Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C:4](=[O:8])[NH:3]1.[C:9]1([CH2:15][CH2:16][C:17](Cl)=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN1CCOCC1>C(OCC)(=O)C>[C:9]1([CH2:15][CH2:16][C:17]([N:3]2[C@@H:2]([CH3:1])[C:6](=[O:7])[O:5][C:4]2=[O:8])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H]1NC(=O)OC1=O
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: C[C@H]1C(=O)OC(=O)N1C(=O)CCc1ccccc1
Reaction time: 2 h
Yield: 55 %

Procedure:
(S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of 3-phenylpropanoyl chloride (658 mg, 3.9 mmol) under ice cooling. Further, a solution of N-methyl-morpholine (394 mg, 3.9 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes, and the resulting mixture was then stirred at the same temperature for 2 hours. The reaction mixture was treated in a similar manner as in Synthesis Process 5 of Example 8 to afford the title compound (408 mg, 55%) as a colorless clear syrup.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:14])[C:7]([CH3:13])=[C:8]([CH3:12])[C:9](=[O:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:15](O)(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C.C(#N)C>[N+]([O-])([O-])=O.[Ag+].O.CCCCCCC>[C:1]([C:5]1[C:6](=[O:14])[C:7]([CH3:13])=[C:8]([CH3:12])[C:9](=[O:11])[C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C(C)C(=O)C(C(C)(C)C)=CC1=O
Reactant: CCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: CCCCCCC
Product: CCCCCCC1=C(C(C)(C)C)C(=O)C(C)=C(C)C1=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 8.6 %

Procedure:
To a 250 ml round bottom flask equipped with a stir-bar was added 5-tert-butyl-2,3-dimethyl-[1,4]benzoquinone (213; 0.68 g, 3.5 mmole), heptanoic acid (0.49 g, 3.7 mmole), AgNO3 (0.64 g, 3.8 mmole), acetonitrile (50 ml) and water (50 ml). The fully homogenous solution was heated to 70° C. under argon while an aqueous solution of K2S2O8 (0.91 g, 4.1 mmole in 30 ml water) was added dropwise over 2.5 hours using a syringe pump. The reaction mixture was allowed to stir an additional 30 minutes at 70° C., then cooled to room temperature. To the mixture was added heptane (100 ml) and water (100 ml). The organic layer was separated and washed with saturated NaHCO3 (1×50 ml) followed by brine (2×100 ml). The organic layer was dried over sodium sulfate and concentrated to a yellow oil. The crude product was further purified by preparative TLC (silica gel: 200×200×2 mm; 100% heptane loading; 5% EtOAc:heptane elution). The fastest running bands, as visualized by UV, were excised, extracted from the silica gel with methyl tert-butyl ether, and the extract concentrated to a yellow oil to give a yellow oil. The residue was further purified by flash chromatography [silica gel: 40 g; 0-20% 100% heptane loading; 0-20% EtOAc/heptane gradient elution] to give pure 2-tert-butyl-3-hexyl-5,6-dimethyl-[1,4]benzoquinone (214; 83 mg, 8.4%) as a yellow oil. 1H NMR (400 MHz; C6D6; ppm): 2.71-2.67 (m, 2H), 1.67-1.66 (m, 6H), 1.51-1.24 (m, 8H), 1.37 (s, 9H), 0.88 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.CN.NC(N)=O.C(CC(O)=O)#N.N[C:24]1[N:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:28](=[O:37])[N:27]([CH3:38])[C:26](=[O:39])[CH:25]=1>>[CH3:26][NH:27][C:28]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:37].[CH3:28][N:29]([CH3:30])[C:24]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9](=[O:10])[N:27]([CH3:38])[C:26](=[O:39])[CH:25]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cn1c(=O)cc(N)n(-c2ccc(F)cc2)c1=O
Agent: CN
Agent: N#CCC(=O)O
Agent: NC(N)=O
Product: CN(C)c1cc(=O)n(C)c(=O)n1-c1ccc(F)cc1
Product: CNC(=O)Nc1ccc(F)cc1

Procedure:
N-Methyl-N'-(4-fluorophenyl)urea was prepared preliminarily from 4-fluorophenyl isocyanate and methylamine by the same procedure as in Reference Example 1. The urea compound as the starting material was reacted with cyanoacetic acid to form a uracil ring. Subsequently, 6-amino-1-(4-fluorophenyl)-3-methyluracil was treated as in Reference Example 2 so that the substituent amino group at the 6-position was converted to a dimethylamino group to yield 6-dimethylamino-1-(4-fluorophenyl)-3-methyluracil. Using a mixed acid that had been prepared with sulfuric acid and nitric acid, a nitro group was introduced into the 5-position of the uracil ring and then reduced with hydrogen gas to prepare 5-amino-6-dimethylamino-1-(4-fluorophenyl)-3-methyluracil.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].CS(C)=O.[Cl-].[NH2:25][C:26]([NH2:28])=[NH2+:27].[OH-].[Na+]>O>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([N:25]=[C:26]([NH2:28])[NH2:27])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=C(N)N)nn12
Yield: 32.2 %

Procedure:
3.36 g 3-(5-nitro-1-methyl-2-imidazolyl)-6-chloro-s-triazolo[ 4,3-b] pyridazine were dissolved in 30 ml. dimethyl sulfoxide and mixed at 70°C., while stirring, with 3.4 g guanidinium chloride. 5 ml. water were then added thereto, followed by the dropwise addition of 2.4 ml. 1ON aqueous sodium hydroxide solution, whereafter the reaction mixture was further stirred for an hour at 70°C. After cooling and diluting with water, the precipitated crystals were filtered off with suction, washed with water and dried in a vacuum. 2.5 g of crude product were thus obtained which, after recrystallization from 25 ml. dimethyl formamide, with the addition of active charcoal, gave 1.17 g 3-(5-nitro-1-methyl-2-imidazolyl)-6-(diaminomethylene-amino)-s-triazolo [4,3-b] pyridazine in the form of a yellow material which melted, with decomposition, at 278° - 280°C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH:14]([CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:37])[NH:22][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])[CH3:13].C(N(CC)CC)C>>[C:12]([CH:14]([CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:37])[NH:22][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])(=[O:11])[CH3:13]
Reactant: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)cc1OC

Procedure:
Analogously to Example 40A, 0.76 g (6.00 mmol) of oxalyl chloride, 1.01 g (12.9 mmol) of dimethyl sulphoxide, 1.95 g (3.93 mmol) of 2-(1-hydroxyethyl)-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenyl-pentanamide and 4.36 g (43.1 mmol) of triethylamine are reacted to give 2-acetyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenylpentanamide.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].O[C:34]1[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37].C1CCC(N=C=NC2CCCCC2)CC1>CC#N.C1COCC1.CN(C1C=CN=CC=1)C>[C:1]([NH:24][CH:25]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:26]([O:28][C:41]1[CH:42]=[CH:43][CH:44]=[CH:34][C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)Oc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoic acid (50 mg, 0.11 mmol) and ethyl 2-hydroxybenzoate (19 mg, 0.11 mmol) in CH3CN/THF (1:1, 0.5 mL) at −10° C. was added DCC (12 mg, 0.11 mmol) and DMAP (1 mg). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by silica chromatography (EtOAc—PE, 0-20%) to afford ethyl 2-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate (40 mg, 67%) as colorless oil. Mass calculated for C37H51NO5=589.80. found: [M+H]+=590.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=1)=[O:5])[CH3:2].Cl.C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:46])[NH2:40])=[CH:37][CH:38]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1c(COc2ccc(C#N)cc2)nc2ccc(N(CCN(C)C)S(=O)(=O)c3ccccc3)cc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2ccc(N(CCN(C)C)S(=O)(=O)c3ccccc3)cc21

Procedure:
Prepared analogously to Example 1e from 1-ethoxycarbonylmethyl-2-[(4-cyanophenyl)-oxymethyl]-6-[N-(2-dimethylaminoethyl)-benzenesulphonylamino]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:14][O:15][CH:16]([O:20][CH3:21])N(C)C>>[CH3:14][O:15][CH:16]([O:20][CH3:21])[N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:9][CH2:10]1
Reactant: COC(OC)N(C)C
Reactant: c1cn(CCC2CCNCC2)cn1
Product: COC(OC)N1CCC(CCn2ccnc2)CC1
Yield: 87 %

Procedure:
The free base 4[2-(imidazol-1-yl)ethyl]piperidine (5.1 g, 28.7 mM) and dimethylformamide dimethyl acetal (23 ml) was heated at 100° C. for 6 hours. Removal of the excess of dimethylformamide dimethyl acetal gave 4-[2-(imidazol-1-yl)ethyl]-1-piperidine carboxaldehyde dimethylacetal (6.32 g, 87%) which was dissolved in CH2Cl2 (27 ml) and added to the mixture of 6-aminopenicillanic acid (5.6 g, 258 mM) and diisopropylethylamine (3.41 ml) in CH2Cl2 (100 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr. and room temperature for 3 hrs. The solvent was then removed and water (100 ml) was added. After being washed with ethylacetate, the aqueous solution, acidified to pH 3, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6-beta)]-6-[[[4 -[2-(1H-imidazol-1-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrate hydrochloride (1.8 g, 16% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=[O:9].S([CH2:24][N+:25]#[C-:26])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([C:8]2[O:9][CH:26]=[N:25][CH:24]=2)[CH:10]=1
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(-c2cnco2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 5-methoxy-2-nitro-benzaldehyde (3.5 g, 19.3 mmol), tosylmethyl-isocyanide (4.5 g, 23.05 mmol) and potassium carbonate (6.7 g, 48.5 mmol) in methanol (40 mL) was stirred at room temperature for 4 h. The resulting red-orange suspension was concentrated and the residue diluted with ethyl acetate. The mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford a yellow oil. This oil was purified via column chromatography on silica gel (gradient elution with 0-10% methanol-methylenechloride) to afford 5-(5-methoxy-2-nitrophenyl)oxazole.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.Cl[CH2:15][CH:16]=O.O.C([O-])(O)=O.[Na+]>CCO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:15]=[CH:16][N:13]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc(N)nn2)cn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2ccc3nccn3n2)cn1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
6-(1-Methyl-1H-pyrazol-4-yl)-pyridazin-3-ylamine (Stage 8.3, 2.41 g, 13.8 mmol) was dissolved in EtOH (18 mL). Chloroacetaldehyde 55% in H2O (1.61 mL, 13.8 mmol) and NaHCO3 (2.3 g, 27.5 mmol) were added. The RM was stirred at 80° C. for 5 h. The solvent was removed and a solution of 5% NaHCO3 was added. The mixture was extracted twice with DCM/MeOH (9/1). The combined organic phases were washed with brine, dried over Na2SO4, and the solvent was removed to afford the title compound as a black solid (tR 1.0 min (conditions 2), MH+=200).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([C@@:8]1([OH:28])[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C:24](=[CH:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)#[CH:7]>O.C1COCC1.CO>[OH:28][C@:8]1([C@:9]2([CH3:10])[C@H:11]([C@H:14]3[C:24](=[CH:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:13]1)[C:6](=[O:2])[CH3:7]
Reactant: C#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reactant: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reaction time: 3 h

Procedure:
Mercuric oxide red (0.064 g) and concentrated sulfuric acid (0.086 ml) are stirred in water (1 ml) for 75 minutes at 67°. This mercuric oxide mixture is added to a mixture of 17β-ethynyl-17α-hydroxyandrosta-4,9(11)-dien-3-one (II A, Example 2, 0.84 g) in THF (5 ml) and methanol (24 ml) at 38°. This mixture is stirred for 3 hours and then cooled to 20°-25°. The mixture is quenched with phosphate buffer (pH=7, 10 ml) and then filtered to remove the insoluble mercury salts. The phases are separated and the aqueous layer is back-extracted with methylene chloride (3 times). The organic phases are combined and washed with saline, dried over sodium sulfate and concentrated under reduced pressure to give the title compound. NMR (CDCl3) 0.70, 1.42, 2.33, 5.60 and 5.80δ.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C@:12]([C:21]3[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=3)([NH2:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][C:10]=2[F:11])[CH2:3][CH2:2]1.[CH3:35][C:36]1[O:37][C:38]([C:44]([F:47])([F:46])[F:45])=[C:39]([C:41](O)=[O:42])[N:40]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C@@:12]([NH:20][C:41]([C:39]3[N:40]=[C:36]([CH3:35])[O:37][C:38]=3[C:44]([F:47])([F:45])[F:46])=[O:42])([C:21]3[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=3)[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][C:10]=2[F:11])[CH2:2][CH2:3]1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(OC2CC2)c1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)N[C@@](Cc2ccccc2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(OC3CC3)c2)c(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
To a solution of (R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine, prepared as described in Procedure 109, 110, 111, 112, 113, 114, 161, (24 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was added 2-methyl-5-(trifluoromethyl)-oxazole-4-carboxylic acid (12 mg, 0.06 mmol), followed by PyBrOP (28 mg, 0.06 mmol) and iPr2NEt (9 mg, 0.065 mmol). The reaction mixture was stirred at rt for 72 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep HPLC (Phenomenex Luna 5μ, 30×100 mm, eluting with 10%-90% MeOH/H2O containing 0.1% TFA, gradient time 10 min, flow rate 40 mL/min) to yield (R)—N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methyl-5-(trifluoromethyl)oxazole-4-carboxamide (Example 347) as a white solid (23 mg, 70% yield). HPLC: RT=2.18 min [M+H] 659.5 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.79, s, 1H, 7.10-7.20, m, 3H, 6.90-7.03, m, 5H, 6.70, s, 1H, 6.68, s, 1H, 6.55-6.58, m, 1H, 5.74-6.00, t, J=52; 4.15, 4.19, d, J=16, 1H, 3.66-3.69, d, J=12, 1H, 3.51-3.54, m, 1H, 0.73-0.80, m, 1H, 0.61-0.69, m, 2H, 0.55-0.60, m, 1H.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([Cl:12])[N:3]=1.S(Cl)(Cl)=O.[CH2:17](N(CC)CC)[CH3:18].C(O)C.C(=O)(O)[O-].[Na+]>CCOCC>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:17][CH3:18])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([Cl:12])[N:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
2,6-Dichloro-5-fluoropyridine-3-carboxylic acid (5.00 g, 23.81 mmol) was mixed with ~13 mL of thionyl chloride under nitrogen. The reaction was heated and the excess thionyl chloride was distilled off. The resulting liquid was diluted with ~5 mL methylene chloride, cooled to 0° C. and treated with 4.98 mL (1.5 equivalents) of triethylamine followed by 2.79 mL (2.0 equivalents) of ethanol dropwise. The reaction was allowed to warm to ambient temperature and stirred for 1 hour. A 1:1 mixture of sodium bicarbonate solution and ether (~80 mL) was added and the organic layer was washed with saturated sodium bicarbonate solution, 1N phosphoric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The residue obtained was flash chromatographed on silica gel eluting with 5% ethyl acetate in hexane to give the title compound (5.32 g, 94%) as a yellow liquid. 1H NMR (CDCl3, 300 MHz) δ 1.42 (t, 3 H), 4.43 (q, 2H), 8.00 (d, 1H). MS (DCl/NH3) m/e 239 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[CH:8][N:7]=[C:6]2[N:17](CC3OC=CC=3)[N:18]=[CH:19][C:5]=12)[CH3:2].[Se](=O)=O>COCCOCCOC>[CH2:1]([O:3][C:4]1[C:9]([C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[CH:8][N:7]=[C:6]2[NH:17][N:18]=[CH:19][C:5]=12)[CH3:2]
Reactant: CCOc1c(C(=O)c2cccs2)cnc2c1cnn2Cc1ccco1
Agent: O=[Se]=O
Solvent: COCCOCCOC
Product: CCOc1c(C(=O)c2cccs2)cnc2[nH]ncc12

Procedure:
3.5 g. of [4-ethoxy-1-(2-furanylmethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-thienylmethanone (0.01 mol.) are treated with 1.22 g. of selenium dioxide (0.011 mol.) in 20 ml. of diethyleneglycol dimethylether at reflux temperature for 1.5 hours with stirring. The precipitated selenium is filtered off and the solution is evaporated to dryness in vacuo. The remaining product, (4-ethoxy-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-thienylmethanone, is recrystallized from butanol, yield 2 g. (75%); m.p. 202°-205°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[CH2:16][CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])[OH:19].CCN(CC)CC>C(Cl)Cl>[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:27])([F:28])[F:29])=[O:19]
Reactant: OC(CCC1OCCO1)c1ccccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC1OCCO1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (115.0 mmol, 10.0 ml) in CH2Cl2 (200 ml) was cooled to −78° C. under an argon atmosphere. DMSO (240.0 mmol, 17.0 ml) was then added slowly, keeping the internal temperature below −50° C. After completing the addition, the solution was held 20 minutes at −78° C. 3-[1,3]Dioxolan-2-yl-1-(2-trifluoromethylphenyl)-propan-1-ol (32.8 g of crude material prepared above) in CH2Cl2 (30 ml) was added slowly, keeping the internal temperature below −50° C. The mixture was held at −78° C. for 30 minutes, then treated with Et3N (480 mmol, 70.0 ml). The mixture was allowed to warm to room temperature, then washed with water (2×75 ml), then concentrated under reduced pressure to give crude 3-[1,3]dioxolan-2-yl-1-(2-trifluoromethyl-phenyl)-propan-1-one, which may be used without further purification. 1H NMR (CDCl3) δ7.00 (1H, d, J=7.7), 7.63-7.50 (2H, m), 7.44 (1H, d, J=7.4), 4.99 (1H, t, J=4.3), 3.97-3.82 (4H, m), 2.98 (2H, t, J=7.3) 2.12 (2H, dt, J=7.4, 4.3).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(CC2CCCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(CC2CCCCO2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.47 g), sodium hydrogen carbonate (2.37 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-6-oxo-4-propyl-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.64 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 68%).