Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([N:25]3C(=O)C4C(=CC=CC=4)C3=O)[CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.O.NN>O1CCCC1>[CH3:1][C:2]1[C:3]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2ccccc2)n1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(C)c(C(=NOCc2cccc(N)n2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
To a solution of 2-{6-[({[(3,6-dimethylpyrazin-2-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (4.08 g, 8.80 mmol) in tetrahydrofuran (60 mL) was added dropwise hydrazine hydrate (2.14 mL, 44.0 mmol). After stirring at room temperature for 6 h, the reaction mixture was filtered, the insolubles washed with ethyl acetate, and the combined filtrates concentrated in vacuo, diluted in ethyl acetate (100 mL), washed with water (70 mL), dried over MgSO4 and concentrated to dryness in vacuo. Purification on silica gel afforded 6-[({[(3,6-dimethylpyrazin-2-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine [1.97 g, yield 64%; HPLC/MS: m/z=334 (M+H); log P(HCOOH)=1.31].
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:23][C@H:24]1[O:29][C@@H:28]([CH3:30])[CH2:27][NH:26][CH2:25]1>C1COCC1>[CH3:30][C@H:28]1[O:29][C@@H:24]([CH3:23])[CH2:25][N:26]([C:2]2[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:27]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(C(=O)O)ccc(F)c2F)C[C@H](C)O1
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2,3,4-trifluorobenzoic acid (25.0 g, 142 mmol) in THF (250 mL), was added lithium bis(trimethylsilyl)amide (1M in THF, 156 mL, 156 mmol) at −78° C. under nitrogen atmosphere and the solution stirred for 45 min. To this was added a premixed solution of cis-2,6-dimethylmorpholine (17.4 mL, 142 mmol) and lithium bis(trimethylsilyl)amide (1M in THF, 156 mL, 156 mmol) (which was stirred for 45 minutes at −78° C., before the addition was made) and stirring continued for 1 h at −78° C. It was brought to room temperature and stirring continued for additional 12 hours. Solvents were evaporated and the residue dissolved in ethyl acetate, which was washed with 1N HCl, water and brine. The organic layer was dried and concentrated to give the title compound as semi-solid. Yield: 27.5 g, (72%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH2:13]([N:20]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.O>[CH2:13]([N:20]1[CH2:24][CH2:23][C@H:22]([NH:25][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc(CN2CC[C@H](NCc3ccc4ccccc4c3)C2)cc1
Reaction time: 18 h

Procedure:
A solution of 2-naphthaldehyde (2.0 g, 12.8 mmol) and (3S)-1-benzyl-3-amino-pyrrolidine (2.37 g, 13.4 mmol) in methanol (30 mL) was stirred under nitrogen at room temperature for 6 hours. Sodium borohydride (969 mg, 25.6 mmol) was added and the reaction mixture left at room temperature for 18 hours. The reaction mixture was diluted with water and extracted into ethyl acetate (×3) and the organics were combined, dried over magnesium sulphate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:0 to 97:3 to yield the title product, 4.01 g.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]3[N:22]=[C:21]4[C:16]([C:17](=[O:31])[C:18]([C:28]([OH:30])=[O:29])=[CH:19][N:20]4[C:23]45[CH2:27][CH:25]([CH2:26]4)[CH2:24]5)=[CH:15][C:14]=3[F:32])[CH2:8]2)C=CC=CC=1.[CH3:33]S([O-])(=O)=O>>[CH3:1][CH:7]1[N:12]([CH3:33])[CH2:11][CH2:10][N:9]([C:13]2[N:22]=[C:21]3[C:16]([C:17](=[O:31])[C:18]([C:28]([OH:30])=[O:29])=[CH:19][N:20]3[C:23]34[CH2:27][CH:25]([CH2:26]3)[CH2:24]4)=[CH:15][C:14]=2[F:32])[CH2:8]1
Reactant: O=C(O)c1cn(C23CC(C2)C3)c2nc(N3CCNC(c4ccccc4)C3)c(F)cc2c1=O
Reactant: CS(=O)(=O)[O-]
Product: CC1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C23CC(C2)C3)CCN1C

Procedure:
7-(3-phenyl-1-piperazinyl)-1-(bicyclo[1.1.1]pent-1-yl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonate;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1ccc(F)cc1F
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccc(F)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(2,4-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].[N:17]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>Cl.O>[C:11]1([C:3]2[C:2]3[N:1]=[N:17][NH:10][C:8](=[O:9])[C:7]=3[CH:6]=[CH:5][N:4]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1ccnc(-c2ccccc2)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]nnc2c(-c3ccccc3)nccc12
Yield: 62.5 %

Procedure:
639 mg of 3-amino-2-phenyl-4-pyridinecarboxamide in 7 ml of concentrated hydrochloric acid were stirred in an ice-bath during the addition of 240 mg of sodium nitrite in 2 ml of water. After 0.5 hour aqueous sodium bicarbonate solution was added until the mixture was basic and the produce was then extracted into ethyl acetate. The ethyl acetate extract was dried over sodium sulphate and evaporated, and the residue was recrystallized from ethanol to yield 420 mg of 8-phenylpyrido[3,4-d]-1,2,3-triazin-4(3H)-one of melting point 211° C. (dec.)
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[C:8]1([CH3:22])[CH:13]=[CH:12][C:11]([S:14]([NH:17][NH:18][C:19]([NH2:21])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[OH-].[K+]>O>[C:8]1([CH3:22])[CH:9]=[CH:10][C:11]([S:14]([N:17]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[NH:18][C:19](=[O:20])[NH2:21])(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)NNC(N)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(NC(N)=O)C(=O)OC(C)C)cc1
Temperature: 10 °C

Procedure:
The reaction is conducted in a 2 liter reaction flask equipped with thermometer, mechanical stirrer, dropping funnel, and an ice-water bath. 400 ml. water is placed in the flask and cooled to 10° C. Then 73.4 g. (0.6 mole) of isopropyl chloroformate is added. The mixture is stirred at 10° C. as a filtered solution of 114.5 g. (0.5 moles) of p-toluenesulfonyl semicarbazide in a mixture of 36.5 g. (0.55 mole) of KOH in 400 ml. of water is dropped in over the period of an hour, keeping the temperature near 10° C. (A small amount (7.5 g.) of caustic insoluble solid is filtered from the p-toluenesultonyl semicarbazide salt solution). The reaction mixture in the flask is stirred for an additional hour as the temperature is allowed to rise to 25° C. (the cooling bath is removed). A heating mantle is applied and the stirred mixture is warmed to 45° C. The warm mixture is then filtered and the white crystalline product washed with water and dried overnight at 60° C. in a circulating hot air oven. Yield 145 g. (98.4%). m.p. 210°-212° C. A sample is treated with concentrated ammonium hydroxide, washed with water and dried. m.p.=211°-213° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16]C(C)(C)C)[CH2:13][C@H:12]1[C:21]1[O:22][C:23]([CH3:26])=[CH:24][N:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:21]1[O:22][C:23]([CH3:26])=[CH:24][N:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc([C@@H]2C[C@@H](OC(C)(C)C)CN2C(=O)OCc2ccccc2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc([C@@H]2C[C@@H](O)CN2C(=O)OCc2ccccc2)o1
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a stirred solution of (2S,4R)-4-tert-butoxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester (2 g, 5.59 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (1.57 mL) in dichloromethane (1:5) at 0° C. and the mixture was then stirred at room temp. for 16 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was then purified by column chromatography to give (2S,4R)-4-hydroxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester (1.1 g, 65.1% yield) as an off white solid. MS calcd. for C16H19N2O4 [(M+H)+] 303.0, obsd. 303.4.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.Br[CH2:19][C:20]([C:22]1[CH:23]=[C+:24][CH:25]=[CH:26][CH:27]=1)=O>C(O)CCC.[Cl-].[Na+].O>[C:7]1([C:5]2[N:6]3[CH:19]=[C:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:1]=[C:2]3[S:3][C:4]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Reactant: O=C(CBr)C1=CC=C[C+]=C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: CCOC(=O)c1sc2nc(-c3ccccc3)cn2c1-c1ccccc1
Temperature: 25 °C
Yield: 18.3 %

Procedure:
A solution of ethyl 2-amino-4-phenylthiazole-5-carboxylate 93 (0.7 g, 2.82 mmol) and 3-(2-bromoacetyl)benzene-1-ylium 68 (0.34 mL, 2.82 mmol) was stirred at 120° C. in butanol (9 mL) for 3 d. The solution was cooled to room temperature, diluted with brine and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to afford ethyl 3,6-diphenylimidazo[2,1-b]thiazole-2-carboxylate 94 (0.18 g, 18% yield) as a tan solid after purification by flash chromatography (0 to 30% MeOH in ethyl acetate) followed by trituration in hexane. LRMS (ESI): (calc) 348.42 (found) 349.2 (MH)+
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([C:26]2[N:31]=[C:30]3[N:32]([CH3:39])[C:33]4[CH2:38][CH2:37][NH:36][CH2:35][C:34]=4[C:29]3=[CH:28][CH:27]=2)[C:22](=[O:40])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([N:36]1[CH2:37][CH2:38][C:33]2[N:32]([CH3:39])[C:30]3[C:29]([C:34]=2[CH2:35]1)=[CH:28][CH:27]=[C:26]([N:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:21][C:22]1=[O:40])[N:31]=3)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc31)CNCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc3n2C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Triethylamine (33 μL, 0.24 mmol), DMAP (5.8 mg, 0.048 mmol) and acetyl chloride (25 μL, 0.36 mmol) were added to a solution of 4-(benzyloxy)-1-(9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2(1H)-one (93 mg, 0.24 mmol) in CH2Cl2 (14 mL) and the resulting solution was stirred at ambient temperature for 2 h under N2. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 0:100 over 20 column volumes and held for 5 column volumes) gave the title compound (86 mg, 83%) as an off-white powder and a mixture of rotomers: mp 206-208° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.01 (t, J=8.5 Hz, 1H), 7.80 (dd, J=7.5, 2.5 Hz, 1H), 7.49-7.36 (m, 5H), 7.33-7.26 (m, 1H), 6.15 (dd, J=8.0, 3.0 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 4.71-4.66 (m, 2H), 3.90-3.81 (m, 2H), 3.67 (m, 3H), 3.00-2.86 (m, 2H), 2.16-2.10 (m, 3H); ESI MS m/z 429 [M+H]; HPLC (Method A)>99% (AUC), tR=18.2 min.
Reaction SMILES: C(OP([CH:9]([C:17]#[N:18])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=O)OCC)C.[F:19][C:20]1[CH:21]=[CH:22][C:23]([N+:28]([O-:30])=[O:29])=[C:24]([CH:27]=1)[CH:25]=O>C1COCC1.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N+:28]([O-:30])=[O:29])=[C:24]([CH:25]=[C:9]([CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:17]#[N:18])[CH:27]=1
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CCOP(=O)(OCC)C(C#N)CC1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC(=Cc1cc(F)ccc1[N+](=O)[O-])CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
[1-Cyano-2-(tetrahydro-pyran-4-yl)-ethyl]-phosphonic acid diethyl ester (5.4 g, 19.6 mmol) was dissolved in THF (100 mL) and cooled to 0° C. Lithium (bistrimethylsilyl)amide (20 mL, 20 mmol, [1M]) was the added dropwise. The resulting mixture was stirred 20 min, and then 5-fluoro-2-nitro-benzaldehyde (3.31 g, 19.6 mmol) was added. The resulting mixture was stirred at room temperature overnight, then diluted with ethyl acetate and washed with saturated aqueous NaHCO3 solution. The organic phase was separated and dried with MgSO4 and filtered. The solvent was removed to yield an oil which was purified by silica column chromatography (120 g column, 20% EtOAc/heptane) to yield a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)=[CH:3][CH:2]=1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH:19][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[N:23]=[C:22]([C:21]([F:37])([F:36])[F:20])[O:26][N:25]=5)[CH:28]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[S:10][CH:11]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccncc3)cs2)CCOCC1
Product: O=C(NCC1(c2nc(-c3ccncc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 38 %

Procedure:
This compound was synthesized from (4-(4-(pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (60 mg, yield 38%): 1H NMR (400 MHz, DMSO-d6) δ 8.82 (t, J=6.3 Hz, 1H), 8.57 (d, J=5.8 Hz, 2H), 8.45 (s, 1H), 8.40 (s, 1H), 8.19 (d, J=7.9 Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.87 (d, J=5.8 Hz, 2H), 7.70 (t, J=7.8 Hz, 1H), 3.87-3.84 (dt, J=12.1 Hz, 3.4 Hz, 2H), 3.59-3.58 (d, J=6.1 Hz, 2H), 3.42 (m, 2H), 2.28-2.24 (d, J=13.4 Hz, 2H), 2.04-1.96 (m, 2H). MS (ESI) m/z: Calculated for C24H20F3N6O3S: 515.12. found: 516.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[NH2:39][CH2:40][CH2:41][C:42]([CH3:45])([OH:44])[CH3:43].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:39][CH2:40][CH2:41][C:42]([OH:44])([CH3:45])[CH3:43])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(O)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 27.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.046 mL, 0.417 mmol), 4-amino-2-methylbutan-2-ol (12.92 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention time=34.1 min) to give (R/S)-2-hydroxy-N-(3-hydroxy-3-methylbutyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (10.5 mg, 0.019 mmol, 26.9% yield): LCMS=517 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.23 (2 H, m), 7.65-7.77 (4 H, m), 7.54-7.66 (3 H, m), 5.10 (1 H, s), 3.32-3.42 (2 H, m), 1.62-1.78 (2 H, m), 1.22 (6 H, s). HPLC Peak RT=9.2 min (Analytical Method A).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:13]([O:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:13]([O:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][CH:22]=1)[O:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: OCC1CCC2(CC1)OCCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(COc2cccc(OCC3CCC4(CC3)OCCO4)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]dec-8-ylmethanol (946 mg), 3-(benzyloxy)phenol (1 g), and triphenylphosphine (1.57 g) in THF (15 mL) was added azodicarboxylate diethyl (944 μL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction liquid was concentrated under reduced pressure, benzene was added to the residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=92/8-85/15) to obtain 8-{[3-(benzyloxy)phenoxy]methyl}-1,4-dioxaspiro[4.5]decane (846 mg).
Reaction SMILES: O[C:2]1([CH:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[N:12]=[CH:11][NH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[N:12]=[CH:11][NH:10][N:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(=C2CCCC2)c2nc[nH]n2)cc1
Reaction time: 2 h
Yield: 31.2 %

Procedure:
7.21 g of crude 4-[1-hydroxycyclopent-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 50 ml of dichloromethane at 0° and stirred at 0° with 24 ml of thionyl chloride for 1 hour. Then the mixture is concentrated to dryness under vacuum, dissolved in 50 ml of dichloromethane, stirred for 2 hours with 32 ml of triethylamine, diluted with water, extracted four times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus obtaining 2.1 g of 4-[1-cyclopentylidene-1-(1,2,4triazolyl)methyl]benzonitrile as the free base, mp 72°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]1.[H-].[Na+].I[CH3:22]>C1COCC1>[OH:13][C:10]([CH3:12])([CH3:11])[CH2:9][C:8]1[N:4]([CH2:3][CH2:2][O:1][CH3:22])[N:5]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1cc(CC(C)(C)O)n(CCO)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CC(C)(C)O)n(CCOC)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of ethyl 1-(2-hydroxyethyl)-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carboxylate (24.6 g, 95.9 mmol) in THF (191 mL) was cooled to 0° C. Sodium hydride (4.6 g of a 60% dispersion in mineral oil, 110 mmol) was added, and iodomethane (6.6 mL, 105 mmol) was added dropwise over a period of ten minutes. The reaction was allowed to warm to ambient temperature and stirred for six hours. The work-up procedure described in Part B of Example 1255 was followed to provide ethyl 5-(2-hydroxy-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate as a light brown oil.
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([I:14])=[C:5]([C:9]([I:13])=[CH:10][C:11]=1[I:12])[C:6]([NH2:8])=[O:7].Br[CH2:16][C:17]([O:19]CC)=[O:18]>C(O)C>[C:6]([C:5]1[C:4]([I:14])=[C:3]([C:11]([I:12])=[CH:10][C:9]=1[I:13])[O:2][CH2:16][C:17]([OH:19])=[O:18])(=[O:7])[NH2:8]
Reactant: NC(=O)c1c(I)cc(I)c(O)c1I
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1c(I)cc(I)c(OCC(=O)O)c1I
Yield: 93.7 %

Procedure:
0.436 g (19 mmol) of sodium is dissolved in 20 ml of ethanol. Then 9.78 g (19 mmol) of 3-hydroxy-2,4,6-triiodobenzamide and subsequently 3.5 g (21 mmol) of ethyl bromoacetate are added thereto. The mixture is heated for one hour to reflux and, after several hours of stirring in an ice bath, the resultant 3-carbamoyl-2,4,6-triiodophenoxyacetic acid ethyl ester is vacuum-filtered, washed with a small amount of ice-cold ethanol, and suspended in 80 ml of water. The mixture is brought to pH 12 by adding concentrated sodium hydroxide solution, stirred for 30 minutes at 60° C., the solution is treated with 1 g of active carbon, filtered, and brought to pH 1 by the dropwise addition of dilute hydrochloric acid. After several hours of stirring in an ice bath, the thus-formed precipitate is vacuum-filtered, washed with water, and dried, thus obtaining 10.2 g (89% of theory) of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid as a white powder, mp 211°-213° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:36])=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[OH:37]C1C=C(O)C=CC=1C(=O)C.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][C:3]([OH:37])=[CH:4][C:5]=2[OH:36])[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(O)cc4O)ccc3c1)n2C1CCCCC1
Yield: 8 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2,4-dihydroxy-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (9.5 mg, 8% yield).