Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15](O)=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4].[NH4+].[Cl-].C1C=CC2N(O)N=[N:36]C=2C=1.C(Cl)CCl>CN(C=O)C>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH2:36])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: On1nnc2ccccc21
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
Boc-Gly-Pro-Nleu-OH (4.1 g, 0.0106 mol.), NH4Cl (1.7 g, 0.032 mol.) and HOBt (1.76 g, 0.013 mol.) were dissolved in 100 ml DMF and the solution was chilled to 0° C. TEA (4.5 ml) was added to the solution slowly while stirring the solution. After a while, EDC (2.6 g, 0.013 mol.) was added to the solution. The stirring was continued overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 350 ml chloroform. The chloroform solution was washed by H2O 2×20 ml, saturated NaHCO3 2×20 ml, brine 2×20 ml, saturated NaHSO4 2×20 ml and brine again until the pH of the brine layer was approximate 7. The organic layer was dried using Na2SO4 and the chloroform was distilled under reduced pressure to obtain the product (3.5 g, 84%). TLC Rf=0.36 (developing solvents: CMA, 85:15:3).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)#[CH:2].C(N(CC)C(C)C)(C)C.[CH2:23]([N:30]=[N+:31]=[N-:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.[Cu]I>[CH2:23]([N:30]1[CH:2]=[C:1]([C:3]2[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=2)[N:32]=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(-c2cn(Cc3ccccc3)nn2)nc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.6 %

Procedure:
To a solution of ethyl 2-ethynyl-4-methylthiazole-5-carboxylate (0.19 g, 0.71 mmol) in tetrahydrofuran (5 mLl) was added copper(I) iodide (0.003 g, 0.014 mmol), N,N-diisopropylethylamine (0.15 mL, 0.74 mmol) and benzylazide (0.11 g, 0.85 mmol). The reaction mixture was stirred at ambient temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:1) to afford the title compound as a yellow solid (0.23 g, 98%): 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.39-7.26 (m, 5H), 5.54 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 2.67 (s, 3H), 1.21 (t, J=7.1 Hz, 3H); MS (ES+) m/z 329.3 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
Benzyl alcohol (13 mL, 125 mmol) was slowly added to a stirred suspension of NaH (95%, 2.86 g, 113 mmol) in toluene (200 mL) at room temperature. After 30 min, 2,4-difluorobenzonitrile (15.3 g, 1100 mmol; Aldrich) was added all at once and stirring continued overnight (18 h). After this, the reaction mixture was washed with water (2×25 mL) and brine (25 ml). The organic layer was dried (Na2SO4), filtered and concentrated to give a white slurry which was triturated with hexanes and filtered to afford the title compound as a white solid (20.34 g, 81% yield). 1H NMR (500 MHz, CDCl3): 7.59-7.55 (1H, m), 7.45-7.34 (5H, m), 6.75-6.71 (2H, m), 5.19 (2H, s); 13C NMR (125.76 MHz, DMSO-d6) δ ppm: 71.16, 98.75, 101.54, 101.75, 108.66, 108.84, 115.83, 127.16, 128.58, 128.94, 135.03, 135.44, 135.54, 162.22, 162.31, 165.26, 167.29. LCMS calcd for C14H11FNO: 228.2; found: 228.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:5][C:4]=1[N+:16]([O-])=O>N.O>[NH2:16][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:3]=1[O:2][CH3:1])[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Agent: N
Solvent: O
Product: COc1ccc(C(=O)CCC(=O)O)cc1N
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
A solution of 3-(4-methoxy-3-nitrobenzoyl) propionic acid (10.5 g.) in 5N ammonia solution (150 ml.) was added in one portion to a stirred hot (90°C) solution of hydrated ferrous sulphate (90 g.) in water (210 ml.) and stirring was continued for 10 minutes more. The hot mixture was filtered through Hyflo and the filtrate was concentrated to 50 ml. volume and neutralised with acetic acid. The mixture was cooled, the precipitated solid collected and purified by crystallisation from dilute methanol to yield the amine, (5.5 g.), m.p. 136°-137°C.
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[S:12]1[C:16]2[S:17][CH2:18][CH2:19][C:20](=[O:21])[C:15]=2[CH:14]=[CH:13]1>C1C=CC=CC=1>[OH:21][C:20]1[C:15]2[CH:14]=[CH:13][S:12][C:16]=2[S:17][CH2:18][C:19]=1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCSc2sccc21
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C(=O)C1=C(O)c2ccsc2SC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of sodium methoxide (21.6 g, 0.4 mole) and dimethyloxalate (47.2 g, 0.4 mole) in benzene (300 ml) is refluxed for 5 min. in order to dissolve most of the solid. To the cooled solution is added a solution of 5,6-dihydro-4H-thieno[2,3-b]-thiopyran-4-one (34 g, 0.2 mole) in benzene (300 ml) and the mixture is stirred for 3 hrs. to give a yellow suspension. The mixture is poured into ice-water mixture (1750 ml). After separating the aqueous layer from the benzene layer, the benzene layer is extracted with 1(N) NaOH solution (250 ml), and the combined aqueous solution is washed once with ether (100 ml) and acidified with (N) HCl. The yellow crystalline glyoxalate is filtered off and dried over P2O5 to give 45.8 g (91%) of the desired product; m.p. 53-56° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[N:11]1.[C-:27]#[N:28].[Na+]>>[C:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[N:11]1)#[N:28]
Reactant: [C-]#N
Reactant: BrCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Product: N#CCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1
Yield: 74.4 %

Procedure:
1-(8-Bromooctyl)-4,5-diphenyltriazole (ex. example 60a) (1.8 g) was reacted with sodium cyanide in a method similar to Example 60b). Work-up and recrystallisation from dichloromethane and hexane gave 1-(8-cyanooctyl)-4,5-diphenyltriazole (1.16 g, 74.4%) as a white solid, m.p. 77°-8° C. Found: C, 77.03; H, 7.25; N, 15.35%; C23H26N4 requires: C, 77.06; H, 7.31; N, 15.63%.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:19])[CH3:18].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl>CN(C)C=O>[CH2:8]([C:7]1[C:2]([O:1][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:3]([C:17](=[O:19])[CH3:18])[C:4]([O:15][CH3:16])=[CH:5][C:6]=1[O:13][CH3:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COc1cc(OC)c(C(C)=O)c(O)c1CCC(C)C
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To 16.7 g of the so-obtained 2'-hydroxy-3'-isopentyl-4',6'-dimethoxyacetophenone and 1.5 g of sodium hydride was added 130 ml of dimethylformamide, and 9.9 g of methyl α-bromoacetate was further added and the mixture was stirred for 1.5 hours at 0° C. and for 2 hours at room temperature to effect reaction. After the reaction, the reaction mixture was made acidic by dilute hydrochloric acid, extracted with diethyl ether and filtered. The solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chromatography [230-400 mesh silica gel, eluting solvent=n-hexane/ethyl acetate (4/1)] to obtain 14.9 g (yield=70.3%) of 3'-isopentyl-4',6'-dimethoxy-2'-methoxycarbonylmethoxyacetophenone.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4](O)[C@H:2]1O.[H][H]>[Pd]>[C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[CH2:4][CH2:2]1
Reactant: [H][H]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: [Pd]
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1

Procedure:
In Step 4, inosine derivative (IV') is subjected to reduction with hydrogen (H2) in an organic solvent over a palladium catalyst. This reduction proceeds with minimum substrate decomposition. This is followed by hydrolysis or ester exchange reaction, giving 2',3'-dideoxyinosine derivative (A').
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20]Br>C(C(C)=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:20][CH2:19][Br:18])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1cc(Br)ccc1OCCBr
Temperature: 80 °C
Yield: 53.9 %

Procedure:
To a stirred solution of 5′-bromo-2′-hydroxyacetophenone (10 g, 46.5 mmol) in methyl ethyl ketone (100 mL) was added K2CO3 (13.5 g, 97.7 mmol) followed by 1,2-dibromoethane (20 mL, 232.5 mmol). The reaction mixture was heated at a mild reflux temperature (ca. 80° C.) for 16 h at which point the reaction flask was cooled to room temperature. The resultant solids were filtered off and the solvent removed by rotary evaporation under reduced pressure. The residue was dissolved in Et2O/EtOAc (4:1, 500 mL) and the precipitated solid (the alkylation dimer) was removed by filtration. The filtrate was washed with 2 N NaOH (100 mL) and the organic portion was dried over Na2SO4 and concentrated in vacuo to give crude 1-(5-bromo-2-(2-bromoethoxy)phenyl)ethanone (8.07 g, 55%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](OS(C(F)(F)F)(=O)=O)[CH:25]=[C:24]([C:36](=[O:38])[CH3:37])[CH:23]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH3:2].[F:47][C:48]1([F:60])[O:52][C:51]2[CH:53]=[CH:54][C:55](B(O)O)=[CH:56][C:50]=2[O:49]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:55]3[CH:54]=[CH:53][C:51]4[O:52][C:48]([F:60])([F:47])[O:49][C:50]=4[CH:56]=3)[CH:25]=[C:24]([C:36](=[O:38])[CH3:37])[CH:23]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH3:2]
Reactant: OB(O)c1ccc2c(c1)OC(F)(F)O2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OS(=O)(=O)C(F)(F)F)cc(C(C)=O)c2)c1CCC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3ccc4c(c3)OC(F)(F)O4)c2)c1CCC(=O)OCC
Temperature: 90 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
To a solution of 4-[3-[6-(3-acetyl-5-trifluoromethanesulfonyloxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (500 mg) in 1,2-dimethoxyethane (5 mL) were added 2,2-difluoro-benzo[1,3]dioxole-5-boronic acid (273 mg), 2 M aq. sodium carbonate solution (1.0 mL) and Pd(PPh3)4 (8 mg) and the resulting mixture was stirred at 90° C. for 3 h. Then the reaction mixture was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 300 mg of the title compound (59% yield). HRMS calcd for C38H44O9F2 [M+Na]+ 705.2845, observed 705.2843.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O.C(O)(C(F)(F)F)=O>>[CH:13]1([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 9.4 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.8 g, 17.4 mmol), 4-formylbenzoic acid, methyl ester (2.87 g, 1.1 equiv.) and TFA (2.7 mL, 2 equiv.) to give the title compound (0.5 g, 9%) as white crystals after recrystallization from isopropanol:H2O.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CO>[N:22]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:10][C:11]4[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)=[CH:5][CH:4]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: C1CNCCN1
Reactant: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Solvent: CO
Product: COC(=O)c1cccc2nc(-c3ccc(CN4CCNCC4)cc3)oc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To the mixture of methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate (250 mg, 0.72 mmol) in methanol (2 mL), was added piperazine (186 mg, 2.16 mmol), and the resulting mixture was stirred at room temperature for 17 hr, then the solvents were evaporated to give methyl 2-(4-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxylate LC-MS (ESI) m/z 352 [M+1]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:37])[NH:24][C:25]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([CH3:36])=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:29]1[C:30]([C:32]([F:34])([F:33])[F:35])=[CH:31][C:25]2[NH:24][C:23](=[O:37])[CH2:22][C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)=[N:27][C:26]=2[CH:28]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c1)=N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(N)(=O)=O)c3)c1)=N2

Procedure:
The title compound was prepared from 3′-(8-methyl-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-3-sulfonic acid tert-butylamide (Example 2) (220 mg, 0.39 mmol) and TFA (5 mL) in DCM (1 mL) according to the general procedure I step 2. Obtained as a light yellow solid (136 mg, 73%). MS (ISP) 473.9 [(M+H)+]; mp 235-239° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[N:11]([O-])=O.[Na+]>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][N:11]=[C:9]2[CH3:10]
Reactant: CCc1cc(Br)ccc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.2 %

Procedure:
To a solution of 4-bromo-2-ethylbenzenamine (1.5 g, 7.50 mmol) in AcOH (20 mL) was added NaNO2 (570 mg, 8.14 mmol). After stirring for 2.5 h at room temperature, the resulting mixture was concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 1% methanol in dichloromethane to afford 5-bromo-3-methyl-1H-indazole as a light red solid (700 mg, 44%).
Reaction SMILES: [CH:1]1([C:4]2[C:12](I)=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:3][CH2:2]1.C([Li])CCC.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1.CCOCC>[CH:1]1([C:4]2[C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCc1cc(C2CC2)c(I)cc1C(=O)O
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 102 %

Procedure:
To a solution of 4-cyclopropyl-2-ethyl-5-iodobenzoic acid (compound 226.5, 500 mg, 1.58 mmol, 1.00 equiv) in THF/Et2O (10/10 mL) under nitrogen at −78° C. was added dropwise n-butyllithium (2.5 M, 1.88 mL, 3.00 equiv) over 3 min. After stirring for 10 min at −78° C., methyl chloroformate (230 mg, 2.43 mmol, 1.50 equiv) was added dropwise at −78° C. The resulting solution was stirred for 40 min at −78° C., then warmed slowly to −35° C. The reaction was carefully quenched with 2 mL of water. The pH was adjusted to ˜4-5 with hydrogen chloride (aq., 1 M). The resulting mixture was extracted with 3×20 mL of ethyl acetate and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield 400 mg the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[K+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(S)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc(SCC(=O)O)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a solution of 4.30 g of 4′-methoxy-biphenyl-4-thiol and 3.34 g of ethyl 2-bromo-acetate in 10 ml of ethanol was added over 5 min a solution of 1.12 g of potassium hydroxide in 20 ml of ethanol. The reaction mixture was stirred at 20° for 4 h and then, 1.68 g of potassium hydroxide and 3 ml of water were added and stirring was continued for 15 h at 20°. The mixture was poured onto 150 ml of ice/water and the pH of the mixture set to 2 by the addition of 3N hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to give 4.21 g of 2-(4′-methoxy-biphenyl-4-ylsulfanyl)-acetic acid as white crystals.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[F:28].[NH:29]1[CH2:33][CH:32]=[CH:31][C@H:30]1[C:34]([OH:36])=[O:35]>>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([N:29]3[CH2:33][CH:32]=[CH:31][C@H:30]3[C:34]([OH:36])=[O:35])=[O:21])=[CH:26][CH:27]=2)=[CH:4][C:3]=1[F:28]
Reactant: O=C(O)c1cccc(COc2ccc(-c3cc(F)c(F)c4ccoc34)cc2)c1
Reactant: O=C(O)[C@@H]1C=CCN1
Product: O=C(O)[C@@H]1C=CCN1C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)c4ccoc34)cc2)c1
Yield: 30 %

Procedure:
An operation similar to that in Step 4 of Example 10 was performed using the compound (38.0 mg, 0.100 mmol) of Step 2 of Example 59 in place of 3-{[4-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)phenoxy]methyl}benzoic acid, and (2S)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (14.7 mg, 0.130 mmol) in place of L-proline to thus obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH3:13][O:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:15]([O:14][CH3:13])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(C(F)(F)F)cc1
Product: CON(Cc1ccc(C(F)(F)F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with O-methyl-N-(4-trifluoromethyl-benzyl)-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (97% yield): mp 110° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.71 (3H, s, OCH3), 4.87 (2H, s, NCH2), 6.40 (1H, s, CH), 7.47 (2H, m, aromatics), 7.59 (2H, m, aromatics). Anal. calcd for C16H16F3NO5: C, 53.49; H, 4.49; N, 3.90. Found: C, 53.48; H, 4.53; N, 3.83.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([C:38]([OH:40])=[O:39])([CH3:37])[CH3:36])[CH:29]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CN(C)C=O>O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([C:38]([O:40][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:39])([CH3:37])[CH3:36])[CH:29]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cccc(OC(C)(C)C(=O)O)c2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(c2cccc(OC(C)(C)C(=O)OCc3ccccc3)c2)C1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Cesium carbonate (24.00 g, 73.67 mmol) and benzyl bromide (8.03 mL, 67.53 mmol) were added sequentially to a solution of of 3-[3-(1-Carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (22.31 g, 61.39 mmol) and dimethylformamide (100 mL) at ambient temperature. The resulting mixture was warmed to 60° C., stirred 1.5 h, cooled to ambient temperature and diluted with water (600 mL). The aqueous solution was extracted with diethyl ether (2×300 mL). The organic extracts were combined and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resultant oil was purified by flash column chromatography (7:1 hexanes/ethyl acetate) to provide 3-[3-(1-Benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a pale-yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[C:15]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)[CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC2C3C(C(=O)N(C4C=C[C:44]([O:47]C)=CC=4)N=3)=CNC=2C=1>>[CH3:44][O:47][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[C:15]([N:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)[CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)=[CH:2][CH:3]=1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)ccc3c-2nn1-c1ccccc1
Reactant: COc1ccc(-n2nc3c4ccc(N)cc4[nH]cc-3c2=O)cc1
Product: COc1ccc(-n2nc3c4ccc(N5CCNCC5)cc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure for 14a using 13c. 1H-NMR (DMSO-d6) δ (ppm): 3.04 (4H, br), 3.75 (3H, s), 3.90 (4H, br), 6.8 (1H, m), 7.26 (2H, m), 7.42 (1H, m), 7.87 (1H, d, J=8.79 Hz), 8.05 (2H, d, J=9.06 Hz), 8.62 (1H, br). m/z 376.4 (MH+).