Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C2C(S([Cl:15])(=O)=O)=CC=CC=2C=NC=1.C(OC(N[C@@H]1CCNC1)=O)(C)(C)C.C(OC([NH:36][C@@H:37]1[CH2:41][CH2:40][N:39]([S:42]([C:45]2[C:46]3[C:47]([CH3:55])=[CH:48][N:49]=[CH:50][C:51]=3[CH:52]=[CH:53][CH:54]=2)(=[O:44])=[O:43])[CH2:38]1)=O)(C)(C)C>>[NH2:36][C@@H:37]1[CH2:41][CH2:40][N:39]([S:42]([C:45]2[C:46]3[C:47]([CH3:55])=[CH:48][N:49]=[CH:50][C:51]=3[CH:52]=[CH:53][CH:54]=2)(=[O:44])=[O:43])[CH2:38]1.[ClH:15]
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Reactant: Cc1cncc2cccc(S(=O)(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Agent: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: Cc1cncc2cccc(S(=O)(=O)N3CC[C@@H](N)C3)c12
Product: Cl

Procedure:
By using 4-methyl-5-isoquinolinesulfonyl chloride instead of 4-bromo-5-isoquinolinesulfonyl chloride, and (R)-3-(tert-butoxycarbonylamino)pyrrolidine instead of (S)-3-(tert-butoxycarbonylamino)pyrrolidine in the method of Example 1-1, (R)-3-(tert-butoxycarbonylamino)-1-(4-methyl-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 513) can be prepared, and then the protective group of Intermediate 5b can be removed according to the method described in Example 1-1, Step B to obtain the title compound as hydrochloride.
Reaction SMILES: Br.Br[CH:3]1[C:8](=[O:9])[CH:7](Br)[C:6]([CH3:12])([CH3:11])[NH:5][C:4]1([CH3:14])[CH3:13].[CH3:15][C:16]1([CH3:23])[O:20][CH:19]([CH2:21][NH2:22])[CH2:18][O:17]1.CC([O-:28])(C)C.[K+]>C(O)(C)C>[CH3:15][C:16]1([CH3:23])[O:20][CH:19]([CH2:21][NH2:22])[CH2:18][O:17]1.[CH3:12][C:6]1([CH3:11])[C:7]([C:8]([OH:9])=[O:28])=[CH:14][C:4]([CH3:3])([CH3:13])[NH:5]1
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)NC(C)(C)C(Br)C(=O)C1Br
Agent: Br
Agent: CC1(C)OCC(CN)O1
Agent: [K+]
Solvent: CC(C)O
Product: CC1(C)C=C(C(=O)O)C(C)(C)N1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
Under agitation, cooling between -5° and 0° C., and covering with argon, 68.94 g (175 mmol) of 3,5-dibromo-2,2,6,6-tetramethylpiperidin-4-one hydrobromide is added in portions to a solution of 22.93 g (175 mmol) of (2,2-dimethyl-1,3-dioxolan-4-yl)methylamine and 58.9 g (525 mmol) of potassium tert-butylate in 700 ml of isopropanol. A white paste is thus obtained which is stirred for one hour without cooling, suctioned off from the solid matter, and concentrated to dryness under vacuum. The residue is distributed between dichloromethane and water. The organic phase is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized. After recrystallization from pentane, 30.1 g (60.9% of theory) of 2,2,5,5-tetramethyl-3-pyrroline-3-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amine is obtained, mp 55°-57° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]([F:48])([F:47])[O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:43]([C:40]4[CH:39]=[CH:38][C:37]([O:36][C:35]([F:34])([F:47])[F:48])=[CH:42][CH:41]=4)(=[O:45])=[O:44])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.12 mmol) and triethylamine 24.2 mg (0.24 mmol) in DCM (6 ml) was added 4-(trifluoromethoxy)benzene-1-sulfonyl chloride (46.8 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Br[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[SH:7][C:4]1[S:3][C:2]([S:1][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][N:5]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Sc1nnc(S)s1
Product: CCOC(=O)C(C)Sc1nnc(S)s1

Procedure:
By following the same procedure as Reference Example 6 using 7.5 of 2,5-dimercapto-1,3,4-thiadiazole and 5.8 g of ethyl 2-bromopropionate as the starting materials, 6.1 g of ethyl 2-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]propionate was obtained as an oily product.
Reaction SMILES: [Mg].BrCCBr.Cl[CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[C:12]([Si:16]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[O:17][CH:18]1[CH:22]([CH2:23][O:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](OS(C(F)(F)F)(=O)=O)=[CH:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].[Na]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCCCCCC.O1CCCC1>[C:12]([Si:16]([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[O:17][C:18]1([CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH2:19][CH2:20][CH:21]=[C:22]1[CH2:23][O:24][C:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C[Si](C)(C)CCl
Reactant: CC(C)(C)[Si](OC1CC=C(OS(=O)(=O)C(F)(F)F)C1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Mg]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: BrCCBr
Product: CC(C)(C)[Si](OC1(C[Si](C)(C)C)CCC=C1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
Magnesium (turning) (33 g, 5.22 mol) was mixed with anhydrous tetrahydrofuran (2 L). 1,2-Dibromoethane (8 ml) was added thereto and stirred for 15 min. To the resulting solution, a mixture of chloromethyltrimethylsilane (364 ml, 2.61 mol) and anhydrous tetrahydrofuran (0.6 L) was added dropwise for 10 min. The mixture solution thus obtained was heated to 40° C. and cooled slowly to precipitate trimethylsilylmethyl magnesium chloride. A mixture of the compound of formula (X) obtained in Example 2-3 (892 g), tetrakis(triphenylphosphine)palladium (37.7 g, 0.033 mmol) and anhydrous tetrahydrofuran (4.5 L) were added to the resulting solution for 20 min dropwise and stirred at room temperature for 1 to 2 hrs. After completion of the reaction, the resulting solution was cooled to 0° C. and 3% aqueous sodium bisulfonate (8 L) was added thereto. The resulting mixture was filtered through Celite, washed with ethyl acetate (4 L). The organic layer thus separated was condensed under a reduced pressure. The residue thus obtained was mixed with heptane (6 L) and Celite (400 g), stirred for 2 hrs, filtered and washed with heptane (2 L). The organic layer thus separated was washed with a mixture of methanol and water mixed in a weight ratio of 6:1 (5.6 L) twice, dried over anhydrous sodium sulfate, filtered, and condensed under a reduced pressure. The residue was crystallized with a mixture of isopropyl alcohol and water to obtain the title compound as a crystalline solid (786 g).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1.Cl[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].[OH-:34].[Na+]>C1COCC1>[CH:23]([N:19]1[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[CH:6][C:5]([CH:3]5[CH2:4][N:1]([S:30]([CH2:29][CH2:28][OH:34])(=[O:32])=[O:31])[CH2:2]5)=[CH:26][C:9]=4[C:10]=3[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: [OH-]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(S(=O)(=O)CCO)C3)cc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.6 %

Procedure:
To a solution of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.20 g, 0.54 mmol) in dry THF (20 mL) at 0° C. was added 2-chloroethanesulfonyl chloride (65 μL, 0.6 mmol) and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was cooled to 0° C. and a further 2-chloroethanesulfonyl chloride (130 μL) was added and the reaction mixture was stirred at RT for 18 hours. An aqueous sodium hydroxide solution (8M, 3.38 mL, 27 mmol) was added and the mixture was heated at 40° C. for 18 hours then concentrated in vacuo. The resultant residue was extracted several times with 10% MeOH in DCM and the combined extracts concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 0-20% MeOH in DCM) followed by preparative HPLC (Gemini C18 column, gradient 5-95% MeOH in H2O+0.1% HCO2H) to give 394 (58 mg, 23%). LCMS: RT=8.45 min, [M+H]+=476. 1H NMR δ (ppm) (DMSO-d6, 80° C.): 8.22 (1 H, d, J=2.31 Hz), 8.01 (1 H, s), 7.33 (1 H, dd, J=8.34, 2.39 Hz), 7.08 (1 H, d, J=8.32 Hz), 5.81-5.73 (1 H, m), 4.53 (2 H, s), 4.37 (2 H, t, J=5.09 Hz), 4.22 (3 H, s), 3.57 (2 H, t, J=6.26 Hz), 3.43 (2 H, t, J=5.09 Hz), 2.79 (2 H, t, J=6.37 Hz), 1.59 (6 H, d, J=6.61 Hz). 1 Exchangeable proton not observed
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11](=[O:17])[CH2:12][C:13](=O)[CH2:14]Cl>C1(C)C=CC=CC=1>[CH3:9][O:10][C:11](=[O:17])[CH2:12][C:13]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]2[CH:14]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)CC(=O)CCl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cn2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
1.28 g (10 mmol) 2-Amino-5-chloropyridine and 1.18 mL (1 eq) 4-chloro-3-oxo-butyric acid methyl ester are heated to 115° C. in 15 mL toluene for 18 h. The resulting brown suspension is evaporated and heated 1 h to 90° C. under high vacuum, then cooled to room temperature and stirred in 100 mL dichloromethane, 10 mL saturated aqueous sodium bicarbonate solution and 40 mL water at 0° C. for one hour. The organic phase is then separated and evaporated to yield a brownish solid that is column chromatographed (silica gel, ethyl acetate/petroleum ether 4:1) to yield 700 mg (31 %) desired product as a beige powder. MS(EI+): 225-227 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(O[CH:18](OCC)[N:19]([CH3:21])[CH3:20])C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1ccc(OC)cc1
Temperature: 135 °C

Procedure:
2 g (0.0103 mol) of ethyl p-methoxyphenylacetate and 9.1 g (10.6 ml, 0.0618 mol) of dimethylformamide diethylacetal were mixed in a 100 ml balloon flask provided with reflux cooler, magnetic stirring and thermometer. The thus obtained solution was heated to reflux (135° C.) for 20 hours. Then the dimethylformamide diethylacetal and the unreacted ethyl p-methoxyphenylacetate were removed by distillation under vacuum, the desired product being obtained as distillation residue. 2,14 g of ethyl α-(p-methoxyphenyl)-β-(dimethylamino)acrylate were thus obtained (Yield: 83%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.[CH3:31][NH:32][C:33]([C:35]1[CH:40]=[C:39]([O:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[C:44]([F:49])[CH:43]=2)[CH:38]=[CH:37][N:36]=1)=[O:34]>C1COCC1.CN(C=O)C>[CH3:31][NH:32][C:33]([C:35]1[CH:40]=[C:39]([O:41][C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:11]([NH:1][C:2]3[CH:3]=[C:4]([O:8][CH3:9])[N:5]=[CH:6][N:7]=3)=[O:13])=[C:44]([F:49])[CH:43]=2)[CH:38]=[CH:37][N:36]=1)=[O:34]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(N)ncn1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(OC)ncn3)c(F)c2)ccn1
Temperature: 70 °C
Yield: 24.2 %

Procedure:
A solution of 6-amino-4-methoxypyrimidine (50.0 mg; 0.39 mmol), triphosgene (43.0 mg; 0.14 mmol) and diisopropylethylamine (60.7 mg; 0.47 mmol) in THF (2.0 mL) was heated at 70° C. for 4 h. A solution of 4-(4-amino-3-fluoro-phenoxy)-pyridine-2-carboxylic acid methylamide (102.3 mg; 0.39 mmol) in DMF (1.0 mL) was then added, and the reaction mixture was heated at 70° C. for another 8 h, then extracted between EtOAc and saturated aqueous NaHCO3. The organic layer was dried and evaporated to give a crude oil that was purified via HPLC to give the title compound (14 mg, 9%). 1H-NMR (CD3OD) δ 8.36 (s, 1H), 8.35 (s, 1H), 8.14 (t, J=8.8 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.00-6.86 (m, 3H), 6.60 (s, 1H), 3.86 (s, 3H), 2.83 (s, 3H); LC-MS m/z 413 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.C([N-]C(C)C)(C)C.[Li+].[I:29]I>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([I:29])=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)ccnc32)cc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Br)ccnc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Example 220A (25 g, 71.2 mmol) in tetrahydrofuran (600 mL) at −78° C. was added slowly 2M lithium diisopropylamide (39.1 mL, 78 mmol) and the mixture was stirred at −78° C. for 1 hour. A solution of iodine (19.87 g, 78 mmol) in tetrahydrofuran (100 mL) was added slowly and the reaction was allowed to warm to room temperature gradually. The reaction mixture was stirred at room temperature for 3 hours and was quenched with saturated aqueous sodium thiosulfate, water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated to give the title compound. MS (CI) m/z 477 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[OH:22][C:23]1([CH3:31])[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C:23]([OH:22])([CH3:31])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(O)CN[C@H](C(N)=O)C1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: CC1(O)C[C@@H](C(N)=O)N(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1
Yield: 11.1 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 50 mg, 176 μmol) was reacted with (2S)-4-hydroxy-4-methylpyrrolidine-2-carboxamide hydrochloride (Example 132 b, 39.7 mg, 176 μmol) and purified by chiral HPLC to obtain the title compound (8 mg, 10%) as white solid, LC-MS (UV peak area, ESI) 93%, 411.1854 [MH+].
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:40])[C@H:13]([OH:39])[C@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:37])[CH2:28][O:29]CC4C=CC=CC=4)=[CH:22][CH:21]=3)[C:15]2=[O:38])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3]>CO.CC(O)=O.[Pd]>[ClH:1].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:40])[C@H:13]([OH:39])[C@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:37])[CH2:28][OH:29])=[CH:22][CH:21]=3)[C:15]2=[O:38])=[CH:9][CH:10]=1)(=[NH:3])[NH2:4]
Reactant: N=C(N)c1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(NC(=O)COCc4ccccc4)cc3)C2=O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(NC(=O)CO)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
To a solution of EXAMPLE 32 (0.12 g) in MeOH—AcOH (20 mL-1 mL), was added 10% Pd—C (20 mg). The reaction mixture was stirred under H2 gas atmosphere at room temperature overnight. The reaction mixture was filtered to remove Pd—C and the filtrate was purified by prep. LC/MS. Before collecting the fractions, conc. HCl was added into each fraction to obtain EXAMPLE 33 (2 mg) as a colorless amorphous solid.
Reaction SMILES: O.Cl.C([O:5][CH:6](OCC)[CH2:7][N:8]([CH3:10])[CH3:9])C.[S:14]([O:17][S:18]([O-:20])=[O:19])([O-:16])=[O:15].[Na+].[Na+]>C(O)C>[S:14]([O:17][S:18]([OH:20])=[O:19])([OH:16])=[O:15].[CH3:9][N:8]([CH2:7][CH:6]=[O:5])[CH3:10]
Reactant: O=S([O-])OS(=O)[O-]
Reactant: CCOC(CN(C)C)OCC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)CC=O
Product: O=S(O)OS(=O)O
Reaction time: 3 h

Procedure:
Water (1 mL) and concentrated hydrochloric acid (2.4 mL) were added to dimethylaminoacetaldehyde diethyl acetal (2.00 g) and heating was carried out for 3 hours at 40° C. Sodium disulfite (3.0 M aqueous solution, 3.6 mL) and ethanol (10 mL) were added on an ice bath and stirring was performed for 1 hour and 30 minutes at room temperature. Filtration was carried out followed by concentration. The resulting residue was evaporated to dryness under reduced pressure at 60° C. to obtain the title compound (1.29 g).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17](Cl)(=O)[C:18](Cl)=O.O[C:24]1[CH:59]=[CH:58][C:27]([CH2:28][N:29]([CH2:50][C:51]([O:53]C(C)(C)C)=[O:52])[C:30](=[O:49])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:48])[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[CH:33][CH:32]=2)=[CH:26][CH:25]=1>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][C:38]([NH:37][C:34]2[CH:33]=[CH:32][C:31]([C:30]([N:29]([CH2:50][C:51]([OH:53])=[O:52])[CH2:28][C:27]3[CH:26]=[CH:25][C:24]([O:16][C:14](=[O:15])[C:11]4[CH:10]=[CH:9][C:8]([CH2:5][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:17][CH3:18])=[CH:13][CH:12]=4)=[CH:59][CH:58]=3)=[O:49])=[CH:36][CH:35]=2)=[O:48])=[CH:45][CH:44]=1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
Prepared using General Procedures 2 then 8: To a stirring solution of 4′-methyl-[1,1′-biphenyl]-4-carboxylic acid (334 mg, 1.57 mmol) in DCM (10 mL) were added DMF (5 drops) and oxalyl chloride (0.14 mL, 1.68 mmol). The reaction mixture was stirred at room temperature for 1 h. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-9 (750 mg, 1.31 mmol) and TEA (0.37 mL, 2.62 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 h then DMAP (30 mg, 0.33 mmol) was added. After a further 2 h at room temperature, the reaction was diluted with DCM (50 mL) and washed with NaHCO3 (50 mL). The organics were pre-absorbed onto silica gel and purified by chromatography (EA/isohexanes). The isolated material was taken up into DCM (10 mL) and TFA (5 mL) was added. After 2 h the solvent was removed under vacuum and solid was evaporated from diethyl ether (5 mL) and isohexanes (20 mL) to give a fine powdery solid. Trituration from DCM/isohexanes and isolation by filtration gave a fine powder that was slurried in water (20 mL) and isolated by filtration. The solid was washed with DCM and isohexanes (9:1, 50 mL) followed by isohexanes (50 mL) to afford 15.3 mg (19%) of 2-(4-(2-(4-methoxyphenyl)acetamido)-N-(4-((4-octylbenzoyl)oxy)benzyl)benzamido)acetic acid 192. LCMS-ESI (m/z) calculated for C40H33F3N2O7: 710; found 711 [M+H]+, tR=8.81 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.96-12.60 (br s, 1H), 10.36 (s, 1H), 8.25-8.16 (m, 2H), 7.94-7.84 (m, 2H), 7.75-7.62 (m, 4H), 7.55-7.27 (m, 9H), 7.25-7.15 (m, 2H), 4.70 (s, 1H), 4.61 (s, 1H), 4.03 (s, 1H), 3.95 (s, 1H), 3.8-3.78 (m, 5H), 2.37 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>>[C:25]1([CH3:30])[C:24]([NH:23][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccccc1N
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Nc3ccccc3C)nc2c1
Yield: 37 %

Procedure:
Methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (300 mg, 0.95 mmol) was stirred in o-toluidine (10 mL) at 145° C. for 3 days in an oil bath. The reaction mixture was concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 3-(o-toluidino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a light yellow solid (145 mg, 37%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:13][CH2:12]1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 5-fluoro-3-(piperidin-4-yl)-1H-indole (0.87 g, 4.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.76 g, 4.0 mmol). The product was isolated as a white foam. Yield 1.14 g (70%). mp 94°-97° C. FDMS m/e=407 (M+ of free base). α[D]589 =+8.36 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: [OH-].[Na+].N1C=[CH:6][N:5]=[N:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:18]([CH3:27])=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH2:17][O:16]2)=[CH:11][CH:10]=1.O.[CH3:29][N:30]1CCCC1=O>>[N:5]1([CH2:17][C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)([OH:16])[C:18]([CH3:27])=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH:6]=[N:30][CH:29]=[N:4]1
Reactant: c1c[nH]nn1
Reactant: CC(=Cc1ccccc1Cl)C1(c2ccc(Cl)cc2)CO1
Reactant: CN1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=Cc1ccccc1Cl)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 95 %

Procedure:
12 g of sodium hydroxide are added to a solution of 70 g of triazole in 300 ml of N-methylpyrrolidone and the mixture is heated for 30 minutes at 50° C. Thereafter, 73 g of 2-(4-chlorophenyl)-2-(1-methyl-2-[2-chlorophenyl]-ethenyl)-oxirane, dissolved in 100 ml of N-methylpyrrolidone, are slowly added dropwise at room temperature. The reaction mixture is stirred for 15 hours at room temperature after which 300 ml of water are added to the solution and the mixture is extracted several times by shaking with methyl tert-butyl ether. The organic phase isolated is washed twice with water and then dried over sodium sulfate and evaporated down. Crystallization of the residue from methyl tert-butyl ether/n-hexane gives 85 g (95%) of 1-(1,2,4-triazol-1-ylmethyl)-1-(4-chlorophenyl)-2-methyl-3-(2-chlorophenyl)-propenol of melting point 141°-143° C.