Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]\[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1.[N+](C1C=C(C(C2C=CC=C([N+]([O-])=O)C=2)=C/C=C/C(NCCCCC2C=NC=CC=2)=O)C=CC=1)([O-])=O>O1CCCC1>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:14]/[CH:13]=[CH:12]\[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: NCCCCc1cccnc1
Reactant: COc1cccc(C(=C/C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Agent: O=C(/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1)NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C\C(=O)NCCCCc2cccnc2)c2cccc(OC)c2)c1
Yield: 39 %

Procedure:
As in Example 134, a solution of (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.2 g) and 3-pyridinebutanamine (0.42 g) in tetrahydrofuran (7 mL) was stirred at room temperature for 1 hour. The crude amide that had been isolated in the usual way, was contaminated with a minor amount of the (E)-isomer. The mixture was separated by HPLC (ethyl acetate) and the desired product was crystallized from ether (2x) to yield 0.48 g of (Z)-5,5-bis(3-methoxyphenyl)- N-[4-(3-pyridinyl)-butyl]-2,4-pentadienamide mp 69°-73° C. Anal. Calculated for C28H30N2O3 : C, 75.99; H, 6.83; N, 6.33 Found: C, 75.79; H, 6.70; N, 6.39.
Reaction SMILES: Cl[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)=[O:3].[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:3])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(CNCc2ccccc2)cc1
Reactant: O=C([O-])c1ccc(C(=O)Cl)cc1
Product: COc1ccc(CN(Cc2ccccc2)C(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-27 from 4-(chlorocarbonyl)benzoate and N-benzyl-1-(4-methoxyphenyl)methanamine. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.72(d, J=7.6 Hz, 3H), 4.26(s, 1H), 4.30(s, 1H), 4.50(s, 1H), 4.55(s, 1H), 6.89(m, 2H), 7.02(m, 1H), 7.10(m, 1H), 7.10(m, 1H), 7.20(m, 1H), 7.28(m, 4H), 7.55(m, 2H), 7.96(m, 2H), 13.13(s, 1H).
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][C:17]=2[NH:29][C:30]([C:32]2[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=2)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:31])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[CH2:26]([N:22]([CH2:23][CH2:24][CH3:25])[C:20]1[CH:19]=[CH:18][C:17]([NH:29][C:30]([C:32]2[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=2)[CH2:35][S:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:31])=[C:16]([C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:49]=[CH:50][CH:51]=[C:3]([C:2]([F:53])([F:1])[F:52])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)[CH:21]=1)[CH2:27][CH3:28]
Reactant: CCCN(CCC)c1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)c1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)-benzyl)carbamoyl)pyridin-2-yl)-4-(dipropylamino)phenyl)carbamoyl)benzylthio)-propanoate (320 mg, 0.43 mmol, 1.00 equiv) in dichloromethane (10 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 108 mg (30%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 9.52 (t, J=6 Hz, 1H), 8.96 (d, J=5.1 Hz, 1H), 8.27 (s, 2H), 7.85 (s, 2H), 7.74 (m, 2H), 7.53 (m, 5H), 7.02 (s, 2H), 4.61 (d, J=5.7 Hz, 2H), 3.87 (s, 2H), 3.39 (s, 4H), 2.61 (m, 2H), 2.50 (m, 2H), 1.53 (t, J=9.3 Hz, 4H), 0.89 (t, J=7.2 Hz, 6H). MS (ES, m/z): 693 [M+H]+.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][C:9]=1[CH3:10].[C:14]1([S:20]([CH:23]=[C:24]2[CH2:27][O:26][CH2:25]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[CH3:10][C:9]1[CH:8]=[CH:7][C:6]([C:24]2([CH2:23][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH2:27][O:26][CH2:25]2)=[CH:5][C:4]=1[OH:3]
Reactant: Cc1ccc(B(O)O)cc1O
Reactant: O=S(=O)(C=C1COC1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(C2(CS(=O)(=O)c3ccccc3)COC2)cc1O
Reaction time: 0.02 h

Procedure:
A solution of KOH (1.5 M in water, 14.2 mL, 21.3 mmol) was added to a solution of [Rh(cod)C1]2 (0.525 g, 1.07 mmol) in dioxane (60 mL). The resulting yellow solution was stirred for 1 min. Then, 3-hydroxy-4-methylphenyl boronic acid (6.48 g, 42.6 mmol) and a solution of 3-((phenylsulfonyl)methylene)oxetane (4.48 g, 21.3 mmol) in dioxane (40 mL) were added in that order. After 1 h, a solution of KOH (1.5 M in water, 14.2 mL, 21.3 mmol) was added. After another 10 min, [Rh(cod)Cl]2 (0.525 g, 1.07 mmol) was added. The resulting mixture was stirred at room temperature overnight, and then partitioned between Et2O and aqueous NH4Cl. The aqueous layer was extracted with Et2O (3×). (During extractions, some solids crashed out in the organic layer, but went back into solution over time). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The dark orange residue was purified by silica gel chromatography (30-100% EtOAc/heptane) to provide 2-methyl-5-(3-((phenylsulfonyl)methyl)oxetan-3-yl)phenol. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.52-7.63 (m, 3 H) 7.41 (t, J=7.71 Hz, 2 H) 6.99 (d, J=7.83 Hz, 1 H) 6.57 (dd, J=7.83, 1.77 Hz, 1 H) 6.50 (d, J=2.02 Hz, 1 H) 4.99 (d, J=6.57 Hz, 2 H) 4.91 (d, J=6.57 Hz, 2 H) 4.03 (s, 2 H) 2.20 (s, 3 H)
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([S:13]([NH:16][C:17]2[CH:18]=[C:19]([C@@H:23]([OH:43])[CH2:24][NH:25][C:26]([CH3:42])([CH3:41])[CH2:27][CH2:28][N:29]3[C:37]4[C:32](=[CH:33][C:34]([C:38]([OH:40])=[O:39])=[CH:35][CH:36]=4)[CH:31]=[CH:30]3)[CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[CH:45]([N:48]([CH:52]([CH3:54])[CH3:53])[CH2:49][CH2:50]Cl)([CH3:47])[CH3:46]>CN(C=O)C.C(OCC)(=O)C>[C:7]1([S:13]([NH:16][C:17]2[CH:18]=[C:19]([C@@H:23]([OH:43])[CH2:24][NH:25][C:26]([CH3:41])([CH3:42])[CH2:27][CH2:28][N:29]3[C:37]4[C:32](=[CH:33][C:34]([C:38]([O:40][CH2:50][CH2:49][N:48]([CH:52]([CH3:54])[CH3:53])[CH:45]([CH3:47])[CH3:46])=[O:39])=[CH:35][CH:36]=4)[CH:31]=[CH:30]3)[CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(CCn1ccc2cc(C(=O)O)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: CC(C)N(CCCl)C(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N(CCOC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium tert. butoxide (58 mg, 0.58 mmol) is added to a solution of 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylic acid [free base (Zwitterion) of Example 6; 300 mg, 0.58 mmol] in 2 ml DMF. Then the reaction mixture is stirred for 10 minutes at RT and 2-diisopropylamino-ethyl chloride hydrochloride (115 mg, 0.58 mmol) is added. After 72 hours stirring at RT the reaction mixture is diluted with 30 ml of ethyl acetate and extracted four times with 15 ml ice water. The organic phase is dried on magnesium sulphate, acidified with about 0.5 ml TFA and the solvent is eliminated in vacuo. The crude product is chromatographed on Microsorb C18-reverse-phase [acetonitrile (0.1% TFA)/water (0.13% TFA)=10:90→100:0].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])N=[C:4]([N:9]2[C@@H:16]3[CH:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[C:19]=1[C:20](O)=[O:21].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[C:19]=1[C:20]([N:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([N:9]([C:4]3[CH:8]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:10]2)[CH2:15]1)=[O:21]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Cc1cc(C)nc(N2CC3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cccc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1 substituting Intermediate 40 for (1R,RS)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid for 2-thiophene-2-yl-benzoic acid. MS (ESI) mass calcd. for O21H21FN6O, 392.4; m/z found, 393.2 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C@@:8]2([C:23]([OH:25])=O)[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]1([C@@H:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C@@:8]2([C:23]([Cl:28])=[O:25])[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2CC3C[C@@]3(C(=O)O)[C@@H]2c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CC3C[C@@]3(C(=O)Cl)[C@@H]2c2ccccc2)cc1
Temperature: 0 °C
Yield: 99.8 %

Procedure:
To racemic Intermediate 43, one enantiomer being (1S,2S)-2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (10.0 g, 28.0 mmol) slurried in toluene (67 mL) was added DMF (3 drops). The mixture was cooled to 0° C. and thionyl chloride (5.72 mL, 78.4 mmol) was added dropwise with stirring. The homogeneous solution was heated to 73° C. for 2.5 hours. The solvent was removed at reduced pressure. The residue was brought up in toluene two times and the solvent was removed at reduced pressure each time to yield the title compounds (10.5 g, quantitative yield) as an oil.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15]OS(C)(=O)=O)=[O:11])[CH2:5][CH2:4]1)[CH3:2].C[C@H]1CC[C@H](NC([C@@H]2C[C@H]2COS(C)(=O)=O)=O)CC1.Cl.[F:41][C:42]([F:56])([F:55])[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:45][CH:44]=1.Cl.ClC1C=C(N2CCNCC2)C=CC=1>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][N:52]2[CH2:51][CH2:50][N:49]([C:46]3[CH:45]=[CH:44][C:43]([C:42]([F:55])([F:56])[F:41])=[CH:48][CH:47]=3)[CH2:54][CH2:53]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1
Agent: CS(=O)(=O)OC[C@@H]1C[C@H]1C(=O)N[C@H]1CC[C@H](C)CC1
Agent: Cl
Agent: Clc1cccc(N2CCNCC2)c1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3ccc(C(F)(F)F)cc3)CC2)CC1

Procedure:
Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for methane sulfonic acid 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(4-trifluoromethyl-phenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound MS m/z=438 (M+H)+, 78.5% pure by HPLC assay.
Reaction SMILES: O[N:2]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:3]1[CH:11]=[C:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([N:21]4[CH:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29](CC6C=CC=CC=6)[CH:30]=5)[N:23]=[CH:22]4)=[C:15]3[C:14]([CH:38]([CH3:40])[CH3:39])=[N:13]2)[CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].C1CCCCC=1.C([OH:55])C>[OH-].[Pd+2].[OH-]>[NH:29]1[CH:30]=[C:26]([C:24]2[N:23]=[CH:22][N:21]([C:20]3[CH:19]=[CH:18][N:17]=[C:16]4[N:12]([C:10]5[CH:9]=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[C:3]([NH:2][CH:41]6[CH2:46][CH2:45][CH:44]([OH:55])[CH2:43][CH2:42]6)[CH:11]=5)[N:13]=[C:14]([CH:38]([CH3:39])[CH3:40])[C:15]=34)[CH:25]=2)[CH:27]=[N:28]1
Reactant: CC(C)c1nn(-c2ccc(C(N)=O)c(N(O)C3CCCCC3)c2)c2nccc(-n3cnc(-c4cnn(Cc5ccccc5)c4)c3)c12
Reactant: CCO
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(NC3CCC(O)CC3)c2)c2nccc(-n3cnc(-c4cn[nH]c4)c3)c12
Temperature: 80 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
Compound (93) (0.010 g) was dissolved in ethanol (1.0 mL). Palladium hydroxide (0.020 g) and cyclohexene (0.5 mL) were added to the resulting solution, followed by stirring under a nitrogen atmosphere at 80° C. for 24 hr. The reaction solution was filtered through celite, and the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (95) (0.005 g, 56%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>C1COCC1>[C:20]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:23])[CH:21]=[CH2:22]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
2-methyl-2-adamantanol (33 g, 0.2 mol) and triethylamine (0.22 mol) were dissolved in 300 ml of THF and then acryloyl chloride (19 g, 0.21 mol) was added slowly thereto using a dropping funnel. Then, the reaction was stirred at room temperature for about 12 hours. After completion of the reaction, excess THF was removed using a rotary evaporator and then the resultant product was poured into water. Then, the resultant product was neutralized with dilute sulfuric acid and extracted using diethyl ether and was then dried over magnesium sulfate. The diethyl ether removed crude product was vacuum-distilled to yield the desired product (yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:21][CH:22]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COC(=O)c1coc(-c2ccc(N)cc2)n1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2)nc1Cl
Yield: 46.4 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.13 g, 0.75 mmol), thionyl chloride (5 mL), methyl 2-(4-aminophenyl)-1,3-oxazole-4-carboxylate obtained in Example (96b) (0.15 g, 0.69 mmol) and pyridine (5 mL), to obtain 0.12 g of the title compound as a light purple solid (47%).
Reaction SMILES: [NH:1]([C:8]1[CH:14]=[C:13]([CH2:15][CH3:16])[C:12]([Cl:17])=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][C:20](O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:2]1([N:1]2[C:8]3[CH:14]=[C:13]([CH2:15][CH3:16])[C:12]([Cl:17])=[CH:11][C:9]=3[N:10]=[C:20]2[CH2:19][Cl:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCl
Reactant: CCc1cc(Nc2ccccc2)c(N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc2c(cc1Cl)nc(CCl)n2-c1ccccc1
Temperature: 130 °C

Procedure:
A mixture of 2-anilino-4-ethyl-5-chloroaniline (3.3 g, 13.4 mmol) prepared in the preceding step (a), polyphosphoric ester (8.9 g) and monochloroacetic acid (1.3 g, 13.4 mmol) was heated for 1 hour at 130° C. under stirring. Water was added to the reaction mixture to decompose an excess of the ester and they were neutralized with sodium carbonate and the occurred oily substance was extracted with chloroform, which was washed, dried, and concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12.Cl.[CH3:18][NH2:19].[OH-].[Na+]>C(O)(C)C.O>[CH3:18][NH:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12
Reactant: CN
Reactant: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CNc1ccnc2cc(-c3cn(C)cn3)sc12
Temperature: 130 °C
Yield: 99.7 %

Procedure:
A stirred suspension of 10 (500 mg, 2 mmol) and methylamine hydrochloride (15 g, 222 mmol) in isopropanol (50 ml) was heated at 130° C. in a sealed flask for four days, then cooled to room temperature. The reaction mixture was poured in water, and the pH was adjusted to ˜10 with 1N NaOH. After extraction of the aqueous phase with AcOEt, the combined organic layer was concentrated and directly purified by flash column chromatography (eluents 2% of NH4OH in methanol/CH2Cl2: 10/90 to 40/60) to afford title compound 344 (487 mg, 99% yield, hydrate form) as a beige solid. MS (m/z): 245.0 (M+H)+..
Reaction SMILES: C([C:5]1[NH:6][C:7]2[C:8]([N:13]=1)=[N:9][CH:10]=[CH:11][CH:12]=2)CCC.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:6]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:13][CH:5]=1
Reactant: CCCCc1nc2ncccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cnc2[nH]cnc2c1

Procedure:
A solution of 6-[(1-oxopentyl)amino)]-2-butylimidazo[4,5-b]pyridine, K2CO3 (956 mg, 6.92 mmol), and 4'-bromomethylbiphenyl-2-tert-butylsulfonamide 1.65 g, 3.46 mmol) in DMF (15 mL) was stirred for 12 h at r.t. The reaction mixture was poured into H2O (50 mL), extracted with EtOAc (2×50 mL), concentrated, and purified (SiO2, 4:1 EtOAc/hexanes) to give 740 mg of 2-butyl-3-[2'-(N-tert-butyl-aminosulfonyl)[1,1']biphenyl-4-yl]methyl-6-[(1-oxopentyl)amino)]-3H-imidazo[4,5-b]pyridine as a foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1>>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)cc1

Procedure:
The title compound was prepared with Intermediate 5c and [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety) using an analogous procedure to that described in Example 1 step d. LCMS (Method 5): Rt 3.76 min, m/z 319 [MH+]. 1H NMR (400 MHz, CDCl3): 1.33 (9H, s), 1.88-2.12 (6H, m), 2.21 (3H, s), 2.21-2.30 (2H, m), 2.33-2.39 (1H, m), 2.37 (3H, s), 3.19-3.24 (1H, m), 3.98-4.02 (1H, m), 5.05-5.12 (1H, m), 5.17 (1H, t, J 4.0), 5.25 (1H, d, J 8.7), 6.25-6.27 (2H, m), 7.03 (1H, dd, J 2.0, 9.8), 7.22-7.34 (6H, m), 7.40 (2H, d, J 8.5), 7.61 (1H, d, J 9.8), 8.27 (1H, m).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:5])[CH2:3][CH3:4].C(N(CC)CC)C.[Cl:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19]>ClCCl>[C@H:2]([NH:5][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][Cl:13])[CH:16]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: CC[C@@H](C)N
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C)NC(=O)c1cccc(CCl)c1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of (R)-butan-2-amine (14.77 mmol, 1.478 mL, 1,081 g) and triethylamine (15.48 mmol, 2.157 mL, 1.566 g) in dichloromethane was added dropwise to a stirred solution of 3-(chloromethyl)benzoyl chloride (14.07 mmol, 2 mL, 2.66 g) in dichloromethane at room temperature. Upon complete addition the reaction was stirred for 2 hours, after which time the solvent was removed under vacuum and ethyl acetate (100 mL) added. The organic solution was then washed with water (200 mL), dried over sodium sulphate and concentrated under vacuum to give the title compound (2.47 g) as a cream solid. MS (ESI) m/z 226.3[M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:14]([CH3:23])[C:13](=[N:24][C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=3[CH3:33])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[F:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:46](=[O:47])[C:45]4[CH:49]=[CH:50][C:42]([F:41])=[CH:43][CH:44]=4)[CH2:21][CH2:22]3)[N:14]([CH3:23])[C:13](=[N:24][C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=3[CH3:33])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N3CCNCC3)n2)cc1OC
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N3CCN(C(=O)c4ccc(F)cc4)CC3)n2)cc1OC
Temperature: 25 °C

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-2-(1-piperazinyl)-4-(2,4,6-trimethylphenylimino)pyrimidine (0.31 g) in tetrahydrofuran (10 ml) were added triethylamine (0.11 ml) and 4-fluorobenzoyl chloride (0.69 ml). The mixture was stirred at ambient temperature for an hour and the reaction was quenched by adding methanol (5 ml). After evaporation of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using a mixture of chloroform and methanol (95:5) to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-[4-(4-fluorobenzoyl)piperazin-1-yl]-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (0.34 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26](Br)[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]
Reactant: CCOC(=O)c1ncc2cc(Br)sc2c1O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)c1ncc2cc(-c3ccc(C(F)(F)F)cc3)sc2c1O

Procedure:
The title compound was prepared from 4-(trifluoromethyl)phenyl boronic acid and 2-bromo-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester, example 21.d, under conditions analogous to experimental example 21.e; MS: (+) m/z 367.9 (M+1)
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: CO/N=C(\COc1ccc(C=O)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(CNc2ccc(CCC(=O)O)cc2)cc1)c1ccccc1

Procedure:
Compound 4 was synthesized from 4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzaldehyde and methyl 3-(4-aminophenyl)propanoate by following the procedure described in Scheme 3.