Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:35])[NH:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[S:9][CH:10]=1)=O)C.COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1>C1COCC1>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[CH:25]=[CH:24][C:22]3[N:23]=[C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:8]5[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=5)[CH:12]=4)[CH2:18][C:19](=[O:35])[NH:20][C:21]=3[CH:27]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(-c3nc(CO)cs3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
To a solution of 2-{3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylic acid ethyl ester (Example 153) (110 mg, 0.23 mmol) in THF (7 mL) was added a 3.5 M solution of sodium dihydrido-bis(2-methoxyethoxy)aluminate in toluene (0.66 mL, 2.3 mmol). The raction mixture was stirred at 23° C. for 15 min. and then poured into ice-cold 10% aq. acetic acid. The mixture was extracted with ethyl acetate and the organic layer was washed successively with H2O, sat. Na2CO3-sol. and brine, dried over Na2SO4 and evaporated in vacuum. The residue was triturated with ethyl acetate to give the title compound as light yellow solid (48 mg).
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH2:4]=[C:5]1[C:22]2[C@:17]([CH3:24])([CH2:18][CH2:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C@@H:11]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[O:26])[CH2:10][CH2:9]3)[CH2:6]1>CCOCC.Cl[Cu]>[CH2:4]([C:5]1[CH2:6][C@@H:7]2[C@@H:16]([C@:17]3([CH3:24])[C:22]=1[CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)[CH2:15][CH2:14][C@@:12]1([CH3:13])[C@H:8]2[CH2:9][CH2:10][C@@H:11]1[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=1)=[O:26])[CH3:1]
Reactant: C=C1C[C@H]2[C@@H]3CC[C@H](C(=O)Nc4ccc(C(F)(F)F)cc4)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Reactant: C[Mg+]
Agent: Cl[Cu]
Agent: [Br-]
Solvent: CCOCC
Product: CCC1=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(=O)Nc4ccc(C(F)(F)F)cc4)CC[C@H]3[C@@H]2C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3.0 M MeMgBr (0.36 mL, 1.09 mmol) in ether under N2 was added 2.2 mL Argon-purged, anhydrous THF. The mixture was cooled to 0° C. CuCl (0.014 g, 0.14 mmol) was added, and the reaction was stirred for 5 min before adding (17β)-6-methylene-3-oxo-N-[4-(trifluoromethyl)phenyl]androst-4-ene-17-carboxamide (3-4) (0.12 g, 0.25 mmol) as a solid. After several hours the reaction was quenched by dropwise addition of 5.0 mL of Ar-purged water, then partitioned between CHCl3 and 10% KHSO4 solution. The organic phase was washed with saturated NaHCO3 solution and brine, then dried with MgSO4 and concentrated. The residue was purified by flash silica gel chromatography (0 to 30% EtOAc/hexane) and concentrated to yield a clear, colorless oil, which was further purified by preparative HPLC (C18; 70% MeOH with 5 to 30% MeCN-water) to provide the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[Na+].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)Cl.CC(C)=O.CC1(C)N([O])C(C)(C)CCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 93.8 %

Procedure:
5 g (32.6 mmol) of 4-nitrobenzylalcohol, 2.7 g (32.9 mmol) of sodium acetate and 10 mg (0.06 mmol) of TEMPO were suspended in 40 ml of methylene chloride in a 100 ml sulphonation flask and the suspension was cooled to (-8)-(-10)° C. while stirring. A solution of 3.03 g (13.0 mmol) of trichloroisocyanuric acid in 20 ml of acetone was dosed in within 1 hour, whereupon the mixture was held at (-5)° C. for 1 hour. Thereafter, the reaction had finished. The white precipitate was filtered off and the filtrate was washed with sodium bicarbonate solution and with sodium chloride solution. The organic phase was concentrated and the residue was recrystallized from diisopropyl ether. There were obtained 4.62 g (94%) of 4-nitrobenzaldehyde, GC content: (97.7%) (area percent).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O[N:16]1[C:21](=[O:22])[CH2:20][CH2:19][C:17]1=[O:18].C(Cl)CCl>C1COCC1>[N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([O:5][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][C:17]1=[O:18])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A mixture of Boc-Aze-OH (5 g, 25 mmol) and HOSu (2.88 g, 25 mmol) in 25 ml of THF was cooled on an ice bath EDC (4.3 ml, 25 mmol) was added and the solution was stirred overnight. It was evaporated, dissolved in ethyl acetate, washed with KHSO4 (aq, 0.3 M), Na2CO3 (aq, 10%), dried (MgSO4) and evaporated. Crystallization from ethyl acetate:petroleum ether afforded 3.78 g (51%) of sub-title compound.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:4])=[O:3].[C:14](Cl)(=[O:17])[CH2:15][CH3:16].C(N(CC)CC)C>CC(C)=O>[CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[N:6]([S:7]([CH3:10])(=[O:9])=[O:8])[C:14](=[O:17])[CH2:15][CH3:16])(=[O:3])=[O:4]
Reactant: CCC(=O)Cl
Reactant: CS(=O)(=O)NN(CCCl)S(C)(=O)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O
Reaction time: 20 h
Yield: 46.3 %

Procedure:
To a stirred solution of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (1.25 g, 0.005 mol) and propionyl chloride (3.20 g, 0.035 mol) in dry acetone (20 mL), triethylamine (0.014 mol) was added dropwise at room temperature. A precipitate was formed immediately. After an additional 20 h, the reaction mixture was filtered and the filtrate evaporated in dryness in vacuo. The residue was taken up in ethyl acetate (100 mL) and washed with dilute hydrochloric acid (3×15 mL), followed by water (2×10 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated to dryness in vacuo. The residue was triturated with petroleum ether to give a solid which, on recrystallization from absolute ethanol, afforded 0.71 g (46.4%) of the title compound: mp 97°-98° C.; 1H NMR (acetone-d6) δ 3.8-4.2 (m, 4 H, CH2CH2), 3.5 and 3.3 (2 s, 6 H, 2 CH3SO2), 2.8 (q, 2 H, COCH2), 1.1 (t, 3 H, COCCH3). Anal. (C7H15C1N2O5S2) C, H, N.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([C:6]([O:8]CC)=O)[N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[OH-].[Li+].Cl.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[C:26]([CH:29]=1)[CH2:27][NH2:28].OC1C2N=NNC=2C=CC=1.C(Cl)CCl.CN1CCOCC1>C(#N)C.O.C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[C:26]([CH:29]=1)[CH2:27][NH:28][C:6]([C@@H:3]1[CH2:4][CH2:5][O:1][N:2]1[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:8]
Reactant: CCOC(=O)[C@@H]1CCON1C(=O)OC(C)(C)C
Reactant: NCc1cc(Cl)ccc1-n1cnnn1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Agent: [Li+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1OCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of 2-tert-butyl 3-ethyl (3S)-isoxazolidine-2,3-dicarboxylate (245 mg, 1.00 mmol) in acetonitrile (2.5 mL) and water (1 mL) was added lithium hydroxide (1 M in water, 1.00 mL, 1.00 mmol) and the mixture was stirred at rt for 30 min. To this solution was added 5-chloro-2-tetrazol-1-yl-benzylamine hydrochloride (295 mg, 1.20 mmol, prepared as described in J. Med. Chem. 2004, 47, 2995), hydroxybenzotriazole (135 mg, 1.00 mmol, as a 20% solution in water, ca 0.65 mL), EDC (288 mg, 1.50 mmol) and NMM (202 mg, 2.00 mmol). The resulting mixture was stirred at rt over night, then diluted with DCM and washed with 1 M HCl and saturated sodium hydrogen carbonate. The organic phase was dried, filtered, evaporated and purified by flash chromatography (DCM/EtOAc gradient from 4:1 to 1:1) to give tert-butyl (3S)-3-{[5-chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}isoxazolidine-2-carboxylate (357 mg, 87%) as an oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.N1CCCCC1.[CH2:34]([OH:39])[CH2:35][CH2:36][C:37]#[CH:38].Cl>[Cu]I>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:38]#[C:37][CH2:36][CH2:35][CH2:34][OH:39])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: C#CCCCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Agent: [Cu]I
Agent: Cl
Solvent: C1CCNCC1
Product: OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Temperature: 0 °C
Yield: 96.8 %

Procedure:
To 3.3 g (7.72 mmol) Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester in 20 ml piperidine 447.0 mg (3.9 mmol) tetrakis(triphenylphosphine)palladium and 73.6 mg (3.9 mmol) CuI were added. At 80° C. 1.43 ml (15.45 mmol) 4-pentyn-1-ol were added slowly, and the solution was stirred for an additional hour. The cooled solution was added to ice water, acidified with 2M HCl and extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 30:1 yielded 2.7 g (96%) 5-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol as orange oil, MS: 361 (M).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:15]([CH3:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:17])[CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[C:15]([CH3:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:17])[CH:8]=1
Reactant: COc1cc(C)c(C(=O)O)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C(=O)O)c(C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boron tribromide solution (1M in DCM, 7.21 mL) was added dropwise to suspension of 4-methoxy-2,5-dimethylbenzoic acid (1 g) in DCM (5 mL) at −78° C. The reaction was allowed to warm to RT and stirred overnight. The reaction was cooled to −78° C. and boron tribromide solution (1M in DCM, 7.21 mL) was added. The reaction was allowed to warm to RT and stirred overnight. The reaction was cautiously poured onto ice (˜50 mL). The resulting aqueous solution was extracted with DCM (5×50 mL). The organic solutions were combined, washed with brine (50 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a tan solid. Yield 0.75 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>O.[Cu]I.C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:1]2[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]2)=[CH:11][CH:10]=1
Reactant: Clc1ccc(I)cc1
Reactant: O=Cc1cc[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccn(-c2ccc(Cl)cc2)n1
Temperature: 110 °C
Yield: 56.9 %

Procedure:
To a mixture of 1H-pyrazole-3-carbaldehyde (1.52 g, 15.82 mmol), 1-chloro-4-iodobenzene (5.66 g, 23.73 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.450 g, 3.16 mmol), copper(I) iodide (0.151 g, 0.791 mmol) and K2CO3 (4.37 g, 31.6 mmol) was added toluene (20 mL). The reaction was sealed and heated to 110° C. for 18 hours. The reaction mixture was then cooled to room temperature and diluted with water (50 mL), and extracted with EtOAc (3×30 mL). The combined organic was then dried (Na2SO4) and concentrated to give crude 1-(4-chlorophenyl)-1H-pyrazole-3-carbaldehyde (1.86 g, 9.0 mmol), to which was added (R)-2-methylpropane-2-sulfinamide (1.20 g, 9.90 mmol), CuSO4 (2.155 g, 13.50 mmol) and DCE (30 ml). The reaction was sealed, heated at 60° C. for 18 hours. A dark green suspension resulted. The reaction mixture was then cooled to 20° C., filtered through a pad of celite, rinsed with DCM. The solution was then concentrated to give final crude product as a light green oil. The residue was purified via silica gel chromatography (EtOAc/Heptane). LCMS (B) m/z 310.3 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][NH:7][C@@H:8]([CH3:16])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[NH:21]([C:27]([O:29][CH2:30][CH:31]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C@H:22]([C:24](O)=[O:25])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[S:1]1[CH:5]=[C:4]([CH2:6][N:7]([C@@H:8]([CH3:16])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])[C:24](=[O:25])[C@@H:22]([NH:21][C:27](=[O:28])[O:29][CH2:30][CH:31]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=3[C:38]3[C:43]2=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH3:23])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: CCOC(OCC)[C@H](C)NCc1csc2ccccc12
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)—N-(benzo[b]thiophen-3-ylmethyl)-1,1-diethoxypropan-2-amine (Compound IX-6) 13.2 g (45 mmol) and Fmoc-Ala-OH 18.3 g (58.8 mmol) were dissolved in DMF (200 ml). HATU (25.6 g, 67.5 mmol) and DIEA (8.7 g, 67.5 mmol) were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was poured into water (800 ml). The solution was extracted with EA (300 ml×3). The combined extracts were dried over Na2SO4 and then filtered. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel is with PE:EA=30:1 to 5:1 to give the title compound 16.9 g, (yield 64%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4C([C:23]([CH3:29])=[N:24][N:25]4C)=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1N2C=CC(B(O)O)=CC2=N[N:42]=1>>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[CH:21][N:42]4[C:23]([CH3:29])=[N:24][N:25]=[C:26]4[CH:27]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nnc2cc(B(O)O)ccn12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccn4c(C)nnc4c3)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate, but using 3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-ylboronic acid instead of 1,3-dimethyl-1H-indazol-6-ylboronic acid. 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.94 (d, J=6.0 Hz, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.58-7.49 (m, 3H), 7.49-7.44 (m, 1H), 5.17 (s, 1H), 4.26-4.16 (m, 2H), 2.81 (s, 3H), 2.61 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 0.98 (s, 9H).
Reaction SMILES: [O:1]([CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][N:31]3[CH:37]=2)=[C:24]([O:38][CH3:39])[CH:23]=1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+].O>O1CCCC1.C(#N)C>[OH:1][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][N:31]3[CH:37]=2)=[C:24]([O:38][CH3:39])[CH:23]=1
Reactant: COc1cc(OCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1-c1cn2cc(I)ccc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: COc1cc(OCCO)ccc1-c1cn2cc(I)ccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
200 mg (corresponding to 0.274 mmol) of 2-[4′-(2″-t-butyldiphenylsiloxyethoxy)-2′-methoxyphenyl]-6-iodoimidazo[1,2-a]pyridine was dissolved in 2.0 mL of tetrahydrofuran, and 0.33 mL of a 1.0 mol/L tetrahydrofuran solution of tetrabutylammoniumfluoride was added thereto. After the reaction mixture was stirred at room temperature for 4 hours, an aqueous sodium hydrogencarbonate solution was added followed by addition of 5.0 mL of water and 1.0 mL of acetonitrile to filter precipitates. The filtered precipitates were washed with water and acetonitrile in this order to obtain 103 mg (corresponding to 0.251 mmol) of 2-[4′-(2″-hydroxyethoxy)-2′-methoxyphenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 7, Step 6).
Reaction SMILES: ClC(OCC)=O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[O:19][C:18]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C@H:29]3[CH2:34][CH2:33][C@H:32]([CH2:35][C:36]([OH:38])=O)[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[O:21])=[N:17][N:16]=1.C[N:40]1CCOCC1.N>C(Cl)Cl.CO>[NH2:40][C:36](=[O:38])[CH2:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:20]([C:18]3[O:19][C:15]([NH:14][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[F:7])=[N:16][N:17]=3)=[O:21])=[CH:28][CH:27]=2)[CH2:30][CH2:31]1
Reactant: CN1CCOCC1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Agent: CCOC(=O)Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: NC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Ethyl chloroformate (0.056 mL, 0.58 mmol) was added dropwise to a stirred solution of (trans-4-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]-phenyl}cyclohexyl)acetic acid (Example 118) (170 mg, 0.39 mmol) and N-methyl morpholine (0.064 mL, 0.58 mmol) in DCM (5 mL) at 0° C. The mixture was stirred for 40 minutes then ammonia (2 mL of a 7M solution in MeOH) was added and stirring was continued for 16 h whilst warming to ambient temperature. Volatile material was removed by evaporation and the residue was triturated with water and washed with 10% ammonium hydroxide solution (10 mL) followed by ether (10 mL) and dried under reduced pressure to give the title compound (121 mg, 71%) as a solid; 1H NMR δ 0.98-1.15 (m, 2H), 1.33-1.50 (m, 2H), 1.63-1.85 (m, 5H), 1.95 (d, 2H), 2.37-2.44 (m, 1H), 6.75 (s, 1H), 7.10-7.35 (m, 5H), 7.66 (d, 2H), 8.03 (t, 1H), 10.78 (s, 1H), 10.99 (s, 1H); MS m/e MH+ 438.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:32]([O:33][CH3:34])=[C:31]([C:35]([NH:37][CH3:38])=[O:36])[CH:30]=[CH:29][C:6]=2[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]3[CH2:16][CH2:17][CH:18]([C:20]([O:22]C)=[O:21])[O:19][C:14]=3[C:13]=2[CH2:26][CH2:27][CH3:28])[CH2:3][CH2:2]1.CO.O.C(OCC)(=O)C>[OH-].[Li+].C(O)(=O)C>[CH:1]1([CH2:4][C:5]2[C:32]([O:33][CH3:34])=[C:31]([C:35]([NH:37][CH3:38])=[O:36])[CH:30]=[CH:29][C:6]=2[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]3[CH2:16][CH2:17][CH:18]([C:20]([OH:22])=[O:21])[O:19][C:14]=3[C:13]=2[CH2:26][CH2:27][CH3:28])[CH2:3][CH2:2]1
Reactant: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CC2CC2)ccc2c1OC(C(=O)OC)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CC2CC2)ccc2c1OC(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 18 (20 mg, 0.038 mmol) was added to 2 drops of 1M lithium hydroxide, about 2 ml of methanol and 1.0 ml of water. The reaction mixture was stirred overnight at room temperature then washed with water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated to yield the crude product. Chromatography of the crude product on silica gel with 90% ethyl acetate, 10% methanol and a trace amount of acetic acid as eluant gave the product.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[ClH:36]>O1CCCC1.ClCCl>[ClH:36].[OH:1][C@@H:2]([CH2:3][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: C1CCNC1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H]2CO2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H](O)CN2CCCC2)c1
Temperature: 45 °C
Yield: 87.3 %

Procedure:
To (R)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one (250 mg, 0.61 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (969 mg, 9.11 mmol) followed by pyrrolidine (0.51 mL, 6.1 mmol). The reaction mixture was heated in a 45° C. oil bath for 3.75 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml) and washed with water (25 mL), brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (233 mg, 0.48 mmol) was dissolved in dichloromethane (2 mL), and HCl (1.25 M solution in methanol, 0.42 mL, 0.53 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (240 mg, 76%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.60 (br s, 1H), 8.20 (s, 1H), 8.02-8.00 (m, 2H), 7.89-7.80 (m, 5H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.5, 2.0 Hz, 1H), 4.57-4.53 (m, 1H), 4.49-4.46 (m, 1H), 4.27 (br s, 1H), 3.25-2.75 (br m, 6H), 1.85 (br s, 4H); ESI MS m/z 483 [M+H]+; HPLC (Method B)>99% (AUC), tR=15.1 min; [α]23D −11.3° (c 0.11, Methanol).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: ClCCOC(c1ccccc1)c1ccccc1
Product: c1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Yield: 75 %

Procedure:
Following a procedure similar to that described in Preparation 5(c), but using 2-(diphenylmethoxy)ethyl chloride and anhydrous piperazine, the title compound was obtained in a yield of 75%.