Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:16])[C:3]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[I-:23].[Na+]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:3]1[C:4]([CH3:16])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=2)[C:2]=1[I:23])[CH3:22]
Reactant: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1I
Temperature: 80 °C

Procedure:
Ethyl 7-chloro-6-(2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5 g, 15.35 mmol) and sodium iodide (9.20 g, 61.4 mmol) were suspended in acetonitrile (80 mL) and the resulting mixture was heated at 80° C. for 2 h. At this point LCMS indicated completion of the reaction and appearance of the desired product. After cooling to rt, the reaction mixture was diluted with ethyl acetate and washed with water and aqueous Na2S2O3. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was triturated with ethyl acetate/hexane to afford ethyl 6-(2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5.7 g, 13.7 mmol, 89% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.32 (s, 1H), 4.51 (d, J=7.0 Hz, 2H), 4.25 (d, J=7.0 Hz, 2H), 4.02 (s, 2H), 2.68 (s, 3H), 1.48 (t, J=7.2 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H). LCMS (M+H)=418.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=[C:2]([NH:19][C:20]2[NH:21][N:22]=[C:23]([CH3:25])[CH:24]=2)[CH:7]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1ccc(CSc2nc(Cl)cc(Cl)n2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CSc2nc(Cl)cc(Nc3cc(C)n[nH]3)n2)cc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
To a solution of above-prepared 4,6-dichloro-2-(4-methoxy-benzylsulfanyl)-pyrimidine (915 mg, 3.04 mmol) and 3-amino-5-methylpyrazole (310 mg, 3.19 mmol) in BuOH (20 mL) is added diisopropylethylamine (0.56 mL, 3.19 mmol) followed by sodium iodide (455 mg, 3.04 mmol). The reaction mixture is stirred for 15 hours at 120° C. The solvent is removed in vacuo and the residue is purified by flash chromatography (SiO2, hexane/AcOEt gardient) to give [6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C:10]3=[N:9][N:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:23][C:24]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:23][C:24]1[C:32]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[N:8][N:9]=[C:10]2[CH2:15]1)=[O:27]
Reactant: c1cc(-c2nnc3n2CCNC3)ccn1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-(4-Pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.150 g, 0.745 mmol, e.g. prepared as described below) was treated with N,N-dimethylformamide (DMF) (3 mL) and cooled to 0° C. Triethylamine (0.109 mL, 0.783 mmol) and N,N-dimethyl-4-pyridinamine (DMAP) (0.009 g, 0.075 mmol) were added at 0° C. under argon and the mixture was stirred for 5 minutes; then 2-chloro-3-(trifluoromethyl)benzoyl chloride (0.199 g, 0.820 mmol, commercially available e.g. from Apollo Scientific or Shanghai FWD Chemicals) was added. The reaction mixture was kept at 0° C. for ½ hour. The reaction was quenched with water, extracted with ethyl acetate (two extractions), and the combined organic phases were washed with a saturated sodium bicarbonate solution, followed by water (four washes). The organic phase was dried, and evaporated to give a yellow oil. The residue was purified by silica gel chromatography using 0-20% of methanol in Dichloromethane as the eluent and then triturated with diethyl ether to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine as a white solid. The solid was dried at 50° C. on the high vacuum for 1 day.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: COc1ccccc1N=C=O
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)Nc1ccc(CC(=O)OC(C)(C)C)cc1C
Reaction time: 27 h
Yield: 76.4 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (1.36 g, 6.15 mmol) and triethylamine (170 ml, 1.23 mmol) in THF (30 ml) was added 2-methoxyphenyl isocyanate (820 ml, 6.15 mmol), and the resulting mixture was stirred for 27 h. The mixture was concentrated to a small volume in vacuo, and hexane was added to the residue to give precipitate, which was collected by filtration to give tert-butyl 4-[N′-(2-methoxyphenyl)ureido]-3-methylphenylacetate (1.74 g, 76%) as a white crystalline material. mp 157–158° C.; 1H-NMR (CDCl3) δ 1.46 (s, 9 H), 2.30 (s, 3 H), 3.50 (s, 2 H), 3.76 (s, 3 H), 6.43 (s, 1 H), 6.83 (br d, J=8.4 Hz, 1 H), 6.95 (br d, J=8.0 Hz, 1 H), 6.98–6.99 (m, 2 H), 7.13 (br s, 1 H), 7.23 (br s, 1 H), 7.48 (d, J=8.8 Hz, 1 H), 8.14 (d, J=8.4 Hz, 1 H); MS (ESI) m/z 371 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:21]([CH3:35])[C:20]1=[O:36]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:21]([CH3:35])[C:20]2=[O:36])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CN1C(=O)C(N)c2ccccc2C1c1ccccc1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-1H-alanine (Example B) and 4-amino-2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 115° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][CH2:11][P:12](=[O:19])([O:16]CC)[O:13]CC.C[Si](Br)(C)C>>[P:12]([CH2:11][NH:10][C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])([OH:19])([OH:16])=[O:13]
Reactant: CCOP(=O)(CN)OCC
Reactant: O=C(O)c1ccc(Br)o1
Agent: C[Si](C)(C)Br
Product: O=C(NCP(=O)(O)O)c1ccc(Br)o1

Procedure:
5-Bromofuroic acid was reacted with diethyl aminomethylphosphonate in a manner similar to that described in Step D, Example 5. The product was treated with TMSBr as described in Step D, Example 1 to provide the title compound (no. 8.01) as a solid. BPLC Rt=3.72 min; negative ion electrospray MS M-1 found: 282/284.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:29]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]([F:29])=[O:11])[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.8 %

Procedure:
(2S,3S)-2-tert-Butoxycarbonylamino-3-phenyl-butyric acid (1.94 g, 6.93 mmol) and pyridine (0.63 mL, 7.74 mmol) were dissolved in dichloromethane (50 mL) at −10° C. Cyanuric fluoride (1.80 mL, 21.1 mmol) was added dropwise. The mixture was stirred for 1 hour and ice-water was added. The mixture was extracted with dichloromethane (2×). The organic extracts were washed with water, brine and dried (sodium sulfate). Evaporation of the solvents gave crude ((1S,2S)-1-fluorocarbonyl-2-phenyl-propyl)-carbamic acid tert-butyl ester (2.2 g) as a cloudy oil which was used in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](Br)=[CH:19][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([C:35]1[CH:36]=[CH:37][C:38]([O:44][CH3:45])=[C:39](B(O)O)[CH:40]=1)([CH3:34])[CH3:33].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([C:10]1[CH:19]=[C:20]([C:39]2[CH:40]=[C:35]([CH:32]([CH3:34])[CH3:33])[CH:36]=[CH:37][C:38]=2[O:44][CH3:45])[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: COCCCNC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COc1ccc(C(C)C)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCCNC(=O)c1cc(-c2cc(C(C)C)ccc2OC)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 91.7 %

Procedure:
The mixture of 2,4-bis-benzyloxy-5-bromo-N-(3-methoxy-propyl)-benzamide (484 mg, 1 mmol) and 5-isopropyl-2-methoxy-phenylboronic acid (388 mg, 2 mmol) was heated in the mixture of toluene (5 ml), ethanol (5 ml) and saturated NaHCO3 (5 ml) under nitrogen in the presence of a catalytic amount of Pd(PPh3)4 (60 mg, 0.056 mmol) at 80° C. for 2-3 h. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (25 ml×3), and the combined organics were washed with water and brine and dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to provide 508 mg of 4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid-(3-methoxypropyl)-amide (92% yield). M.p.: 142-144 C; 400 MHz 1H NMR (CDCl3) δ: 8.16 (s, 1H), 7.92 (t, J=5.6 Hz, 1H), 7.43-7.38 (m, 5H), 7.33-7.26 (m, 5H), 7.17 (dd, J=8.4, 2.4 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.59 (s, 1H), 5.11 (s, 2H), 5.06 (s, 2H), 3.72 (s, 3H), 3.44 (q, J=5.6 Hz, 2H), 3.30 (t, J=6.4 Hz, 2H), 3.22 (s, 3H), 2.87 (m, 1H), 1.69 (pent, J=6.4 Hz, 2H), 1.23 (d, J=6.8 Hz, 6H); LCMS: 554 [M+H].
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(C(=O)O)CC1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a stirring solution of 1-Boc-4-methoxycarbonyl-3,4-didehydropiperidine (28.81 g, 119 mmol) in methanol (300 mL) was added 1 N aqueous sodium hydroxide (300 mL). After stirring overnight, the solvent was removed by rotary evaporation and the residue was partitioned between water and diethyl ether. The aqueous phase was separated and washed with diethyl ether, acidified to pH 2.5 with conc. HCl, then extracted with diethyl ether. The organic extract was then washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 25.16 g (93%) of a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:36]/[O:37][CH2:38][CH2:39][F:40])/[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24]CC4C=CC(OC)=CC=4)=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:41][N:42]([CH2:44][C:45]1[S:49][CH:48]=[N:47][C:46]=1[CH3:50])[CH3:43]>>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:36]/[O:37][CH2:38][CH2:39][F:40])/[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:42]([CH3:43])([CH3:41])[CH2:44][C:45]4[S:49][CH:48]=[N:47][C:46]=4[CH3:50])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: Cc1ncsc1CN(C)C
Reactant: COc1ccc(COC(=O)C2=C(/C=C/CI)CS[C@@H]3[C@H](NC(=O)/C(=N\OCCF)c4nsc(N)n4)C(=O)N23)cc1
Product: Cc1ncsc1C[N+](C)(C)C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCCF)c3nsc(N)n3)[C@H]2SC1
Yield: 34.5 %

Procedure:
p-methoxybenzyl 7β[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-fluoroethoxyiminoacetamido]-3-[(E)-3-iodo-1-propen-1-yl]3-cephem-4-carboxylate(1.1 g) and 5-dimethylaminomethyl-4-methylthiazol (0.36 g) were reacted in the same manner as discribed in Example 13 to obtain the target product(330 mg).
Reaction SMILES: [OH:1][C:2]1([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.C1COCC1.C([Li])CCC.C1(C#CC2(O)C=CC([CH2:42][CH2:43][C:44]3([CH3:52])[O:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][O:45]3)(O)C=C2)C=CC=CC=1>CN1C(=O)N(C)CCC1>[OH:1][C:2]1([C:9]#[C:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]([CH2:42][CH2:43][C:44]2([CH3:52])[O:45][CH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][O:49]2)[CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1
Reactant: CC1(C)COC(C)(CCC2(O)C=CC(O)(C#Cc3ccccc3)C=C2)OC1
Reactant: O=C1C=CC(O)(C#Cc2ccccc2)C=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC1(C)COC(C)(CCC2CC(=O)C=CC2(O)C#Cc2ccccc2)OC1
Temperature: -78 °C

Procedure:
4-Hydroxy-4-(phenylethynyl)-2,5-cyclohexadiene-1-one (1.26 g, 0.006 mole), the compound of Example 1a and 25 mL of dry THF were placed in a dry 100 mL, three-necked round-bottomed flask under nitrogen. The reaction was cooled to -78° C. and treated dropwise with n-butyllithium (4 mL of 1.48M). The reaction was allowed to warm slowly to about 0° C. During this time, a white slurry formed. The reaction was cooled to -78° C. and treated with 4.6 mL of DMPU and one equivalent of the Grignard reagent prepared in Example 1b. The reaction was allowed to warm slowly to RT over a period of 1 hr, then quenched with ammonium chloride solution and extracted into ether. The ether extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated in vacuo. The residue was dried under vacuum overnight. The crude product was chromatographed using a flash silica gel column eluting with 1:4 EtOAc/hexane to yield a first compound-bearing fraction containing 1.5 g (68%) of the title 1,2-1,4 adduct and a third compound-bearing fraction containing 0.31 g (14%) of 1-(phenylethynyl)-4-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2,5-cyclohexadiene-1,4-diol, the 1,2-1,2 adduct.
Reaction SMILES: CC1(C)CO[C:5]2([CH2:27][CH2:26][C:10]3[N:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]4[N:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18](=[O:19])[C:9]=3[CH2:8]2)[O:4]C1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(=O)CC>[C:20]1([N:11]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:19])[C:9]3[CH2:8][C:5](=[O:4])[CH2:27][CH2:26][C:10]2=3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)COC2(CCc3c(c(=O)c4cccnc4n3-c3ccccc3)C2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCC(C)=O
Product: O=C1CCc2c(c(=O)c3cccnc3n2-c2ccccc2)C1

Procedure:
Reflux 6,8,9,10-tetrahydro-5',5'-dimethyl-10-phenyl-spiro[benzo[b][1,8]naphthyridin-7-(5H),2'-[1,3]dioxan]-5-one (32 mmoles) with water (6 ml) and p-toluenesulfonic acid monohydrate (3.2 g) dissolved in 2-butanone (319 ml) for 3 days. Monitor the progress of hydrolysis by thin-layer chromatography. When hydrolysis is complete, cool the solution and evaporate the 2-butanone. Wash a CH2Cl2 solution of the residue with aqueous NaHCO3 solution and with water. Evaporate the CH2Cl2 after drying the organic solution, and crystallize the residue from C2H5OH--CHCl3 to obtain 6,8,9,10-tetrahydro-10-phenyl-benzo[b][1,8]naphthyridin-5,7-dione, m.p. 244°-247° C. (d).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][CH2:7][CH3:8])[CH:3]=[O:4].[Br-].[Mg+2].[CH:12]#[CH:13].[Br-]>>[CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][CH2:7][CH3:8])[CH:3]([OH:4])[C:12]#[CH:13]
Reactant: CCCCC(C)(C)C=O
Reactant: C#C
Agent: [Br-]
Agent: [Mg+2]
Product: C#CC(O)C(C)(C)CCCC

Procedure:
The acetylenic alcohol intermediates are produced by reaction of the appropriate carbonyl compounds with an organometallic acetylene reagent, e.g. acetylene magnesium bromide. Typically, 2,2-dimethyl-n-hexaldehyde is contacted with acetylene magnesium bromide and the adduct hydrolyzed to afford 4,4-dimethyl-1-octyn-3-ol. The acetylenic alcohols in which the alcohol group is tertiary are obtained from the appropriate ketones. 2,2-Dimethyl-n-hexaldehyde, for example, is converted to 3,3-dimethyl-2-heptanone by reaction with methyl magnesium bromide followed by hydrolysis of the adduct and oxidation of the secondary alcohol group with chrominum trioxide. That ketone is then contacted with acetylene magnesium bromide and the adduct hydrolyzed to afford 3,4,4-trimethyl-1-octyn-3-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][NH:8][C:9]2[C:10]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[C:18]1([C:17]2[C:10]3[C:9]([NH:8][CH2:7][CH2:6][C:5]4[CH:30]=[CH:31][C:2]([NH:1][C:39]([NH:38][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:40])=[CH:3][CH:4]=4)=[N:14][CH:13]=[N:12][C:11]=3[O:15][C:16]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(CCNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)cc1
Solvent: CC#N
Product: O=C(Nc1ccccc1)Nc1ccc(CCNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a solution of N-(4-aminophenethyl)-5,6-diphenylfuro[2,3-d]pyrimidin-4-amine (0.195 g) in acetonitrile (10 mL) was added phenyl isocyanate (0.063 g). After stirring at room temperature for 16 h, the reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (1:1), to give 1-(4-(2-(5,6-diphenylfuro[2,3-d]pyrimidin-4-ylamino)ethyl)phenyl)-3-phenylurea (0.240 g, 95%). 1H-NMR (CDCl3, 300 MHz): δ 8.42 (s, 1 H), 7.58 (brs, 1 H), 7.43-7.39 (m, 5 H), 7.33-7.18 (m, 11 H), 7.03-6.98 (m, 1 H), 6.86-6.83 (m, 2 H), 4.67 (t, 1 H), 3.63 (q, 2 H), 2.66 (t, 2 H). LC-MS (ESI) m/z 526.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
4-Aminobenzoic acid (0.94 g, 6.85 mmol) was dissolved in 5 mL of pyridine and dodecanoyl chloride (1.58 mL, 6.85 mmol) was added. The mixture was stirred for 4 h at room temperature. The product was precipitated by dilution with water (50 mL), filtered, and dried to provide 1.96 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH:5]=[CH:6][C:7]1[C:8]([C:13]([OH:15])=[O:14])=[CH:9][CH:10]=[CH:11][CH:12]=1.[C:19](C1C=CC=CC=1CCC1C=C(C)C=CC=1)(O)=O>[Pd].CN(C)C=O>[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1[CH:1]=[CH:19][CH:16]=[CH:17][CH:18]=1)([OH:15])=[O:14]
Reactant: Cc1cccc(C=Cc2ccccc2C(=O)O)c1
Reactant: Cc1cccc(CCc2ccccc2C(=O)O)c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1CCCCc1ccccc1

Procedure:
A solution of 53.0 gm. of 3'-methylstilbene-2-carboxylic acid in 230 ml. dimethylformamide containing 2.0 gm. of 5% palladium on carbon is hydrogenated in a Parr shaker at 60 p.s.i. for 11/2 hours. The solution is filtered and added to ether and water. The organic layer is washed with water, then dried and evaporated. The product is recrystallized from ether-hexane to give 48 gm., 90%, of 3-(o-carboxyphenethyl)toluene, m.p. 82°-84° C. Use of 3'-ethylenestilbene-2-carboxylic acid gives a similar yield of 3-(o-carboxyphenethyl)ethylbenzene.
Reaction SMILES: [C:1]([OH:17])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S(Cl)([Cl:20])=O>C1CCCCC1>[C:1]([Cl:20])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCC(=O)Cl
Temperature: 80 °C
Yield: 63.6 %

Procedure:
In a one L (liter) two-necked flask were placed 160.0 g (0.66 mol) of pentadecanoic acid and 200 milliliter (mL) of cyclohexane, and the flask was equipped with a 100 mL dropping funnel containing 83.3 g (0.7 mol) of thionyl chloride and a reflux tube. Then, the pentadecanoic acid was completely dissolved under heating and stirring of the flask in an oil bath at 80° C. Thereafter the thionyl chloride was added dropwise over a period of 2 hours, and further the oil bath was maintained at 80° C. for one hour. From the resultant reaction mixture were removed the cyclohexane and the thionyl chloride under reduced pressure by means of an aspirator. The resultant crude reaction product was subjected to vacuum distillation. Thus 110.0 g (0.42 mol) of pentadecanoyl chloride was obtained in a yield of 63.9% based on the fed pentadecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:47]([S:54]SC(=N)N)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.O>C(O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([S:54][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])=[N:11]1
Reactant: N=C(N)SSCc1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2SCc2ccccc2)c1
Reaction time: 3 h

Procedure:
1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-tetradecanamidoanilino)-5-oxo-2-pyrazoline (21.4 g) was dissolved in 80% ethanol (ratio by volume of water:20%), and 2.42 g of anhydrous potassium carbonate was added thereto. The solution was refluxed with heating. 8.2 g of S-benzylthioisothiourea hydrochloride was added to the solution and the solution was vigorously stirred for 3 hours. After confirming the conclusion of the reaction by thin film chromatography, the reaction container was cooled with water. The formed crystals were separated by filtration and dissolved in 100 ml of hot ethanol. Insoluble materials were separated by filtration, and the filtrate was cooled. The resulting colorless crystals were Compound (1). The melting point was 182° to 185° C. and the yield was 12 g.