Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Azidobenzoic acid (858 mg, 5.15 mmol), HOBt (704 mg, 5.15 mmol, 1.0 eq.) and N-(2-aminoethyl)piperidine (0.788 ml, 5.41 mmol, 1.05 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.21 g, 6.19 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml) and washed with 5% aqueous sodium carbonate solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated at 30° C. or below to give the title compound as a pale-yellow oil.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:24]3[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccc(Cl)c(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)ccc3Cl)CC2)c(OC)nc1C
Yield: 70 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin3-yl)carbamate and 1-(2-chloro-5-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][CH:19]([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:19]([F:18])[F:30])=[CH:26][CH:25]=2)=[O:29])[CH2:7]1
Reactant: O=C=Nc1ccc(OC(F)F)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(OC(F)F)cc1

Procedure:
Example 16 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-(difluoromethoxy)-4-isocyanatobenzene (19.1 μl) to give the title compound (0.0252 g). LC-MS (System A): Rt 2.41 mins, Mass Spectrum m/z 460 [MH+].
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:22])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:14][C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(-c2nc(NC(=O)c3ccccc3)sc2-c2ccncc2)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 65.7 %

Procedure:
To a solution of [4-[4-(1,1-Dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.62 mmol) and 4-dimethylaminopyridine (0.05 g, 0.39 mmol) in N,N-dimethylacetamide (5 mL) was added benzoyl chloride (0.15 g, 1.94 mmol), and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured an aqueous sodium hydrogencarbonate and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.44 g, yield 66%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(S(O[CH2:23][CH2:24][C:25]2[S:26][C:27]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:28]=3[CH:29]=2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[CH3:41][C@@H:42]1[CH2:46][CH2:45][CH2:44][NH:43]1.C(#N)C>>[Br:34][C:31]1[CH:32]=[CH:33][C:27]2[S:26][C:25]([CH2:24][CH2:23][N:43]3[CH2:44][CH2:45][CH2:46][C@H:42]3[CH3:41])=[CH:29][C:28]=2[CH:30]=1
Reactant: C[C@@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)ccc3s2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2s1
Temperature: 55 °C
Yield: 73.3 %

Procedure:
Toluene-4-sulfonic acid, the product from Example 165D (0.45 g), and K2CO3 (0.23 g, 1.5 eq) was treated with a solution of (2R)-2-methylpyrrolidine solution in acetonitrile (11.1 g, 12.6 mg/g of solution, 1.5 eq). The mixture was heated at 55° C. for 24 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was dissolved in 30 mL EtOAc, washed with 2×10 mL water, concentrated, and the residue was purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to provide the title compound as an oil (0.26 g, 73.3%). 1HNMR (CDCl3, δ) 1.10 (d, 3H), 1.4-2.0 (m, 4H), 2.20 (q, 1H), 2.30-2.50 (m, 2H), 3.00-3.23 (m, 4H), 6.97 (s, 1H), 7.33 (d of d, 1H), 7.60 (d, 1H), 7.78 (d, 1H). MS (m/z): 324, 326 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=2)[CH2:25][CH2:24]1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(C)cc3)c3ccc(C)cc3)CC2)ccc1F

Procedure:
Example 10 prepared from bis(4-methylphenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.30–8.13 (m, 1H), 8.08–7.92 (br, 1H), 7.43–6.89 (m, 9H), 6.76–6.61 (br, 1H), 4.98–4.79 (br, 1H), 4.70 (s, 1H), 3.39–3.16 (m, 4H), 2.83–2.63 (m, 2H), 2.63–2.47 (m, 1H), 2.45–2.12 (m, 4H), 2.27 (s, 6H), 2.02–1.64 (m, 8H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 544.4 (M+H)+.
Reaction SMILES: CON(C)[C:4](=[O:47])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[CH3:49][Mg]Br>O1CCCC1.S([O-])(O)(=O)=O.[K+]>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][N:7]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@@H:6]([CH2:5][C:4](=[O:47])[CH3:49])[CH2:11]2)=[CH:17][CH:16]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 1 h

Procedure:
To a stirred solution of 0.79 g of N-methoxy-2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-N-methyl-acetamide in 10 ml of tetrahydrofuran are added 1.3 ml of a 3M solution of methyl magnesium bromide in tetrahydrofuran at 0° C. The reaction mixture is stirred for 1 hour, diluted with an aqueous solution of 1N potassium hydrogen sulfate, extracted with tert-butyl methyl ether. The organic phases are combined and dried over sodium sulfate. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.20 (EtOAc-heptane 1:1); Rt=5.14.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:13](Cl)(=[O:15])=[O:14])([O-:3])=[O:2].[NH2:17][C:18]1[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=1>C(Cl)Cl>[CH3:23][N:21]1[CH:22]=[C:18]([NH:17][S:13]([C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14])[CH:19]=[N:20]1
Reactant: Cn1cc(N)cn1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: Cn1cc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1
Temperature: -5 °C

Procedure:
2,4-Dinitrobenzenesulphonyl chloride (3.1 g) was added dropwise to a stirred solution of 4-amino-1-methylpyrazole (2.55 g) in methylene chloride (50 ml) that had been cooled to −5° C. The resultant mixture was stirred at this temperature for 5 minutes. The mixture was washed in turn with water, a 5% aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulphate and filtered. There was thus obtained a solution of N-(1-methylpyrazol-4-yl)-2,4-dinitrobenzenesulphonamide; Mass Spectrum: M+H+ 328.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[C:18]([CH3:24])[N:17]=3)[CH:13]=2)[N:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:7]=1[CH2:35][C:36]([OH:38])=[O:37])=[O:5])C.[OH-:39].[Na+]>CCO>[NH2:23][C:22]([C:21]1[C:16]([O:15][C:12]2[CH:11]=[C:10]3[C:9](=[CH:14][CH:13]=2)[N:8]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=2)[C:7]([CH2:6][C:4]([OH:3])=[O:5])=[C:35]3[C:36]([OH:38])=[O:37])=[N:17][C:18]([CH3:24])=[CH:19][CH:20]=1)=[O:39]
Reactant: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3nc(C)ccc3C#N)cc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(N)=O)c(Oc2ccc3c(c2)c(C(=O)O)c(CC(=O)O)n3-c2ccc(OC(C)C)cc2)n1
Temperature: 80 °C

Procedure:
The title compound was prepared in accordance with step (b) Example 24 from (2-carboxymethyl-5-(3-cyano-6-methyl-2-pyridinyloxy)-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (184 mg, 0.36 mmol, see step (b) Example 28), NaOH (aq, 2 M, 0.9 mL) and EtOH (1.5 mL). The mixture was heated at 80° C. for 4 h and the title compound was isolated as described before. Yield 40 mg (22%), mp 196° C.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1.[F:30][C:31]([F:35])([F:34])[CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:30][C:31]([F:35])([F:34])[CH2:32][O:17][C@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](OCC(F)(F)F)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 13.6 %

Procedure:
Di-tert-butyl azodicarboxylate (2.96 g, 12.83 mmol) was added to an ice cooled mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (2.00 g, 10.70 mmol), 2,2,2-trifluoroethanol (10.70 g, 106.95 mmol) and triphenylphosphine (3.37 g, 12.83 mmol) in THF (24 mL). The mixture was stirred at 70 C for 18 h. The mixture was concentrated under vacuum and the residue was purified by FCC, eluting with a gradient of EtOAc in heptane to afford tert-butyl (3S)-3-(2,2,2-trifluoroethoxy)pyrrolidine-1-carboxylate (0.393 g, 14%). This was dissolved in hydrogen chloride solution (4M in 1,4-dioxane, 3 mL, 12 mmol) and the mixture was stirred for 2 h. The mixture was concentrated to afford (3S)-3-(2,2,2-trifluoroethoxy)pyrrolidine hydrochloride (0.203 g, 68% yield). This was combined with 2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Intermediate 60, 0.1 g, 0.259 mmol) and potassium carbonate (0.13 g, 0.952 mmol) in DMF (2 mL) and the reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated and the residue dissolved in EtOAc. This was washed with saturated aq. sodium bicarbonate followed by brine, then dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC, Method D, to afford the title compound (0.006 g, 6%).
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13].[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16]>>[OH:19][C:15]([CH3:18])([CH3:17])[CH2:16][O:3][N:4]1[C:9]([CH3:10])([CH3:11])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13]
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Agent: OO
Product: CC(C)(O)CON1C(C)(C)CC(=O)CC1(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 2.5 %

Procedure:
A solution of 1.0 g (15 mmol) of 50% aqueous hydrogen peroxide in 5 mL of tert-butyl alcohol is added over 30 minutes at 60° C. to a mixture of 0.5 g (2.9 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one, 0.1 g (0.16 mmol) of N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(II) chloride (Jacobsen's catalyst), and 10 mL of tert-butyl alcohol. The reaction is stirred overnight at 60° C. Gas chromatography shows 2.5% of the title compound is present in the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Yield: 79 %

Procedure:
2-Amino-3-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one. 1-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 116 part a to d except using 3,5-dichloro-2-nitrobenzaldehyde (2.1 g) and decaborane (0.41 g) in part a to yield [2-(tert-butyldimethylsilanyloxy)propyl]-(3,5-dichloro-2-nitrobenzyl)amine (1.2 g, 32%). 3,5-Dichloro-2-nitrobenzaldehyde (2.2 g, 79%) was prepared by nitration of 3,5-dichlorobenzaldehyde (2.2 g) in a mixture of nitric acid (1.5 mL) and sulfuric acid (8 mL) at 0° C. for 30 minutes.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[C:8]([C:14]1[NH:18][N:17]=[N:16][N:15]=1)[C:7]2=[O:19])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[C:8]([C:14]1[NH:18][N:17]=[N:16][N:15]=1)[C:7]2=[O:19])[CH3:2]
Reactant: CC(=O)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a suspension of 0.128 part of 6-acetyl-3-(1H-tetrazol-5-yl)chromone in 5 parts by volume of methanol is added under stirring 0.020 part of sodium borohydride. The resulting mixture is stirred at room temperature for 2 minutes and then refluxed for 2 minutes. The solvent is distilled off and to the residue is added 10 parts by volume of 1N-hydrochloric acid. The resulting precipitates are recovered by filtration and recrystallized twice from ethanol to obtain 0.013 part of 6-(1-hydroxyethyl)-3-(1H-tetrazol-5-yl)chromone as colorless crystals melting at 234°-236° C(decomposition with foaming).
Reaction SMILES: C1C2C(COC([N:18]3[C@H:27]([C:28](O)=[O:29])[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:31]([C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH2:40][NH:41][CH2:42][CH2:43][C:38]=2[C:37](=[O:44])[O:36]1)[CH:32]([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:31]([C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH2:40][N:41]([C:28]([C@@H:27]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][NH:18]3)=[O:29])[CH2:42][CH2:43][C:38]=2[C:37](=[O:44])[O:36]1)[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)[C@@H]1Cc3ccccc3CN1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (147 mg, 0.369 mmol), 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol), and N,N′-diisopropylethylamine (112 mg, 0.870 mmol) in THF (5 mL) was added BOP reagent (144 mg, 0.326 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness, re-dissolved in 20% piperidine in DMF (5 mL), and stirred at room temperature for 1 hour. The crude reaction mixture was concentrated and purified by column chromatography (12 g, SiO2, 0 to 100% ethyl acetate in hexanes) to provide 3-isobutyl-3-phenyl-5-((S)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (54 mg, 68%) as a mixture of diastereoisomers in form of white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81-1.01 (m, 6H), 1.59-1.74 (m, 1H), 1.75-1.88 (m, 1H), 2.26-2.52 (m, 3H), 2.71-2.85 (m, 1H), 2.87-3.10 (m, 1H), 3.37-3.72 (m, 2H), 3.76-3.99 (m, 2H), 4.00-4.15 (m, 3H), 4.62-4.86 (m, 1H), 7.01-7.22 (m, 4H), 7.28-7.45 (m, 5H); MS m/z 431 (M+H)+, 429 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11](O)[CH3:12])[CH:8]=[CH:9][CH:10]=1.C1(P([N:33]=[N+:34]=[N-:35])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1(C)C=CC=CC=1>[N:33]([CH:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][C:3]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=1[NH2:1])[CH3:12])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1cccc(Oc2ccc(Cl)cc2N)c1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(N=[N+]=[N-])c1cccc(Oc2ccc(Cl)cc2N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the product from Example 170c in toluene (25 mL) was added diphenylphosphoryl azide (1.72 g, 6.23 mmol), followed by 1,8-diazabicyclo[4.3.0]undec-7-ene (0.95 g, 6.2 mmol). The mixture was stirred at 25° C. for 18 h. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The crude product was purified on silica gel, eluting with hexanes/ethyl acetate/methanol (85:17:3) to provide the title compound (700 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:50][C:51]1[CH:59]=[CH:58][C:54]([CH2:55][CH2:56][NH2:57])=[CH:53][CH:52]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:57][CH2:56][CH2:55][C:54]3[CH:58]=[CH:59][C:51]([CH3:50])=[CH:52][CH:53]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1ccc(CCN)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (75 mg, 0.20 mmol) and 1-hydroxybenzotriazole hydrate (34 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) at ambient temperature was added solid 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (47 mg, 0.24 mmol). The resulting solution was stirred at ambient temperature for 20 minutes, and 4-methylphenethylamine (30 mg, 0.23 mmol) was added. After stirring was at ambient temperature for a further 30 minutes, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with brine (2 mL), then dried over sodium sulfate and concentrated to afford ethyl 6-chloro-7-(4-(4-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless oil (96 mg, 96% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].CCN(CC)CC.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:31]([NH:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (1.20 g, 5.42 mmol) and Et3N (830 ml, 5.95 mmol) in THF (10 ml) was added phenyl isocyanate (650 ml, 5.98 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 3-methyl-4-(N′-phenylureido)phenylacetate (1.12 g, 61%) as a white crystalline powder. mp 143-145° C; 1H-NMR (CDCl3) δ1.47 (s, 9 H), 2.09 (s, 3 H), 3.47 (s, 2 H), 6.44 (s, 1H), 7.01-7.07 (m, 4 H), 7.16-7.27 (m, 2 H), 7.30-7.33 (m, 2 H), 7.45-7.47 (m, 1 H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.[O:26]1C[CH:27]1[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:39]=[C:38]([C:40]3[O:44][N:43]=[C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:41]=3[C:51]([F:54])([F:53])[F:52])[O:37][N:36]=2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[OH:26][CH:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:39]=[C:38]([C:40]3[O:44][N:43]=[C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:41]=3[C:51]([F:54])([F:53])[F:52])[O:37][N:36]=2)=[CH:31][CH:30]=1)[CH2:6][N:8]1[CH2:9][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Yield: 1.6 %

Procedure:
2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)acetic acid (53.9 mg, 0.250 mmol) was treated with TFA/DCM for 1 hour. Solvents were removed in vacuo and the resulting material was dried. The solids were dissolved in 2-propanol (5 mL) and 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (50 mg, 0.125 mmol) and cesium carbonate (245 mg, 0.751 mmol) were added. The reaction mixture was treated at 90° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. After concentration, the material was repurified by HPLC to yield 1 mg of 2-(1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)azetidin-3-yl)acetic acid as a TFA salt. MS (m+1)=515. HPLC Peak RT=3.24 minutes(Analytical Method A). Purity=95%.