Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f16) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:14](Cl)(Cl)=[O:15].C1(C)C=CC=CC=1.[OH-].[Na+]>C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)=[C:14]=[O:15]
Reactant: O=C(Cl)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-2-cyanobenzotrifluoride (1a) (2.0 g, 10.7 mmol) in ethyl acetate (6 mL) at 0° C. under argon, was added dropwise a 2.0 M solution of phosgene in toluene (6.5 mL, 12.9 mmol). The solution was stirred 30 min at 0° C. and allowed to return at room temperature. Toluene (3 mL) was then added to the ethyl acetate and the resulting solution was refluxed for 3 hrs using a Dean-Stark apparatus, equipped with an HCl trap (solid NaOH). The first 6 mL of distilled solvent was removed and replaced by toluene (6 mL). The solution was then filtrated and evaporated to give compound 8a (1.6 g) as an orange oil which was directly used for the next step. IR: 2268 (strong), 2232 (weak) cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)=[C:5]2[NH:14][CH:15]=[C:16]([C:17](=[O:37])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[N:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[N:29]=[N:28][N:27]=4)[CH2:22][CH2:21]3)=[O:19])[C:4]=12.[H-].[Na+].[CH3:40]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:13]=[CH:12][N:11]([CH3:40])[N:10]=2)=[C:5]2[NH:14][CH:15]=[C:16]([C:17](=[O:37])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[N:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[N:29]=[N:28][N:27]=4)[CH2:22][CH2:21]3)=[O:19])[C:4]=12
Reactant: COc1cnc(-c2cc[nH]n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnc(-c2ccn(C)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Yield: 23.9 %

Procedure:
To a solution of 1-(4-methoxy-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.069 g, 0.138 mmol) in DMF (3 mL) was added NaH (0.055 g, 1.381 mmol). The mixture was stirred for ten minutes and MeI (0.017 mL, 0.276 mmol) was added. After being stirred for 45 minutes, the mixture was quenched with water. The mixture was concentrated under reduced pressure. The resulting residue was diluted with DMF and was passed through a plug of cotton to remove solids. The DMF solution was purified by prep HPLC to give 1-(4-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione as a light-yellow solid (0.017 g, 0.033 mmol, 33.1% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 12.37 (s, 1H) 8.67 (dd, J=4.88, 1.22 Hz, 1H) 8.33 (s, 1H) 8.13-8.18 (m, 1H) 8.05 (s, 1H) 7.93 (d, J=2.14 Hz, 1H) 7.85 (d, J=7.93 Hz, 1H) 7.64 (dd, J=7.48, 4.73 Hz, 1H) 6.99 (s, 1H) 4.05 (s, 3H) 4.00 (s, 3H) 3.70-3.74 (m, 2H) 3.40-3.48 (m, 4H) 3.24-3.29 (m, 2H). LCMS: m/e 514.38 (M+H)+, ret time 1.820 min (method 1).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:24][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:18][CH2:19][C:20]([CH3:24])([OH:23])[CH2:21][CH2:22]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: C[Mg]Cl
Reactant: O=C1CCC(Nc2nccc(-n3nnc4ccccc43)n2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC(Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexanone (764 mg, 2.5 mmol) in 80 mL of THF, cooled at −78° C., was added dropwise methylmagnesium chloride (3.5 mL, 3.0 M in THF, 10.5 mmol). The reaction mixture immediately turned bright yellow in color; it was then allowed to warm to RT. The reaction did not reach completion, so it was re-cooled to −78° C. and an additional aliquot of MeMgCl (3 mL, 9 mmol) was added. The resulting mixture was warmed to RT and then poured onto an aqueous solution of NH4Cl; it was extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and filtered; the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (1-5/99-95 MeOH/CH2Cl2) to give: a less polar trans-isomer (130 mg, 16% yield, mp=193.0-195.4° C.; MS=325 (M+H)+), and the more polar cis-isomer (360 mg, 45% yield, mp=202.1-205.6° C.; MS=325 (M+H)+) as white crystalline solids.
Reaction SMILES: Cl.[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:4]#[N:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:7]1([C:3]([NH:2][S:14]([CH3:13])(=[O:16])=[O:15])([CH3:6])[C:4]#[N:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(N)(C#N)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C#N)(NS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a mixture of 2 g (0.0109 mole) 2-amino-2-phenyl-propionitrile hydrochloride (the product of Example 11) in methylene chloride (about 50 ml), 2.6 g (0.0218 mole) 4-dimethylaminopyridine was added, followed by 1.3 g (0.0109 mole) methanesulfonyl chloride in 10 ml methylene chloride in an exothermic addition. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into 100 ml ice water. The layers were separated using a separatory funnel. The organic (methylene chloride) phase was washed twice with water, dried over magnesium sulfate, filtered and stripped to give 2 g of the above-identified product as an orange slush.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:37][CH2:36]2)=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[N:33]=[CH:32][C:31]([CH2:34][N:35]5[CH2:36][CH2:37][N:38]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:39][CH2:40]5)=[CH:30][CH:29]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CCOC(=O)CN1CCN(Cc2ccc(Cl)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1CCN(Cc2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1

Procedure:
Compound 347 was prepared as an off-white solid (TFA salt) from compound 4 and compound 348 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.57 (1 H, s), 9.27 (1 H, s), 8.60 (2 H, s), 8.47 (1 H, d, J=2.0 Hz), 8.32-8.43 (1 H, m), 8.07 (1 H, dd, J=8.8, 2.2 Hz), 5.46 (1 H, dq, J=9.0, 8.9 Hz), 4.12-4.28 (4 H, m), 3.65 (2 H, br. s.), 2.96-3.21 (8 H, m), 2.48-2.61 (2 H, m), 2.15-2.31 (4 H, m), 1.85-1.99 (2 H, m), 1.28 (3 H, t, J=7.2 Hz). LCMS-ESI (POS), M/Z, M+1: Found 515.2.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[O:30][CH2:31][CH3:32])#[N:19]>C1COCC1.C1COCC1.CN(C=O)C>[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([O:30][CH2:31][CH3:32])[CH:22]=2)(=[O:28])=[O:27])[C:8]=1[CH3:16]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1cc(S(=O)(=O)n2c(C)c(CC(=O)OC)c3cccnc32)ccc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, ice-cooled (0° C.) suspension of sodium hydride (26.3 mg of a 60% dispersion in mineral oil, 0.686 mmol) in dry THF (10 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.1 g, 0.49 mmol) in THF/DMF (4 ml of a 3:1 mixture). The reaction mixture is stirred at 0° C. for 1 hour and then treated with 4-cyano-3-ethoxy-benzenesulfonyl chloride (168 mg, 0.686 mmol) in dry THF (1 ml). Stirring continued at 0° C. for 10 minutes and at room temperature for 10 minutes and then the reaction mixture is poured onto water (50 ml). The mixture is extracted with ethyl acetate (2×50 ml) and the organic portions are combined, washed brine (50 ml), dried (MgS04) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) to yield the titled product. (MH+414).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1.[OH-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(Cl)ccc4o3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of methyl 2-(5-chlorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (152 mg, 0.37 mmol) in tetrahydrofuran (30 mL) was added sodium hydroxide (48.6 mg, 1.22 mmol) and water (2 ml) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 2-(5-chlorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (60 mg, 41%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][N:27]([CH2:29][C:30]#[CH:31])[CH2:26][C@H:25]3[C:32](OC(C)(C)C)=[O:33])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[NH2:46][OH:47]>>[OH:47][NH:46][C:32]([C@H:25]1[C@@H:24]([NH:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:19][CH:18]=2)(=[O:22])=[O:21])[CH2:28][N:27]([CH2:29][C:30]#[CH:31])[CH2:26]1)=[O:33]
Reactant: NO
Reactant: C#CCN1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)NO)C1
Yield: 54 %

Procedure:
According to the procedure of Example 17, Steps 4 and 5, 117 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-prop-2-yn-1-ylpyrrolidine-3-carboxylate, was treated with trifluoroacetic acid, followed by the reaction with hydroxylamine to give 56 mg of cis-N-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-1-prop-2-yn-1-ylpyrrolidine-3-carboxamide in 54% yield. MS: 495 2(M+H)+
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:20][C:19](=[O:21])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].C(O)(C)(C)C.[H][H]>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH2:5][C@@H:6]2[CH2:20][C:19](=[O:21])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Yield: 37.3 %

Procedure:
An ambient temperature mixture of benzyl 2-azido-carbapen-2-em-3-carboxylate (7.7 mg, 27 micromol) and palladium on calcium carbonate poisoned with lead (12.8 mg) in dry dioxane (0.80 ml) containing t-butanol (50 microliter) was stirred while hydrogen was bubbled through for 20 min. The mixture was filtered and the solid washed with diethyl ether (3×0.5 ml). The combined filtrate and washes were concentrated to 0.5 ml under vacuum, and the residue was chromatographed on one 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plate developed with 1:1 (v/v) toluene-ethyl acetate. The band centered at Rf 0.2 was eluted with ethyl acetate and the eluate was evaporated under vacuum to provide 2.6 mg (37%) benzyl 2-amino-carbapen-2-em-3-carboxylate as a light yellow glass; I.R. (neat film): 3450, 3330, 1780, 1690 cm-1 ; NMR (CDCl3): δ2.81 dd (J1 =4 Hz, J2 =16 Hz, 1H), 2.93 m (2H), 3.21 dd (J1 =5 Hz, J2 =16 Hz, 1H), 5.25 d (J=13 Hz, 1H), 5.32 d (J=13 Hz, 1H), 7.37 m (5H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>C1COCC1>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:3][CH2:2][NH:1][S:18]([C:16]1[S:17][C:13]([Cl:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1)(=[O:20])=[O:19])([CH3:8])([CH3:10])[CH3:9]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 71.9 %

Procedure:
To a stirred solution of tert-butyl N-(2-aminoethyl)-carbamate (0.46 g, 2.87 mmol) in THF (6 ml) was added at 0° C. (ice water bath) 5-chloro-4-nitrothiophene-2-sulfonyl chloride (0.5 g, 1.91 mmol) and triethylamine (0.29 ml, 2.1 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (ethyl acetate/heptane), and subsequent crystallization from ethyl acetate/hexane to yield [2-(5-chloro-4-nitro-thiophene-2-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (0.53 g, 72%) as a light yellow solid. MS (ISP) 384.1 [(M−H)−], mp 147° C.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([C:9]1[CH:37]=[CH:36][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH:31]4[CH2:35][CH2:34][S:33][CH2:32]4)=[O:29])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].ClC1C=C(C=CC=1)C(OO)=[O:45]>ClCCl>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH:31]4[CH2:35][CH2:34][S:33](=[O:45])[CH2:32]4)=[O:29])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:36][CH:37]=1)([OH:8])[C:2]([F:38])([F:1])[F:39]
Reactant: O=C(Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)NC1CCSC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)NC1CCS(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To an ice-cooled solution of 1-(4-((1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidin-4-yl)methyl)phenyl)-3-(tetrahydrothiophen-3-yl)urea (0.243 mmol, 140 mg) in dichloromethane was added 3-chloroperoxybenzoic acid (0.243 mmol, 54.5 mg) and the resulting mixture was stirred for 30 minutes. Additional 3-chloroperoxybenzoic acid (0.243 mmol, 54.5 mg) was added and reaction stirred for 1.5 hours. The reaction was concentrated under vacuum. The residue was purified by silica column chromatography (eluent: 2% methanol in dichloromethane-7% methanol in dichloromethane) and SCX chromatography to give the title compound (77.1 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:26]=[O:27]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]2[N:6]([C:8]([CH:26]=[O:27])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)cn2cc(-c3ccc(F)cc3)nc12
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Br)cn2c(C=O)c(-c3ccc(F)cc3)nc12
Yield: 85 %

Procedure:
6-Bromo-2-(4-fluorophenyl)-8-methylimidazo[1,2-a]pyridine (6 g, 0.021 moles) was treated was treated with phosphorous oxychloride (2.8 mL) in N,N-dimethylformamide in a similar manner as described in Example 2 to give 6-bromo-2-(4-fluorophenyl)-8-methylimidazo[1,2-a]pyridine-3-carbaldehyde (5.7 g, 85%) as a white solid. 1H NMR (CDCl3): δ 10.04 (s, 1H), 9.73 (s, 1H), 7.86 (q, 2H), 7.53 (s, 1H), 7.25 (t, 2H), 2.75 (s, 3H); 19F NMR (CDCl3) δ −111.0; MS m/z 334 (M+1).
Reaction SMILES: [C:1]([N:20]1[C:24](/[CH:25]=[CH:26]/[CH2:27][OH:28])=[N:23][CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[C].[Pd]>[C:1]([N:20]1[C:24]([CH2:25][CH2:26][CH2:27][OH:28])=[N:23][CH:22]=[N:21]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC/C=C/c1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Product: OCCCc1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 74.3 %

Procedure:
A stirred solution of E-3(1-trityl-1,2,4-triazol-5-yl)prop-2-en-1-ol (9.5 g, prepared as described in Example 9) in dichloromethane (100 ml) was hydrogenated over 5% palladium-carbon (50 mg) at room temperature and pressure for four hours. The mixture was filtered through Hyflo Super-Cel, evaporated under reduced pressure and chromatographed, using ethyl acetate-hexane (4:1), then ethyl acetate, as eluants, to give 3(1-trityl-1,2,4-triazol-5-yl)propanol (7.1 g, m.p. 150°-152° C.). NMR (CDCl3): δ1.4(2H,m), 2.2(2H,t), 3.45(2H,t), 7.1-7.3(15H,m), 7.9(1H,s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:19][C:20]1[CH:24]=[C:23]([CH:25]=O)[NH:22][N:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:25]\[C:23]3[NH:22][N:21]=[C:20]([CH3:19])[CH:24]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: Cc1cc(C=O)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C)n[nH]1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added 3-methyl-1H-pyrazole-5-carbaldehyde 93 (70.8 mg, 0.404 mmol). PTSA (153.8 mg, 0.808 mmol) was added to the reaction mass, then stirred at 120° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude 94 and was purified through flash chromatography by using 100-200 mesh silica gel eluting at 2% MeOH in DCM to afford yellow coloured solid compound (E)-6-methoxy-2-((3-methyl-1H-pyrazol-5-yl)methylene)-5-morpholino-2, 3-dihydro-1H-inden-1-one 94.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[C:19]([CH2:26][S:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1)[C:18]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:17]2[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[C:19]([CH2:26][S:27]([C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1)=[O:6])[C:18]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:17]2[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1
Reactant: CCOC(=O)c1c(CSc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1c(CS(=O)c2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.4 %

Procedure:
m-Chloroperoxybenzoic acid (85%, 830 mg) was added in small portions under ice-cooling to a solution of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[(1-methylimidazol- 2-yl)thiomethyl]quinoline-3-carboxylate (3.0 g) in dichloromethane (75 ml). The reaction mixture was stirred at room temperature for 2.5 hours, washed successively with 5% NaHSO3 aqueous solution, saturated aqueous solution of sodium bicarbonate and water, and dried (MgSO4). The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate/methanol (10:1, v/v), ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2- [(1-methylimidazol-2-yl)sulfinylmethyl]quinoline-3-carboxylate (1.8 g, 58%) was obtained and recrystallized from acetone-ethyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7]2.[C:16]([O-])([O-:18])=[O:17].[K+].[K+].C(=O)=O>>[OH:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:7]2
Reactant: Oc1cccc2ccc(C(F)(F)F)nc12
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc2ccc(C(F)(F)F)nc2c1O
Temperature: 170 °C
Yield: 48.4 %

Procedure:
8-Hydroxy-2-trifluoromethylquinoline (3.2 g) and K2CO3 (6.22 g) are placed in a stainless steel bomb. The bomb is pressurized slightly with CO2 and flushed 3×, then pressurized to approximately 800 psi CO2. The bomb is heated to 170° C., reaching a final pressure of approximately 1200 psi. This temperature and pressure are maintained for 7 days after which time the bomb is cooled and the pressure released. The solid residue is dissolved in a minimal amount of warm water. Any undissolved material is filtered and the aqueous filtrate is acidified to pH 4 with conc. HCl. The resulting tan solid is filtered and dried. The product is recrystallized with Et2O to give a light tan solid (1.87 g).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[S:22][C:23]=3[CH3:24])[CH3:18])=[CH:11][C:8]=2[S:9][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C>[CH3:24][C:23]1[S:22][C:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=2)=[N:20][C:19]=1[CH:17]([CH3:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:7]2[C:6]([CH2:5][C:4]([OH:35])=[O:3])=[CH:10][S:9][C:8]=2[CH:11]=1
Reactant: CCOC(=O)Cc1csc2cc(OCC(C)c3nc(-c4ccc(C(F)(F)F)cc4)sc3C)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)COc1ccc2c(CC(=O)O)csc2c1

Procedure:
(6-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propoxy}-benzo[b]thiophen-3-yl)-acetic acid ethyl ester (100 mg) is taken into ethanol (1 mL) and treated with NaOH (5.0 N, 1 mL) at 50° C. for 2 hrs. The reaction mixture is acidified with 5 N HCl, extracted with ethyl ether, dried over sodium sulfate. Concentration yields the title compound. MS (ES): 492.1(M++1), the structure is also confirmed by proton NMR.