. The volatiles were removed and the residue was purified via flash column chromatography (40 g of silica gel, 50% EtOAc/Hexanes) gave a red oil. MS m/z (M+H) 309.2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:17]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.N>O1CCCC1>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(N)c(C(N)=O)cc1OC
Temperature: 7.5 °C
Yield: 60.3 %

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed 2-amino-4,5-dimethoxybenzoic acid (20 g, 101.43 mmol, 1.00 equiv), tetrahydrofuran (400 mL), EDC.HCl (39 g, 203.44 mmol, 2.01 equiv) and HOBt (27.5 g, 203.52 mmol, 2.01 equiv). This was followed by the addition of 4-methylmorpholine (20.6 g, 203.96 mmol, 2.01 equiv) dropwise with stirring at 5-10° C. To this was added ammonia (30 mL) dropwise with stirring at 5-10° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 300 mL of ethyl acetate. The resulting mixture was washed with 1×300 mL of brine. The aqueous layer was extracted with 5×100 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 12 g (crude, 61.2% yield) of 2-amino-4,5-dimethoxybenzamide as a yellow solid. MS (ESI) m/z 197 [M+H]+
Reaction SMILES: [CH:1]1[C:10]2[N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[C:7]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[O:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:42])([F:41])[S+]1C2C=CC=CC=2C2C=CC=CC1=2.O>CN(C=O)C>[F:26][C:27]([F:42])([F:41])[C:11]1[N:9]2[C:10]3[CH:1]=[CH:2][CH:3]=[N:4][C:5]=3[O:6][C:7]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:8]2=[CH:13][CH:12]=1
Reactant: FC(F)(F)[s+]1c2ccccc2c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1cccc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1c(C(F)(F)F)ccc12
Yield: 51.6 %

Procedure:
A solution of tert-butyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (134 mg, 0.393 mmol) and 5-(trifluoromethyl)dibenzothiophen-5-ium (99.4 mg, 0.393 mmol) in DMF (2 mL) was stirred at 80° C. for 1.5 hours. The mixture was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with water and brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (1-30% EtOAc/hexanes) to give tert-butyl 9′-(trifluoromethyl)spiro-[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (83 mg, 56%). ESI-MS m/z calc. 409.2. found 410.5 (M+1)+; Retention time: 1.92 minutes (3 min run).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][S:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:21][CH:22]=[C:23]([CH2:31][CH2:32][CH2:33]OS(C3C=CC(C)=CC=3)(=O)=O)[C:24]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1.O>C(#N)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[NH:21][CH:22]=[C:23]([CH2:31][CH2:32][CH2:33][SH:10]3[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]3)[C:24]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc(-c2[nH]cc(CCC[SH]3CCNCC3)c2-c2ccncc2)cc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
163 mg (1.18 mmol) of potassium carbonate and 122 μl (1.29 mmol) of thiomorpholine were added to a solution of 450 mg (1.07 mmol) of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-4-[3-(p-toluenesulfonyloxy)propyl]-1H-pyrrole [prepared as described in step 23(iv) above] in 50 ml of acetonitrile. The resulting mixture was heated under reflux overnight. After cooling the reaction mixture to room temperature, water was added and then this was extracted with ethyl acetate. The organic extract was washed with water and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 95:5 by volume mixture of ethyl acetate and methanol as the eluant to give 340 mg (yield 83%) of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:23]=1.[N:24]#CBr>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][N:19]([C:22]#[N:24])[CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:23]=1
Reactant: N#CBr
Reactant: CN1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Solvent: c1ccccc1
Product: N#CN1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Dissolve 16.2 grams (0.05 mole) of 8-chloro-6,11-dihydro-11-(1-methyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (prepared by the methods described in U.S. Pat. No. 3,326,924) in 300 mL of dry benzene. To this solution, add slowly under nitrogen a solution of cyanogen bromide (6.4 g) dissolved in 75 mL of benzene. Allow this mixture to stir at room temperature overnight (approximately 20 hours).
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](Cl)(=[O:29])[CH:27]=[CH2:28].Cl>C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:29])[CH:27]=[CH2:28]
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a 500-ml four-necked flask equipped with a thermometer, stirring apparatus, condenser and dropping funnel were added 82.0 g (0.241 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 200 g of toluene and 23.9 g (0.290 mole) of triethylamine. After replacing the air in the container with nitrogen, 25 g (0.276 mole) of acryloyl chloride was added dropwise with stirring. After completion of the dropwise addition, stirring was continued for 1 hour, excess triethylamine was neutralized with a dilute hydrochloric acid and the formed triethylamine hydrochloride was then removed by washing with water. Toluene was then removed by evaporation from the toluene layer after completion of the washing, and the residue obtained was recrystallized from 20 g of n-hexane to obtain 90.0 g of 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate as a white crystal. Melting point, 132°-134° C. Yield, 95%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]([NH2:33])[C@@H:25]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:33][C@@H:26]5[C:27]6[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:24][C@H:25]5[OH:34])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 150 °C
Yield: 16.1 %

Procedure:
A stirred mixture of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (120 mg, 0.346 mmol) from Step 4 of Example 70, (1R,2R)-(−)-trans-1-amino-2-indanol (103 mg, 0.692 mmol), and DIEA (89 mg, 0.692 mmol) in anhydrous DMA (2.5 mL) was heated in a Biotage microwave synthesizer at 150° C. for 30 min. LCMS analysis indicated that the reaction was incomplete. Additional (1R,2R)-(−)-trans-1-amino-2-indanol (103 mg, 0.692 mmol) and DIEA (89 mg, 0.692 mmol) were added and the mixture was further heated in a Biotage microwave synthesizer at 150° C. for 2 h. After the reaction mixture was cooled to rt, it was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-1-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (24 mg, 16%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.40-8.50 (m, 2H), 8.09 (dd, J=2.6, 9.4 Hz, 1H), 7.73 (d, J=1.1 Hz, 1H), 7.32-7.39 (m, 1H), 7.10-7.31 (m, 5H), 5.47-6.00 (m, 3H), 5.18 (t, J=7.1 Hz, 1H), 4.30 (d, J=3.6 Hz, 1H), 3.16 (dd, J=7.0, 15.6 Hz, 1H), 2.74 (dd, J=7.1, 15.5 Hz, 1H). LCMS (ESI) m/z 432 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH3:14]>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH2:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: C1CCOC1
Product: Cc1ccc2nc(Cl)nc(N)c2c1

Procedure:
A mixture of 2,4-dichloro-6-methylquinazoline (500 mg, 2.348 mmol) and a solution of ammonia in tetrahydrofuran (20 mL, 3.0 M) was stirred in an ice-bath for 2 hours. The resulting mixture was concentrated in vauco to afford 454 mg of the crude product as a white solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](O[C@@H](C1C=C(Cl)C=CC=1C1C=CC=CC=1)C1CCN(C2C=CC(C(O)=O)=CC=2)CC1)(C(C)(C)C)(C)C.[CH2:75]([N:77]([CH2:80][C@H:81]1[N:86]([CH2:87][CH2:88][C@@H:89]([NH:98][C:99]2[CH:104]=[CH:103][C:102]([S:105]([NH2:108])(=[O:107])=[O:106])=[CH:101][C:100]=2[S:109]([C:112]([F:115])([F:114])[F:113])(=[O:111])=[O:110])[CH2:90][S:91][C:92]2[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=2)[CH2:85][CH2:84][O:83][CH2:82]1)[CH2:78][CH3:79])[CH3:76]>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:108][S:105]([C:102]3[CH:103]=[CH:104][C:99]([NH:98][C@H:89]([CH2:88][CH2:87][N:86]4[CH2:85][CH2:84][O:83][CH2:82][C@H:81]4[CH2:80][N:77]([CH2:78][CH3:79])[CH2:75][CH3:76])[CH2:90][S:91][C:92]4[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=4)=[C:100]([S:109]([C:112]([F:113])([F:115])[F:114])(=[O:111])=[O:110])[CH:101]=3)(=[O:106])=[O:107])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)C[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)(C)[Si](C)(C)O[C@@H](c1cc(Cl)ccc1-c1ccccc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CCN(CC)C[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 55 %

Procedure:
The title product (100 mg, yield: 55%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 89. (R)-4-(4-((tert-Butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid, (INTERMEDIATE 13, 84 mg, 0.16 mmol) and 4-((R)-4-((R)-3-((diethylamino)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 92, 100 mg, 0.16 mmol) were used as starting materials. The resulting product was purified by column chromatography (ISCO, eluting with 0→20% MeOH/DCM for 19 minutes), providing the title product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:21]1[CH:22]=[CH:23][C:24]2[N:29](O)N=[N:27][C:25]=2[CH:26]=1.N1C=CC=CC=1CN>ClCCl>[N:27]1[CH:23]=[CH:22][CH:21]=[CH:26][C:25]=1[CH2:24][NH:29][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: On1nnc2ccccc21
Agent: NCc1ccccn1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCc1ccccn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid (11.6 g, 50 mmol) in dichloromethane (100 mL) is added EDC (14.4 g, 75 mmol), HOBT (7.65 g, 50 mmol), and 2-pyridylmethylamine (6.48 g, 60 mmol). The resulting solution is stirred at 25° C. for 18 h, then diluted with dichloromethane (200 mL) and washed with 2 M hydrochloric acid and 2 M sodium hydroxide. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to provide (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid 2-pyridylmethylamide as a white solid (16 g, 100% yield).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:19][C:17]([CH2:16][CH2:15][NH:14][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3])=[O:18]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNS(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
It is obtained by reacting 4-chlorosulfonyl-benzoic acid (1 eq) with H-βAla-OMe×HCl in CH2Cl2 using diisopropylethylamine (2 eq) as base. After 30 minutes at room temperature the reaction mixture is extracted with water and the organic layer is dried over Na2SO4. Removal of the solvent gives the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.C(OCCO)C.[Cl:26][C:27]1[C:33]([O:34][CH3:35])=[CH:32][C:30]([NH2:31])=[C:29]([CH3:36])[CH:28]=1.Cl.N1C=CC=CC=1>>[Cl:26][C:27]1[C:33]([O:34][CH3:35])=[CH:32][C:30]([NH:31][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)=[C:29]([CH3:36])[CH:28]=1
Reactant: COc1cc(N)c(C)cc1Cl
Reactant: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3c2sc2ccc([N+](=O)[O-])cc23)c(C)cc1Cl
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of 286 mg (0.99 mmol) of 4-chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 10 mL of 2-ethoxyethanol containing 131 mg (1.42 mmol) of 4-chloro-5-methoxy-2-methylaniline (WO 8501939A1) and 131 mg of pyridine hydrochloride is heated at reflux temperature overnight. The reaction mixture is cooled slightly and an additional 100 mg (0.58 mmol) of 4-chloro-5-methoxy-2-methylaniline is added and the reaction mixture is heated at reflux temperature overnight. The mixture is cooled to room temperature and the solid is collected by filtration, then suspended in methanol. Aqueous ammonium hydroxide is added and the mixture is partitioned between ethyl acetate and water. The organic layer is washed with water, then dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant solid is collected by filtration, and washed with diethyl ether to give 110 mg (26%) of a tan solid, mp>305° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=S)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:21](CC)CC)C>CN(C=O)C.C(OCC)(=O)C.Cl[Hg]Cl>[C:6]([NH:8][C:9](=[NH:21])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 129.9 %

Procedure:
To a solution of amine 228 (126 mg, 0.42 mmol), N,N'-bis-tert-butoxycarbonylthiourea (127 mg, 0.46 mmol), and triethylamine (123 μL, 0.88 mmol) in DMF (4 mL) at 0° C. was added HgCl2 (125 mg, 0.46 mmol). The mixture was stirred at 0° C. for 30 min and at room temperature for 1.5 h. The reaction was diluted with ethyl acetate and filtered through celite. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated NaCl, dried (MgSO4), filtered and the solvent was evaporated. The crude product was purified on silica gel (2/1, 1/1-hexane/ethyl acetate) to afford bis-Boc-guanidine 251 (155 mg, 69%) as a solid: 1H NMR (CDCl3) δ11.40 (s, 1H), 8.66 (d, 1H, J=7.9), 6.8 (s, 1H), 6.22 (d, 1H, J=8.9), 4.43-4.34 (m, 1H), 4.19-4.08 (m, 1H), 4.03 (m, 1H), 3.76 (s, 3H), 3.35 (m, 1H), 2.79 (dd, 1H, J=5.4, 17.7), 2.47-2.36 (m, 1H), 1.92 (s, 3H), 1.50, 1.49 (2 s, 18H), 0.89 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[OH-].[OH-].[Na+].Cl.[N+:18]([CH3:21])([O-:20])=[O:19]>O.CO>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:21][N+:18]([O-:20])=[O:19]
Reactant: C[N+](=O)[O-]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(C=C[N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Compound 2 was prepared according to the procedure of A. Kalir et al. [Isr. J. Chem. 5: 129-136 (1967)]. To a 100-mL round bottom flask, 6.674 g of powdered 3-methoxy-2-nitrobenzaldehyde (98%, Aldrich) (36.87 mmol), 2.1 mL of nitromethane (39 mmol), and 15.5 mL of methanol were added. This suspension was cooled to approximately 5° C., and 5.6 mL of 9.5N aqueous hydroxide (53 mmol) was added. An additional 1 mL of nitromethane, 9.5N aqueous sodium hydroxide, and methanol was added. The reaction mixture was stirred for 1 hr at approximately 5° C. Over the course of the hour an additional 5 mL of methanol was added. After 1 hr the precipitate was dissolved in 25 mL of water. This solution was added to 20 mL of 10% aqueous hydrochloric acid. The resulting precipitate was extracted with three 100-mL portions, one 50-mL portion, and finally one 25-mL portion of diethyl ether. The ether extracts were combined, dried with MgSO4, and filtered. The ether was removed by rotary evaporation and the residue was refluxed for 5 min in 31 mL of acetic anhydride and 3.566 g of anhydrous sodium acetate. The solution was allowed to cool and then was diluted with water. The precipitate was collected. Recrystallization from hot methanol with a recovery of a second crop of crystals from the mother liquor yielded 5.891 g (71%) of 2 as yellow crystals: 1H NMR (CDCl3) δ 3.94 (s, 3H, OCH3), 7.19 (d, 2H, J=8.3 Hz), 7.50 (m, 2H), 7.85 (d, 1H, J=13.7 Hz).