Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:28]1CCN2C(=NCCC2)CC1.C=O>C1COCC1>[C:18]1([CH2:17][C:11](=[CH2:28])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)P(=O)(OCC)OCC
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cc1cccc2ccccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.92 g of lithium chloride was sun-pended in 50 ml of dry THF, and 15 g of ethyl 2-diethylphosphono-3-(1-naphthyl)propionate was dropwise added thereto. Then, 16 ml of a 50% dry THF solution of DBU was dropwise added thereto, and 2.01 g of paraformaldehyde suspended in dry THF was added thereto. The mixture was stirred at room temperature for 3 hours, and the insolubles were removed by filtration and washed with a small amount of diethyl ether. The washing solution and and the filtrate were put together, and the solvent was distilled off. The resulting syrup was dissolved in 180+ml of diethyl ether. The diethyl ether layer was washed sequentially with a 10% citric acid aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydride sodium sulfate. The solvent was distilled off, and the syrup thereby obtained was purified by silica gel column chromatography (n-hexane/diethyl ether=20/1) to obtain 6.48 g of ethyl 2-(1-naphthyl)methyl-2-propenoate as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([NH:11][C:12]2[NH:13][CH2:14][CH2:15][N:16]=2)[CH:3]=1.[Br:17]Br.N>>[Br:17][C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: BrBr
Reactant: Clc1cc(NC2=NCCN2)cc2[nH]cnc12
Agent: N
Product: Clc1cc(NC2=NCCN2)c(Br)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 33 %

Procedure:
To a solution of 7-chloro-5-(2-imidazolin-2-ylamino)benzimidazole (0.61 g, 2.6 mmol) in 10 ml of ACOH was added 0.3 ml of Br2. Resulting reaction mixture was stirred for 12 h at 25° C. and concentrated in vacuo, yielding an oil, which was subjected to column chromatography (NH3 sat'd 30% MeOH/EtOAc) to yield 0.23 g (0.85 mmol, 33%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from MeOH to afford 0.12 g (12%) of the product as a light yellow solid: mp 244-246° C.; Anal. Calc. for C10H9N5BrCl.1.0C4H4O4.0.5H2O requires C, 37.77; H, 3.17; N, 18.35. Found: C, 37.75; H, 3.08; N, 18.21.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][C:4]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:40])C=CC=CC=1>O1CCCC1>[CH3:16][O:15][C:13](=[O:14])[CH:12]([OH:40])[C:4]1[S:5][C:6]2[C:11]([C:2](=[O:1])[C:3]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)Cc1sc2ccccc2c(=O)c1-c1ccccc1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1sc2ccccc2c(=O)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Under a nitrogen atmosphere, the compound obtained in (1) above (0.16 mmol, 50 mg) was dissolved in tetrahydrofuran (3.0 mL), and the solution was cooled to −78° C. Then, 0.24 mL of lithium hexamethyldisilazide (a 1.0 M solution) was added thereto dropwise, and stirred for 10 min. A Davis reagent (0.32 mmol, 84 mg) was added to the resulting solution, and stirred for 30 min. After the disappearance of the starting materials was confirmed by thin-layer chromatography, the reaction was terminated by adding a saturated aqueous ammonium solution to the reaction solution. Then, the organic substances were extracted with ethyl acetate, and the obtained organic layer was dried over magnesium sulfate. The solvents were evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (0.15 mmol, 50 mg) was obtained in a 95% yield.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: C=CC(=O)OCC
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(C#N)cc1
Temperature: 110 °C
Yield: 94 %

Procedure:
To the mixture of 4-bromobenzonitrile (2.6 g, 14.28 mmol), Pd(OAc)2 (0.064 g, 0.286 mmol) and tri-o-tolylphosphine (0.261 g, 0.857 mmol) in dry DMF (20 mL) was added ethyl 2-propenoate (2.282 mL, 21.43 mmol) and TEA (3.98 mL, 28.6 mmol). It was heated at 110° C. for 1 h. Purification via a flash column chromatography then provided the title compound as a white solid (2.7 g, 92% yield). LCMS: rt=3.03 Min, [M+H+]=202.0
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][C:16]1[CH:17]=[C:18]([C:22]([CH3:30])([CH2:28][CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:19]=[CH:20][CH:21]=1>>[CH3:30][C:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]3)[CH:17]=1)([CH2:28][CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: CCOC(=O)C(C)(CC)c1cccc(O)c1
Product: CCOC(=O)C(C)(CC)c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Yield: 44 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with ethyl 2-(3-hydroxyphenyl)-2-methylbutyrate to give ethyl 2-methyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyrate in 44% yield as a gum.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][S:25][CH2:24][CH2:23]2)=[N:11][CH:10]=1.[OH:39]OS([O-])=O.[K+]>CO>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][S:25](=[O:39])[CH2:24][CH2:23]2)=[N:11][CH:10]=1
Reactant: O=S([O-])OO
Reactant: Cc1ccccc1-c1cc(N2CCSCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1-c1cc(N2CCS(=O)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 159.9 %

Procedure:
To a solution of 1.24 g (2.24 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-thiomorpholin-4-yl-4-o-tolyl-nicotinamide (step a)) in 25 ml methanol were added 689 mg (1.12 mmol) Oxone® at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. Quenching with 5 ml 40% aqueous sodium hydrogen sulfite solution was followed by addition of 6 ml 1N sodium hydroxide solution to adjust the pH to 7-8. The mixture was diluted with 50 ml water and extracted with 3 150-ml portions of dichloromethane. The combined extracts were dried with sodium sulfate and concentrated to give 1.20 g of crude product. Flash chromatography afforded 1.02 g (79.9%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1([CH3:36])[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:35])[CH:30]=2)[NH:25]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:35][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:36])([CH3:23])[CH:33]=[C:32]2[CH3:34]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: CC1=CC(C)(C)Nc2ccc(O)cc21
Product: COc1cc2c(Oc3ccc4c(c3)C(C)=CC(C)(C)N4)ncnc2cc1OCCCN1CCCC1
Yield: 47.4 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 9), was reacted with 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg, 0.5 mmol), (IZV. ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), to give 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline (90 mg, 47%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][C:22]([N:31]1[CH:35]=[C:34]([NH2:36])[N:33]=[CH:32]1)([CH3:30])[CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:30][C:22]([N:31]1[CH:35]=[C:34]([NH:36][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:33]=[CH:32]1)([CH3:21])[CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CC(C)(CN1CCCCC1)n1cnc(N)c1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCCCC2)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 1-(1,1-Dimethyl-2-piperidin-1-yl-ethyl)-1H-imidazol-4-ylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.5, 24.1, 25.8, 25.9, 26.7, 28.2, 28.9, 29.8, 36.6, 38.8, 52.8, 56.8, 59.1, 60.9, 69.1, 100.8, 101.0, 101.3, 104.6, 110.7, 110.8, 118.2, 131.3, 137.2, 139.9, 172.3; MS m/z 488.3 (M+1).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:43])[C@H:8]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:41])[NH:32][O:33]C(OCC(C)C)C)=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(Cl)Cl.O1CCOCC1>[CH:1]1([O:6][C:7](=[O:43])[C@H:8]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:41])[NH:32][OH:33])=[CH:21][CH:22]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(C)ONC(=O)CCCCCCC(=O)Nc1ccc(CN[C@@H](C(=O)OC2CCCC2)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(CCCCCCC(=O)Nc1ccc(CN[C@@H](C(=O)OC2CCCC2)c2ccccc2)cc1)NO

Procedure:
(R)-{4-[7-(1-Isobutoxy-ethoxycarbamoyl)-heptanoylamino]-benzylamino}-phenyl-acetic acid cyclopentyl ester (50 mg, 0.08 mmol, 1 eq) was dissolved in DCM (0.5 mL) and stirred with 4M HCl in dioxane (0.2 mL) for 30 min. The resulting salt was concentrated, dissolved in methanol and purified by preparative HPLC to yield compound (83). LCMS purity 94%, m/z 496 [M++H]+, 1H NMR (300 MHz, MeOD), δ: 1.41-1.95 (16H, m, 8×CH2), 2.15-2.17 (2H, m, CH2), 2.40 (2H, t, J=7.2 Hz, CH2), 4.16 (2H, q, J=13.5 Hz, CH2), 5.12 (1H, s, CH), 5.27-5.30 (1H, m, CH), 7.40 (2H, d, J=8.7 Hz, Ar—H), 7.50-7.56 (5H, m, Ar—H), 7.67 (2H, d, J=8.7 Hz, Ar—H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(NCc2ccccc2)c1-c1ccccc1

Procedure:
7-Chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (0.5 g) and benzylamine (20 ml) was heated under reflux for 24 h. The reaction was concentrated under high vacuum and the residue was triturated with diethyl ether and filtered. The filtrate was evaporated and purified by chromatography (25% ethyl acetate-dichloromethane eluent) to give the title compound as a white solid (0.045 g); mp 179° C. (diethyl ether). Found: C, 72.63; H, 4.45; N, 7.65. C22H17ClN2O.0.1H2O requires C, 72.87; H, 4.78; o N, 7.72%; δ (360 MHz, DMSO-d6) 3.81 (2H, d, J=4.8 Hz, PhCH2NH), 8.67 (1H, t, J=4.8 Hz, PhCH2NH), 6.85 (2H, d, J=6.5 Hz, ortho aromatics), 7.10-7.33 (11H, m, aromatics), 8.16 (1H, d, J=8.8 Hz, 5-H), 11.23 (1H, br s, NH); m/z (EI) 360 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:16]([Si:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)Cl)([CH3:19])([CH3:18])[CH3:17]>ClCCl>[Si:20]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCC1CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.00 g (43.41 mmol) of 4-piperidinemethanol are dissolved in 400 ml of dichloromethane, and 9.1 ml (65.11 mmol) of triethylamine, 212 mg (1.74 mmol) of 4-N,N-dimethylaminopyridine and 16.9 ml (65.12 mmol) of tert-butyldiphenylchlorosilane are added in succession. The reaction mixture is stirred at RT for 8 h. After addition of 50 ml of dichloromethane the mixture is washed once with 20 ml of water and once with 20 ml of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate. The crude product is used in the next reaction without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:16](OCC)[CH:17]([CH3:25])[CH:18](OCC)OCC)C>CC(O)=O>[CH3:25][C:17]1[CH:16]=[N:12][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[CH:18]=1
Reactant: CCOC(OCC)C(C)C(OCC)OCC
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Solvent: CC(=O)O
Product: Cc1cnc2cc(-c3ccccc3)nn2c1
Temperature: 100 °C
Yield: 45 %

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5-amine x120 (31.4 mmol, 1 eq, 5 g) in AcOH (30 ml) is added 1,1,3,3-tetraethoxy-2-methylpropane x121 (31.4 mmol, 1 eq, 7.36 g). The mixture is heated at 100° C. during 4 hours. After evaporation of the solvent under reduced pressure, the crude product is poured in saturated NaHCO3 aqueous solution and then extracted with AcOEt. The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduce pressure. The crude mixture is recristallized in AcOEt to afford 6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x122 as a solid (3 g).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Ca+2]>C(O)C>[N:20]1([C:13]2[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=[CH:2][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1N1CCCCC1
Yield: 91.2 %

Procedure:
Proceeding as in example 2, with 0.035 mole (10.4 g) of 2,4'-dichloro-5-nitro-benzophenone and 0.07 mole (6 g) of piperidine and 0.035 mole (5 g) of calcium carbonate mixed in ethanol, 11 g (Yield: 97%) of the expected product are obtained after recrystallization in ethanol. M.P.=141° C.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]3[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=3)=[O:37])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:42]([C:41]4[CH:40]=[CH:39][C:38]([C:36]([NH:35][C:32]5[CH:31]=[CH:30][C:29]([N:26]6[CH2:25][CH2:24][O:23][CH2:28][CH2:27]6)=[CH:34][CH:33]=5)=[O:37])=[CH:45][CH:44]=4)[NH:18][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: N#Cc1ccc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc(N6CCOCC6)cc5)cc4)[nH]c3c2)cc1

Procedure:
Compound 641 was prepared according to the procedure similar to that described in Scheme III from 1-(4-cyanobenzyloxy)-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C32H27N5O3: 530.21; found: 530.10.
Reaction SMILES: C1(C)C=CC(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]2[N:20]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH:21]=[CH:22][CH:23]=2)(=O)=O)=CC=1.ClCCl.Cl>[OH-].[K+]>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=[C:11]1[C:19]1[N:20]([CH2:24][C:25]([OH:27])=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cccn3CC(=O)OC(C)(C)C)cc3cccnc32)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)Cn1cccc1-c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 19 h
Yield: 64.1 %

Procedure:
A suspension of [2-(1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-pyrrol-1-yl]-acetic acid, tert-butyl ester [400 mg, Reference Example 76] in methanolic potassium hydroxide solution (15.4 mL, 100 mg/mL) was agitated for 19 hours at room temperature then treated with dichloromethane (15 mL). This mixture was titrated with aqueous hydrochloric acid (1N) to adjust the pH to 2, then decanted. The organic phase was separated and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with water (15 mL) and then evaporated yielding the title compound (137 mg). LC-MS: METHOD C: RT=2.20 minutes, 242.1[M+H]+ and 198.1 (decarboxylated fragment).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=O)[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][OH:23].Cl.N1C=CC=CC=1>CCO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=[N:22][OH:23])[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 70 °C

Procedure:
General Procedure P. 1-(5,6-Diphenyl-pyridin-2-yl)-ethanone (Compound 75, 119 mg, 0.44 mmol), NH2OH—HCl (103 mg, 1.48 mmol) and pyridine (272 mg, 0.27 mmol) was dissolved in EtOH (2 ml), and the mixture was heated to 70° C. under nitrogen for 3 hours. The reaction was quenched with water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, and dried over Na2SO4. The filtered solvents were concentrated in vacuo, and the residue was purified by silica gel chromatography (15% ethyl acetate in hexane) to give title compound as an oil.
Reaction SMILES: [CH:1]([N:3]1[CH:8]([C:9]([O:11]CC)=[O:10])[CH2:7][C:6](=[CH2:14])[CH2:5][CH:4]1[C:15]([O:17]CC)=[O:16])=[O:2]>C1CCCCC1.C(OCC)(=O)C>[CH:1]([N:3]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][C:6](=[CH2:14])[CH2:5][CH:4]1[C:15]([OH:17])=[O:16])=[O:2]
Reactant: C=C1CC(C(=O)OCC)N(C=O)C(C(=O)OCC)C1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C=C1CC(C(=O)O)N(C=O)C(C(=O)O)C1
Yield: 51.2 %

Procedure:
Using the procedure of Step D of Example 1, 997 mg of the product of Step C were reacted to obtain 404 mg of the desired product with a Rf=0.2, eluant ethanol-ammonium hydroxide (8-2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([OH:37])(=O)=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.P(Cl)(Cl)([Cl:46])=O.O>C(#N)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([Cl:46])(=[O:37])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(-c2c(S(=O)(=O)O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(-c2c(S(=O)(=O)Cl)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
To a suspension of (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (prepared in Example 196) (315 mg) in acetonitrile (2.2 ml) were added pyridine (94 mg) and phosphorus oxychloride (365 mg) and the resulting mixture was stirred at room temperature for thirty minutes. To the reaction mixture was added water (5 ml) followed by an addition of ethyl acetate (10 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid chloride (330 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C(C)C)[C:5]([I:12])=[CH:4][C:3]=1[C:13]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[O:15][N:14]=1.ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[Cl:1][C:2]1[C:3]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[CH:4][C:5]([I:12])=[C:6]([OH:8])[CH:7]=1
Reactant: CCCc1ccc(-c2nc(-c3cc(I)c(OC(C)C)cc3Cl)no2)cc1
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: CCCc1ccc(-c2nc(-c3cc(I)c(O)cc3Cl)no2)cc1
Yield: 55 %

Procedure:
When the product of Step B was substituted for 5-(3-chloro-4-propoxy phenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 55% yield, as creamy solid. 1H NMR (CDCl3) 8.37 (s, 1H); 8.10 (d, 2H, J=8.25 Hz); 7.33 (d, 2H, J=8.25 Hz); 7.16 (s, 1H); 5.78 (b, 1H); 2.67 (t, 2H, J=7.38 Hz); 1.74-1.56 (m, 2H); 0.96 (t, 3H, J=7.32 Hz).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][N:4]([CH3:8])[C:3]1=[O:9].[CH3:10][C:11]([C:14]1[C:19]([OH:20])=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:17]=[C:16]([CH:25]=[O:26])[N:15]=1)([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.ClCCl.[Zn]>[CH3:13][C:11]([C:14]1[C:19]([OH:20])=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:17]=[C:16]([CH:25]([OH:26])[CH:2]2[CH2:7][CH2:6][O:5][N:4]([CH3:8])[C:3]2=[O:9])[N:15]=1)([CH3:10])[CH3:12]
Reactant: CN1OCCC(Br)C1=O
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1OCCC(C(O)c2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)C1=O
Yield: 39.1 %

Procedure:
A mixture of 1.1 g (5.7 mmol) of 4-bromo tetrahydro-2-methyl 2H 1,2-oxazin-3-one, Example 1, 1.2 g (5.1 mmol) of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinecarboxaldehyde, Example 6, and 0.75 g (11 mmol) of zinc dust in 30 mL of toluene was stirred at reflux for 18 hours. The cooled reaction mixture was diluted with dichloromethane and vigorously stirred. The zinc was filtered and washed with dichloromethane. The combined filtrates were evaporated to a foam. The residue was purified by flash chromatography (silica gel, 15% ethyl acetate in hexane elution) to give 0.70 g (39%) of the title compound as an oil mixture of diastereomers; MS m/e 352 (M+ 1).