Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:27]([O:29]CC)=[CH2:28])CCC.FC1C(C(C2N3N=C(C(=O)C)C=CC3=NC=2)C)=C(F)C=C2C=1C=NN2C>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][C:8]3[N:6]4[N:7]=[C:2]([C:27](=[O:29])[CH3:28])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(=O)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 51.4 %

Procedure:
The title compound as a light yellow solid (500 mg, 51%) was synthesized from 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (950 mg, 3.21 mmol), tributyl(1-ethoxy-vinyl)stannane (1.142 ml, 3.37 mmol) and tetrakis-(triphenylphosphine)-palladium (186 mg, 0.161 mmol) in DMF using the same procedure as described in the synthesis of compound 31.4. LCMS (method B): [MH]+=304.1, tR=1.71 min.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([O:8][C:9]([C:11]1([C:39](OCC)=[O:40])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:27]=[CH:26]3)=[CH:20][CH:21]=1)=O)C>C(O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([N:28]2[C:29]3[C:25](=[CH:24][C:23]([O:22][C:19]4[N:18]=[CH:17][C:16]([N:12]5[C:11]6([C:39](=[O:40])[NH:5][C:3](=[O:4])[NH:2][C:9]6=[O:8])[CH2:15][CH2:14][CH2:13]5)=[CH:21][CH:20]=4)=[CH:31][CH:30]=3)[CH:26]=[N:27]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: O=C1NC(=O)C2(CCCN2c2ccc(Oc3ccc4c(cnn4-c4ccc(F)cc4)c3)nc2)C(=O)N1
Temperature: 80 °C

Procedure:
To a flame dried flask is added ethanol (6 mL) and freshly cut sodium metal (62.4 mg, 2.71 mmol). The solution is stirred until homogenous. Recrystallized urea (98 mg, 1.63 mmol) is added and the solution is stirred at room temperature for 5 minutes. 1-{6-[1-(4-Fluoro-phenyl)-1H-indazol-5-yloxy]-pyridin-3-yl}-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.54 mmol) is added, and the solution is heated to 80° C. for 30 minutes, then cooled to 50° C. and stirred for 16 hours. The reaction is then quenched by the addition of 10 mL water, and 1N hydrochloric acid is added to adjust the pH to 5. The aqueous layer is extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers are washed with saturated sodium chloride, dried with magnesium sulfate, filtered, and concentrated under vacuum to produce crude product. This material is chromatographed on silica gel (ISCO MPLC purification, 30 minutes, 50-100% ethyl acetate gradient, Biotage flash 40s column) to provide 1-{6-[1-(4-Fluoro-phenyl)-1H-indazol-5-yloxy]-pyridin-3-yl}-1,7,9-triaza-spiro[4.5]decane-6,8,10-trione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[S:19][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.[C:36]1([CH3:45])[C:37]([N:42]=[C:43]=[O:44])=[CH:38][CH:39]=[CH:40][CH:41]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:43]([NH:42][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH3:45])=[O:44])=[CH:26][CH:27]=2)[S:19][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OCc2csc(Cc3ccc(N)cc3)n2)c(OC)c1
Reactant: Cc1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2csc(Cc3ccc(NC(=O)Nc4ccccc4C)cc3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94 %

Procedure:
To a solution of ethyl 3-methoxy-4-[2-(4-aminobenzyl)-4-thiazolyl]methoxybenzoate (87.8 mg, 0.220 mmol) in THF (2.0 mL) was added triethylamine (30.5 ul, 0.220 mmol) and o-tolyl isocyanate (30 μl), and the reaction mixture was stirred at room temp for 21 hr. The reaction mixture was poured into ice-water and the resulting precipitates filtered off. The filtrate was extracted with CHCl3, washed with H2O, and brine. The extract was dried over Na2SO4. The solvent was removed under a reduced pressure to afford 110.4 mg (94%) ethyl 3-methoxy4-[2-[4-[N′-(2-methylphenyl) ureido]benzyl]-4-thiazolyl]methoxybenzoate as a pale yellow crystalline powder. 1H-NMR (400 MHz, CDCl3) δ 1.38 (t, J=7.3 Hz, 3H), 2.28 (s, 3H), 3.92 (s, 3H), 4.28 (s, 2H), 4.35 (q, J=7.3 Hz, 2H), 5.29 (s, 2H), 6.20 (s, 1H), 6.47 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 7.20 (s, 1H), 7.24 (s, 2H), 7.27 (s, 2H), 7.33 (d, J=8.3 Hz, 2H), 7.49 (d, J=7.3 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.63 (dd, J=2.0, 8.3 Hz, 1H); MS (FAB) m/z 532 (M++1).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][S:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)(=[O:7])=[O:6].O.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[C:8]([S:5]([O:4][CH2:3][C:2]([CH3:29])([CH3:1])[CH3:28])(=[O:7])=[O:6])[CH:13]=1
Reactant: CC(C)(C)COS(=O)(=O)c1cc([N+](=O)[O-])ccc1C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)COS(=O)(=O)c1cc(N)ccc1C=Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
5-Nitro-2-[2-(4-nitro-phenyl)-vinyl]-benzenesulfonic acid 2,2-dimethylpropyl ester (Example 56, 1.10 g, 2.62 mmol) was dissolved in 52 mL of ethyl acetate. Tin chloride dihydrate (2.95 g, 13.1 mmol) was added and a reflux condenser attached. The solution was heated to reflux and stirred overnight. After cooling to room temperature the solution was diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate. The whole mixture was filtered thru Celite and the aqueous layer discarded. The organic layer was then washed with brine and dried over MgSO4. After concentration on a rotovap the crude material was purified by a gradient flash column using 3 to 10% ethyl acetate in dichloromethane as the eluant to afford 0.33 g of the title compound as a oily red solid (35%): 1HNMR (CDCl3): δ7.63 (d, J=9 Hz, 1H), 7.58 (d, J=16 Hz, 1H), 7.33 (d, J=9 Hz, 2H), 7.31 (d, J=3 Hz, 1H), 6.89 (dd, J=9 Hz, 3 Hz, 1H), 6.86 (d, J=16 Hz, 1H), 6.68 (d, J=9 Hz, 2H), 3.89 (br s, 4H), 3.61 (s, 2H), 0.86 (s, 9H); MS (ES-POS): [M+H]+ 361; Analytical HPLC determined that this compound was 90% pure by C-18 reverse phase.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:27]1[CH:31]=[C:30]([CH2:32][OH:33])[N:29]=[CH:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:34]([O:41][CH:42]([C:46]1[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][CH:47]=1)[C:43](O)=[O:44])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>ClCCl>[Si:34]([O:41][CH:42]([C:46]1[CH:47]=[CH:48][C:49]([C:52]#[N:53])=[CH:50][CH:51]=1)[C:43]([O:33][CH2:32][C:30]1[N:29]=[CH:28][N:27]([C:8]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:31]=1)=[O:44])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)O)c1ccc(C#N)cc1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC(C(=O)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 mmol of triethylamine and 1.0 mmol propanephosphonic acid cyclic anhydride [68957-94-8] (50% in ethyl acetate) are added to a solution of 1.0 mmol of (1-trityl-1H-imidazol-4-yl)methanol [33769-07-2] and 1.0 mmol of (tert-butyldimethylsilanyloxy)(4-cyanophenyl)acetic acid in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature for 3 hours and diluted with dichloromethane. The phases are separated and the organic phase is washed with 1M HCl and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][Si](C(C)(C)C)(C)C)[CH2:16][CH2:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(O)(=O)C.O1CCCC1.[OH-].[Na+]>O>[O:1]=[C:2]([N:14]1[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)N1CCC(O)CC1
Temperature: 75 °C

Procedure:
Mix 1-oxododecyl-4-(O-tert-butyldimethylsilyloxy)piperidine (3.5 mmol) with a solution of acetic acid (9 mL), tetrahydrofuran (6 mL) and water (6 mL). Heat at 75° C. overnight. Cool to room temperature and make basic with 10% sodium hydroxide and extract into methylene chloride. Wash with water, then with brine and dry (Na2SO4). Evaporate the solvent in vacuo and purify by flash chromatography (5% methanol/methylene chloride) to give the title compound. 587E-115
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]([Cl:18])=[CH:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[CH:11]=[C:10]([Cl:18])[Cl:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C=C(Cl)Cl)CCCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: ClCCl
Product: CC(C)(C=C(Cl)Cl)CCOc1ccc(Cl)cc1
Yield: 86 %

Procedure:
128 g (1 mol) of 4-chlorophenol, 201 g (1 mol) of 1,1,5-trichloro-3,3-dimethyl-1-pentene (II) and 138 g (1 mol) of potassium carbonate in 1 liter of diethylene glycol dimethyl ether are heated under reflux for 10 hours. The mixture is then diluted with methylene chloride and extracted by shaking several times with water. The organic phase is freed of solvent on a rotary evaporator and then distilled at a boiling point of 135°-140° C./0.1 mbar. 252 g (0.86 mol, which is 86% of theory) of 5-(4-chlorophenoxy)-1,1-dichloro-3,3-dimethyl-1-pentene are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH3:19])[N:9]=2)=[CH:4][CH:3]=1.[Br:20]Br>C(O)(=O)C.CN(C=O)C>[Br:20][C:11]1[N:10]([CH3:19])[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(F)cc2)n1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1Br
Temperature: 80 °C
Yield: 35 %

Procedure:
To a solution of 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (2.7 g, 10.67 mmol) (prepared in accordance with Example A-212) in acetic acid (30 mL) and DMF (13 mL) was added bromine (19.5 g, 122.0 mmol). The solution was heated at 80° C. overnight. TLC indicated that the reaction was complete. The mixture was quenched slowly with K2CO3 (25 g). When pH was about 5, a precipitate was formed. The precipitate was washed with water (50 mL×5) to give 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (1.24 g, 35%): mp 174.38° C.; Mass spectrum m/z=332, 334; 1H NMR was consistent with the proposed structure. Anal. Calc'd for C15H11N3FBr.0.2H2O: C, 53.66; H, 3.42; N, 12.51. Found: C, 53.58; H, 3.12; N, 12.43.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:19]O>>[C:1]([CH2:9][CH2:10][C:11]([O:13][CH3:19])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccccc1
Yield: 100 %

Procedure:
To a 1.0 L round bottom flask was added 49.25 g (0.276 mol) of 3-benzoylpropionic acid. To this was added 700 mL of ACS methanol and the solution stirred until all of the acid had dissolved. To this solution was added approximately 2.0 mL of conc. H2SO4 and the reaction refluxed for 2.5 hours. The reaction can be monitored by HPLC. After the reaction was determined to be complete, the methanol was removed on the rotoevaporator and to the residual oil was added ethyl acetate (~500 mL). To the ethyl acetate layer was then added 150 mL of a saturated sodium carbonate solution. The layers were extracted and allowed to separate. The organic layer was then dried (MgSO4), filtered and concentrated to yield methyl 3-benzoylpropionate (1) as a light yellow oil. Yield 53.30 g; yield 100%; >97% cp.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:30]=[CH:29][C:28]([F:27])=[CH:33][C:32]=2[F:34])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: OB(O)c1ccc(F)cc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(F)cc2F)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 2,4-difluorophenyl-boronic acid, 5-(2,4-difluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of an off-white foam (yield=87%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=C(C4C=CC(/C=C/C(O)=O)=CC=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:37][C:38]1[N:43]([CH2:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[C:42](=[O:51])[N:41]([CH2:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[C:40](=[O:59])[C:39]=1[N:60]=O.[CH:62]([C:64]1[CH:72]=[CH:71][CH:70]=[CH:69][C:65]=1[C:66]([OH:68])=[O:67])=O>>[CH:30]1([CH2:29][N:10]2[C:11]([NH2:12])=[C:15]([NH2:14])[C:16](=[O:17])[N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:9]2=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1.[CH:53]1([CH2:52][N:41]2[C:40](=[O:59])[C:39]3[N:60]=[C:62]([C:64]4[CH:72]=[CH:71][CH:70]=[CH:69][C:65]=4[C:66]([OH:68])=[O:67])[NH:37][C:38]=3[N:43]([CH2:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[C:42]2=[O:51])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Product: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Product: O=C(O)c1ccccc1-c1nc2c(=O)n(CC3CCCCC3)c(=O)n(CC3CCCCC3)c2[nH]1

Procedure:
1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was prepared as in part (d) of Example 1 by reduction of 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (2.00 g) and immediately condensed with 2-formylbenzoic acid (Aldrich, 1.424 g) by the method of J. Perumattam (Synthetic Commun. 1989, 19: 3367–3370) to give title compound as an off-white solid off-white solid (1.22 g, 46%), m.p. 271–274° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [C:1]([CH2:8][CH2:9][CH:10]([NH2:31])[C:11]([O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:17]([O:19][CH2:20]C)=[O:18])[C:12]([O:14][CH2:15]C)=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+]>CO>[C:23]([O:22][CH3:11])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:1]([CH2:8][CH2:9][CH:10]([NH2:31])[C:11]([OH:22])([C:12]([O:14][CH3:15])=[O:13])[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CCOC(=O)C(OC(=O)c1ccccc1)(C(=O)OCC)C(N)CCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C(O)(C(=O)OC)C(N)CCC(=O)OC(C)(C)C
Product: COC(=O)c1ccccc1
Reaction time: 1 h
Yield: 129 %

Procedure:
A mixture of 4 g of ethyl 5-BOC-amino-2-benzoyloxy-2-ethoxycarbonyl-pentanoate and 2 g of K2CO3 in 40 ml of anhydrous methanol, cooled to 0°-5° C., is stirred for 1 h. After filtration of the potassium carbonate excess, the solution is acidified to pH 6 with 2N HCl and filtered from the salts which separate. Solvent is evaporated off under vacuum and the residue is partitioned between cold water and ethyl acetate. The organic phase is washed repeatedly with a 5% K2CO3 cold solution and with water to neutrality, dried over sodium sulfate and evaporated to dryness. The residue (3 g) is eluted, purified on 30 g of silica gel, eluent hexane-ethyl acetate from 95:5 to 80:20, to give methyl benzoate and 1.8 g of methyl 5-BOC-amino-2-hydroxy-2-methoxycarbonyl-pentanoate (oil).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH:7]([C:10]1[CH:11]=C(C2C=CC=CC=2)[CH:13]=[C:14]([CH:27]([CH3:29])[CH3:28])[C:15]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)([CH3:9])[CH3:8].CO[CH:38](OC)[CH2:39][NH2:40].[C:43]1([CH3:50])[C:44](C)=[CH:45][CH:46]=[CH:47][CH:48]=1>C1COCC1>[CH:27]([C:14]1[CH:13]=[C:50]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:11]=[C:10]([CH:7]([CH3:8])[CH3:9])[C:15]=1[N:16]1[CH:38]=[CH:39][N:40]=[C:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)([CH3:28])[CH3:29]
Reactant: COc1cccc(C(=O)Nc2c(C(C)C)cc(-c3ccccc3)cc2C(C)C)c1
Reactant: Cc1ccccc1C
Reactant: COC(CN)OC
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1cccc(-c2nccn2-c2c(C(C)C)cc(-c3ccccc3)cc2C(C)C)c1
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Phosphorous (V) pentachloride (7.99 g, 38.4 mmol) was added slowly to a solution of N-(3,5-diisopropyl-[1,1′-biphenyl]-4-yl)-3-methoxybenzamide (9.92 g, 25.6 mmol) in xylene (260 mL) with stirrer at rt under a nitrogen atmosphere. The reaction mixture was heated to 130-135° C. (oil both temp) for 1.5 h. Xylene (approximately 200 mL) was remove at 140° C. to yield a crude oil, which was cooled down to 0° C. with ice bath. 120 mL of THF was added. To this cold THF solution was added dropwise a solution of 2,2-dimethoxyethanamine (55.8 ml, 512 mmol) in THF (140 mL) over a period of 50 min. The reaction mixture was warmed up and stirred at rt overnight. The reaction mixture was concentrated in vacuum and THF (260 mL) was added. The undissolved solid (2,2-dimethoxyethanamine HCl salt) was removed by filtration. 32 mL of 6.0 N HCl was added to the filtrate and the mixture was heated at 90° C. for 3 h. The reaction mixture was cooled down and neutralized with aq. Na2CO3 to pH 11. THF was removed in vacuum and the remaining aqueous mixture was extracted with AcOEt (3×350 mL). The combined AcOEt extracts were washed with water and brine, and then purified by silica gel column chromatography using hexane/AcOEt: 7/3 as eluant. Pure fractions were combined and concentrated to afford an off-white solid (5.6 g, 53%).
Reaction SMILES: CO.C[C:4](C)([O-:6])C.[K+].F[C:10]1[CH:17]=[C:16]([C:18]2[N:22]([CH3:23])[C:21]([C:24]([CH3:36])([O:26][C:27]3[C:32]([F:33])=[CH:31][C:30]([F:34])=[CH:29][C:28]=3[F:35])[CH3:25])=[N:20][N:19]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].O>C1COCC1>[CH3:4][O:6][C:10]1[CH:17]=[C:16]([C:18]2[N:22]([CH3:23])[C:21]([C:24]([CH3:36])([O:26][C:27]3[C:32]([F:33])=[CH:31][C:30]([F:34])=[CH:29][C:28]=3[F:35])[CH3:25])=[N:20][N:19]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: Cn1c(-c2ccc(C#N)c(F)c2)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2nnc(C(C)(C)Oc3c(F)cc(F)cc3F)n2C)ccc1C#N
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
Methanol (0.060 ml) was added to a solution of potassium tert-butoxide (130 mg) in THF (6 ml) under ice cooling, followed by stirring for 15 minutes under ice cooling. 2-fluoro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}benzonitrile (300 mg) was added to the reaction mixture, followed by stirring for one hour, while slowly elevating to room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 30:70 linear gradient) to obtain 2-methoxy-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}benzonitrile (192 mg), as a colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][C:17]=2[CH3:32])[C:10]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:9]1=2)=[O:6].[C:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])[CH3:40].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[C:39]([N:42]1[CH2:47][CH2:46][N:45]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:33])[C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[CH:18][C:17]=3[CH3:32])[C:10]3[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:9]2=3)=[O:6])[CH2:44][CH2:43]1)(=[O:41])[CH3:40]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CCCCl)c3cc(Cl)ccc32)c(C)c1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCN(CCCC(=O)OC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)CC1
Yield: 51.5 %

Procedure:
7-Chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-chlorobutyrate (0.5 g) was dissolved in acetonitrile (10 ml). 1-Acetylpiperazine (0.35 g), sodium iodide (0.41 g), and sodium carbonate (0.19 g) were added to the solution, and the mixture was heated under reflux for 19 hours. The reactant was poured into water, and the mixture was extracted with ethyl acetate, washed with water, dried over sodium carbonate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1→100:10) to obtain 0.3 g of 7-chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-(4-acetylpiperazin-1-yl)butyrate as colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14](OC(C)(C)C)=O)=[CH:8][CH:7]=2.[C:21]1([C:27]2[N:32]=[N:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.[OH-].[Na+]>>[C:21]1([C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:14]([CH2:13][C:9]4[CH:10]=[C:11]5[C:6](=[CH:7][CH:8]=4)[N:5]=[CH:4][C:3]([OH:2])=[CH:12]5)=[N:34][N:33]=3)[N:32]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.3 g, 1 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.3 g, 2 mmol), and HYDROCHLORIC ACID (0.3 ml, 11 mmol) as solvent. The vial was sealed and first heated at 100° C. for 20 min then placed into CEM microwave for 20 min. at 180° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH. The ppt. was collected by filtration. The ppt. was washed with water and dried. The solid was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2, DCM:MeOH=95%:5%, Flow=40 mL/min) to afford the desired product as gray solid. MS m/z: 354.2 (M+H). Calc'd. for C21H15N5O−353.37.