Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH3:25])[S:8]([N:11]1[CH:15]=[C:14]([CH2:16][C:17]([CH3:24])([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH2:19])[N:13]=[CH:12]1)(=[O:10])=[O:9].[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40](OC)=[O:41])=[CH:35][CH:34]=2)=[N:31][CH:32]=1>O1CCCC1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40]([C:12]3[N:11]([S:8]([N:7]([CH3:6])[CH3:25])(=[O:10])=[O:9])[CH:15]=[C:14]([CH2:16][C:17]([CH3:24])([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH2:19])[N:13]=3)=[O:41])=[CH:35][CH:34]=2)=[N:31][CH:32]=1
Reactant: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)cn1)C(F)(F)F
Reactant: COC(=O)Cc1ccc(-c2ccc(F)cn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(-c3ccc(F)cn3)cc2)n1)C(F)(F)F
Temperature: -10 °C
Reaction time: 3 h

Procedure:
n-Butyllithium (1.6 M in hexane) (4.19 mL, 6.7 mmol) was added to a −78° C. solution of N,N-dimethyl-4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole-1-sulfonamide (Intermediate 4) (1.74 g, 5.59 mmol) in tetrahydrofuran (6 mL). After warming to −10° C. over 1 h, methyl [4-(5-fluoropyridin-2-yl)phenyl]acetate (1.14 g, 5.59 mmol) in tetrahydrofuran (6 mL) was added and the reaction allowed to warm to ambient temperature. After stirring at ambient temperature for 3 h, the reaction mixture was quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 2>{[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole-1-sulfonamide.
Reaction SMILES: CO[C:3]1[C:8]([Cl:9])=[N:7][C:6](Cl)=[C:5]([C:11]([OH:13])=[O:12])[N:4]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:18][NH2:19].[CH2:25](N(CC)CC)C.C1(C)C=CC=CC=1>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:25][O:13][C:11]([C:5]1[C:6]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:15]([Cl:14])[CH:16]=2)=[N:7][C:8]([Cl:9])=[CH:3][N:4]=1)=[O:12]
Reactant: CCN(CC)CC
Reactant: COc1ccc(CN)cc1Cl
Reactant: COc1nc(C(=O)O)c(Cl)nc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ncc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 2-methoxycarboxy-3,5-dichloropyrazine (prepared in the above (2)) 234 mg, 3-chloro-4-methoxybenzylamine 204 mg, triethylamine 0.17 ml and anhydrous toluene 3 ml is stirred for 7 hours at room temperature. The reaction mixture is diluted with a 10% aqueous citric acid solution and the solution is extracted with ethyl acetate. The extract is washed with water and an aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is purified and separated with silica gel chromatography (silica gel 5 mg, solvent; hexane:chloroform=1:1) and then the desired fraction is concentrated in vacuo to give 2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-chloropyrazine as a pale yellow crystalline powder 102 mg. mp 149-151° C., MS(m/z): 342(M+H)+
Reaction SMILES: Br[CH2:2][C:3]([N:5]=[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]1[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4].[NH3:20].[I-].[Na+].C(Cl)(Cl)[Cl:24]>CO.Cl>[ClH:24].[NH2:20][CH2:2][C:3]([N:5]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[CH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]1=2)=[O:4]
Reactant: O=C(CBr)N=C1C=CC=CC1C=Cc1ccccc1
Reactant: ClC(Cl)Cl
Reactant: N
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: NCC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: -33 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 2.2 g (7 mmol) of crude N-bromoacetyl-iminostilbene (38) in 25 mL of chloroform was added carefully to 250 mL of condensed liquid ammonia at -33° C. To the reaction mixture 6.0 g (40 mmol) of sodium iodide was added, the mixture was stirred at -33° C. for 2 hours and evaporated overnight. A water-white oily solution remained and 50 mL of water was added. The solution was extracted with 2×150 mL of chloroform. The solvent was dried over Na2SO4 and evaporated to yield a clear oil that was dissolved in 25 mL of methanol saturated with hydrochloric acid (g). The resulting solution was concentrated and 25 mL of acetonitrile was added. The solid material precipitated was collected and washed with 10 mL of acetonitrile. Recrystallization in methanol/ether gave 1.8 g (6.2 mmol, 90%) of 5-(aminoacetyl)-5H-dibenzo[b,f]azepinehydrochloride (39). NMR, IR and MS data confirmed compound identity.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[N:8]=2)=[O:4].C1C(=O)N([Br:34])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH2:15][Br:34])=[CH:11][CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[N:8]=2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Yield: 98.1 %

Procedure:
In a 50 mL pear-shaped flask, 3-methyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (0.45 g, 1.24 mmol), NBS (221 mg, 1.24 mmol) and benzoyl peroxide (60.2 mg, 0.248 mmol) were combined with carbon tetrachloride (12 mL) to give a light yellow suspension. The reaction mixture was refluxed for 2 hr. The reaction mixture was cooled, diluted with methylene chloride (50 mL), washed with saturated aqueous NaHCO3 (1×20 mL), and brine (1×20 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give crude 3-bromomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (536.6 mg, 97.9%) as a pale yellow solid. The material was not further purified. 1H NMR (DMSO-d6) δ ppm 8.89 (d, J=8.2 Hz, 1H) 7.99 (d, J=8.2 Hz, 1H) 7.44-7.62 (m, 5H) 4.53 (s, 2H) 3.55 (s, 3H). MS calcd. for C18H12BrF3N2O3 [(M+H)+] 442.0, obsd. 443.0.
Reaction SMILES: [CH:1]1[C:6](=O)C=C(C(O)=O)[O:3][C:2]=1C(O)=O.C(O[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C.CC(C)=O.[O-]CC.[Na+]>>[O:3]=[C:2]([CH2:1][CH3:6])[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C(O)c1cc(=O)cc(C(=O)O)o1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)C(=O)CC

Procedure:
Riegel, Zwilgmeyer, Organic Syntheses Coll., Vol. II, 126 (1943) and Huang et al. CA 98(3):16549v describe the preparation of chelidonic acid. In a first step rapid addition of 1.03 equivalents of diethyloxalate and 1 equivalent of acetone to a slight excess of sodium ethoxide yields ethyl dioxovalerate as the major product. In a second step another equivalent of diethyloxalate and hot sodium ethoxide solution is quickly added to the reaction causing a Claisen condensation with ethyl dioxovalerate. Acetone diethyloxalate ester is formed and exists as a disodium complex. In a third step ethanol is distilled off resulting in a cake-like product. In a further step, disodium acetone diethyloxalate complex is converted to its hydrogenated form by rapid, cold neutralization with hydrochloric acid. In a fifth step the neutralized acetone diethyloxalate is returned to the reactor after filtering and another equivalent of HCl added to promote cyclization and refluxed. The resulting chelidonic acid is cold filtered.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.[CH3:10][NH2:11]>Br>[CH3:10][NH:11][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(CO)ccn1
Reactant: CN
Agent: Br
Product: CNCc1ccnc(C)c1
Yield: 68 %

Procedure:
A stirred solution of 0.86 g (6.98 mmol) of 2-methyl-4-hydroxymethylpyridine (R. B. Katz et al., Synthetic Communications, 19, 1989, 317-325) in 48% aqueous HBr was heated at reflux for four days. The reaction mixture was cooled and added dropwise to 20 ml of 40% aqueous methylamine. The volatiles were removed under reduced pressure, and the residue was slurried in CH2Cl2 and then filtered. The filter cake was washed with CH2Cl2, EtOAc, CH3CN, and 10% MeOH in CH3CN. The filtrate was concentrated, and the residue was flash chromatographed on silica, eluting CH2Cl2 :NH3 -saturated MeOH (9:1). Consequently, 0.65 g (68% yield) of methyl-(2-methyl-pyridin-4-ylmethyl)-amine (39) was obtained as a colorless liquid.
Reaction SMILES: I[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CC(OC)(C)C.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>[Se:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=1
Reactant: Ic1ccc[se]1
Reactant: OB(O)c1ccccc1O
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: COC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1ccc(-c2ccc[se]2)cc1

Procedure:
A mixture of 27.9 g (0.11 mol) of 2-iodoselenophene, 15.0 g (0.11 mol) of 2-hydroxyphenylboronic acid, 6.8 g (5.88 mmol) of tetrakis(triphenylphosphine)palladium(0) and 235 ml of 2 N sodium carbonate soln. in 600 ml of toluene/ethanol (1:1) is heated under reflux for 19 h. The mixture is diluted with MTBE and washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:MTBE=4:1→1:1). Further purification is carried out by digestion in cold n-heptane; 4-selenophen-2-ylphenol is obtained as a beige solid.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C:8]3[S:15][CH:16]=[CH:17][C:7]=3[C:6]=2[C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([CH3:28])[CH2:25][NH:26][CH3:27])=[CH:20][CH:19]=1.[CH2:29]=O>>[ClH:1].[CH3:29][N:26]([CH3:27])[CH2:25][C@@H:24]([C:21]1[CH:22]=[CH:23][C:18]([C:5]2[C:6]3[C:7]4[CH:17]=[CH:16][S:15][C:8]=4[C:9](=[O:14])[NH:10][C:11]=3[CH:12]=[CH:13][C:4]=2[OH:3])=[CH:19][CH:20]=1)[CH3:28]
Reactant: C=O
Reactant: CNC[C@H](C)c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Agent: Cl
Product: C[C@@H](CN(C)C)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 61.3 %

Procedure:
Following the procedure outlined for Example 1387, (R)-8-methoxy-9-(4-(1-(methylamino)propan-2-yl)phenyl)thieno[2,3-c]quinolin-4(5H)-one hydrochloride (40 mg, 0.11 mmol) was reacted with paraformaldehyde (7 mg, 0.21 mmol) and after purification the resulting material was converted to the hydrochloride salt as outlined in General Procedure D-2 to afford the desired product (28 mg, 67%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.65-7.52 (m, 3H), 7.44-7.32 (m, 3H), 7.18 (d, J=8.9 Hz, 1H), 6.12 (d, J=5.4 Hz, 1H), 3.62 (d, J=3.1 Hz, 1H), 3.46 (dd, J=13.2, 4.7 Hz, 2H), 2.97 (s, 3H), 2.94 (s, 3H), 1.49 (d, J=6.6 Hz, 3H); ESI MS m/z 379 [C22H22N2O2S+H]+; HPLC >99% (AUC), tR=8.57 min.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.C(Cl)(Cl)Cl.C(OO)(=[O:24])C.[OH-].[Na+]>CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH3:14])=[O:24])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(=O)OO
Reactant: CCCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCS(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
3.81 G. of 1-acetamido-2-nitro-4-n-propylthiobenzene in 35 ml. chloroform is treated at -20° to -15° C with a solution of 3.0 g. 40% peracetic acid in 3 ml. methanol. The mixture is allowed to warm to 20° C and stirred at 15°-25° C for four hours, then washed with sodium bisulfite solution and sodium bicarbonate solution. Removal of the chloroform leaves a gum which is treated on a steam bath, with 15 ml. 5N sodium hydroxide for one hour. The mixture is cooled, extracted with chloroform, separated and the solvent removed. The crude residue is recrystallized from benzene yielding 1-amino-2-nitro-4-n-propylsulfinylbenzene.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(Cl)ccc(C(=O)O)c1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(Cl)c(C(=O)O)cc([N+](=O)[O-])c1Cl
Temperature: 50 °C

Procedure:
30 g of 2,4-dichloro-3-methylbenzoic acid are initially introduced into 83 ml of concentrated H2SO4. 16.7 g of KNO3 are added in portions with ice cooling. The mixture is subsequently warmed at 50° C. for a further 2 hours and then poured onto ice. The nitro compound is isolated and recrystallized from toluene. Melting point 152°-4° C., yield: 24 g.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH2:33][CH2:34][CH3:35]>ClCCl.CN(C)C1C=CN=CC=1>[C:32]([NH:18][S:15]([C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:6][CH:5]=2)[CH:10]=1)(=[O:17])=[O:16])(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC(=O)Cl
Reactant: Cc1oc(S(N)(=O)=O)cc1COc1ccc(-c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NS(=O)(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a stirred solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid amide (45) (50 mg, 0.146 mmoles) in dichloromethane (5.0 ml) was added triethylamine (26 μl, 0.189 mmoles), dimethyl-pyridin-4-yl-amine (1 mg) and butyryl chloride (19 μl, 0.184 mmoles). After stirring for 16 hours at room temperature the reaction mixture was concentrated in-vacuo, and the residue was purified by HPLC to give compound 61 as an off-white solid (48 mg). LC/MS System C: Rt=3.82 mins, m/z (ES−)=412 ((M−H) for C22H23NO5S).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[C:37]([NH:15][C:13]([C:11]1[C:10]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[CH:22][CH:23]=2)=[N:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=1)=[O:14])(=[O:39])[CH3:38]
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(N)=O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Yield: 48 %

Procedure:
A mixture of 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxamide (0.50 g) and acetic anhydride (20 mL) was heated under reflux for 4 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine and concentrated to give N-acetyl-1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxamide as colorless crystals (0.25 g, yield 48%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 193-194° C.
Reaction SMILES: C(C[O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:20])[C:8]=2[CH:7]=1)(O)=O.C1(O)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1SSC1C=CC=CC=1C(O)=O>>[OH:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:20])[C:8]=2[CH:7]=1
Reactant: O=C(O)COc1ccc2sc3ccccc3c(=O)c2c1
Agent: O=C(O)c1ccccc1SSc1ccccc1C(=O)O
Solvent: Oc1ccccc1
Product: O=c1c2ccccc2sc2ccc(O)cc12
Yield: 60 %

Procedure:
An example of a conventional synthetic route to 2-carboxymethoxythioxanthone involves three stages. Firstly, phenol is reacted with dithiobisbenzoic acid to produce 2-hydroxythioxanthone in a 60% yield. Secondly, the 2-hydroxythioxanthone is reacted with ethyl bromoacetate to produce the ethyl ester of 2-carboxymethoxythioxanthone in 75% yield. Thirdly, the ester is hydrolysed by acidification to produce the desired product in 90% yield. These three stages form an inefficient and time-consuming process to provide a product that is a dark colour, contains impurities and by-products and is produced with only an overall yield of 40% from the starting material.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][C:17]1([NH2:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.Cl.C(N(CC)CC)C>O1CCOCC1.O>[NH2:23][C:17]1([CH2:16][NH:15][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1(N)CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: NC1(CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CCOCC1
Temperature: 110 °C

Procedure:
A mixture of 4-chloro-3-nitrobenzenesulfonamide, 4-(aminomethyl)tetrahydro-2H-pyran-4-amine, hydrochloric acid and triethylamine in dioxane (10 mL) was heated at 110° C. overnight. After cooling, the mixture was diluted with water (10 mL), and filtered.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[CH:4][N:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>C(Cl)(Cl)Cl.O>[CH:34]1([NH:37][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[N:10][N:11]4[C:16]=3[CH2:15][CH2:14][CH2:13][N:12]4[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH:5]=[CH:4][N:3]=2)[CH2:36][CH2:35]1
Reactant: O=C(OCc1ccccc1)N1CCCc2c(-c3ccnc(Cl)n3)c(-c3ccc(F)cc3)nn21
Reactant: NC1CC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn21
Reaction time: 0.08 h

Procedure:
A solution of the phenylmethyl 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-5,6-dihydropyrazolo[1,5-b]pyridazine-7(4H)-carboxylate (i.e. the product of Step C) (464 mg, 1.0 mmol) and cyclopropylamine (1.3 mL, 18.5 mmol) in chloroform (3 mL) was heated at 120° C. in a sealed tube under microwave irradiation for 1 h and then at 160° C. for 5 minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-100% ethyl acetate in hexanes as eluant to give 240 mg of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[C:3]([F:16])([F:15])[C:4]1[NH:9][C:8](=[O:10])[C:7]([C:11](OC)=[O:12])=[CH:6][CH:5]=1.Cl>C(N)CC>[F:21][C:2]([F:1])([C:17]([F:20])([F:19])[F:18])[C:3]([F:15])([F:16])[C:4]1[NH:9][C:8](=[O:10])[C:7]([C:11]([NH:9][CH2:8][CH2:7][CH3:6])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O
Agent: Cl
Solvent: CCCN
Product: CCCNC(=O)c1ccc(C(F)(F)C(F)(F)C(F)(F)F)[nH]c1=O

Procedure:
250 mg (0.78 mmol) of methyl 6-(heptafluoropropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate in 5 ml of propylamine were heated under reflux for 5 h. The mixture was then adjusted to pH 2 by addition of 1N hydrochloric acid and extracted with dichloromethane. Drying and concentration gave 240 mg (88% of theory) of a beige powder.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][CH:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])=[S:17])[NH:13][C:12]1=[O:36])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[C:38]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)(=[O:41])[CH:39]=[O:40]>C1C=CC=CC=1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][CH:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=2)=[O:23])=[S:17])[N:13]([CH:39]([OH:40])[C:38]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=2)=[O:41])[C:12]1=[O:36])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: c1ccccc1
Solvent: O
Product: CC(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 74.7 %

Procedure:
A mixture of 230 mg (0.40 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-[1-methyl-2-p-nitrobenzyloxycarbonylaminoethylthio(thiocarbonyl)]thioazetidin-2-one, 182 mg (0.80 mmole) of p-nitrobenzyl glyoxylate hydrate and 5 ml of benzene was heated under reflux for 10 hours. After completion of the reaction the solvent was distilled off and the resulting residue was subjected to column chromatography through 10 g of silica gel eluted with a 7-10% v/v solution of ethyl acetate in benzene to afford 234 mg (yield 75%) of the desired product as a yellow oil.
Reaction SMILES: [C:1]1([PH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(CCC)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[Br:68])(=O)=O.C(N(C(C)C)CC)(C)C.Cl>C1(C)C=CC=CC=1>[Br:68][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=1[P:11]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(Pc3cccc4ccccc34)cccc2c1
Reactant: O=S(=O)(Oc1ccccc1Br)C(F)(F)F
Agent: CCCP(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
Into a four-neck flask were weighed 16.89 g (59.0 mmol) of di(1-naphthyl)phosphine, 1.27 g (2.5 mmol) of Pd2(dba)3CHCl3 (dba represents dibenzylideneacetone), and 1.01 g (2.5 mmol) of diphenylphosphinopropane. The atmosphere of the reaction vessel fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen. Thereto were added 150 mL of toluene, 15.00 g (49.2 mmol) of 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), and 9.53 g (73.8 mmol) of diisopropylethylamine, followed by 16 hours of heating at reflux. After the completion of the reaction, the reaction mixture was cooled to room temperature and poured into 150 mL of 5% hydrochloric acid aqueous solution. After 30 minutes of stirring, the layers were separated from each other. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. Toluene was removed by evaporation and the residue was purified by silica gel column chromatography to obtain the title compound (10.68 g, a pale yellow solid). Yield 49.2%.