Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[OH-].[Na+].Cl>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
To 40 ml of an aqueous solution of 4.00 g (23.2 mmol) of ethyl 2-aminothiazole-4-carboxylate was added 1.86 g (46.5 mmol) of sodium hydroxide, followed by stirring at room temperature for 5 hours. The reaction liquid was adjusted to pH 1 by the addition of concentrated hydrochloric acid, and the precipitated crystals were collected by filtration to prepare 2.84 g (yield 85%) of a target compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1([C:11](=[O:13])[CH3:12])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1([C:11](=[O:13])[CH2:12][Br:36])[CH2:9][CH2:10]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C1(C(C)=O)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)C1(C(=O)CBr)CC1
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a stirred solution of 15 (3.30 g, 17.9 mmol) in methylene chloride (150 mL) and triethylamine (5.01 mL, 3.61 g, 35.7 mmol), was added dropwise triethylsilyl trifluoromethanesulphonate (4.07 mL, 4.72 g 17.9 mmol) at 0° C. After 20 minutes, N-bromosuccinimide (3.53 g, 19.8 mmol) was added, and the cooling bath was removed. Water (50 mL) was then added, and the mixture was extracted with methylene chloride (3×100 mL). The organic phase was dried over anhydrous MgSO4, concentrated under reduced pressure, and the residue was purified by column chromatography (3-10% ethyl acetate/hexane) to give 3.42 g (13.0 mmol; 73% yield) of 16. 1H NMR MHz, CDCl3) δ 0.96 (3H, t, J=7.4 Hz), 1.47 (2H, m), 1.60-1.66 (6H, m), 4.16 (2H, t, J=6.7 Hz), 4.50 (2H, s). 13C NMR (100 MHz, CDCl3) δ 13.7, 19.2, 21.2, 30.5, 33.2, 35.1, 65.5, 170.4, 197.6. MS (EI) m/z 264 (40, M+), 262 (39, M+), 208 (20), 206 (20), 190 (56), 188 (54), 183 (71), 169 (100); exact mass (ESI) calculated for C10H15O3BrNa ([M+Na]+) 285.0102, found 285.0114.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)=O)=[CH:2]1.S1C=C[CH:21]=[C:20]1CCCC(O)=O.Cl.CN(C)CCCN=C=NCC.N1CCC[C@H](C(OCC)=O)C1>>[S:1]1[CH:2]=[CH:21][CH:20]=[C:5]1[CH2:4][CH2:3][CH2:6][N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccsc2)C1
Reactant: O=C(O)CCCc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)[C@H]1CCCNC1
Agent: Cl
Product: CCOC(=O)[C@H]1CCCN(CCCc2cccs2)C1

Procedure:
This reaction was run in the same manner as ethyl 1-(3-thiophenecarbonyl)-3-piperidinecarboxylate, starting with commercially available 4-(2-thienyl)butyric acid (280 μl; 1.93 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (367.7 mg; 1.92 mmol) and (S)-ethyl nipecotate (300 μl; 1.94 mmol). The crude product was purified by chromatography on silica eluting with 30% ethyl acetatel70% hexane to 40% ethyl acetate/60% hexane in a single step gradient, giving (S)-ethyl 1-(2-thienylpropyl)-3-piperidinecarboxylate (181.7 mg) as a colorless oil. MS m/z (positive ion) 411 (MH++Et3N; 40), 332 (M+Na+; 30), 310 (MH+; 100), 101 (Et3NH+; 30).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16]CC)=O)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:16])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)nc2)nc1C
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)nc2)sc1C(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
A mixture of ethyl 2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazole-5-carboxylate i98 (0.47 g, 1 eq, 1.84 mmol), morpholine (0.19 g, 1.2 eq, 2.21 mmol) and triethylamine (0.5 ml, 2 eq, 3.68 mmol) in dichloromethane (15 ml) is cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.39 g, 1.1 eq, 2.02 mmol) and 1-hydroxybenzotriazole (0.05 g, 0.2 eq, 0.37 mmol) are then added to the solution and the mixture is stirred 24 h at room temperature. The mixture is then washed with water and a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to give 0.53 g of 4-{[2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]carbonyl}morpholine i99.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[CH3:25][NH:26][CH2:27][CH2:28][OH:29]>O>[OH2:29].[NH2:16][C:8]1[C:7]2[N:17]=[C:4]([CH2:3][N:26]([CH2:27][CH2:28][OH:29])[CH3:25])[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1.[NH2:16][C:8]1[C:7]2[N:17]=[C:4]([CH2:3][N:26]([CH3:25])[CH2:27][CH2:28][OH:29])[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CNCCO
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2Cc1ccccc1
Agent: Cl
Solvent: O
Product: CN(CCO)Cc1nc2c(N)nc3ccccc3c2n1Cc1ccccc1
Temperature: 130 °C

Procedure:
2-Chloromethyl-1-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (Example 28, prepared from 1.4 g of the alcohol) was added to N-methylethanolamine (20 mL). The mixture was heated in an oil bath for 3 hr at about 130° C. The solution was diluted with water and the mixture extracted with diethyl ether (7×200 mL). The combined extracts were washed with saturated sodium chloride solution and evaporated to dryness to yield an orange solid. The crude product was recrystallized from methanol/dichloromethane. m.p. 188-195° C. Analysis: Calculated: C, 68.1; H, 6.5; N, 18.9. Found: C, 68.4; H, 6.5: N, 18.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:23]#[C:24][CH2:25][S:26][CH2:27][CH3:28])=[CH:17][C:16]=3[F:29])=[O:11])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](/[CH:23]=[CH:24]\[CH2:25][S:26][CH2:27][CH3:28])=[CH:17][C:16]=3[F:29])=[O:11])=[CH:6][CH:7]=1
Reactant: CCSCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCSC/C=C\c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 3 h

Procedure:
A mixture of N-[(4-Chlorophenyl)methyl]-6-[3-(ethylthio)-1-propynyl]-8-fluoro-4-hydroxy-3-quinolinecarboxamide from Example No. 127 (0.15 g) and Pd/C (10%, 0.06 g) in 3:1 CH2Cl2 /MeOH (20 mL) are placed on a Parr hydrogenator under 40 psi of H2 and shaken for 3 h. The reaction mixture is then filtered through Celite and concentrated in vacuo. Crystallization from MeOH affords the title compound as a solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([Br:18])[CH:13]=1.[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C>[Br:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:19])=[O:2])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1ccccc1NCc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.0 g (31.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester is dissolved in 290 ml of ethanol and mixed with 31.2 ml of 2 M sodium hydroxide solution. After having been stirred overnight at room temperature, the ethanol is drawn off, and the aqueous phase is shaken out with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid. The precipitate that is formed is suctioned off and dried. 5.93 g (62%) of 2-[(2-bromo-pyridin-4-ytmethyl)-amino]-benzoic acid accumulates in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(OCC)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:36]
Reactant: OCCCCOCc1cc(Br)ccc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(Br)cc1COCCCCBr
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butanol (7.03 g, 26.3 mmol) in diethyl ether (88 ml) was treated with triphenylphosphine (8.97 g, 34.2 mmol) and carbon tetrabromide (11.3 g, 34.2 mmol). The cloudy solution was stirred at ambient temperature for about 30 hours. The precipitate was removed by filtration and the filtrate was concentrated. The desired title intermediate was purified from the filtrate by bulb to bulb distillation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)[CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: OCc1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 107 %

Procedure:
To a solution of 3-bromo-5-(hydroxymethyl)phenol (3.0 g, 14.77 mmol) in DMF (15 mL) under a N2 atmosphere was added potassium carbonate (4.08 g, 29.55 mmol) and the mixture was stirred for 20 min. 2-Chloro-5-(trifluoromethyl)pyridine (2.68 g, 14.77 mmol) was added at RT and then the reaction was refluxed at 110° C. overnight. The reaction mixture was cooled and water was added. The mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (5.5 g) which was used in the next step without purification. 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.41 (s, 1H), 7.24 (s, 1H), 7.19 (s, 1H), 7.04 (d, J=9 Hz, 1H), 4.71 (s, 2H); m/z (348, 349.9, M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH2:6][CH:7]=[CH:8][CH2:9][PH:10](=[O:12])[OH:11].I[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH2:6][CH:7]=[CH:8][CH2:9][PH:10](=[O:11])[O:12][CH2:20][CH3:21]
Reactant: COc1cc(CC=CC[PH](=O)O)ccc1[N+](=O)[O-]
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCO[PH](=O)CC=CCc1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (3-methoxy-4-nitrobenzyl)prop-2-en-1-ylphosphinic acid (Compound 37F, 1.28 g, 4.72 mmol) and iodoethane (1.47 g, 9.44 mmol) in DMF (5.0 mL) was charged with potassium carbonate (1.30 g, 9.44 mmol). The reaction mixture was allowed to stir at rt for 16 hours. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (25 mL). The organic layer was washed with water (10 mL), washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure to yield a yellow oil. The crude material was purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent to afford the title compound as 1.08 g of a yellow oil (77%). 1H NMR (CDCl3, 400 MHz): δ=7.84 (d, J=8.3 Hz, 1H), 7.11 (t, J=1.8 Hz, 1H), 6.92 (td, J=1.8, 8.3 Hz, 1H), 5.76-5.90 (m, 1H), 5.18-5.32 (m, 2H), 4.00-4.14 (m, 2H), 3.98 (s, 3H), 3.19 (d, J=16.4 Hz, 2H), 2.60 (dd, J=7.3, 17.7 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H). MS (ESI): m/z 300.10 [M+H]+. UPLC: tR=1.22 min (UPLC-TOF: polar—3 min).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[C:15]([O:18][CH2:19][CH:20]([CH2:31][O:32][NH2:33])[O:21][CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])(=[O:17])[CH3:16].C(N(CC)CC)C>O1CCOCC1>[C:15]([O:18][CH2:19][CH:20]([O:21][CH2:22][P:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:30])[CH2:31][O:32][NH:33][C:2]1[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=1[NH:8][CH:9]=[O:10])(=[O:17])[CH3:16]
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CCOP(=O)(COC(CON)COC(C)=O)OCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOP(=O)(COC(CONc1nc(NC=O)nc(Cl)c1NC=O)COC(C)=O)OCC
Temperature: 120 °C
Yield: 81.4 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (0.475 mg, 2 mmol), diethyl [2-acetoxy-1-(aminooxymethyl)ethoxy)methylphosphonate (0.60 mg, 2 mmol) and triethylamine (0.54 ml, 4 mmol) in dry dioxan (20 ml) was heated at 120° C. for 5 hours. The reaction mixture was cooled to ambient temperature, filtered, and the filtrate evaporated to leave a yellow oil. The oil was chromatographed on silica gel (eluant dichloromethane:methanol 97:3) to give the title compound as a pale yellow solid (0.81 g, 80%). 1H NMR: δH [(CD3)2SO] 1.23 (2×3H, 2×t, J=7 Hz, (OCH2CH3)2), 2.03 (3H,s, COCH3), 3.80-4.35 (11H,m, CH2CHCH2 +(OCH2CH3)2 +OCH2P), 8.16 (1H,br.s, sharpens to s. on D2O, CHO), 9.26 (1H,d,J=9.9 Hz. collapses to s. on D2O. CHO), 9.45 (1H,br.s, D2O exchangeable, NH), 10.8-10.95 (2H,m, D2O exchangeable 2×NH). Found: C,37.36; H,5.37; N,13.43%; C16H25N5O9PCl.H2O requires: C,37.18; H,5.27; N,13.55%. m/z: observed 497.1082; C16H25N5O9PCl(M+) requires 497.1078.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].O1CCCC1.[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CCOCC>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC[Mg]Br
Reactant: O=Cc1ccccc1Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCC(O)c1ccccc1Br

Procedure:
Following General Procedure K and using 2-bromo-benzaldehyde (1.5 g, 8 mmol), 15 mL of anhydrous tetrahydrofuran, and a 2M solution of n-hexyl magnesium bromide solution in ether (6 mL, 12 mmol) followed by flash column chromatography using 10% ethyl acetate in hexane, the title compound was obtained (1.86 g, 85%).
Reaction SMILES: [C:1]1([C:12]([OH:14])=O)[CH:2]=[CH:3][CH:4]=[C:5]2[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][C:6]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:48][C:44]1[CH:43]=[C:42]([CH:40]([OH:41])[CH:39]([NH:38][C:12]([C:1]2[CH:2]=[CH:3][CH:4]=[C:5]3[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][C:6]=23)=[O:14])[CH2:49][C:50]2[CH:55]=[CH:54][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:60])([CH3:58])[CH3:59])=[CH:52][CH:51]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CC(C)(C)C(F)(F)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(F)(F)c1ccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (216 mg, 1.15 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg, 1.15 mmol) and 1-hydroxybenzotriazole monohydrate (176 mg, 1.15 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol (0.40 g, 1.09 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide (316 mg, 54%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[OH-].[NH4+:16]>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:16])(=[O:13])=[O:12]
Reactant: [NH4+]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
In a round bottom flask under nitrogen was placed commercially available 2-methyl-5-nitrobenzene sulphonyl chloride (2.36 g, 10.0 mmol) and 75 L dry ethyl ether was added. The solution was cooled to 0° C. and concentrated ammonium hydroxide (10 mL) was added. After stirring overnight, the mixture was filtered and then diluted with dichloromethane (150 mL). The organic layer was separated and dried over MgSO4. The solution was then concentrated to afford 820 mg of the title compound as a white solid (38%): 1HNMR (DMSO-d6) δ8.61 (d, J=2.5 Hz, 1H), 8.35 (dd, J=8 Hz, 2.5 Hz, 1H), 7.79 (br s, 2H), 7.70 (d, J=8 Hz, 1H), 2.71 (s, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[OH:21][C:22]([CH3:45])([CH3:44])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38](=[O:43])[C:39]([OH:42])([CH3:41])[CH3:40])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:24]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23](=[O:24])[C:22]([OH:21])([CH3:45])[CH3:44])=[CH:30][CH:29]=1)[C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:43])[C:39]([OH:42])([CH3:41])[CH3:40])=[CH:34][CH:33]=1
Reactant: CC(C)(O)C(=O)c1ccc(Cc2ccc(C(=O)C(C)(C)O)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(O)C(=O)c1ccc(C(Br)c2ccc(C(=O)C(C)(C)O)cc2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
11.2 g (0.063 mol) N-bromosuccinimide, and 0.12 g AIBN (2,2-azobis(2-methylpropionitrile)) were suspended in 50 ml carbon tetrachloride and heated to 40° C. under argon. Then a solution of 20.45 g (0.06 mol) of 2-Hydroxy-1{-4-[4-(2-hydroxy-2-methyl-propionyl)-benzyl]-phenyl}2-methyl-propan-1-one (known from PCT Int. Appl. WO 2003040076) in 50 ml carbon tetrachloride was added dropwise over 15 min. After stirring at 75° C. for 3 h, the reaction mixture was cooled to 25° C., filtered, and washed neutral with water, dried over magnesium sulfate and concentrated by evaporation. The raw product (28.4 g) was a brownish resin that was pure enough for further derivatization of the benzylic bromide. The structure was confirmed by 1H-NMR (CDCl3): δ [ppm]: 8.04 (d, 4H), 7.53 (d, 4H), 6.28 (s, 1H, benzylic), 3.95, (s, 2H, OH), 1.61 (s, 12H),
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]=[CH2:3].[CH3:15][O:16][SiH:17]([O:20][CH3:21])[O:18][CH3:19]>[Pt]>[CH3:15][O:16][Si:17]([CH2:3][CH2:2][CH2:1][O:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][Si:17]([O:20][CH3:21])([O:18][CH3:19])[O:16][CH3:15])=[O:9])([O:20][CH3:21])[O:18][CH3:19]
Reactant: CO[SiH](OC)OC
Reactant: C=CCOC(=O)CCC(=O)OCC=C
Agent: [Pt]
Product: CO[Si](CCCOC(=O)CCC(=O)OCCC[Si](OC)(OC)OC)(OC)OC
Yield: 84 %

Procedure:
A 250 milliliter round-bottom flask was equipped with a reflux condenser, a stir bar, a nitrogen inlet, and charged with 100 grams diallylsuccinate (0.504 moles) and 30 parts per million Platinum (64.1 microliters (μl) of a 5% Karstedt's solution). The mixture was heated and stirred at 70° C. for 5 minutes after which time trimethoxysilane was slowly added (145 milliliters; 135 grams; 1.11 mol). The mixture was allowed to react for 24 hours after which time the excess trimethoxysilane was stripped in vacuo. A yield of 184 grams of bis(trimethoxysilylpropyl)succinate (84% yield) was obtained. The purity and identity of the product were determined by proton nuclear magnetic resonance spectroscopy (4.1 ppm 4H triplet, 3.5 ppm 18H singlet, 2.6 ppm 4H singlet, 1.8 ppm 4H multiplet, 0.6 ppm 4H triplet).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:31]/[O:32][CH2:33][CH:34]=[CH2:35])/[C:27]([O:29][CH3:30])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>O1CCCC1>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:31]/[O:32][CH2:33][CH:34]=[CH2:35])/[C:27]([O:29][CH3:30])=[O:28])[N:25]=1
Reactant: C=CCO/N=C(\C(=O)OC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: C1CCOC1
Solvent: O=CO
Product: C=CCO/N=C(\C(=O)OC)c1csc(N)n1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
In 32 ml of tetrahydrofuran is dissolved 6.45 g of methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-allyloxyiminoacetate, followed by addition of 32 ml of 50% formic acid. The mixture is stirred at 60° C. for 40 minutes. The reaction mixture is concentrated under reduced pressure and the solid residue is dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride in this order, and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is purified by column chromatography [silica gel: 150 g; eluent: hexane-ethyl acetate (1:1)]. The solvent is distilled off and the solid residue is washed with hexane and a small amount of ether in this order, and then dried to give methyl 2-(2-amino-4-thiazolyl)-(Z)-2-allyloxyiminoacetate, m.p. 133°-134° C.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O1CCOCC1.N1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(O)C>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(C(=O)n2cc(F)c(=O)[nH]c2=O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 49.2 %

Procedure:
1.3 g (0.01 mole) of 5-fluorouracil was suspended in a mixed solution of 40 ml. of dioxane and 2 ml. of pyridine. 1.7 g (0.01 mole) of p-methoxybenzoyl chloride in 5 ml. of dioxane was added to the suspension and stirred at 80°C. for 5 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and a resinous residue was obtained. The residue was dissolved in ethanol and filtered. After cooling to 0°C., the resulting crystals were filtered and dried to give 1.30 g (49.2% yield) of 5-fluoro-1-(p-methoxybenzoyl)uracil. The product was recrystallized from dioxane-ethanol and white needles melting at 200°-201°C. were obtained. The results of an elementary analysis thereof were well in agreement with the calculated value as follows: