Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]([CH3:15])[C:12]([OH:14])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[S:22]1[CH:26]=[N:25][N:24]=[C:23]1[NH2:27]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]([CH3:15])[C:12]([NH:27][C:23]3[S:22][CH:26]=[N:25][N:24]=3)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C(=O)O)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reactant: Nc1nncs1
Product: CC(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc2[nH]ncc2c1
Yield: 42 %

Procedure:
Example 151 was prepared from 3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid (40 mg, 0.26 mmol) and 1,3,4-thiadiazol-2-amine using General Coupling Method A to give 6 mg (42% yield). MS found: (M+H)+=364. 400 MHz 1H-NMR (CDCl3) δ 8.77 (s, 1H); 7.90 (s, 1H); 7.75 (s, 1H); 7.75 (s, 1H); 7.47 (m, 4H); 7.36 (app t, 2H); 7.25 (dd, 2H); 4.35 (d, 1H); 3.87 (m, 1H); 1.31 (d, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].[S:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[S:26].CCCCCC>C(O)(=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:30]3[S:24][C:25](=[S:26])[NH:27][C:28]3=[O:29])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(OCCCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCCCc2ccccc2)cc1
Temperature: 100 °C

Procedure:
Under nitrogen purge in a three-neck round bottom flask 4-(3-phenylpropoxy)benzaldehyde (0.79 g, 3.29 mmol) was dissolved in acetic acid (16 ml). To this solution was added sodium acetate (0.94 g, 11.5 mmol) and rhodanine (0.44 g, 3.30 mmol). The reaction mixture was then heated to 100° C. and maintained at this temperature for about three days. The progress of the reaction was monitored by thin layer chromatography (4:1 hexane:ethyl acetate).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][F:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([C:3]1[C:11]([N:12]([CH2:13][CH2:14][CH2:15][F:16])[CH3:17])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccccc2c1NCCCF
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1nn2ccccc2c1N(C)CCCF
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.4 %

Procedure:
A solution of 2-ethyl-N-(3-fluoropropyl)pyrazolo[1,5-a]pyridin-3-amine (0.301 g, 1.36 mmol) in DMF (4 mL) was treated with K2CO3 (0.200 g, 1.45 mmol) and methyl iodide (0.06 mL, 0.96 mmol). The reaction was stirred at room temperature for 22 hours then concentrated in vacuo. The residue was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 and the combined organics was dried over MgSO4, concentrated in vacuo to give 0.190 g (84%) of a brown oil as the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=6.9 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.08–7.05 (m, 1H), 6.73–6.70 (m, 1H), 4.56 (dt, J=47.5, 5.9 Hz, 2H), 3.09 (t, J=7.0 Hz, 2H), 2.78 (s, 3H), 2.71 (q, J=7.6 Hz, 2H), 1.77–1.64 (m, 2H), 1.24 (t, J=7.6, Hz 3H); 13C NMR (100 MHz, DMSO-d6) δ 152.3, 135.2, 128.7, 122.1, 120.9, 116.4, 110.6, 82.6 (d, J=161.4 Hz), 52.4 (d, J=5.2 Hz), 43.6, 29.0 (d, J=19.3 Hz), 19.0, 13.5; 19F NMR (376 MHz, DMSO-d6) −219.0 (m); HRMS (FAB) calcd for C13H18FN3+H 236.1563. found 236.1573.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:9]
Reactant: COc1ccccn1
Reactant: OO
Solvent: CC(=O)O
Product: COc1cccc[n+]1[O-]
Temperature: 80 °C

Procedure:
This compound, originally prepared by H. J. Den Hertog and M. Van Ammers, Rec. Trav. Chim. 1955, 74, 1160, was synthesized using a different procedure. To a solution of 21.83 of 2-methoxypyridine (0.2 mol) in glacial acetic acid (80 ml), was cautiously added 30% hydrogen peroxide (20 ml). The stirred mixture was heated to 80° C. for 3 hrs, and cooled to room temperature. An additional 20 ml of 30% H2O2 was added, and the clear solution was heated at 80° C. for 12 hrs. The solution was concentrated to half the original volume under vacuum, and 100 ml of water was added. The solution was reconcentrated, and the process was repeated two times (2×100 ml H2O). The syrup was placed under vacuum to remove remaining water and acetic acid. After time, a white solid formed. The material obtained in quantitative yield was used without further purification; M.P. 128°-130° C.; IR (KBr) 3447, 1613, 1570, 1508 1447, 1316, 1214, 1015, 764 cm-1 ; 1H NMR (CDCl3) δ 4.05 (s, 3H), 6.91 (d, 1H, J=8.0 Hz), 6.92 (m, 1H), 7.33 (dt, 2H, J=8.0, 1.6 Hz), 8.3 (dd, 1H, J=6.3, 1.6 Hz). HRMS Calcd. for C6H7NO2 : 125.0477. Found: 125.0474.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:27][S:28]SC.CCCCCC>C1COCC1>[CH3:27][S:28][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CSSC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(SC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.8 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (2.0 g, 7.75 mmol) in THF (100.0 mL) was cooled to −78° C. followed by drop wise addition of LDA (1.80 M in THF, 8.80 mL, 15.56 mmol) and the mixture stirred at the same temperature for 45 min followed by addition of dimethyl disulfide (2.21 mL, 23.25 mmol) at −78° C. The temperature of the reaction was slowly raised up to rt and left to stir for 6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 5% EtOAc:hexane to obtain the product as an orange viscous liquid (1.90 g, 83% yield). MS: 304.19 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][C:15]([NH2:17])=[O:16]>S(Cl)(Cl)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:14][C:15]([NH2:17])=[O:16])=[O:13]
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc2ccccc2c1
Solvent: O=S(Cl)Cl
Product: NC(=O)NC(=O)c1ccc2ccccc2c1
Yield: 69.5 %

Procedure:
The above compound was prepared, following the procedure of Example 14a from 2-napthoic acid (8.2 g, 47.7 mmol), thionyl chloride (40 ml) and urea (10 g, 167 mmol) to give the title compound (7.1 g), mp 207°-208° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][OH:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:9][CH2:8][CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cn1cccc1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2cccn2C)cc1
Reaction time: 6 h
Yield: 76.8 %

Procedure:
To a stirred and cooled (±5° C.) mixture of 20.7 parts of 1-methyl-1H-pyrrole-2-ethanol and 200 parts of dry pyridine are added portionwise 35.9 parts of 4-methylbenzenesulfonyl chloride. Upon completion, stirring is continued for 6 hours at about 5° C. The reaction mixture is allowed to stand overnight at 0° C. and poured onto water. The product is extracted with benzene. The extract is washed successively with a 20% hydrochloric acid solution, water, a 10% sodium carbonate solution and with water, dried, filtered and evaporated, yielding 33.4 parts (76.8%) of 2-(1-methyl-1H-pyrrol-2-yl)ethyl 4-methylbenzenesulfonate as an oily residue.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1ccc(CO)cn1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: COCCOc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1
Yield: 63.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 142 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.2 g) and 3-hydroxymethyl-6-(2-methoxyethoxy)pyridine (0.55 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.07 g) was obtained.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C@H:32]([C:39]([NH:41][C@H:42]([CH:47]=[N:48][NH:49][C:50]([NH2:52])=[O:51])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1.CN1CCOCC1>CN(C)C=O.ClCCl>[CH2:12]([CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:31][C@H:32]([C:39]([NH:41][C@H:42]([CH:47]=[N:48][NH:49][C:50]([NH2:52])=[O:51])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
A mixture of 240 mg of 2-benzyl-3-phenylpropionic acid and 170 mg of 1,1'-carbonyldiimidazole was added to 10 ml of dry dichloromethane, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was added to a solution of 650 mg of L-histidyl-L-leucinal semicarbazone.2p-toluenesulfonic acid salt and 200 mg of N-methylmorpholine in 10 ml of dry N,N-dimethylformamide, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: dichloromethane/methanol=10/1 by volume) to obtain 162 mg of N-(2-benzyl-3-phenylpropionyl)-L-histidyl-L-leucinal semicarbazone as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]1[N:22]=[C:21]([CH2:23][OH:24])[S:20][N:19]=1.ClCCl.C(OCC)C.[CH3:33][N:34](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:12]1([CH2:11][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[C:33]#[N:34])[C:7]([C:18]3[N:22]=[C:21]([CH2:23][OH:24])[S:20][N:19]=3)=[CH:8]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OCc1nc(-c2cn(CC3CCCCC3)c3c(Br)cccc23)ns1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1cccc2c(-c3nsc(CO)n3)cn(CC3CCCCC3)c12

Procedure:
A suspension of [3-(7-bromo-1-cyclohexylmethyl-1H-indol-3-yl)-[1,2,4]thiadiazol-5-yl]-methanol (prepared from 7-bromoindole as described in Example 7; 2×250 mg, 0.16 mmol), zinc (II) cyanide (2×72 mg, 0.61 mmol) and tetrakis(triphenylphosphine)-palladium(0) (2×21 mg, 18.3 μmol) in DMF (2×4 ml) was subjected to microwave irradiation at 200° C. for 5 min using an Emrys™ Optimizer EXP. The reactions were combined and poured into a separating funnel, to this was added dichloromethane (˜50 ml). The organics were washed successively with water (2×20 ml), 1M aqueous HCl (20 ml) and brine (20 ml), dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The resulting oil was purified by flash column chromatography eluting with 50-100% (v/v) dichloromethane in heptane and then diethyl ether to give 1-cyclohexylmethyl-3-(5-hydroxymethyl-[1,2,4]thiadiazol-3-yl)-1H-indole-7-carbonitrile (416 mg, 1.18 mmol) as a light yellow oil which crystallised on standing.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1>>[F:10][C:7]1[CH:8]=[CH:9][C:2]([C:15]2([OH:18])[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[C:3]([CH2:4][OH:5])[CH:6]=1
Reactant: OCc1cc(F)ccc1Br
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(O)(c2ccc(F)cc2CO)CC1

Procedure:
Reaction of 2-bromo-5-fluorobenzyl alcohol and 1-methyl-4-piperidone by the method described in Example 16a provides 4-(5-fluoro-α-hydroxy-2-tolyl)-4-hydroxy-1-methylpiperidine.
Reaction SMILES: [CH2:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30]C)=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O>O.O1CCOCC1.C(O)C>[CH2:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:2]
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O=CO
Product: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCc1occc1-2
Yield: 21.5 %

Procedure:
A mixture of methyl 7-[2-((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl-amino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 46, 0.096 g) and lithium hydroxide monohydrate (0.168 g) in water (0.8 mL) and dioxane (3.2 mL), was sealed in a microwave vial and irradiated in the microwave at 135° C. for 45 minutes. After cooling, the mixture was diluted with ethanol, acidified with formic acid and evaporated to dryness. The residue was triturated with 10% methanol in DCM, filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with DMAW 350. The product was azeotroped with toluene and ethanol and the residue was triturated with ethyl acetate to give 7-[2-((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylic acid (0.020 g) as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[N:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10].C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O.[CH2:24](O)[CH3:25]>O>[NH2:10][C:9]1[CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:6]=[CH:5][C:24]=1[C:25]1[NH:3][C:4]2[CH:5]=[N:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=2[N:10]=1
Reactant: CCO
Reactant: CC(C)(C)c1cc(N)c(N)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: O
Product: CC(C)(C)c1cc(N)c(-c2nc3cc(C(C)(C)C)ncc3[nH]2)cn1
Reaction time: 0.5 h

Procedure:
Procedure analogous to 18) S47, using 71.4 g (300 mmol) of 3,4-diamino-6-tert-butylpyridine dihydrochloride (S50) instead of 90.5 g (500 mmol) of o-phenylenediamine dihydrochloride. After cooling, the deep-blue melt is dissolved in a mixture of 150 ml of ethanol and 300 ml of water at elevated temperature, and a solution of 25 g of sodium carbonate in 100 ml of water is then added dropwise with vigorous stirring (note: foaming, evolution of carbon dioxide). When the addition is complete, the mixture is stirred for a further 30 min., the brown solid is then filtered off with suction, washed three times with 100 ml of water each time and dried in vacuo. Yield: 40.5 g, 74% of a 1:1 mixture of the product and 2,6-di-tert-butyl-3H-imidazo[4,5-c]pyridine, which is reacted without further purification.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H-].[Na+].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>CN(C)C=O>[C:1]1([CH2:7][O:8][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COc1ccc(CCl)cc1
Reactant: OCC1=CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCC2=CCCCC2)cc1
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a mixture of cyclohexenylmethanol (2.50 g, 22.3 mmol) in N,N-dimethylformamide (40 mL) and sodium hydride (60% dispersion in mineral oil, 0.89 g, 22.3 mmol) was added in portions at 0° C. The reaction mixture was stirred for 0.5 hour, then added 1-(chloromethyl)-4-methoxybenzene (3.49 g, 22.3 mmol). The reaction mixture was stirred for another 0.5 hour and quenched with slow addition of water (50 mL). The organic layer was extracted with ethyl acetate (80 mL) and concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10%) to afford the title compound as a colorless liquid (3.50 g, 68%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[C:24]1[NH:28][C:27]2[CH:29]=[CH:30][C:31]([C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[CH:39]=[C:38]([C:43]3[CH:63]=[CH:62][C:46]5[NH:47][C:48]([C@@H:50]6[CH2:54][CH2:53][CH2:52][N:51]6C(OC(C)(C)C)=O)=[N:49][C:45]=5[CH:44]=3)[CH:37]=[CH:36]4)=[CH:32][C:26]=2[N:25]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11]>C(Cl)Cl>[CH3:15][CH:14]([CH3:16])[C@H:13]([NH:12][C:10](=[O:11])[O:9][CH3:8])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[C:24]1[NH:28][C:27]2[CH:29]=[CH:30][C:31]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[C:38]([C:43]5[CH:63]=[CH:62][C:46]6[NH:47][C:48]([C@@H:50]7[CH2:54][CH2:53][CH2:52][NH:51]7)=[N:49][C:45]=6[CH:44]=5)[CH:39]=4)[CH:34]=3)=[CH:32][C:26]=2[N:25]=1)=[O:18]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(-c3ccc4cc(-c5ccc6[nH]c([C@@H]7CCCN7C(=O)OC(C)(C)C)nc6c5)ccc4c3)ccc2[nH]1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(-c3ccc4cc(-c5ccc6[nH]c([C@@H]7CCCN7)nc6c5)ccc4c3)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of a TFA salt of tert-butyl (2S)-2-(5-(6-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate (445 mg) in DCM (10 mL) at room temp was added TFA (1 mL, 13 mmol). The mixture was stirred at rt for 3 h, concentrated, and the residue was diluted in MeOH, loaded onto a Strata XC MCX cartridge and washed with methanol. The compound was release from the cartridge by eluting with a solution of 2M ammonia in methanol and then evaporated under reduced pressure to give methyl ((1S)-2-methyl-1-(((2S)-2-(5-(6-(2-((2S)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate (275 mg) as orange solid LC-MS retention time 1.120 min; m/z 656.27 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.26 (br s, 1H), 8.22 (br s, 1H), 8.08-8.16 (m, 3H), 8.04-8.08 (m, 1H), 8.03 (s, 1H), 7.86-7.96 (m, 3H), 7.73-7.82 (m, 2H), 5.88-5.93 (m, 0.1H), 5.37-5.44 (m, 0.9H), 5.07-5.15 (m, 1H), 4.28-4.33 (m, 1H), 4.12-4.19 (m, 0.8H), 4.06-4.10 (m, 0.2H), 3.94-4.02 (m, 1H), 3.59-3.75 (m, 4H), 3.50-3.59 (m, 1H), 2.63-2.74 (m, 2H), 2.41-2.47 (m, 1H), 2.23-2.40 (m, 5H), 2.06-2.16 (m, 1H), 1.00-1.04 (m, 0.4H), 0.94-1.00 (m, 3H), 0.88-0.93 (m, 2.6H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:21]=2[S:20](=[O:30])(=[O:29])[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:38]1[CH:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=1>CS(C)=O>[Br:44][C:41]1[CH:42]=[CH:43][C:38]([O:28][C:26]2[CH:25]=[CH:24][C:22]3[NH:23][C:18]([C:3]4[C:4](=[O:17])[N:5]([NH:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]5[C:11]([C:2]=4[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=5)=[N:19][S:20](=[O:29])(=[O:30])[C:21]=3[CH:27]=2)=[N:39][CH:40]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(Oc4ccc(Br)cn4)ccc3N2)c(O)c2ccccc21
Temperature: 110 °C
Yield: 64.6 %

Procedure:
A mixture of the product of Example 321C (40.0 mg, 0.09 mmol), cesium carbonate (112 mg, 0.34 mmol), and 2,5-dibromopyridine (40.0 mg, 0.17 mmol) in dimethylsulfoxide (1.2 mL) was stirred while heating at 110° C. in a microwave reactor for 20 minutes. After cooling to 25° C., the purple mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with an additional portion of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a step gradient (0-100%) of dichloromethane in hexanes to give the title compound as an off-white solid (34.0 mg, 63%). MS (ESI−) m/z 582 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.05 (d, J=6.62 Hz, 6 H) 1.93 (m, 1 H) 2.73 (m, 2 H) 6.35 (m, 1 H) 7.19 (d, J=8.82 Hz, 1 H) 7.45 (m, 1 H) 7.61 (dd, J=8.82, 2.57 Hz, 1 H) 7.77 (m, 2 H) 7.94 (m, 2 H) 8.13 (dd, J=8.82, 2.57 Hz, 1 H) 8.19 (m, 1 H) 8.31 (d, J=2.21 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6](Br)[CH:5]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])O1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CN=N1>C(OCC)(=O)C.O.C(O)CC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])[CH:5]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: COC(=O)c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1c[nH]nn1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(F)c(-c2ccccc2O)c1

Procedure:
To a solution of 2 g (8.45 mmol) of methyl-3-bromo-4-fluorobenzoate in 28 Ml of toluene at RT was added 0.49 g (0.42 mmol) of tetrakis(triphenyl phosphine)palladium(0), 1.95 g (8.9 mmol) of 2-(4,4,5,5,-tetramethyl-1.3.2-dioxaborolan-2-yl)phenol, 5.1 Ml (10.15 mmol) of 2M aqueous sodium carbonate solution and 14 Ml of n-propanol. The reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled and diluted with ethyl acetate and water. The organic fraction was separated and washed with saturated NaCl solution (brine), dried over MgSO4, filtered and the filtrate was concentrated to an oil which was purified by chromatography (silica, 90:1, 30:1 successively CH2Cl2:acetone) to give the title compound. Mass Spectrum (ESI) m/e (M+1): 247.0.