Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[CH3:3]C(C)=O.[NH:7]1[CH2:12][CH2:11][O:10][C@H:9]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@:16]3([C:34]4[C:25](=[CH:26][C:27]5[O:32][CH2:31][CH2:30][O:29][C:28]=5[CH:33]=4)[O:24][CH2:23]3)[C:15]2=[O:35])[CH2:8]1.N1CCC(CN2C3C(=CC=CC=3)C3(C4C(=CC5OCCOC=5C=4)OC3)C2=O)CC1>ClCCCl.O1CCCC1>[CH3:3][N:7]1[CH2:12][CH2:11][O:10][C@H:9]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@:16]3([C:34]4[C:25](=[CH:26][C:27]5[O:32][CH2:31][CH2:30][O:29][C:28]=5[CH:33]=4)[O:24][CH2:23]3)[C:15]2=[O:35])[CH2:8]1
Reactant: O=C1N(C[C@@H]2CNCCO2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: CC(C)=O
Agent: C=O
Agent: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN1CCO[C@H](CN2C(=O)[C@@]3(COc4cc5c(cc43)OCCO5)c3ccccc32)C1

Procedure:
Following the procedure described in EXAMPLE 11.100 and making non-critical variations using 37% w/w aqueous formaldehyde to replace acetone, tetrahydrofuran to replace 1,2-dichloroethane and (8S)-1′-[(2S)-morpholin-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrocholride, (8S)-1′-{[(2S)-4-methylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (68%) as a colorless solid: mp 85-90° C.; 1H NMR (300 MHz, CDCl3) δ 7.27 (d, J=7.5 Hz, 1H), 7.15-6.98 (m, 3H), 6.47 (s, 1H), 6.20 (s, 1H), 4.86 (d, J=9.0 Hz, 1H), 4.61 (d, J=9.0 Hz, 1H), 4.19-4.05 (m, 4H), 3.92-3.56 (m, 5H), 2.76 (d, J=11.4 Hz, 1H), 2.60 (d, J=11.4 Hz, 1H), 2.26 (s, 3H), 2.17-2.05 (m, 1H), 1.97-1.87 (m, 1H); 13C NMR (300 MHz, CDCl3) δ177.6, 155.1, 144.5, 142.6, 138.2, 132.0, 128.7, 123.6, 123.2, 121.0, 111.4, 109.4, 99.2, 80.0, 73.5, 66.7, 64.4, 63.8, 58.1, 57.8, 54.6, 46.3, 43.1; MS (ES+) m/z 409.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2OCO[C:6]=2[CH:5]=[C:4]([C:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[NH2:26])[CH:3]=1.[H-].[Na+].[P:29](Cl)([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[NH:26][P:29]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30])[CH:5]=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:7]=1
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Reactant: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(Nc1c(-c2cc(Cl)cc(C(F)(F)F)c2)c(C(F)(F)F)nn1-c1ncccn1)OCC
Reaction time: 12 h
Yield: 23 %

Procedure:
To a mixture of 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.766 g, 2.00 mmol) and NaH (0.054 g, 2.20 mmol) in tetrahydrofuran at 0° C. is added diethyl chlorophosphate (0.414 g, 2.40 mmol). The mixture is allowed to reach room temperature (20-25° C.) and further stirred for 12 hours. The reaction was diluted with water and extracted with ethyl acetate; the organic layer separated and further washed with water and then dried and concentrated. The residue was re-crystallized with a mixture of ethyl acetate and petrole ether to give the title compound (125 mg; 12%).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11]([OH:13])=[O:12].[OH-].[Na+].[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.Cl>O1CCOCC1.O>[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][C@@H:3]2[C:11]([OH:13])=[O:12])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: O=C(O)[C@H]1Cc2ccccc2N1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)N2c3ccccc3C[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a solution of the title C compound, (R)-2,3-dihydro-1H-indole-2-carboxylic acid hydrochloride (0.92 g, 4.6 mmol), 1N aqueous sodium hydroxide (12.0 mL, 12 mmol) and water (25 mL) at room temperature is added dropwise a solution of 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride (1.65 g, 4.6 mmol) in dioxane (33 mL). Upon completion of the addition, the pH of the reaction mixture is monitored and maintained between 7–8 by slow addition of 1N aqueous sodium hydroxide over the next 2 hours. The reaction mixture is stirred overnight at room temperature. The solution is poured into crushed ice and the resulting mixture is acidified to pH 2–3 with 1N aqueous hydrochloric acid (11 mL). The precipitate that forms is collected, washed with water and dried under high vacuum overnight to give 1.5 g of (R)-1-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid: [M+1]+=491.2, [M−1]−=489.1
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:26]=O)[CH:19]=[C:20]2[C:25]=1[O:24][CH2:23][CH2:22][CH2:21]2.C[Si]([C:32]#[N:33])(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>ClCCl>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:26]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][CH:9]=2)[C:32]#[N:33])[CH:19]=[C:20]2[C:25]=1[O:24][CH2:23][CH2:22][CH2:21]2
Reactant: COc1cc(C=O)cc2c1OCCC2
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc2c1OCCC2

Procedure:
After adding 700 mg of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 770 mg of 8-methoxychromane-6-carbaldehyde [CAS No. 81258-23-3], 1 g of MS3A and 1.1 ml of trimethylsilyl cyanide to a solution of 250 mg of Yb(OTf)3 in 5 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with 100 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to give a crude product of (8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=1[F:32].[CH:33]1([C:36]#[C:37][C:38]([O:40][CH3:41])=[O:39])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:33]1([C:36]2[C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]4[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=4[F:32])[N:15]3[N:14]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)C#CC1CC1
Reactant: Cc1cc[n+](N)c(OCc2c(F)ccc(F)c2F)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(C2CC2)nn2c(OCc3c(F)ccc(F)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
1.45 g (3.00 mmol, purity 98%) of 1-amino-4-methyl-2-[(2,3,6-trifluorobenzyl)oxy]pyridinium 2,4,6-trimethylbenzenesulphonate from Example 155A were dissolved in 9.7 ml of DMF and admixed with 670 mg (5.40 mmol) of methyl 3-cyclopropylprop-2-ynoate. 747 mg (5.40 mmol) of potassium carbonate was added and the mixture was stirred at RT for 3 h. Subsequently, the mixture was poured onto 73 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 462 mg of the title compound were obtained (33% of theory; 85% purity).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:11]([NH:13][C:14](=[O:18])[CH:15]([NH2:17])[CH3:16])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[N:17][CH:15]([CH3:16])[C:14](=[O:18])[NH:13][C:11]=3[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(NC(=O)C(C)N)c2C(=O)c2ccccc2Cl)C1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NC(C)C(=O)N3)C1
Yield: 49.3 %

Procedure:
636.8 g of 6 -acetyl-2-(2-aminopropionylamino)-3-(2-chlorobenzoyl)-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine was dissolved in 2.3 liters of toluene, 637 ml of pyridine and 94.3 ml of acetic acid and reflused over day and night while removing water from the reaction system. After removal of the reaction solution by distillation, benzene was added, followed by cooling and filtering the resultant crystals to obtain 300 g of the intended product.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C(#N)C>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[CH:3][N:4]=1)=[O:13]
Reactant: Cc1cnc(N)s1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cnc(NC(=O)C(C)(C)C)s1
Reaction time: 0.25 h

Procedure:
5-Methylthiazol-2-amine (5.71 g, 50.0 mmol) and pivaloyl chloride (6.78 mL, 55.0 mmol) were mixed in anhydrous acetonitrile (80 mL) and treated with triethylamine (14.0 mL, 100 mmol) resulting in an exotherm. After 15 minutes, the warm suspension was cooled for 5 minutes with a water bath. The solids were collected by filtration and rinsed with more acetonitrile. The filtrate was partially concentrated and the solids which precipitated were also collected by filtration and rinsed with acetonitrile. The two crops were combined and rinsed with water, and when solids precipitated from the filtrate they were collected by filtration and added to the previously collected material. The crude product was washed with 1:1 dichloromethane/hexanes and dried under vacuum to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:37][O:38][CH3:39])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](OCC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.[BH4-].[Li+].O>O1CCCC1.CO>[CH3:1][O:2][CH2:3][CH:4]([CH2:37][O:38][CH3:39])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][CH2:21][OH:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(COC)COC)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 51.5 %

Procedure:
Ethyl [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (220 mg) was dissolved in a mixture of tetrahydrofuran (2 mL) and methanol (1 mL). Lithium borohydride (41 mg) was added to the mixture at 0° C. and the mixture was stirred at room temperature for 6.5 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (methanol/ethyl acetate/hexane=0/40/60 to 15/85/0, volume ratio) to give an orange oil. The oil was crystallized from acetonitrile. The crystals were recrystallized from acetonitrile-diethyl ether to give the title compound (105 mg, 75%) as colorless crystals. MS 536 (MH+). mp 69-71° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(C)C=CC=CC=1.Cl>O>[C:13]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid (5.0 g, 38.7 mmol) and NaOH (1.86 g, 46.5 mmol) in H2O (15 ml) was added dropwise a 50% solution of benzyl chloroformate in toluene (13.6 mL, 40.6 mmol) over a period of half an hour at 0° C. The reaction mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was acidified with dil. HCl (pH 3) and extracted with ethyl acetate (3×100 ml). The combined organic phases were dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (silica gel, elution with 30% ethyl acetate/n-hexanes) to afford piperidine-1,4-dicarboxylic acid monobenzyl ester (VI) (6.5 g, 64%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:21][CH3:22])=[C:7]([CH:20]=1)[O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[CH2:11][CH2:10]1)#[N:2].C(O)(=O)C.S(=O)(=O)(O)O.[N+:32]([O-])([OH:34])=[O:33].N.C(#N)CC>[N+]([O-])(O)=O.O>[C:1]([C:3]1[C:4]([N+:32]([O-:34])=[O:33])=[CH:5][C:6]([O:21][CH3:22])=[C:7]([CH:20]=1)[O:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[CH2:13][CH2:14]1)#[N:2]
Reactant: O=[N+]([O-])O
Reactant: CNC(=O)CN1CCC(Oc2cc(C#N)ccc2OC)CC1
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CCC#N
Product: CNC(=O)CN1CCC(Oc2cc(C#N)c([N+](=O)[O-])cc2OC)CC1
Temperature: 5 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
2-[4-(5-Cyano-2-methoxyphenoxy)piperidin-1-yl]-N-methylacetamide (4, 8.78 g, 26.11 mmoles) was suspended in acetic acid (22.82 g, 364.87 mmoles) and the resulting reaction mixture cooled to 5° C. To this was added sulfuric acid (23.64 g, 234.95 mmoles) maintaining the reaction temperature below 30° C. To the resulting solution was added nitric acid (2.40 g, 26.63 mmoles). The reaction mixture was then heated to 35° C. and held for 3 hours. Additional nitric acid (117 mg, 1.31 mmoles) and sulphuric acid (1.31 g 13.1 mmoles) were charged and the reaction mixture was heated at 35° C. for 30 minutes. The solution was cooled to 20° C. and quenched with aqueous ammonia (92.45 g 1.36 moles), resulting in an increase in temperature to 50° C. To the resulting slurry was added, propionitrile (61.58 g 1.12 moles) and water (19 g). The reaction mixture was heated to 80° C. resulting in a clear solution, which upon settling gave two layers. The bottom layer was removed. The reaction mixture was cooled to 20° C. resulting in a thick slurry. The solid was isolated by filtration, washed with propionitrile (6.16 g 112.0 mmoles) and dried to afford the title compound (7.44 g, 82% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, 2H) 1.97 (m, 2H) 2.35 (m, 2H) 2.61 (d, J=4.7 Hz, 3H) 2.66 (m, 2H) 2.90 (s, 2H) 3.96 (s, 3H) 4.73 (tt, J=8.4, 4.0 Hz, 1H) 7.71 (q, J=4.7 Hz, 1H) 7.82 (s, 1H) 7.86 (s, 1H). Mass Spectrum: m/z (M+H)+ 349.2
Reaction SMILES: O=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C(Cl)Cl>[C:9]([S:12]([N:14]=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:13])([CH3:11])([CH3:10])[CH3:8]
Reactant: CC(C)(C)S(N)=O
Reactant: CCOC(=O)C=O
Solvent: ClCCl
Product: CCOC(=O)C=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of ethyl 2-oxoacetate (50% solution in toluene; 4.066 g; 20.00 mmol), 2-methylpropane-2-sulfinamide (2.424 g; 20.00 mmol), and 4 angstrom molecular sieves (60 g) in anh. DCM (250 ml) was stirred at rt, under nitrogen, for 65 h. The reaction mixture was then filtered over celite, and the separated solids were washed with AcOEt (3×200 ml). The filtrate was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording ethyl 2-((tert-butylsulfinyl)imino)acetate as a yellow oil.
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](O)=[O:4].CN1CCOCC1.Cl.[NH2:40][C@@H:41]([CH3:46])[C:42]([NH:44][CH3:45])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>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:40][C@@H:41]([CH3:46])[C:42]([NH:44][CH3:45])=[O:43])=[O:4]
Reactant: CNC(=O)[C@H](C)N
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](C)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 41.3 %

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, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), (S)-2-amino-N-methylpropanamide-HCl (6.43 mg, 0.046 mmol), and HATU (31.7 mg, 0.083 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-methyl(S)propanamide (9.6 mg, 0.019 mmol, 40.2% yield): LCMS=516.1 [M+H]+; 1H NMR (Mixture of Diastereomers, 400 MHz, methanol-d4) δ ppm 8.11-8.25 (4 H, m), 7.50-7.78 (14 H, m), 5.16 (2 H, d, J=3.08 Hz), 4.37 (2 H, qd, J=7.08, 1.43 Hz), 2.75 (3 H, s), 2.72 (3 H, s), 1.39 (3 H, d, J=7.26 Hz), 1.35 (3 H, d, J=7.04 Hz); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.3 min+2.4 min (mixture of diastereomers).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14](O)=[O:15])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([Cl:24])=[O:15])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a 100 mL flask, 1-(3,5-dichloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (0.40 g, 1.22 mmol), dichloromethane (10 mL) and oxalyl dichloride (0.31 g, 2.44 mmol) were added sequentially. After five drops of N,N-dimethyl formamide were added, a large amount of gas was released. After being stirred for 8 hours at room temperature, the reaction mixture was concentrated under reduced pressure. Then toluene (30 mL) was added, and was concentrated again under vacuum to give the product (0.42 g) as yellow solid in 100% yield.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[O:4][CH2:3]1.[CH:15](=O)[CH3:16].[BH3-]C#N.[Na+]>>[CH2:15]([N:7]1[C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[O:4][CH2:3][CH:2]1[CH3:1])[CH3:16]
Reactant: CC1COc2cc([N+](=O)[O-])ccc2N1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN1c2ccc([N+](=O)[O-])cc2OCC1C
Yield: 64.8 %

Procedure:
This compound was prepared by General Method 3 (EXAMPLE 1) from (±)-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine (200 mg, 1.0 mmol), acetaldehyde (455 mg, 10.3 mmol) and NaBH3CN (314 mg, 5.0 mmol) to afford 144 mg (63%) of 4-ethyl-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine. Data for (±)-4-ethyl-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine: Rf 0.80 (3:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 7.80 (dd, 1H, J=8.9, 2.6), 7.66 (d, 1H, J=2.6), 6.55 (d, 1H, J=9.2), 4.07 (dd, 1H, J=10.7,2.5), 3.96 (dd, 1H, J=10.7, 2.6), 3.60 (m, 1H), 3.55-3.35 (m, 2H), 1.29 (d, 3H, J=6.6), 1.24 (t, 3H, J=7.0).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=[O:7])C>CO.O>[CH3:16][C:12]1[N:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)=[C:8]([C:6]([OH:7])=[O:5])[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1nc2cccc(C)n2c1-c1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc2nc(C(=O)O)c(-c3cccc(C(F)(F)F)c3)n12
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Potassium hydroxide (0.2 g, 0.003 mol) was added to a suspension of 5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (compound p, 0.35 g, 0.0010 mol) in methanol (0.4 mL) and water (4.7 mL). Stirred at 80° C. for 1 hour. The methanol was removed and 6N HCl added to the residue until pH approx. 5. The white solid that formed was filtered to give 290 mg of 5-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine-2-carboxylic acid as a white solid. Rf 0.20, 100% ethyl acetate; MS m/z 319 (M−H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:21])[CH3:20])#[CH:11]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]2[N:18]([C:19](=[O:21])[CH3:20])[C:13]3[C:12]([CH:10]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: C#Cc1ccccc1NC(C)=O
Product: COc1ccc(-c2cc3ccccc3n2C(C)=O)cc1
Yield: 60 %

Procedure:
The general procedure was used to convert 1-iodo-4-methoxybenzene and N-(2-ethynylphenyl)acetamide to the title product. Purification by flash chromatography gave the analytically pure product as a slightly yellow solid, 60% yield. 1H NMR (300 MHz, DMSO) δ 8.23-8.21 (d, J=8.1, 1H), 7.56-7.54 (d, J=7.5, 1H), 7.43-7.40 (d, J=8.8, 2H), 7.31-7.21 (m, 2H), 7.02-7.00 (d, J=8.8, 2H) 6.64 (s, 1H), 3.78 (s, 3H), 2.03 (s, 3H). 13C NMR (75 MHz, DMSO) δ 171.96, 160.37, 140.53, 137.75, 131.13, 129.71, 126.58, 125.29, 124.24, 121.18, 116.30, 114.97, 111.10, 56.06, 28.33. Anal. Calcd. for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found C, 76.90; H, 5.74; N, 5.08. m.p.: 68-71° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[NH3:15]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Solvent: CCO
Product: CC(=O)c1ccc(N)c(S(N)(=O)=O)c1

Procedure:
A solution of 5-acetyl-2-fluorobenzenesulphonamide (0.5 g) in ethanol (40 ml) saturated with ammonia was heated at 100° in a bomb overnight. Concentration of the resultant solution yielded a yellow crystalline solid, 0.4 g, m.p. 263°-264° (from ethanol).