Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C([O:8][CH:9]=[C:10]([C:16](OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])C>[O-]CC.[Na+].C(O)C.ClCCl>[CH3:3][C:2]1[NH:4][C:9](=[O:8])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:5]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cnc(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.4 %

Procedure:
Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 mL of a 21% solution, 0.20 mole) for 5 minutes. Diethyl ethoxymethylenemalonate (31.5 mL, 0.15 mole) was added, and the reaction mixture was refluxed for 5 hours. The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 mL). The solution was filtered, washing the solid cake with dichloromethane. The filtrate was concentrated at reduced pressure. The residue was dissolved in dichloromethane (150 mL) and 2.0N HCl (30 mL). The pH of the aqueous layer was 1. The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in hot dichloromethane (50 mL). Ethyl acetate was added (50 mL). The product precipitated. The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 mL). The resulting crystals were filtered, then washed with ethyl acetate (20 mL) followed by hexanes (50 mL) to yield the title compound (7.22 g, 27%) as off-white crystals. Rf =0.27 (silica gel, 10% isopropanol in dichloromethane). The title compound also was prepared by the route described in Example 102.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([OH:18])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4].[CH3:19][N:20]1[CH2:24]C[C@@H:22](O)[CH2:21]1>C1(C)C=CC=CC=1>[CH3:19][N:20]1[CH2:21][CH2:22][C@@H:1]([O:2][C:3]([C:5]2([OH:18])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:4])[CH2:24]1
Reactant: CN1CC[C@@H](O)C1
Reactant: COC(=O)C1(O)c2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Product: CN1CC[C@@H](OC(=O)C2(O)c3ccccc3-c3ccccc32)C1
Yield: 30.7 %

Procedure:
0.980 g (0.0041 mol) of 9-Hydroxy-9H-fluorene-9-carboxylic acid methyl ester were dissolved in 30 ml of toluene. To this solution 0.412 g (0.0041 mol) of (3R)-1-methylpyrrolidin-3-ol (Intermediate I-19) and a catalitic amount of Na(0) were added and the mixture was refluxed using a Dean-Stark system for 24 hours. The reaction mixture was cooled, and extracted with HCl 2N. The aqueous layer was basified with K2CO3 and extracted with AcOEt (3×100 ml). The organic layers were combined, dried over Na2SO4 and evaporated to dryness to yield a residue which was purified by chromatography on silica gel eluting with chloroform plus isopropanol (0%→20%). Appropiate fractions were combined and evaporated to give 0.390 g (31%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][NH:16][CH:17]=2)=[CH:7][C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][NH:16][CH:17]=2)=[CH:7][C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cn[nH]c2)cc1C=O
Product: COc1cc(OC)c(-c2cn[nH]c2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-(1H-pyrazol-4-yl)-benzaldehyde (Ex-74B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3 including an acid work-up. Yellow solid, mp>250° C. 1H-NMR (DMSO-d6) δ 12.42 (bs, 1H), 8.20–8.03 (m, 8H), 7.85 (d, J=16.1 Hz), 6.74 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H). MS m/z=379 ([M+H]+, 100%).
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([OH:18])([CH3:17])[C:6]([NH:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[O:7])C.[OH-].[Li+]>O1CCCC1.O>[OH:18][C:5]([CH3:17])([C:6]([NH:8][CH2:9][C:10]([F:15])([F:16])[C:11]([F:12])([F:14])[F:13])=[O:7])[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(C)(O)C(=O)NCC(F)(F)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a solution of 2.91 g (9.93 mmol) 2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid ethyl ester in 50 ml of tetrahydrofurane were added 0.42 g (9,92 mmol) of lithium hydroxide in 20 ml of water and the mixture was stirred overnight at room temperature. After concentration in vacuo water (50 ml) was added and the mixture was acidified to pH 1. Extraction with ethylacetate gave 2.46 g (94%) of the title compound as a solid, MS m/e (%): 263.9 (M−H, 100).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH:12]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.[Ni]>[CH:12]1([NH:20][CH2:7][C:6]2[CH:1]=[CH:2][C:3]3[O:11][CH2:10][O:9][C:4]=3[CH:5]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: NC1CCCCCCC1
Agent: [Ni]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: c1cc2c(cc1CNC1CCCCCCC1)OCO2

Procedure:
16.5 g of piperonal, 12,7a g of cyclooctylamine and a catalytical amount of p-toluene-sulfonic acid were hydrogenated for 6 hours in 500 ml of methanol over Raney nickel at 100° C/100 atmospheres gauge pressure. After removal of the catalyst, evaporation of the solution and treatment of the residue with methanolic HCl, there were obtained 23 g of N-cyclooctyl-3,4-methylenedioxy-benzylamine. Melting point 164°-165° C (from ethanol/ether).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=3[C:18]#[N:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:31][C:32]([NH2:34])=[NH:33]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:17]=3[C:18]([NH2:19])=[N:33][C:32]([NH2:34])=[N:31]4)[CH2:12][CH2:13]2)=[O:7])=[CH:25][CH:26]=1
Reactant: N=C(N)N
Reactant: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccc(Cl)cc4)CC3)cccc2n1
Yield: 60.7 %

Procedure:
2-[1-(4-Chlorobenzoyl)piperidin-4-ylmethoxy]-6-fluorobenzonitrile (110 mg, 0.3 mmol) and guanidine carbonate (53 mg; 0.3 mmol) were heated at 140° C. in dimethylacetamide for 4 hours. The mixture was cooled and triturated with water for 45 minutes. Solids were filter off and triturated with 3 mL of ethanol. Solids were collected by filtration and dried to afford 75 mg of title compound (59% yield) 1HNMR (400 MHz, DMSO-d6) δ 7.52 (m, 2H), 7.43 (m, 2H), 7.35 (t, J=8.4 Hz, 1H), 7.17 (br d, J=15.2 Hz, 2H), 6.77 (dd, J=8.4, 0.8 Hz, 1H), 6.54 (d, J=7.2 Hz, 1H), 5.95 (br s, 2H), 4.51 (br s, 1H), 4.03 (d, J=6.4 Hz, 2H), 3.59 (br s, 1H), 3.11 (br s, 1H), 2.84 (br s, 1H), 2.22 (m, 1H), 1.87 (br s, 1H), 1.76 (br s, 1H), 1.3 (br d, J=10.4 Hz, 2H). MS m/z (ESI) 412 (M−H)+.
Reaction SMILES: C(OC(N1[C@H](C(=O)N[C@H](C(O)=O)CC2C=CC(C3C=CN=C(C)C=3C)=CC=2)CC2C=C3OC[C@H](C4C=CC(O)=CC=4)OC3=CC=2C1)=O)(C)(C)C.FC(F)(F)C1CCC(CO)CC1.C[O:64][C:65](=[O:126])[C@@H:66]([NH:82][C:83]([C@@H:85]1[CH2:94][C:93]2[CH:92]=[C:91]3[O:95][CH2:96][C@H:97]([C:99]4[CH:104]=[CH:103][C:102]([O:105][CH2:106][CH:107]5[CH2:112][CH2:111][CH:110]([C:113]([F:116])([F:115])[F:114])[CH2:109][CH2:108]5)=[CH:101][CH:100]=4)[O:98][C:90]3=[CH:89][C:88]=2[CH2:87][N:86]1[C:117]([C:119]1[N:120]=[C:121]([CH3:125])[O:122][C:123]=1[CH3:124])=[O:118])=[O:84])[CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=2[CH3:81])=[CH:70][CH:69]=1.C(Cl)CCl.CC1OC(C)=C(C(O)=O)N=1>C(Cl)Cl>[CH3:125][C:121]1[O:122][C:123]([CH3:124])=[C:119]([C:117]([N:86]2[C@H:85]([C:83]([NH:82][C@@H:66]([CH2:67][C:68]3[CH:73]=[CH:72][C:71]([C:74]4[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=4[CH3:81])=[CH:70][CH:69]=3)[C:65]([OH:126])=[O:64])=[O:84])[CH2:94][C:93]3[CH:92]=[C:91]4[O:95][CH2:96][C@H:97]([C:99]5[CH:100]=[CH:101][C:102]([O:105][CH2:106][CH:107]6[CH2:108][CH2:109][CH:110]([C:113]([F:114])([F:116])[F:115])[CH2:111][CH2:112]6)=[CH:103][CH:104]=5)[O:98][C:90]4=[CH:89][C:88]=3[CH2:87]2)=[O:118])[N:120]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1ccc(OCC2CCC(C(F)(F)F)CC2)cc1)CO3
Agent: Cc1nc(C(=O)O)c(C)o1
Agent: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)OC(C)(C)C)O[C@@H](c3ccc(O)cc3)CO5)C(=O)O)cc2)c1C
Agent: OCC1CCC(C(F)(F)F)CC1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCC3CCC(C(F)(F)F)CC3)cc2)O4)c(C)o1
Reaction time: 0.67 h

Procedure:
(3S,8S)-8-{(S)-1-Carboxy-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-ethyl-carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester was coupled with (4-trifluoromethyl-cyclohexyl)-methanol according to the General Procedure K. The resulting product was converted to (S)-2-({(3S,8S)-7-(2,5-dimethyl-oxazole-4-carbonyl)-3-[4-(4-trifluoromethyl-cyclohexyl-methoxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester according to General Procedure C, then the residue was suspended in DCM. TEA (3 eq.) added and the mixture was concentrated. In a separate vial, EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred for 40 minutes. This solution was added to the above mixture and stirred for 16 hours. The reaction mixture was directly purified over silica (hexanes; 1:1 hexanes/EtOAc; 1:1 hexanes EtOAc+1% MeOH). This ester was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 868.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH:16]=[C:15]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13]1)(C(C)(C)C)(C)C.Cl.[Si](O[Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>CCO>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:15]1[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:17](=[O:18])[CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1cc(C(N)=O)c(Nc2ccc(I)cc2F)cc1=O
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: NC(=O)c1cn(CCCO)c(=O)cc1Nc1ccc(I)cc1F

Procedure:
1-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was dissolved in EtOH and treated with 1 M HCl, as for example 22, step D, deprotecting the t-butyldimethylsilyl ether to give 4-(2-fluoro-4-iodoanilino)-1-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid which was recrystallised from EtOAc/MeOH (86%), m.p. (EtOAc/MeOH) 220-223° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.40 (s, 1H), 8.29 (s, 1H), 7.91 (br s, 1H), 7.72 (dd, J=10.2, 1.8 Hz, 1H), 7.56 (br d, J=8.4 Hz, 1H), 7.46 (br s, 1H), 7.30 (t, J=8.5 Hz, 1H), 5.56 (s, 1H), 4.58 (t, J=5.1 Hz, 1H), 3.86 (t, J=7.2 Hz, 2H), 3.41 (q, J=5.7 Hz, 2H), 1.79 (pentet, J=6.6 Hz, 2H). Anal. Calcd for C15H15FIN3O3: C, 41.8; H, 3.5; N, 9.8. Found: C, 42.0; H, 3.4; N, 9.6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[Li]CCCC.Cl.C[CH2:19][O:20]C(C)=O>C1COCC1>[F:1][C:2]1[C:3]([CH:19]=[O:20])=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(F)cc1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)c(C=O)c1OC
Temperature: -78 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a cold (−78° C.) solution of 4-fluoro-1,2-dimethoxybenzene (15.00 g, 96.05 mmol) in anhydrous THF (150 mL) was added n-BuLi (84.5 mL, 211.32 mmol, 2.5 M solution in hexanes) under nitrogen and stirred it for 3 h at −78° C. Quenched the reaction with DMF (75 mL) at −65° C., added 2N HCl (300 mL) dropwise and further stirred for 30 min. Two layers separation was observed. Aqueous layer was extracted with EtOAc. Combined organic layers were washed with water, brine and dried over MgSO4. Filtered the ethyl acetate layer and concentrated it in vacuo. The title compound was purified by flash column chromatography using pure hexanes then 10 and 20% EtOAc in hexanes which provided 14.40 g (78.19 mmol, 82%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 7.36 (dd, J=9.0, 5.1 Hz, 1H), 7.03 (t, J=9.6 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ ppm −131.68-−131.66 (m, 1F).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:29]#[N:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH2:39]Br.C([O-])([O-])=O.[K+].[K+].[CH3:47][N:48](C=O)C>>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:38][CH2:39][NH:48][CH3:47])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:29]#[N:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(OCCNC)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To the product of Example 57 (62 mg, 0.12 mmol) in anhydrous DMF (2 mL) were added 1,2-dibromoethane (100 mL, 10 equiv) and anhydrous K2CO3 (166 mg, 10 equiv). The suspension was shaken overnight at 60° C. in a sealed tube. After cooling, the reaction mixture was concentrated under reduced pressure, diluted with DCM and acetone, and filtered. The filtrate was concentrated to give a residue, which was purified by chromatography on silica gel, eluting with MeOH-DCM (1:19) to give a yellow solid, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[Cl:8].[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>C(#N)C>[CH2:11]([NH:15][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[Cl:8])[CH2:12][CH2:13][CH3:14].[CH2:11]([NH:15][C:7]1[CH:6]=[N:5][N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[Cl:1])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Solvent: CC#N
Product: CCCCNc1c(Cl)cnn(C)c1=O
Product: CCCCNc1cnn(C)c(=O)c1Cl

Procedure:
A mixture of 4,5-dichloro-2-methylpyridazin-3(2H)-one (358 mg, 2 mmol) and butan-1-amine (585 mg, 8 mmol) in acetonitrile was refluxed for 16 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, brine, dried with MgSO4, filtered, and concentrated. Purification of the residue by chromatography (hexanes-EtOAc 1:1) afforded 170 mg of 4-(butylamino)-5-chloro-2-methylpyridazin-3(2H)-one and 260 mg of 5-(butylamino)-4-chloro-2-methylpyridazin-3(2H)-one. MS (ESI) m/z 215 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[Cl:18])[C:5](OC)=[O:6].Cl.[CH:21]([NH2:23])=[NH:22]>>[Cl:18][C:11]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=1[O:9][C:4]1[C:5]([OH:6])=[N:22][CH:21]=[N:23][C:3]=1[OH:2]
Reactant: N=CN
Reactant: COC(=O)C(Oc1cc(OC)ccc1Cl)C(=O)OC
Agent: Cl
Product: COc1ccc(Cl)c(Oc2c(O)ncnc2O)c1

Procedure:
5-(2-Chloro-5-methoxy-phenoxy)-pyrimidine-4,6-diol was prepared from 2-(2-chloro-5-methoxy-phenoxy)-malonic acid dimethyl ester and formamidine hydrochloride according to the procedure described in Referential Example 1c.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32]OS(C5C=CC(C)=CC=5)(=O)=O)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1.[CH3:54][NH:55][CH3:56]>C(N(CC)CC)C>[CH3:54][N:55]([CH3:56])[CH2:32][CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]2[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:45])[CH2:19][CH:18]2[O:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=3[CH:12]=2)=[CH:25][CH:26]=1
Reactant: CNC
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCOS(=O)(=O)c4ccc(C)cc4)cc3)cc21
Solvent: CCN(CC)CC
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCN(C)C)cc3)cc21

Procedure:
A solution of 0.193 g of benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[2-(toluene-4-sulphonyloxy)ethoxy]phenyl}piperidine-1-carboxylate (Example 267c), 0.131 g of triethylamine and 1.769 g of dimethylamine (33% in ethanol) is stirred at room temperature for 3 days and then concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (200:10:1 dichloromethane-methanol-conc. ammonia); Rt=4.40.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]1[C:9]([CH3:22])=[C:10]([CH3:21])[C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]=1[CH3:20].N1C=CC=CC=1>ClCCl>[CH3:1][CH:2]([CH3:6])[C:3]([O:7][C:8]1[C:9]([CH3:22])=[C:10]([CH3:21])[C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]=1[CH3:20])=[O:4]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)C(C)(C)O2
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OC(=O)C(C)C)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A solution of 2-methylpropionylchloride (isobutyryl-chloride, 8.05 g, 75.55 mmol) in dichloromethane (10 mL) is added dropwise at 0° C. and under nitrogen to a solution of 5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one (12.8 g, 58.11 mmol) and pyridine (5.97 g, 61 mmol) in dichloromethane (58 mL). The ice bath is removed and the mixture is stirred for 2 hrs at room temperature. Water (10 mL) is added and the organic phase is washed with 2N hydrochloric acid (100 mL), water (100 mL), 10% sodium bicarbonate (100 mL) and brine. The solution is dried (magnesium sulfate) and evaporated to dryness to give 17 g (100%) of 5-(2-methylpropionoxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one as an oil which is used without purification for the next step. Rf=0.5 (heptane/ethyl acetate 90:10)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[CH3:28][CH:27]([CH3:29])[C:26]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:30]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and0.11 μL (0.11 mmol) isobutyryl chloride. NMR was consistent with the proposed compound.
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.[CH3:32][C:33]1[O:37][N:36]=[C:35]([CH2:38][NH2:39])[CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][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:10][CH:11]=1)[C:3]([NH:39][CH2:38][C:35]1[CH:34]=[C:33]([CH3:32])[O:37][N:36]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cc1cc(CN)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)no1
Reaction time: 1 h
Yield: 48.3 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 25 mg, 0.058 mmol), (5-methylisoxazol-3-yl)methanamine (9.75 mg, 0.087 mmol), HATU (28.7 mg, 0.075 mmol), and 4-methylmorpholine (23.45 mg, 0.232 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=14.0 min) to provide 2-hydroxy-N-((5-methylisoxazol-3-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15 mg, 0.028 mmol, 48.2% yield) as a single enantiomers. LCMS=526.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.23 (2 H, m), 7.50-7.82 (7 H, m), 5.98 (1 H, s), 5.18 (1 H, s), 4.43 (2 H, s), 2.36 (3 H, s); HPLC peak RT=10.0 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@@H:6]([C:12]3[CH2:16]C[CH2:14][C:13]=3[CH3:17])[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl>>[Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]([CH3:16])=[C:13]([CH3:17])[CH3:14])[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC1=C([C@H]2CN(C)CCc3cc(Cl)c(O)cc32)CCC1
Agent: Cl
Product: CC(C)=C(C)[C@@H]1CN(C)CCc2cc(Cl)c(O)cc21

Procedure:
(R)-7-chloro-8-hydroxy-3-methyl-(2-methyl-1-cyclopentenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. of hydrochloride 249-251° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3]1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]([F:29])([F:28])[CH2:26]I>CN(C=O)C>[CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:26][C:25]([F:29])([F:28])[F:24])[C:10](=[O:11])[C:5]=2[C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:3]1
Reactant: FC(F)(F)CI
Reactant: Cn1cc(-c2ccccc2)c2c(=O)[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 90 °C
Yield: 61.3 %

Procedure:
To a stirring suspension of 7-methyl-5-phenyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (0.86 g, 3.82 mmol) in anhydrous DMF (30 ml) was added potassium carbonate (1.06 g, 7.64 mmol) and 1,1,1-trifluoro-2-iodoethane (0.564 ml, 5.73 mmol). The mixture was heated to 90° C. for 16 h. A further portion of potassium carbonate (1.06 g, 7.64 mmol) and 1,1,1-trifluoro-2-iodoethane (0.564 ml, 5.73 mmol) were added and the mixture heated to 90° C. for 24 h. The mixture was cooled and partitioned between brine/water (1:1, 300 ml) and ethyl acetate (75 ml). The aqueous portion was separated and extracted with ethyl acetate (3×75 ml). The combined organic fractions were washed with brine/water (1:1, 4×75 ml), dried (anhydrous sodium sulfate), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient 0-30% ethyl acetate in cyclohexane) to afford the title compound (719 mg, 61%). LCMS RT=1.25 min, M+H+=308.0.