Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH2:9][CH3:10])[C:7](=[O:25])[CH2:6]1)[C@@H:20]1[C:15](=[CH:16][C:17](=[O:24])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:3])[CH3:2].C(OCC)(OCC)O[CH2:28][CH3:29].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>O1CCOCC1.CCOCC>[C:1]([O:4][C@@H:5]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH2:9][CH3:10])[C:7](=[O:25])[CH2:6]1)[C@@H:20]1[C:15]([CH:16]=[C:17]([O:24][CH2:28][CH3:29])[CH2:18][CH2:19]1)=[CH:14][CH2:13]3)(=[O:3])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C[C@H](OC(C)=O)[C@@H]34)[C@H]2CC1

Procedure:
Under argon, 2.0 g of 15α-acetoxy-18-methyl-4-estrene-3,17-dione in 60 ml of dioxane is agitated at room temperature for 20 hours with 6 ml of triethyl orthoformate and 40 mg of p-toluenesulfonic acid. After adding 2 ml of pyridine, the mixture is diluted with ether, washed with water, and dried. The crude product is recrystallized from acetone/hexane. Yield: 1.6 g of 15α-acetoxy-3-ethoxy-18-methyl-3,5-estradien-17-one. Melting point: 202° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[ClH:25].Cl.FC1C=C(NC(NC(=O)CC2C=CC=CC=2F)=S)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.[CH3:64][O:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][C:73]([N:75]=[C:76]=[S:77])=[O:74]>>[ClH:25].[ClH:25].[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:76]([NH:75][C:73](=[O:74])[CH2:72][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=2[O:65][CH3:64])=[S:77])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: COc1ccccc1CC(=O)N=C=S
Agent: Cl
Agent: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4F)cc3F)c2s1
Product: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1

Procedure:
Starting from the compound 219, following the procedure described above for the synthesis of 303a (example 232) but replacing 2-(2-fluorophenyl)acetyl isothiocyanate with 2-(2-methoxyphenyl)acetyl isothiocyanate, title compound 303b was obtained in 44% as an off-white solid. 1H NMR (d-DMSO) δ (ppm): 12.55 (s, 1H), 11.73 (s, 1H), 8.62 (m, 1H), 8.09(m, 1H), 7.65 (s, 1H), 7.57 (m, 1H), 7.43 (s, 1H), 7.27-7.20 (m, 1H), 6.98(d, 1H, J=8.2 Hz), 6.90(dt, 1H, J1=10 Hz, J2=7.4 Hz), 6.79 (m, 1H), 4.02 (s, 3H), 3.81 (s, 2H), 3.77 (s, 3H). MS (m/z): 548.3 (M+H) (found).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([Br:12])[CH:11]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25].[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:25])[O:13][C:8]1[CH:9]=[C:10]([Br:12])[CH:11]=[C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])[CH:7]=1
Reactant: Cc1ccccc1N=C=O
Reactant: COC(COc1cc(O)cc(Br)c1)OC
Agent: [N-]=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(COc1cc(Br)cc(OC(=O)Nc2ccccc2C)c1)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Dimethoxyethoxy)-5-bromophenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. 2-Methylphenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-dimethoxyethoxy)-5-bromophenyl] N-2-methylphenylcarbamate as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH:15]1([S+](C2C=CC=CC=2)C2C=CC=CC=2)[CH2:17][CH2:16]1.CC(C)([O-:34])C.[K+].F[B-](F)(F)F.[H+]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH2:17][CH2:15][C:16]2=[O:34])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: c1ccc([S+](c2ccccc2)C2CC2)cc1
Reactant: CC(C)(C)[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCC1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-chloro-benzaldehyde (142 mg, 1 mmol) and cyclopropyldiphenylsulfonium tetrafluoroborate (317 mg, 1 mmol) in 10 ml dry THF, cooled to 0° C., was added dropwise, with stirring, a slurry of potassium tert. butoxide (1.4 ml 1M). After addition was complete the reaction was stirred 30 min. and 1M tetrafluoroboric acid (10% in THF) (10 ml) was added. The mixture was allowed to warm to room temperature and was taken up into ether and the ether solution was washed with saturated NaHCO3, brine and water and was dried. Filtration and concentration by rotary evaporation gave an oil. Chromatography over silica gel and elution i-Hx:ether 5:1 gave 2-(4-chlorophenyl)cyclobutanone as an oil. (180 mg, 83%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:4]=[CH:5][C:6]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18](O)=[O:19])=[N:10]2)=[N:7][CH:8]=1.[NH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26]>>[OH:26][CH2:25][C:24]([NH:23][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:6]2[CH:5]=[N:4][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:8][N:7]=2)[N:10]=1)=[O:19])([CH3:28])[CH3:27]
Reactant: O=C(O)c1nn(-c2cnc(C(F)(F)F)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(C(F)(F)F)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using (1aR,5aR)-2-(5-trifluoromethylpyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 2-amino-2-methylpropan-1-ol. LCMS m/z=382.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.3, 4.0 Hz, 1H), 1.28 (td, J=7.8, 5.2 Hz, 1H), 1.49 (s, 6H), 2.30-2.36 (m, 1H), 2.74-2.78 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.02 (dd, J=16.6, 6.2 Hz, 1H), 3.71 (s, 2H), 4.43 (bs, 1H), 6.94 (s, 1H), 8.77 (s, 1H), 9.32 (s, 1H).
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[NH2:10][C:11]1[C:12]([N+:21]([O-])=O)=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=1.[C:24]([OH:27])(=O)[CH3:25]>C(O)C>[N+:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=1[NH:21][CH2:25][CH2:24][OH:27])([O-:6])=[O:5]
Reactant: O
Reactant: Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1NCCO
Temperature: 55 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a suspension of sodium perborate tetrahydrate (7.69 g, 50 mmol) in acetic acid (30 mL) a solution of 3-amino-2-nitrobenzotrifluoride (2.06 g, 10 mmol) in acetic acid (25 mL) was added dropwise at 55° C. over 1.5 h. The mixture was stirred at 55° C. overnight. Precipitated material was filtered off, and the filtrate was concentrated in vacuo. The residue was suspended in 2 M hydrochloric acid and filtered. The precipitate was washed with 2 M hydrochloric acid and water, and then dried in vacuum at room temperature affording a yellow solid, 1.14 g. This material was suspended in ethanol (10 mL), and a solution of ethanolarine (1.10 g, 18.1 mmol) in ethanol (10 mL) was added. The reaction mixture was heated at reflux for 20 min, and then allowed to cool to room temperature. The volatiles were removed in vacuo. The residue was purified by column chromatography on silica using heptane/ethyl acetate, 80:20 as an eluent affording 0.72 g (29% yield) of 2-{[2-nitro-6-(trifluoromethyl)phenyl]amino}ethanol as an orange oil. MS (ESI) m/z 249 (M−H]. 1H NMR (400 MHz, CDCl3) δ ppm 3.38-3.34 (m, 2H), 3.85-3.82 (m, 2H), 6.88-6.84 (m, 2H), 7.77 (dd, J=7.8, 1.3 Hz, 1H), 8.11 (dd, J=8.3, 1.5 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH2:33])[CH:28]=[CH:29][CH:30]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH:33][C:17]([C:14]([CH3:15])([O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH2:21][CH3:22])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=2)[CH3:16])=[O:19])[CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Reactant: NCCc1cccc(Cl)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2cccc(Cl)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(3-chloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H28ClNO5 [M−H]−: 434.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[C:12](=[O:16])[CH2:13][CH2:14][O:15][C:10]=2[C:9]=1[CH2:19][CH2:20][CH3:21].C([O:24][C:25](=[O:48])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([O:44]CC)=[O:43])[CH:37]=2)=[O:35])[C:29]=1O)C.CCCCCC.C(OCC)(=[O:57])C>>[C:42]([C:38]1[CH:37]=[C:36]([C:34]([C:30]2[CH:31]=[CH:32][C:33]([O:57][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:18]=[CH:17][C:11]4[C:12](=[O:16])[CH2:13][CH2:14][O:15][C:10]=4[C:9]=3[CH2:19][CH2:20][CH3:21])=[C:28]([CH2:27][CH2:26][C:25]([OH:24])=[O:48])[CH:29]=2)=[O:35])[CH:41]=[CH:40][CH:39]=1)([OH:44])=[O:43]
Reactant: CCCc1c(OCCCCCBr)ccc2c1OCCC2=O
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CCc1cccc(C(=O)c2cccc(C(=O)OCC)c2)c1O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 52 %

Procedure:
Starting with 0.275 g (0.78 mmol) of 7-[(5-bromopentyl)oxy]-2,3-dihydro-8-propyl-4H-1-benzopyran-4-one, and 0.286 g (0.77 mmol) of 5-[[(3-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, 5-[(3-carboxyphenyl)carbonyl]-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid (0.163 g; 52% overall yield) was obtained, as a white solid, mp 122°-128° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 19.
Reaction SMILES: C([O:5]OC(C)(C)C)(C)(C)C.[Se](=O)=O.[C:14]([C@H:18]1[CH2:23][CH2:22][C@H:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([CH3:35])[CH:29]=[CH:28]3)[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.C(Cl)(Cl)Cl>[C:14]([C@H:18]1[CH2:23][CH2:22][C@H:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([CH:35]=[O:5])[CH:29]=[CH:28]3)[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(C=O)ccc3c2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Di-tert-butyl peroxide (1.93 mL, 10.5 mmol) was added to a suspension of Selenium dioxide (2.68 g, 24.1 mmol) in 1,4-Dioxane (24.00 mL, 307.5 mmol). The mixture was stirred for 30 minutes, then 6-(trans-4-tert-Butyl-cyclohexyloxy)-2-methyl-quinoline (3.12 g, 10.5 mmol) was added as a solution in 1,4-Dioxane and the mixture was heated overnight at 50° C. The reaction mixture was then cooled to room temperature, diluted in chloroform and filtered through a pad of celite. The filtrate was washed with water. The layers were separated and the combined organic phase was dried over MgSO4, filtered, concentrated under reduced pressure, adsorbed onto silica gel and purified by flash chromatography (0-30% EtOAc in hexanes) to give the title compound as a pale yellow solid in 20% yield. ESI-MS (M+H+): 312.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.[NH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:23])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: NN1CCOCC1
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NN3CCOCC3)cn2)cn1
Yield: 62 %

Procedure:
As described for example 43c, 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.203 mmol) was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (56 mg, 62%) which was obtained as a white foam after purification by chromatography (reverse phase HPLC then silica, ethyl acetate). MS: m/e=449.2 [M+H]+.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.Cl.[NH2:61][CH2:62][CH2:63][S:64]([NH2:67])(=[O:66])=[O:65]>>[NH2:67][S:64]([CH2:63][CH2:62][NH:61][S:53]([C:33]1[C:32]2[C:36](=[CH:37][CH:38]=[C:30]([Br:29])[CH:31]=2)[NH:35][C:34]=1[C:48]([NH2:7])=[O:50])(=[O:54])=[O:55])(=[O:66])=[O:65]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: NCCS(N)(=O)=O
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)NCCS(N)(=O)=O

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with 2-aminoethanesulfonamide hydrochloride, the title compound was obtained as a white solid. HRMS (ES) exact mass calculated for C11H13BrN4O5S2Na (M+Na+): 446.9403. Found 446.9404.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].Br[CH2:20][C:21]([N:23]([CH2:30][CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].CC1C(=O)NC(C2C=CC=CC=2)=NC=1C.BrCC(N(CCC)CCC)=O>>[CH2:30]([N:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](=[O:22])[CH2:20][O:18][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[N:4]=1)[CH3:31]
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c(=O)c1C
Reactant: CCN(C(=O)CBr)c1ccccc1
Agent: CCCN(CCC)C(=O)CBr
Agent: Cc1nc(-c2ccccc2)[nH]c(=O)c1C
Product: CCN(C(=O)COc1nc(-c2ccc([N+](=O)[O-])cc2)nc(C)c1C)c1ccccc1

Procedure:
The same procedures as Example 136 are repeated except that 5,6-dimetyl-2-(4-nitrophenyl)-4-(3H)-pyrimidinone and 2-bromo-N-ethyl-N-phenylacetamide are used instead of 5,6-dimethyl-2-phenyl-4-(3H)-pyrimidinone and 2-bromo-N,N-dipropylacetamide, respectively. The product thus obtained is recrystallized from acetonitrile to give the desired compound, m.p. 89-190° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH:14]=O.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[O:11][CH3:10])[S:7][CH:8]=1
Reactant: Nc1nc(CCl)cs1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nc(CCl)cs2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The HCl salt of 4-(chloromethyl)thiazol-2-amine (10 mmol) was suspended in DCM (50 ml), and 2,4-dimethoxybenzaldehyde (1.0 eq. of) and DIEA (1.0 eq.) were added. To the mixture, acetic acid (1 ml) was added followed by addition of sodium triacetoxyborohydride (2.5 eq.) and the reaction was stirred at room temperature overnight. The reaction mixture was filtered through Celite and washed with DCM. The filtrate was concentrated and purified by column chromatography using 0-10% gradient of 7 N ammonia/MeOH and DCM to give 4-(chloromethyl)-N-(2,4-dimethoxybenzyl)thiazol-2-amine.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=[O:14]>>[Cl-:11].[Cl:11][CH2:12][C:13](=[O:14])[CH2:15][N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1]
Reactant: O=C(CCl)CCl
Reactant: Cc1nc2ccccc2s1
Product: Cc1sc2ccccc2[n+]1CC(=O)CCl
Product: [Cl-]
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A mixture of 2-methylbenzothiazole (10 g) and 40 mL 1,3-dichloroacetone is stirred at 120° C. for 24 hours. The resulting gummy solid is triturated with ethyl acetate several times. The resulting solid is collected by suction filtration and dried under vacuum. The product is used without further purification.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-:11].[Na+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>CS(C)=O>[CH2:13]([O:11][C:9]1[CH:10]=[CH:2][CH:3]=[CH:4][C:5]=1[C:6]([OH:8])=[O:7])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: [OH-]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccccc1C(=O)O
Temperature: 80 °C

Procedure:
19.20 grams (150 mmol) of 4-hydroxybenzoic acid was added to an aqueous solution of sodium hydroxide (12.00 grams in 120 milliliters of water) and the mixture stirred until all the solid had dissolved. The solution was added in a portionwise manner over a period of about 5 minutes so that the temperature of the reaction mixture did not exceed 85° C. to 480 milliliters of dimethylsulfoxide which had previously been warmed to 80° C. To the resulting solution was added dropwise 28.95 grams (150 mmol) of n-octylbromide over about five to ten minutes. The mixture was then allowed to cool to room temperature over a period of about four hours; then it was poured into 1200 milliliters of ice water. Concentrated hydrochloric acid (30 mL) then was added to precipitate the desired octyloxybenzoic acid. The precipitate was recovered by filtration, washed with water and thereafter recrystallized from isopropanol to obtain octyloxybenzoic acid, m.p. 97°-102° C.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:4]=1.S(C1C=CC(C)=CC=1)(O[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=O)=O.O>CN(C)P(=O)(N(C)C)N(C)C>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][O:24][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:10]=2[CH2:25][OH:26])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)C)cc1
Reactant: COc1cc2cc(CO)c(CO)c(-c3cccnc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COc1cc2cc(COCC(C)(C)C)c(CO)c(-c3cccnc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride in hexamethylphosphoric triamide (40 ml) is added a solution of 1-(3-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene in hexamethylphosphoramide (10 ml) under ice-cooling. The mixture is warmed to room temperature, and then stirred for 30 minutes. To the reaction solution is added neo-pentyl tosylate (3.67 g), and the mixture is reacted at 100° C. for 30 minutes. The mixture is allowed to cool, and thereto is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated. The resulting residue is subjected to silica gel column chromatography (eluent; chloroform:acetone=5:1), and the desired fractions are concentrated to give 1-(3-pyridyl)-2-hydroxymethyl-3-neo-pentyloxymethyl-6,7-dimethoxynaphthalene (1.5 g) as an oily product.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:13]1([C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)O)[OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[C:2]12([O:14][C:13]3[CH:15]=[CH:17][CH:18]=[CH:19][C:20]=3[O:1]1)[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2
Reactant: Oc1ccccc1O
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCC2(CC1)Oc1ccccc1O2

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (22.75 g) and pyrocatechol (14.75 g) in toluene (200 mL) was added catalytic amount of para-toluenesulfonic acid monohydrate and the mixture was stirred under reflux and a Dean-Stark trap overnight. The mixture was diluted with diethyl ether (600 mL) and washed with aqueous NaHCO3, water and brine. After drying over Na2SO4, the mixture was filtered and the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][C:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.N1CCCCC1.[NH2:20][C:21]1[C:22]([CH:27]=O)=[N:23][CH:24]=[CH:25][N:26]=1>C1(C)C=CC=CC=1>[N:23]1[CH:24]=[CH:25][N:26]=[C:21]2[N:20]=[C:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:2]([C:1]([O:11][CH2:12][CH3:13])=[O:10])=[CH:27][C:22]=12
Reactant: Nc1nccnc1C=O
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2nccnc2nc1C(=O)OCC
Yield: 27.9 %

Procedure:
Diethyl oxalacetate, (4.7 g, 0.025 mol) and piperidine (1.66 g, 1.93 mL) are added to 3-aminopyrazine-2-carboxaldehyde (2.4 g, 0.0195 mol) dissolved in 250 mL of toluene. After the reaction mixture is refluxed for two hours, the toluene is removed under reduced pressure to give a dark red oily residue. The product is purified by column chromatography on silica gel (hexane:EtOAc, 4:1). affording 3.1 g (58% yield), of the crude desired product. Crystallization from ether-hexane (4:1) gives analytically pure compound 1.5 g (28%) having a melting point 83°-85° C.
Reaction SMILES: [B:1]([F:4])([F:3])[F:2].CCOCC.[NH2:10][C:11]1[C:12]([Cl:31])=[CH:13][C:14]([F:30])=[C:15]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])[CH:16]=1.[N:32](OCCC(C)C)=O.CCCCC>C(Cl)Cl>[F:2][B-:1]([F:25])([F:4])[F:3].[Cl:31][C:12]1[CH:13]=[C:14]([F:30])[C:15]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:16][C:11]=1[N+:10]#[N:32]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: FB(F)F
Reactant: CC(C)CCON=O
Solvent: ClCCl
Solvent: CCCCC
Solvent: CCOCC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc([N+]#N)c(Cl)cc2F)c1=O
Product: F[B-](F)(F)F
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
4.24 g of boron trifluoride etherate and 6.75 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1 -methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione are placed at -15° C. in 50 ml of methylene chloride. A solution of 3.2 ml of isopentyl nitrite in 20 ml of methylene chloride is added dropwise to the mixture within 20 minutes while cooling. The mixture is subsequently stirred at 5° C. for 45 minutes, 25 treated with 50 ml of n-pentane and the resulting crystals are filtered off. There is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo -3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzenediazonium tetrafluoroborate. m.p. 191° C. (decomposition).