Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH:40][C:41]2[CH:46]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:44]=[C:43]([O:56][CH3:57])[CH:42]=2)(=[O:39])=[O:38])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:45]2[CH:46]=[C:41]([NH:40][S:37]([CH2:36][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)(=[O:38])=[O:39])[CH:42]=[C:43]([O:56][CH3:57])[CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(NS(=O)(=O)Cc2ccc(F)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)Cc2ccc(F)cc2)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.27 mmol) were added 1-(4-fluorophenyl)-N-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (138 mg, 0.33 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (22 mg, 0.03 mmol) and 273 μl of a 2M aqueous solution of cesium carbonate in dioxane (5 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0 to 80%, hexane-ethyl acetate) to give 155 mg (85% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Nc1ccc(O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a solution of 4-bromobenzoic acid in DMF (0.10 M), 3 eq of NMM, 1.5 eq of Py-BOP and 1.1 eq of 4-aminophenol were added and the mixture was stirred at RT for 20 min. DMF was concentrated in vacuo and the residue diluted with EtOAc and aqueous HCl (1N). The resultant precipitate was filtered off and dried in vacuo to afford the title compound (73%); MS (ES+) m/z 292 (M+H)+, m/z 294 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O[CH2:12][C:13]1[O:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:12]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[C:13]2[O:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=2)=[CH:3]1
Reactant: Cn1ccc2ccccc21
Reactant: O=Cc1ccc(CO)o1
Product: Cn1cc(C(c2ccc(CO)o2)c2cn(C)c3ccccc23)c2ccccc21

Procedure:
The compound Bis(1-methylindol-3-yl)-(5-hydroxymethyl-2-furyl)methane was prepared following general procedure A, starting from N-methyl indole and 5-hydroxy methyl furfural. LC: Tr 2.25 min, MS: 371 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in example 1 but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and ethanesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]2[CH2:16][C:15]3[C:14]([OH:17])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:25][N:26]([CH3:30])[C:27](=[O:28])[O:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][N:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:9]2
Reactant: CN(C)C(=O)Cl
Reactant: Oc1cccc2c1CN(Nc1ccncc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cccc2c1CN(Nc1ccncc1)C2
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a mixture of 2,3-dihydro-2-(4-pyridinylamino)-1H-isoindol-4-ol (1.20 g), triethylamine (1.18 g) and chloroform (35 ml), was added dimethylcarbamyl chloride (0.68 g) with stirring, at ambient temperature, under nitrogen. The reaction mixture was heated under reflux for 3 hrs, poured into dilute sodium bicarbonate solution (100 ml), and the layers were separated. The aqueous phase was extracted with chloroform, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica, eluting with 10-15% methanol/dichloromethane. The appropriate fractions were collected and concentrated to give 953 mg (60%) of product. Recrystallization from dichloromethane-heptane gave the analytical sample, mp 183-185° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:15]([CH:18](C(OC)=O)[C:19]([O:21][CH3:22])=[O:20])([O-])=[O:16]>C1(C)C=C(C)C=C(C)C=1>[C:1]1([C:7]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[N:15][O:16][C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Reactant: C(#Cc1ccccc1)c1ccccc1
Solvent: Cc1cc(C)cc(C)c1
Product: COC(=O)c1noc(-c2ccccc2)c1-c1ccccc1
Temperature: 150 °C
Yield: 14 %

Procedure:
A mixture of 1,2-diphenylethyne (1.53 g, 8.6 mmol) and dimethyl 2-nitromalonate (1.05 mL, 7.83 mmol) in mesitylene (11 ml) was heated to 150° C. for 18 hr. The volatiles were removed in vacuo and the residue was chromatographed on a 5×12 cm silica gel column eluting with 0-10% EtOAc/hexanes. The essentially pure fractions containing product were concentrated to afford methyl 4,5-diphenylisoxazole-3-carboxylate (307 mg, 1.1 mmol, 14.04% yield) as a light yellow solid. HPLC retention time=1.85 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10](O)=[O:11].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C1C=CC=CC=1>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10]([Cl:24])=[O:11]
Reactant: Cc1cc([N+](=O)[O-])c(Oc2ccc(F)cc2F)cc1C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cc([N+](=O)[O-])c(Oc2ccc(F)cc2F)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.9 %

Procedure:
A mixture of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoic acid (1.4 g) and phosphorus pentachloride (1 g) in benzene (10 ml) was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure to give an oil of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoyl chloride (1.6 g). A solution of diethyl malonate (0.88 g) and ethanol (0.5 ml) in ether (5 ml) was added dropwise to a stirred solution of magnesium (132 mg), ethanol (0.2 ml), and carbon tetrachloride (0.3 ml) in ether (5 ml) at room temperature. The mixture was stirred for 1 hour at room temperature and refluxed for 30 minutes. To the resulting mixture was added dropwise a solution of 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoyl chloride (1.6 g) in ether (3 ml) at 5° C. The mixture was stirred for 2 hours at room temperature and refluxed for 1 hour. The reaction mixture was poured into 10% sulfuric acid (40 ml) and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to give an oil of diethyl 5-(2,4-difluorophenoxy)-2-methyl-4-nitrobenzoylmalonate (2.1 g).
Reaction SMILES: CN([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[NH:15][CH3:16])=[CH:9][CH:8]=1)=[CH2:6])C.C1(OC([Cl:27])=O)C=CC=CC=1>C(Cl)Cl>[Cl:27][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[NH:15][CH3:16])=[CH:9][CH:8]=1)=[CH2:6]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C=C(CN(C)C)c1ccc(NC(=O)NC)cc1
Solvent: ClCCl
Product: C=C(CCl)c1ccc(NC(=O)NC)cc1

Procedure:
To a solution of 13.85 g (0.06 Mol) N'-[4(1-dimethylaminomethyl-ethenyl)phenyl]-N-methyl urea in 180 ml absolute CH2Cl2 are added dropwise, at 20°-30°, within 20 minutes, 9.4 g (0.06 Mol) chloroformic acid phenyl ester in 50 ml absolute CH2Cl2.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:21])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[S:17])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33].Cl>C(#N)C>[C:32]([O:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:21])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[S:17])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2)(=[O:34])[CH3:33]
Reactant: CCOC(=S)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC(=S)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OC(C)=O)C(=O)OC2
Reaction time: 2 h

Procedure:
To a solution of 1.6 g of ethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-thiohexenoate in 120 ml of acetonitrile at 0° C. was added 0.74 ml of pyridine followed by 1.0 ml of acetyl chloride. After stirring for 2 hours the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic solution was dried over anhydrous magnesium sulfate and evaporated to an oil, which was triturated with ether to give ethyl (E)-6-(1,3-dihydro-4-acetoxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-thiohexenoate, m.p. 81°-84° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:34][C:35]1[CH:40]=[C:39]([C:41]2[O:42][CH:43]=[C:44]([CH2:46][N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[N:45]=2)[CH:38]=[CH:37][C:36]=1[OH:53].[N:54]1([CH2:60][CH2:61][CH2:62]O)[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1.Cl>O1CCCC1>[F:34][C:35]1[CH:40]=[C:39]([C:41]2[O:42][CH:43]=[C:44]([CH2:46][N:47]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]3)[N:45]=2)[CH:38]=[CH:37][C:36]=1[O:53][CH2:62][CH2:61][CH2:60][N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: Oc1ccc(-c2nc(CN3CCCCC3)co2)cc1F
Reactant: OCCCN1CCCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(-c2nc(CN3CCCCC3)co2)ccc1OCCCN1CCCCC1
Reaction time: 48 h
Yield: 20 %

Procedure:
To a solution of triphenylphosphine (0.81 g, 3.08 mmol, 1 eq) in dry tetrahydrofuran at 0° C. is added dropwise diisopropylazodicarboxylate (0.61 ml, 3.08 mmol, 1 eq). A solution of 2-fluoro-4-[4-(1-piperidinylmethyl)-1,3-oxazol-2-yl]phenol i68 (0.85 g, 3.08 mmol, 1 eq) and 3-(1-piperidinyl)-1-propanol (0.44 g, 3.08 mmol, 1 eq) in tetrahydrofuran is added dropwise to the mixture at 0° C. After 2 days, the mixture is poured onto 0.5 N hydrochloric acid and extracted with diethyl ether. The aqueous phase is basified with 1 N sodium hydroxide to pH 9 and extracted with ethyl acetate. The organic layer is dried on magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography over silica gel to afford 0.25 g of 1-(3-{2-fluoro-4-[4-(piperidin-1-ylmethyl)-1,3-oxazol-2-yl]phenoxy}propyl)piperidine 88 as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[O:12][C:11]=2[CH3:22])[N:3]=1.ClC1C=CC(C2OC(C)=C(CO)C=2)=CC=1.[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C([O-])([O-])=O.[K+].[K+]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:12][C:11]([CH3:22])=[C:10]([CH2:9][O:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([N:38]4[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]4)[N:3]=3)[CH:14]=2)=[CH:16][CH:17]=1
Reactant: C1CNCCN1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1COc1cncc(Cl)n1
Agent: Cc1oc(-c2ccc(Cl)cc2)cc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc(-c2ccc(Cl)cc2)cc1COc1cncc(N2CCNCC2)n1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[5-(4-chlorophenyl)-2-methylfuran-3-ylmethoxy]pyrazine [3.14 g, 9.39 mmol; obtained according to the procedure of example 50, step 1, starting from 5-(4-chlorophenyl)-3-hydroxymethyl-2-methylfuran], piperazine (2.47 g, 28.6 mmol) and K2CO3 (1.36 g, 9.86 mmol) with the exception that the final filtration through alumina was omitted. The yield of the of the title compound was 2.11 g (58%) which was obtained as a beige colored solid. Purity 100% (HPLC). MS m/z 384 (M)+. HRMS m/z calcd for C20H21ClN4O2 (M)+ 384.1353, found 384.1357.
Reaction SMILES: FC(F)(F)OC1C=CC(N2C(=O)C=CS2)=CC=1.[F:18][C:19]([F:35])([F:34])[O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[CH:30]=[C:29]([Cl:33])[S:28]2)=[CH:23][CH:22]=1.S(Cl)([Cl:39])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:35][C:19]([F:18])([F:34])[O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[C:30]([Cl:39])=[C:29]([Cl:33])[S:28]2)=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1cc(Cl)sn1-c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: O=c1ccsn1-c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cl)c(Cl)sn1-c1ccc(OC(F)(F)F)cc1
Yield: 70.2 %

Procedure:
First, a mixture containing 6.4 g of 2-(4-trifluoromethoxyphenyl)-4-isothiazolin-3-on and 5.1 g of 2-(4-trifluoromethoxyphenyl)-5-chloro-4-isothiazolin-3-on was suspended in 100 ml of dichloromethane, after which 19 g of sulfuryl chloride was then added dropwise to the suspension at room temperature, and the resultant mixture was stirred for 12 hours. After completion of the reaction, 200 ml of a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the dichloromethane layer was separated. The aqueous layer was extracted with 150 ml of dichloromethane. The combined dichloromethane layer was washed with water, dried with magnesium sulfate, and concentrated. The concentrate was purified by column chromatography (hexane:ethyl acetate=6:1) to give 4 g of 2-(4-trifluoromethoxyphenyl)-4,5-dichloro-4-isothiazolin-3-on (compound (13); m.p., 129°-130° C.).
Reaction SMILES: [F:1][C:2]([F:22])([C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4]I.[P:23]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])[O:24]CC.[I-]>>[CH2:31]([O:30][P:23]([CH2:4][CH2:3][C:2]([F:1])([F:22])[C:6]([F:20])([F:21])[C:7]([F:18])([F:19])[C:8]([F:16])([F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])(=[O:24])[O:27][CH2:28][CH3:29])[CH3:32]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: CCOP(OCC)OCC
Agent: [I-]
Product: CCOP(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC

Procedure:
3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluoro-1-iodooctane (5.68 g, 11.98 mmol) and P(OEt)3 (4 ml, excess) were placed in a 50 ml RBF fitted with a reflux condenser. The mixture was subjected to microwave irradiation (300 W) for 2 hours (max. temp ca. 155° C.) after which time the starting iodide was no longer visible by TLC. Volatiles were distilled in vacuo (150° C., 0.01 torr) to give the crude material as a thick yellow oil. Column chromatography (silica gel, EtOAc elution) afforded the desired product as a thick pale yellow oil. Yield 3.71 g, 64%. Analysis found (calculated) %: C, 29.25 (29.77); H, 2.96 (2.91). 1H NMR (CDCl3, 400 MHz, 298 K): δ 4.11 (m, 4H), 2.36 (m, 2H), 1.98 (m, 2H), 1.33 (t, J=7 Hz). 13C{1H} NMR (CDCl3, 100 MHz, 298 K): δ 121-105 (m, C-F coupling unresolved), 62.18 (d, JC-P=6 Hz), 25.15 (t, JC-F=24 Hz), 17.10 (d of t, JC-P=148 Hz, JC-F=4 Hz), 16.34 (d, JC-P=6 Hz). 31P{1H} NMR (CDCl3, 162 MHz, 298 K): δ 28.96. MS (FAB, m/z): 485 ([M+H]+, 100%). Exact mass found (calculated for [M+H]+, m/z): 485.05499 (485.05513).
Reaction SMILES: [Li]CCCC.CO[CH:8](OC)[CH2:9][NH2:10].[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]#[N:19].N>CCCCCC.C1COCC1>[NH:10]1[CH:9]=[CH:8][N:19]=[C:18]1[C:14]1[S:13][CH:17]=[CH:16][N:15]=1
Reactant: N#Cc1nccs1
Reactant: COC(CN)OC
Agent: N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1c[nH]c(-c2nccs2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of nBuLi (2.0 eq) in hexane was added under argon to a solution of 2,2-dimethoxyethanamine (2.0 eq) in THF at −78° C. After stirring for 30 min, thiazole-2-carbonitrile (2-Im-2, 3.0 g, 1.0 eq) was added and the resulting solution was stirred at 0° C. for 2 h, then quenched with 20 mL of 5% MeOH in water. The volatiles were removed and 6N HCl was added to adjust to pH=1. The acidic solution was refluxed overnight, cooled to rt then poured into a mixture of ice and aqueous Na2CO3. This was extracted with EtOAc and the organic layer was concentrated to give Imadazole 2. LCMS (0.01% Ammonia): 152.1 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 13.19 (bs, 1H), 7.98 (d, 1H, J=3.0 Hz), 7.82 (d, 1H, J=3.0 Hz), 7.36 (s, 1H), 7.14 (s, 1H).
Reaction SMILES: COCCOC.Cl[C:8]1[S:12][N:11]=[C:10]([S:13][CH3:14])[N:9]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:14][S:13][C:10]1[N:9]=[C:8]([C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:15])[S:12][N:11]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1nsc(-c2ccccc2Cl)n1
Yield: 50.8 %

Procedure:
To 25 ml of 1,2-dimethoxyethane were added 2.0 g of 5-chloro-3-methylthio-1,2,4-thiadiazole, 2.25 g of 3-chlorophenylboronic acid, 694 mg of tetrakistriphenylphosphine palladium and about 25 ml of a 2 M aqueous sodium carbonate solution, and the mixture was heated under reflux for 3 hours in a nitrogen atmosphere. Then, the reaction mixture was poured into water, and the mixture was extracted with t-butyl methyl ether. The organic layer was dried with anhydrous sodium sulfate, and the residue obtained by concentration was subjected to silica gel column chromatography to obtain 1.48 g of 3-methylthio-5-(2-chlorophenyl)-1,2,4-thiadiazole.
Reaction SMILES: [NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Cl:13][C:14]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:15]=1[C:16](C1C=CC=CC=1)=[O:17].S(=O)(=O)(O)[OH:31]>C(O)(=O)C>[Cl:13][C:14]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:15]=1[C:16]([OH:17])=[O:31]
Reactant: O=C(c1ccccc1)c1cc(F)c(F)cc1Cl
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C(O)c1cc(F)c(F)cc1Cl
Temperature: 90 °C
Yield: 80.8 %

Procedure:
8 g of ammonium peroxodisulfate are introduced into 5 g (19.8 mmol ) of 2-chloro-4,5-difluorobenzophenone and 20 g of glacial acetic acid and the mixture is heated at 90° C. (12 h). 100 g of 70% sulfuric acid are then added and the mixture is heated for 2 h at 150° C. Dilution with 200 g of water and filtration gives 3.1 g (16.0 mmol, 81%) of 2-chloro-4,5-difluorobenzoic acid (purity (GC) ca. 92%). Recrystallization from water gives 2.5 g of product melting at 104° C.-105° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Na].[C:9]([CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:10].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[CH2:22][NH:23][NH2:24]>O1CCOCC1>[NH2:10][C:9]1[N:23]([CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[F:19])[N:24]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1
Reactant: CCOC(=O)C(=O)CC#N
Reactant: NNCc1ccccc1F
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
111.75 g (75 ml, 0.98 mol) of trifluoroacetic acid are added to 100 g (0.613 mol) of the sodium salt of ethyl cyanopyruvate (preparation in analogy to Borsche and Manteuffel, Liebigs Ann. 1934, 512, 97) in 2.51 of dioxane under argon with efficient stirring at room temperature, and the mixture is stirred for 10 min, during which most of the precursor dissolves. Then 85.93 g (0.613 mol) of 2-fluorobenzyl-hydrazine are added, and the mixture is boiled overnight. After cooling, the sodium trifluoroacetate crystals which have separated out are filtered off with suction and washed with dioxane, and the crude solution is reacted further.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:44]([O:43][C:42]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1)=[O:48])([CH3:47])([CH3:46])[CH3:45]
Reactant: CCOC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCCCCNC(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 65 °C
Yield: 55.9 %

Procedure:
To a solution of ethyl 4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.5 g) in DMF (8 mL) was added tert-butyl 6-bromohexylcarbamate (1.1 g) and K2CO3 (0.9 g). The mixture was heated to 65° C. for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc (250 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by recrystallization in MeOH to give ethyl 4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.2 g).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2].P(Cl)(Cl)([Cl:23])=O.[OH-].[NH4+]>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:23])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1O
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1Cl
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A mixture of 28.8 g of 3-carbethoxy-4-hydroxy-6,7-dimethoxyquinoline and 16.6 ml of phosphorous oxychloride was stirred at 1 10° C. for 30 min, cooled to 0° C., and treated with a mixture of ice and ammonium hydroxide. The resulting grey solid was filtered, washed with water and ether, and dried, mp 147-150° C.