Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
A 2 L 24/40 three necked round-bottom flask equipped with a mechanical stirrer, a reflux condenser and a stopper, was charged with 15.427 g (72 mmol) of 4-methyl-2'-nitro[1,1'-biphenyl], 1.2 L of carbon tetrachloride, 14.164 g (80 mmol) of N-bromosuccinimide, and 0.50 g of 2,2'-azobis-(2-methylpropionitrile). The stirred reaction mixture was refluxed under a nitrogen atmosphere for 4 hours, then cooled to room temperature and filtered. The filtrate was evaporated in vacuo and the residual oil was purified on a silica gel flash chromatography column eluted with 10% ethyl acetate-hexane. Evaporation of the pure fractions afforded the product as a yellow crystalline solid (7.83 g, 37%) which had: mp 109°-110° C.; NMR (CDCl3): δ 4.52 (s, 2H), 7.24-7.30 (m, 2H), 7.40-7.52 (m, 4H), 7.58-7.65 (m, 1H), 7.86 (d, J=10 Hz, 1H); MS (FAB) m/e 294 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:4]1([C:10]([OH:12])=O)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)[CH3:3].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.[C:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=1[CH2:42][NH2:43])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:34][C:33]=1[CH2:42][NH:43][C:10]([C:4]1([CH:2]([OH:1])[CH3:3])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)=[O:12])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(O)C1(C(=O)O)CCC(=O)C1
Reactant: CC(C)(C)Oc1ccc(C(F)(F)F)cc1CN
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(O)C1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)CCC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(1-hydroxyethyl)-3-oxocyclopentanecarboxylic acid (3.54 g, 20.6 mmol), 1-hydroxy-7-azabenzotriazole (4.14 g, 30.9 mmol), and EDC (5.92 g, 30.9 mmol) in 70 mL of DCM was stirred at rt for 10 min then 1-[2-tert-butoxy-5-(trifluoromethyl)phenyl]methanamine (5.08 g, 20.6 mmol) was added in 10 mL of DCM. The resulting mixture was stirred at rt for 50 min, then was diluted with DCM and washed with water followed by brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 85% ethyl acetate/hexanes) provided N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-(1-hydroxyethyl)-3-oxocyclopentanecarboxamide as a mixture of threo and erythro enantiomer pairs.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cccc(Br)c1
Product: OC(c1ccccc1)c1cccc(Br)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 1, using 3-bromobenzaldehyde and phenylmagnesium bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:18]=[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:20]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:18]=[C:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCc1cc(CCN)cc(Cc2ccc(F)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
4-chlorobenzenesulphonyl chloride (352 mg) was added portionwise to a stirred solution of ethyl 3-(2-aminoethyl)-5-[(4-fluorophenyl)methyl]benzenepropanoate (500 mg) and triethylamine (0.25 ml) in dry dichloromethane (5 ml) at room temperature. The solution was stirred at room temperature for 5 hours and then washed with water and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane first gave impurity followed by pure product. The product fractions were combined and evaporated to give the title compound as an oil (560 mg); Rf 0.2 (SS 3). Found: C,62.08; H,5.47; N,2.73. C26H27ClFNO4S requires C,61.96; H,5.40; N,2.78%.
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])C(=O)OC(C)(C)C)=[CH:17][N:18]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][NH:20][CH2:28][CH2:29][O:30][CH3:31])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(C)C)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(C)C)cc4F)c3s2)n1C
Yield: 55.9 %

Procedure:
The solution of urea 314 (150 mg, 0.245 mmol) and TFA (1 mL, 12.98 mmol) in DCM mL) was stirred 4 hr at room temperature and concentrated. The residue was partitioned between EtOAc/NaHCO3 sat. solution. The solid was collected by filtration and combined with organic layer. The mixture was concentrated and the residue was purified via Biotage (EA/MeOH 0-40%, 12 g Silicycle HR column). Collected fractions gave the desired product 315 (70 mg, 0.137 mmol, 55.8% yield) as a white solid. 1HNMR (dmso-d6) δ (ppm) 1H: 8.67 (s, 1H), 8.48 (d, 1H, J=5.5 Hz), 7.91 (s, 1H), 7.65 (dd, 1H, J1=13.7 Hz, J2=2.6 Hz), 7.32 (t, 1H, J=9.0 Hz), 7.07 (m, 2H), 6.63 (d, 1H, J=5.5 Hz), 6.13 (d, 1H, J=7.6 Hz), 4.04 (s, br, 2H), 3.08 (s, 3H), 3.72 (m, 1H), 3.47 (t, 2H, J=5.2 Hz), 3.24 (s, 3H), 2.94 (m, 2H), 1.07 (s, 3H, 1.05 (s, 3H) (presumably a mono-TFA salt). MS: 513.4 (MH)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C1COCCN1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cc(Cl)ccc1N1CCOCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A 50 mL round-bottom flask was charged with 5-chloro-2-fluorobenzaldehyde (3.00 g, 18.9 mmol, 1.00 equiv), morpholine (2.50 g, 28.7 mmol, 1.52 equiv), potassium carbonate (6.50 g, 47.0 mmol, 2.49 equiv), methyl sulfoxide (20 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and diluted with H2O (50 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/9) to provide 3.24 g (76% yield) of 5-chloro-2-(morpholin-4-yl)benzaldehyde as brown oil. LCMS (ESI, m/z): 226 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([N:17]=[C:18]=[O:19])[CH:2]=1.[CH2:20]([CH:22]([NH:25][OH:26])[CH2:23][CH3:24])[CH3:21]>O1CCCC1>[CH2:7]([C:6]1[CH:5]=[CH:4][C:3]([NH:17][C:18](=[O:19])[N:25]([OH:26])[CH:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[CH:2][CH:1]=1)[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:16])[N:25]([CH:22]([CH2:23][CH3:24])[CH2:20][CH3:21])[OH:26])=[CH:10][CH:9]=1
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Reactant: CCC(CC)NO
Solvent: C1CCOC1
Product: CCC(CC)N(O)C(=O)Nc1ccc(Cc2ccc(NC(=O)N(O)C(CC)CC)cc2)cc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
A solution of 4,4'-methylenebis(phenylisocyanate) (1.5 g, 6.0 mmol) and tetrahydrofuran (75 ml) was charged with N-(1-ethylpropyl)hydroxylamine (1.5 g, 14.5 mmol) and maintained at ambient temperature for 16 hr. The solvent was removed in vacuo to provide the crude product as a white solid. Recrystallization from ethyl acetate.backslash.hexanes provided 1.0 g of the desired product as a white powder: MP: 196.0-198.0° C. (decomp); 1H NMR (300 MHz, DMSO): δ 9.16 (s, 2H), 8.78 (s, 2H), 7.50 (d, J=8.5 Hz, 4H), 7.05 (d, J=8.5 Hz, 4H), 3.96-3.87 (m 2H), 3.77 (s, 2H), 1.59-1.31 (m, 8H), 0.85-0.80 (t, J=7.3 Hz, 12H); 13C NMR (75 MHz, DMSO): δ 157.7, 137.4, 134.9, 128.2, 119.1, 59.6, 24.5, 11.0; IR (KBr): 3395, 3147, 2966, 2931, 2875, 1641, 1590, 1528, 1461, 1413, 1328, 1312, 1225, 1150, 815, 761 cm-1 ; MS (FAB): m/e 457.2804 (457.2815 calc'd for C25H37N4O4, M+H); Anal. calc'd for C25H36N4O4 : C, 65.76; H, 7.95; N, 12.27. Found: C, 65.53; H, 7.87; N, 12.11.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>CN(C)C=O>[Cl:23][CH2:24][C:25]([N:13]1[CH2:14][CH2:15][CH2:16][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc(N2CCCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCl)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
22.1 g (0.1 mol) of 1-(4-nitrophenyl)[1,4]diazepane, 8.3 g (0.06 mol) of potassium carbonate and 120 ml of dimethylformamide were mixed together in a reactor. 8.3 ml (0.11 mol) of chloroacetyl chloride were added to this stirred suspension, while maintaining the temperature between 15 and 25° C. After stirring for about ten hours at room temperature, 400 g of slightly hydrochloric ice-cold water were added to the mixture: a yellow gum crystallized. After filtering off by suction, washing with water and drying under vacuum over phosphorus pentoxide, 22.4 g of yellow crystals were obtained (yield=75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([C:14]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(C(OCC)=O)[C:15]([O:17]CC)=[O:16])=[CH:12][N:11]=[C:10]1[S:32][CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH:14]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:15]([OH:17])=[O:16])=[CH:12][N:11]=[C:10]1[S:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCSc1ncc(C(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCSc1ncc(C(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
A mixture of diethyl [1-{(2-chlorophenyl)methyl}-2- propylthio-1H-imidazol-5-yl]phenylmethyl-malonate (0.66 g, 1.28 mmol), sodium carbonate (1.36 g, 1.28 mmol), ethanol (15 mL) and water (10 mL)was refluxed on a steam bath for 18 hours. The mixture was concentrated to a small volume, some insolubles were filtered, the aqueous layer was washed with diethyl ether and then the aqueous phase was adjusted to pH 3.4 with aqueous hydrochloric acid. The product was extracted into methylene chloride, washed with water, dried and concentrated to give 2-[1-{(2-chlorophenyl)methyl}-2- propylthio-1H-imidazol-5-yl]-3-phenyl-propionic acid; mp 60°-63° C.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].C(=O)([O-])[O-].[Na+].[Na+].I[CH2:17][C:18](N)=[O:19].Cl>O>[O:19]=[C:18]1[NH:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6][CH2:17]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: NC(=O)CI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CSCC(C(=O)O)N1
Reaction time: 1 h

Procedure:
A solution of 1.75 g (10 mmole) of L-cysteine hydrochloride monohydrate dissolved in 50 ml of water was adjusted to pH 8.0 with 1M sodium carbonate. Under nitrogen gas stream, 1.85 g (10 mmole) of monoiodoacetamide and 1M sodium carbonate were added alternately while maintaining pH at 8.0. After the reaction was carried out at room temperature for 1 hour, further the reaction was carried out in a sealed tube at 100° C. for 2 hours. To the reaction mixture was added 4N HCl to adjust the pH to 3.25, followed by concentration to dryness. The residue was extracted with hot ethanol, and after cooling, the crystals were collected by filtration and recrystallized from hot ethanol. Yield: 560 mg (34.8%), melting point: 182° to 184° C., Fab mass analysis [M+H]+= 162.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([SH:9])[N:3]=1.Cl[CH2:11][C:12]1[C:17]([CH3:18])=[C:16]([S:19][CH2:20][CH2:21][CH2:22][S:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([C:30]([N+:33]([O-:35])=[O:34])=[CH:31][N:32]=3)[N:29]=2)[CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>CC(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:11][C:12]2[C:17]([CH3:18])=[C:16]([S:19][CH2:20][CH2:21][CH2:22][S:23][C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30]([N+:33]([O-:35])=[O:34])=[CH:31][N:32]=4)[N:29]=3)[CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Reactant: Cc1cc(C)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cc(C)nc(SCc2nccc(SCCCSc3ccc4ncc([N+](=O)[O-])n4n3)c2C)n1
Temperature: 0 °C

Procedure:
A suspension of 4,6-dimethyl-pyrimidine-2-thiol (0.35 g, 2.5 mmol) and 6-[3-(2-chloromethyl-3-methyl-pyridin-4-ylsulfanyl)-propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine (1.03 g, 2.5 mmol) in 2-propanol (50 ml) is heated under reflux for 4 h under a nitrogen atmosphere. After cooling, the mixture is treated with ice water (100 ml), adjusted to pH 10 with 40% strength sodium hydroxide solution, and extracted with ethyl acetate. The combined extracts are washed with sodium carbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized from acetonitrile to give the title compound as a colourless solid, 0.93 g (76%). M.p. 145-7° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2ccc3c(c2)CC(CCO)O3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1Cc2cc(-c3ccc(C#N)cc3)ccc2O1
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of Example 67C (0.23 g, 0.87 mmol) and methanesulfonyl chloride (0.075 mL, 0.96 mmol) in CH2Cl2 (5 mL) at 0° C. was added triethylamine (0.13 mL, 9.4 mmol). The mixture was stirred for 30 minutes, diluted with CH2Cl2 (75 mL), washed with water (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on silica using CH2Cl2 to provide the titled compound (0.278 g, 90%). 1HNMR (CDCl3): H NMR: 1.95 (m, 2H), 2.93 (m, 2H), 3.00 (s, 3H), 3.46 (m, 2H), 5.00 (m, 1H), 6.81 (d, J=7 Hz, 1H), 7.40 (m, 2H), 7.65 (m, 4H); MS (DCI) 343 (M+), 361 (M+NH4+).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13].C(N(CC)CC)C>C(O)C>[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: ClCCCCBr
Reactant: Sc1ccncc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: ClCCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a suspension of 33.35 g (0.30 mol) of 4-mercaptopyridine and 51.44 g (0.30 mol) of 1-bromo-4-chlorobutane in 500 ml of ethanol, 41.9 ml (0.30 mol) of triethylamine was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off and chloroform was added to the residue. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexane =1:1) to give 54.27 g of the desired compound (89.7% yield, colorless oil).
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](O)=[O:11])[CH2:2]1.S(Cl)([Cl:16])=O>>[CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([Cl:16])=[O:11])[CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: CC1CCC(C(C)C)C(C(=O)O)C1
Product: CC1CCC(C(C)C)C(C(=O)Cl)C1

Procedure:
p-Menthane-3-carboxylic acid (1.84g.), was heated under reflux with thionyl chloride (4 ml.) for 3 hours. The excess of thionyl chloride was then distilled off in vacuo. The crude produce p-menth-3-oyl chloride was dissolved in diethyl ether (25 ml.) and the ethereal solution was added with stirring and cooling to a solution of ethylamine (1.0 ml. of 70% w/s solution in water) and sodium hydroxide (0.4g.) in water (25 ml.). The mixture was stirred for one hour and the ethereal layer was then separated. The aqueous layer was washed with ether (25 ml.) and the combined ethereal solution was washed with dilute hydrochloric acid and then water. The ether solution was dried (MgSO4) and evaporated to give a white crystalline solid. The solid was recrystallised from acetone: water (9:1) by dissolving the crystals at room temperature and then cooling to produce N-ethyl-p-menthane-3-carboxamide as a white crystalline solid, mp. 82.5°-84.5°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Reactant: Nc1cccc(Br)c1
Product: COCC1COc2cc3ncnc(Nc4cccc(Br)c4)c3cc2O1
Yield: 55 %

Procedure:
The titled compound (25 mg, 63%, m.p. 268-274° C.) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (30 mg, 0.113 mmol) and 3-bromoaniline (39 mg, 0.226 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[C:12](Cl)(Cl)=[O:13]>C(O)(=O)C.ClC1C=CC=CC=1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH2:7][CH2:8][CH2:9][N:10]3[C:12]1=[O:13]
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc2c1NCCC2
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: O=c1[nH]c2cccc3c2n1CCC3
Yield: 88 %

Procedure:
To a solution of 10.77 g of 8-amino- 1,2,3,4-tetrahydroquinoline in glacial acetic acid (30 ml) was added dropwise a 21.75% solution of phosgene in chlorobenzene (30 ml), under nitrogen, with stirring. After the addition was complete, the mixture was heated under reflux, with stirring for one hr and evaporated. The residue was taken up in 10% ammonium hydroxide solution (75 ml) and extracted with dichloromethane. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. Ether was added to the residue and the mixture was chilled. The precipitate was collected to give 11.2 g (88%) of product.
Reaction SMILES: [CH2:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33](O)[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:39]2)=[CH:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:1][CH:2]=[CH2:3])[CH2:11][CH3:12])[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:39]2)=[CH:26]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: C=CCc1ccccc1OC(CC)C(=O)O
Product: C=CCc1ccccc1OC(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 95.1 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.80 g of (2RS)-2-(2-allylphenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.30 g of the title compound as a colorless foam.
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>C1COCC1>[I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2-iodo-3-methyl benzoic acid (1310 mg, 5 mmol) and thionyl chloride (730 μL, 10 mmol) were dissolved into THF (10 mL) and stirred at RT for 4 days. The solvents were removed in vacuo and the resulting residue was dissolved into EtOAc, washed with brine. The combined organic layers were dried (MgSO4) and the solvents were removed in vacuo resulting in an oil that was used without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of ethyl 2-[2-chloro-4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (155 mg, 0.34 mmol) in THF (2 mL) was added LiOH (2M aqueous solution, 2.5 mL, 2.5 mmol, 7.4 eq). The reaction mixture was stirred at room temperature for 2 h, then the organic solvent was removed in vacuo. The residue that remained was diluted with water and adjusted to pH 4-6 by addition of diluted HCl. The solid precipitate that formed was collected by filtration, washed with water and dried in vacuo to afford a crude product which was crystallized from DCM (1 mL) and hexane (20 mL) to give the title compound (I(o)) as a white solid (100 mg, 69%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH3:14])[CH3:2].[Cl:16][S:17](O)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:9][C:8]=1[CH2:13][CH3:14])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)COc1ccccc1CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1CC

Procedure:
A solution of crude ethyl(2-ethylphenoxy)acetate (intermediate 107) in chloroform (6 ml) was stirred with chlorosulfonic acid (1.33 ml) at ambient temperature for 4 hours. The reaction mixture was quenched by the addition of ice and the organic mixture separated by using a hydrophobic frit. The title compound was isolated by evaporation of this filtrate.