Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=3)[CH:29]=[C:30](C(N3CCNCC3)=O)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].C(OC(CCC1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C(O)=O)C=C(C2C=CC=C(F)C=2)C=1)=O)C.C(O[C:97]([N:99]1[CH2:105][CH2:104][CH2:103][NH:102][CH2:101][CH2:100]1)=[O:98])(C)(C)C>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=3)[CH:29]=[C:30]([C:97]([N:99]3[CH2:105][CH2:104][CH2:103][NH:102][CH2:101][CH2:100]3)=[O:98])[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCNCC3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCCNCC3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared by the same method as 4-(2-(2-carboxy-ethyl)-3-{6-[3′-fluoro-5-(piperazine-1-carbonyl)-biphenyl-3-yloxy]-hexyl}-phenoxy)-butyric acid starting from 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid and [1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7]C2C(O)=CC=CC=2)=[CH:3][CH:2]=1.[C:15]1([CH2:21][C:22]2[CH:29]=[CH:28][CH:27]=[C:24]([CH:25]=[O:26])[C:23]=2[OH:30])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Br)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:4]1([CH2:7][O:30][C:23]2[C:22]([CH2:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:29][CH:28]=[CH:27][C:24]=2[CH:25]=[O:26])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Oc1ccccc1Cc1ccccc1
Reactant: O=Cc1cccc(Cc2ccccc2)c1O
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(Cc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Yield: 71 %

Procedure:
Using the method of Tramposch, Kung and Blau (J. Med. Chem. (1983) 26, 121), 2-hydroxydiphenylmethane was converted to 3-(phenylmethyl)salicylaldehyde in 56% yield: NMR (CDCl3) 11.35 (s, 1H), 9.35 (s, 1H), 7.45-6.85 (m, 8H), 4.00 (s, 2H); Mass spec (CI) 213. This hydroxyaldehyde (31.3 g, 0.147 mole) was treated with benzyl bromide (25.2 g, 0.147 mole) and potassium carbonate (22.1 g, 0.16 mole) in N,N-dimethylformamide (180 mL) at 100° overnight. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Distillation of the residue (170°-185°, 0.1 torr) provided the title material as a pale yellow viscous oil in 71% yield. NMR (CDCl3) 10.3 (s, 1H), 7.8-7.1 (m, 13H), 4.9 (s, 2H), 4.05 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[C:4]1[O:8][CH2:7][CH2:6][CH:5]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH2:10]([O:9][CH2:3][C:4]1[O:8][CH2:7][CH2:6][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC1=CCCO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C1=C(COCc2ccccc2)OCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.69 g of sodium hydride (as a 55% w/w suspension in mineral oil) were suspended in 150 ml of dimethylformamide, and 17.64 g of 4,5-dihydrofurfuryl alcohol (prepared as described in Preparation 48) in 30 ml of dimethylformamide were added dropwise at 5°-10° C. over 30 minutes, whilst ice-cooling. The mixture was stirred at room temperature for 1 hour, and then 20.93 ml of benzyl bromide were added dropwise thereto at 10°-15° C. over a further 30 minutes, whilst ice-cooling. The reaction mixture was stirred at room temperature for 1 hour, poured into 2 liters of water and extracted twice with ethyl acetate. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure, to give 17.8 g of an oily residue. This residue was purified by column chromatography through 400 g of silica gel. Those fractions eluted with a 7:100 by volume mixture of hexane and diethyl ether afforded 3.71 g of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+].O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20][OH:21])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1
Reactant: CSc1nccc(CC(=O)c2ccc(F)cc2)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CSc1nccc(CC(=NO)c2ccc(F)cc2)n1
Reaction time: 24 h
Yield: 498.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone (91.49 g,48 mmol) in acetonitrile (1.8 L) was added hydroxylamine hydrochloride (121 g, 91.7 mol) and sodium acetate (139 g, 1.7 mol). The reaction was stirred for 24 hours before 100 mL of water was added. The reaction was stirred for 24 hours. The mixture was filtered through a glass frit and the filtrate partitioned between dichloromethane and water. The layers were separated and the aqueous phase extracted with dichloromethane (2×500 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (300 mL), washed with brine (300 mL), dried over magnesium sulfate, filtered and concentrated. The residue was recrystalized from dichloromethane and hexanes to yield 66.4 g (69%) of 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone oxime. 1H NMR (CDCl3): δ 8.75 (m, 1H), 8.42 (d, 1H), 7.75 (dd, 2H), 7.09 (t, 2H), 6.98 (d, 1H), 4.29 (s, 2H), 2.54 (s, 3H). MS m/z 278 (M+1).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[O:28]>ClCCl>[OH:28][N:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:20])[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccccc1N=O
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccccc1N(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), 1-methyl-2-nitrosobenzene (121 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 60 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([CH3:18])=[CH:16][C:15](=[O:19])[NH:14]1)=[O:12].Cl[Si](C)(C)C.[Cl:40][CH2:41][CH2:42]OS(C(F)(F)F)(=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17](=[CH2:18])[CH:16]([CH2:42][CH2:41][Cl:40])[C:15](=[O:19])[NH:14]1)=[O:12]
Reactant: COC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC(=O)C=C1C
Reactant: O=S(=O)(OCCCl)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C1C(CCCl)C(=O)NC1(C(=O)OC)C(O[Si](C)(C)C(C)(C)C)C1CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Lithium diisopropylamide solution (0.67 M solution in tetrahydrofuran, 0.09 ml, 0.06 mmol, 1.0 equiv) was added dropwise via syringe to a stirred solution of 2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (23 mg, 0.06 mmol, 1.0 equiv) in tetrahydrofuran (1.5 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Chlorotrimethylsilane (8 μl, 6.8 mg, 0.06 mmol, 1.0 equiv) was added and the resultant solution was stirred at −78° C. for 2.5 h. Another equiv of lithium diisopropylamide solution (0.67 M solution in tetrahydrofuran, 0.09 ml, 0.06 mmol, 1.0 equiv) was added dropwise at −78° C. The reaction mixture was stirred −78° C. for 30 min. A stock solution of trifluoro-methanesulfonic acid 2-chloro-ethyl ester in toluene (2.45 M, 0.1 ml, 0.24 mmol, 4.0 equiv) was added dropwise via syringe at −78° C. The reaction mixture was stirred at −78° C. for 50 min. A buffer solution (pH=7, 5 ml) was added at −78° C. The organic layer was separated, washed with brine solution (5 ml), dried over sodium sulfate and the solids were filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (10% ethyl acetate-hexanes initially, grading to 20% ethyl acetate-hexanes) to furnish 2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-4-(2-chloro-ethyl)-3-methylene-5-oxo-pyrrolidine-2-carboxylic acid methyl ester (16 mg, 59%) along with recovered starting material (5 mg, 22%).
Reaction SMILES: C(NC(C)C)(C)C.[Li].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[Li+].CC([N-]C(C)C)C.[CH3:40][C:41]([S:44]([N:46]=[C:47]1[CH2:50][O:49][CH2:48]1)=[O:45])([CH3:43])[CH3:42]>C1COCC1>[CH3:43][C:41]([S:44]([NH:46][C:47]1([C:19]2[S:20][C:16]([C:14]3[CH:13]=[C:12]([NH:21][C:22]4[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH:11]=[C:10]([CH3:9])[CH:15]=3)=[CH:17][N:18]=2)[CH2:50][O:49][CH2:48]1)=[O:45])([CH3:40])[CH3:42]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)COC3)s2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A solution of lithium diisopropylamine (1.8 M, 4.96 mL, 8.92 mmol) in THF (8 mL) was placed under an Argon atmosphere and was cooled to −78° C. A solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 4, 1200 mg, 3.57 mmol) in THF (8 mL) was cooled to −78° C. and added drop wise to the LDA solution. The reaction mixture was stirred 30 minutes at −78° C. The product of Step 1 (625 mg, 3.57 mmol) in THF (8 mL) was added drop wise and the reaction was allowed to warm to room temperature overnight. The mixture was quenched with brine, diluted with ethyl acetate. The organics were washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (20-100% ethyl acetate in hexanes) to afford 2-methyl-N-{3-[5-(3-methyl-5-[[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl]propane-2-sulfinamide (1.10 g, 2.140 mmol, 60.0% yield). MS ESI: [M+H]+ m/z 512.1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C>[N:1]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1CN=[N+]=[N-]
Reaction time: 8 h

Procedure:
Sodium azide (158 mg, 2.43 mmol) was added to a solution of methyl 2-(bromomethyl)-5-chlorobenzoate (518 mg, 1.97 mmol) in 3 mL of DMF at room temperature. After stirring overnight, reaction mixture was quenched with 25 mL of water. Aqueous was extracted with ethyl acetate (3×30 mL) and combined organics were washed with water (2×40 mL) and 50 mL of brine. Organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield methyl 2-(azidomethyl)-5-chlorobenzoate which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]12[CH:10]([OH:11])[O:9][CH2:8][CH:7]1[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:11][CH:10]1[O:9][CH2:8][CH:7]2[C:2]1([CH3:1])[CH:3]1[CH2:12][CH:6]2[CH2:5][CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC12C3CCC(C3)C1COC2O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1OCC2C3CCC(C3)C12C
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of 63 g of 2-methyl-4-oxatricyclo[5.2.1.02,6]decan-3-ol, 42 g of pyridine, and 51 g of acetic anhydride was heated at 50° C. for 5 hours. The reaction mixture was concentrated. The concentrate was purified by distillation, obtaining 74 g (yield 96%) of the target compound.
Reaction SMILES: [C:1]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:2].N1CCCCC1.[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45]([NH:47][CH2:48][C:49]3[CH:57]=[CH:56][C:52](C(O)=O)=[CH:51][CH:50]=3)=[O:46])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C.C(N(CC)C(C)C)C>[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45]([NH:47][CH2:48][C:49]3[CH:50]=[CH:51][C:52]([C:1]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:2])=[CH:56][CH:57]=3)=[O:46])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCC1c2ccccc2-c2ccccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CCN(CC)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C(O)CCNC(=O)c1ccc(CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To the above resin bound Fmoc β-alanine was added 500 μL of a 20% solution of piperidine in DMF. Upon shaking for 30 min, the resin was drained and washed with 1 mL DMF containing 1-hydroxybenzotriazole (50 mg/mL) and DMF (2×1 mL). Then 200 μmol 4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]benzoic acid (74.2 mg) dissolved in a mixture of 430 μL DMF and 70 μL diethylisopropylamine was added followed by 200 μmol bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 93 mg) dissolved in 500 μL DMF. The mixture was shaken for 4 hours at 25° C. followed by filtration and washing of the resin with 3×1 mL DMF.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][C@H:9]([NH2:11])[CH2:8][CH2:7][N:6]1[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4].[OH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](O)=[O:31]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][C@H:9]([NH:11][C:30]([C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]=2[OH:19])=[O:31])[CH2:8][CH2:7][N:6]1[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)CCN1CC1CCCCC1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CCN1CC1CCCCC1

Procedure:
(2S,4R)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]piperidine-2-carboxylic acid methyl ester was prepared from (2S,4R)-4-amino-1-cyclohexylmethyl-piperidine-2-carboxylic acid methyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C25H33N2O4 [(M+H)+] 425, obsd. 425.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].Cl[C:15]1[N:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:1][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=2[CH:12]=[O:13])[N:16]=[N:17][CH:18]=1
Reactant: COc1cnnc(Cl)c1
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1O
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1cnnc(Oc2c(C=O)c(C(F)(F)F)nn2C)c1
Yield: 55.8 %

Procedure:
5-Hydroxy-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxaldehyde (3.0 g, 0.015 mole), 3-chloro-5-methoxypyridazine (2.3 g, 0.015 mole), 2,6-lutidine (2.8 g, 0.025 mole), and toluene (80 mL) were heated in a flask equipped with a short Vigreux column until 5 mL of solvent had distilled. The mixture was then held at reflux for 4 hours, cooled, poured into 1% hydrochloric acid, and extracted with a mixture of ether and ethyl acetate. The combined extracts were washed with 1% hydrochloric acid, 1% sodium hydroxide, 5% sodium chloride, then dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/cyclohexane to give 5-[(5-methoxy-3-pyridazinyl)oxy]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxaldehyde (2.53 g, 55% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]3)[N:7]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:6]=2[CH:21]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:32](=[O:33])[CH2:31][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:35][C:36]4[CH:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:37]=4)[CH2:11]3)[N:7]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:6]=2[CH:21]=1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(Cl)cc21

Procedure:
(R)-6-Chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (32D) (0.135 mmol, 0.055 g) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.197 mmol, 0.053 g) and N-methylmorpholine (0.706 mmol, 0.079 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.197 mmol, 0.075 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-Butyl (R)-4-((R)-3-(6-chloro-1-(3-methoxypropyl)-1H-benz o[d]imidazol-2-yl)piperidine-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (32E) as a clear oil that was used directly onto the next step. ESI-MS: m/z 619.5 (M+H)+,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14]O)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:40])CC)C.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][F:40])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:33])([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCO)c1=O)c1cccc(C(F)(F)F)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCF)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
50 mg (0.10 mmol) of 2-[3-(4-chlorophenyl)-4-(2-hydroxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 396 are dissolved in 1.5 ml of dichloromethane and treated at −10° C. with 20.5 μl (0.155 mmol) of diethylaminosulphur trifluoride. This is warmed to RT within 1 hr. Next, the reaction solution is treated with 5 ml of water and extracted twice with 5 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 37 mg (73% of theory) of the target compound are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(O)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.5 %

Procedure:
A solution of 4-amino-phenol (1.00 g, 9.2 mmol) and triethylamine (1.42 ml, 10.1 mmol) was cooled to 0° C. and 4-trifluoromethyl-benzoyl chloride (1.36 ml, 9.2 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction mixture was poured in water (50 ml). A precipitate was collected by filtration and taken up in ethyl acetate (200 ml). The organic solution was washed with 1N HCl (100 ml), water (100 ml), brine (100 ml), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound as a pale yellow solid (1.98 g, 77% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:15]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[CH:26]=1)[CH:22]=O)([CH3:17])[CH3:16].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:21]2[CH:24]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[CH:26]=[C:19]([O:18][CH:15]([CH3:17])[CH3:16])[CH:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Oc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)cc(OC(C)C)c1
Temperature: 100 °C

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (4.0 g, 20.0 mmol, 1.0 equiv), 3,5-diisopropoxy-benzaldehyde (5.33 g, 24.0 mmol, 1.2 equiv; intermediate D7, vide infra) and acetic acid (4.6 mL, 4.80 g, 80.0 mmol, 4.0 equiv) in ethanol (16 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyanoborohydride (2.51 g, 40.0 mmol, 2.0 equiv), dissolved in ethanol (8 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 10 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified on a Isolute flash NH2 chromatography column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.23 g (40%) of the title compound. MS (ISP): 407.4 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7](O)(=O)[C:8]([CH3:11])([CH3:10])[CH3:9].P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1>[C:8]([C:11]1[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]=1)([CH3:10])([CH3:9])[CH3:7]
Reactant: CNC(=S)NN
Reactant: CC(C)(C)C(=O)O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CNc1nnc(C(C)(C)C)s1
Yield: 80 %

Procedure:
To a solution of 91.6 g of 4-methylthiosemicarbazide and 102.3 g of pivalic acid in 400 ml of dioxane at 90° is added slowly 160.5 g of phosphorus oxychloride at such a rate that the reaction temperature is maintained at 85°-90° C. without external heating. When the addition is complete, the mixture is heated at 85°-90° C until HCl evolution ceases (several hours), is cooled and the supernatant liquid decanted from the solid mass in the flask. The mass is broken up, slurried with 700 ml of water and made basic (pH 8-9) by the slow addition of sodium hydroxide pellets. The resulting precipitate is filtered, washed with water, air dried and recrystallized from hexane to give 119.4 g (80% yield) of 2-tert.butyl-5-methylamino-1,3,4-thiadiazole, m.p. 79°-81°.