Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH2:13])[CH2:8][CH2:7]2.[CH:14]1([C:17]2[C:25]3[C:20](=[N:21][C:22]([O:27][CH2:28][C:29](O)=[O:30])=[CH:23][C:24]=3[CH3:26])[N:19]([CH3:32])[N:18]=2)[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:14]1([C:17]2[C:25]3[C:20](=[N:21][C:22]([O:27][CH2:28][C:29]([NH:13][CH:9]4[C:10]5[C:6](=[CH:5][C:4]([O:3][CH3:2])=[CH:12][CH:11]=5)[CH2:7][CH2:8]4)=[O:30])=[CH:23][C:24]=3[CH3:26])[N:19]([CH3:32])[N:18]=2)[CH2:15][CH2:16]1
Reactant: COc1ccc2c(c1)CCC2N
Reactant: Cc1cc(OCC(=O)O)nc2c1c(C1CC1)nn2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCC2NC(=O)COc1cc(C)c2c(C3CC3)nn(C)c2n1
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To the solution of 5-methoxy-indan-1-ylamine hydrochloride (92 mg, 0.46 mmol) and (3-cyclopropyl-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (building block A7, 120 mg, 0.46 mmol) in DMF (6 ml) were added DIPEA (0.24 ml, 1.38 mmol) and HATU (210 mg, 0.55 mmol) and the reaction was stirred at it for 30 min. The mixture was diluted with EtOAc, washed with aqueous bicarbonate solution and brine, dried over sodium sulfate, and the solvents were evaporated under reduced pressure. Purification by preparative HPLC (Gilson GX-281, Waters Sunfire C18, 5 μm, 30×100 mm with guard column 19×10 mm, solvent A: water with 0.1% TFA, solvent B: acetonitrile, gradient 40-60% B in 15 min, flow reate 50 ml/min) gave the title compound as colorless solid (140 mg, 75%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.40 (d, 1H), 7.02 (d, 1H), 6.81 (s, 1H), 6.68 (d, 1H), 6.48 (s, 1H), 5.26 (dd, 1H), 4.80 (s, 2H), 3.76 (s, 3H), 3.71 (s, 3H), 2.91-2.88 (m, 1H), 2.78-2.73 (m, 1H), 2.66 (s, 3H), 2.38-2.33 (m, 1H), 2.28-2.24 (m, 1H), 1.89-1.82 (m, 1H), 0.92-0.85 (m, 4H); LCMS RtH=3.095 min; [M+H]+=407.2]
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:22])=[CH:13][C:14]4[C:19]([CH:20]=3)=[CH:18][C:17]([Br:21])=[CH:16][CH:15]=4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30]Cl>CN(C=O)C>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COCCOCCl
Reactant: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCOc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2

Procedure:
17.85 g (0.05 mol) of 3-(1-adamantyl)-6-bromo-2-naphthol and 200 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. 1.8 g (0.06 mol) of sodium hydride (80% in oil) was added portionwise and the reaction mixture was stirred until gas evolution had ceased. 6.9 ml (0.06 mol) of methoxyethoxymethyl chloride were then added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-cold water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and heptane (40/60). 19.5 g (87%) of the expected compound were collected, which compound had a melting point of 99°-100° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:2]=1.[N:15]1[NH:16][N:17]=[N:18][C:19]=1[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.[NH2:28][C:29]([NH2:31])=[O:30].Cl>CCO>[N:15]1[NH:16][N:17]=[N:18][C:19]=1[C:20]1[CH:27]=[CH:26][C:23]([CH:24]2[C:8]([C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:31][C:29](=[O:30])[NH:28]2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(-c2nn[nH]n2)cc1
Reactant: NC(N)=O
Reactant: O=C(Cc1ccsc1)c1cccnc1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2cccnc2)=C(c2ccsc2)C(c2ccc(-c3nn[nH]n3)cc2)N1
Yield: 35.8 %

Procedure:
A mixture of 1-(pyridin-3-yl)-2-(thiophen-3-yl)ethanone (Intermediate 56) (80 mg, 0.39 mmol), 4-(2H-tetrazol-5-yl)benzaldehyde (300 mg), urea (120 mg, 2.0 mmol) and conc. HCl (0.5 mL) in EtOH (5 mL) was refluxed under N2 overnight. The mixture was concentrated under reduced pressure and purified by prep-HPLC (0.1% TFA as additive) to give Compound 166 (56 mg, yield 35%) as yellow solid. 1H NMR (CD3OD 400 MHz): δ 8.71-8.61 (m, 2H), 8.30 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.85-7.78 (m, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.22 (dd, J=2.8 Hz, J=4.8 Hz, 1H), 6.89 (dd, J=1.6 Hz, J=3.2 Hz, 1H), 6.56 (dd, J=1.2 Hz, J=5.2 Hz, 1H), 5.50 (s, 1H). MS (ESI): m/z 402.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClC(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][Br:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Cl)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(CBr)n1
Yield: 77.2 %

Procedure:
6-Chloro-2-methylpyridine (20 g), (Ex Aldrich), N-bromosuccinimide (31 g), benzoyl peroxide (570 mg) and tetrachloromethane (250 ml) were heated together under reflux and under irradiation from a powerful lamp for 6 hours. After standard work-up and purification by column chromatography (silica; 5% ether in hexane), 6-chloro-2-bromomethylpyridine (25 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[NH:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH:32]=O)=[CH:31][C:26]=2[N:25]=[CH:24]1>>[NH:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:22][CH2:21][C:19]5[O:20][C:16]([CH3:15])=[CH:17][CH:18]=5)=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)=[CH:31][C:26]=2[N:25]=[CH:24]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=Cc1ccc2[nH]cnc2c1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NCc4ccc5[nH]cnc5c4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=384.1 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 1H-benzimidazole-5-carbaldehyde as described in example 26.
Reaction SMILES: [CH2:1]1[C:3]([CH2:6][OH:7])([CH2:4]O)[CH2:2]1.C(Cl)Cl.[BrH:11].[CH3:12][C:13](=[O:17])OCC>C(O)(=O)C.O>[C:13]([O:7][CH2:6][C:3]1([CH2:4][Br:11])[CH2:2][CH2:1]1)(=[O:17])[CH3:12]
Reactant: CCOC(C)=O
Reactant: OCC1(CO)CC1
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCC1(CBr)CC1
Reaction time: 2 h

Procedure:
A 3 L 3-neck round bottle flask was equipped with mechanical stirrer, a thermometer, a nitrogen inlet and an additional funnel. To the flask was charged 200 g of 1,1-cyclopropyldimethanol and 200 mL of methylene chloride. The mixture was cooled to 0˜5° C. 1440 g of 33% HBr in glacial acetic acid was slowly added to reaction solution and kept the temperature below 20° C. After the addition, the reaction mixture was stirred at between 10° C. and 18° C. for about 2 hours and then warmed to 16˜22° C. and stirred about 1 hour. When the starting material of 1,1-cyclopropyldimethanol was disappeared (checked by TLC, mobile phase:EA/hx=1/3(V/V)), 1000 mL of water was added to the reaction mixture with stirring over 30 min and kept the temperature below 20° C. The layers were separated and the aqueous layer was back extracted with 300 mL methylene chloride. To the combined organic layers was added 400 ml of water, and then was neutralized to pH 6˜7 with 10% NaOH aqueous solution. The organic layers were concentrated to obtain 396 g of crude [1-(bromomethyl)cyclopropyl]methyl acetate.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13].C(N(CC)CC)C.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:8][N:7]1[C:2]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[C:3]([CH:12]=[O:13])[C:4](=[O:11])[N:5]([CH3:10])[C:6]1=[O:9]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(N2CCN(c3ccccc3)CC2)c(C=O)c(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
To an ice-cooled, stirred solution of 6-chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (0.600 g, 2.96 mmol) and triethyl-amine (0.45 ml, 3.26 mmol) in dichloromethane (20 ml), a solution of N-phenylpiperazine (0.49 ml, 3.26 mmol) in dichloromethane (10 ml) was added dropwise. The resulting suspension was stirred at room temperature until the starting material was consumed (3.5 h, monitored by TLC). Then the reaction mixture was washed with water (3×10 ml), and the organic phase was dried over 20, anhydrous MgSO4. The solvent was evaporated in vacuo, and the brown oily crude product was purified by column chromatography with a mixture of dichloromethane:ethyl acetate (1:1) as the eluent and crystallized from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7][Cl:8])=[CH:4][CH:3]=1.[CH3:12][NH:13][C:14](=[S:17])[NH:15][NH2:16]>>[ClH:8].[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[CH2:7][S:17][C:14]([NH:13][CH3:12])=[N:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CNC(=S)NN
Product: CNC1=NN=C(c2ccc(F)cc2)CS1
Product: Cl

Procedure:
8.63 g of 4-fluorophenacyl chloride and 4.66 g of 4-methyl-thiosemicarbazide are reacted by using the conditions of Example 1. The resultant product is recrystallized from methanol/ethyl acetate yielding 5.6 g of 5-(4-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine hydrochloride. M.p. 139°-141° C. The product compound is dried under high vacuum at 65° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)=[O:4].I[C:16]1C=CC(N)=CC=1C>>[F:14][C:2]([F:1])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[C:8]([CH3:16])[CH:7]=1)=[O:4]
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Reactant: Cc1cc(N)ccc1I
Product: Cc1cc(NC(=O)C(F)(F)F)ccc1I

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 32, using 4-iodo-3-methylaniline as a substrate. ES/MS calcd. for C9H7F3INO 328.95. Found m/z=330 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([O:13][C:14](=[N:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH:29]([F:31])[F:30])(=[O:21])=[O:20])OCC)[CH3:12]>O1CCCC1.CCOCC>[F:31][CH:29]([F:30])[O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:18][C:14](=[N:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1)[O:13][CH2:11][CH3:12])(=[O:21])=[O:20]
Reactant: COc1cc(C)nc(N)n1
Reactant: CCOC(=NS(=O)(=O)c1ccccc1OC(F)F)OCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=Nc1nc(C)cc(OC)n1)NS(=O)(=O)c1ccccc1OC(F)F
Temperature: 25 °C

Procedure:
To a solution of 11.2 g (0.1 mol) of potassium tertbutylate in 125 ml of tetrahydrofuran are added at room temperature, with stirring, 13.9 g (0.1 mol) of 2-amino-4-methoxy-6-methylpyrimidine. Stirring is maintained for 2 hours at room temperature, and 32.3 g (0.1 mol) of N-(2-difluoromethoxy-benzenesulfonyl)-imido carbonic acid diethyl ester (obtained according to Example 1) are then added, the reaction mixture being stirred for a further 20 hours. The mixture is subsequently concentrated by evaporation, and the residue is taken up in water and rendered acid with hydrochloric acid. The acid solution is extracted with ethyl acetate; the organic phases are then collected, dried, and concentrated by evaporation to leave a solid residue, which is suspended in ether and again filtered off. The yield is 34.5 g (83% of theory) of the above sulfonylisourea, m.p. 131°-133° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]#[N:20])[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:22].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]([NH2:20])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(-c3ccc(F)cc3)cc(C#N)nc2c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc2c(-c3ccc(F)cc3)cc(C(N)=O)nc2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-(4-Fluorophenyl)-7-methylquinoline-2-carbonitrile (1-6, 25 mg, 0.095 mmol, 1.0 equiv.) was dissolved in acetone (2.3 mL)/water (1.5 mL) and sodium percarbonate (79.0 mg, 0.477 mmol, 5.0 equiv) was added. The resulting mixture was stirred at 50° C. for 1 hour. The mixture was cooled and concentrated. The crude residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier). Fractions containing product were pooled and treated with Na2CO3. The resulting mixture was extracted with CHCl3. The combined organic layers were dried (MgSO4), filtered, and concentrated to afford 4-(4-fluorophenyl)-7-methylquinoline-2-carboxamide (1-7). LRMS m/z (M+H)+ 280.9 found, 281.3 required.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCOC=[CH:18][C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl.O.[CH2:29](O)C>>[CH2:24]([O:23][C:21]([C:20]1[CH:29]=[N:13][N:12]([C:3]2[C:2]([F:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=2)[C:19]=1[CH3:18])=[O:22])[CH3:25]
Reactant: CCO
Reactant: CCOC=CC(=O)CC(=O)OCC
Reactant: NNc1ncc(C(F)(F)F)cc1F
Agent: Cl
Solvent: O
Product: CCOC(=O)c1cnn(-c2ncc(C(F)(F)F)cc2F)c1C

Procedure:
To a solution of 3-fluoro-5-(trifluoromethyl)pyridin-2-ylhydrazine in ethanol (166 ml) were added ethyl (2-ethoxymethylene)acetoacetate (4.52 g) synthesized according to the method described in J. Chem. Soc. Perkin trans. I, p. 1875 (1988) and 1 N hydrochloric acid aqueous solution (110 ml), and stirred under reflux for 3 hours. After the mixture was allowed to cool, to the reaction solution was added water, the precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under air blow to give 1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (5.16 g) as a white solid. MS (ESI) m/z: 318 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH2:5][C@H:6]([N:8]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:7].NN.[ClH:26]>C(O)C.C(OCC)(=O)C.CCOCC>[ClH:26].[F:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH2:5][C@H:6]([NH2:8])[CH3:7]
Reactant: C[C@H](COc1cc(F)ccc1F)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@@H](N)COc1cc(F)ccc1F
Temperature: 25 °C

Procedure:
To 5.4 g (R)-2-[2-(2,5-difluorophenoxy)-1-methylethyl]-1H-isoindole-1,3(2H)-dione in 250 mL absolute ethanol was added 6.0 mL hydrazine. The solution was heated to reflux for 100 minutes. A white precipitate formed. The reaction was allowed to cool to room temperature and was filtered to remove the precipitate. Concentration of the filtrate gave a gummy paste which was taken up in ethyl acetate and washed once with brine and twice with 100 mL 1N hydrochloric acid. The combined acidic aqueous layers were basified with 1N sodium hydroxide and extracted three times with ethyl acetate. The combined organic extracts were dried and the solvent was removed to afford an oil. The oil was diluted with dry ether and 30 mL of 1N hydrochloric acid in ether was added. The resulting white precipitate was collected by filtration and dried to give the title compound of Step B as a white powder: mp 127–130° C., 1H NMR (Me2SO-d6) δ 1.30 (d, 3H), 3.60 (m, 1H), 4.22 (m, 2H), 6.80 (m, 1H), 7.22 (m, 2H), 8.30 (br s, 3H).
Reaction SMILES: [CH:1](/[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Br:25][CH2:26][CH2:27]Br>C(C(C)=O)C(C)C>[Br:25][CH2:26][CH2:27][O:18][C:15]1[CH:14]=[CH:13][C:12](/[CH:1]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:17][CH:16]=1
Reactant: BrCCBr
Reactant: CCCCCCCCC/C=C\c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCCCCCCCC/C=C\c1ccc(OCCBr)cc1
Yield: 40.8 %

Procedure:
4-[(Z)-1-Undecenyl]phenol, (2.30 g, 9.30 mmol) and anhydrous potassium carbonate, (1.93 g, 14.0 mmol) in methyl isobutyl ketone (100 ml) were stirred and treated with 1,2-dibromoethane, (5.27 g, 29 mmol). The mixture was refluxed for 24 h after which time a further aliquot of 1,2-dibromoethane, (5.27 g, 28 mmol) was added. The mixture was refluxed a further 24 h, then cooled and washed with water, (twice). The organic phase was dried, (MgSO4), and evaporated in vacuo to an oil. Purification by column chromatography on silica gel, eluting with n-hexane then dichloromethane gave 1.34 g (41%) of the title compound as a white crystalline solid mp 40°-1° C. νmax (mull) 1510, 1573 (weak) 1610 cm-1, δ (CDCl3) 0.86 (3H, distorted t, terminal CH3), 1.26 (14H, m, (CH2)7), 2.26 (2H, m, allylic CH2), 3.60 (2H, t, J 6 Hz, CH2Br), 4.26 (2H, t, J 6 Hz, OCH2) 5.56 (1H, d.t, Jd 12 Hz, Jt 7 Hz, =CH--alkyl), 6.32 (1H, d, J 12 Hz, ArCH=), 7.06 (4H, ABq, Δν 33 Hz, J 9 Hz, C6H4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:14].[F:16][C:17]([F:29])([F:28])[CH:18](OS(C(F)(F)F)(=O)=O)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][CH:18]([CH3:19])[C:17]([F:29])([F:28])[F:16]
Reactant: CC(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C(F)(F)F
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 21.7 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid methyl ester (WO 2002074774), 32.5 mmol trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester [212556-43-9] and 43.4 mmol potassium carbonate in 87 ml DMF was stirred at 80° C. for 48 hours. After cooling to room temperature, the mixture was concentrated in vacuo, resuspended in water and stirred for 1 hour. Filtration yielded the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([S:12][CH3:13])[N:6]=1)[CH2:2][CH:3]=[CH2:4].CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCOCC1>[CH2:1]([C:5]1[N:6]=[C:7]([S:12][CH3:13])[N:8]=[C:9]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:10]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCc1cc(Cl)nc(SC)n1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=CCCc1cc(N2CCOCC2)nc(SC)n1
Temperature: 80 °C

Procedure:
To a solution of 4-(3-buten-1-yl)-6-chloro-2-(methylthio)-pyrimidine (26.66 mmol) and DIPEA (5.1 mL, 29.33 mmol) in 1,4-dioxane (100 mL) at room temperature was added morpholine (2.6 mL, 29.33 mmol). The reaction mixture was stirred and heated at 80° C. overnight. After the reaction was completed, the volatiles were removed by evaporation in vacuo. The residue was purified by column chromatography (hexane/EtOAc=8:1 to 4:1) to provide the title compound. MH+266.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.S(=O)(=O)=O.N1C=CC=CC=1.C(N(CC)CC)C>CS(C)=O>[O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
A solution of the sub-title product of step (i) (17.9 g) in DMSO (100 mL) was added dropwise over 15 minutes to a solution of pyridine sulphur trioxide (44.7 g) and triethylamine (39.3 mL) in DMSO (200 ml) at 0° C. (slight exotherm to 5C). The mixture was warmed to RT after 5 minutes and stirred for 16 hours. The mixture was poured into ice/water and extracted twice with ethyl acetate. The combined organics were washed with brine, dried over is sodium sulfate and concentrated in vacuo to give crude product. The crude product was purified by flash silica chromatography, elution 100% dichloromethane. Pure fractions were evaporated to dryness to afford the sub-title product (17.9 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1.ClC(Cl)(Cl)C(Cl)=O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)([C:25]([OH:27])=[O:26])O>C(OCC)C>[F:11][C:2]([F:1])([F:10])[CH2:3][CH2:4][C:5]1[NH:6][C:7]([C:25]([OH:27])=[O:26])=[CH:8][CH:9]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: FC(F)(F)CCc1ccc[nH]1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)c1ccc(CCC(F)(F)F)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
2-(3,3,3-Trifluoro-propyl)-1H-pyrrole (8.15 mmol, 1.33 g) was added to a solution of trichloroacetyl chloride (8.15 mmol, 0.91 ml) in diethyl ether (10 ml). The resulting solution was held at room temperature for 1 h, then concentrated under reduced pressure. The resulting solid was dissolved in 1:1 dioxane-water (20 ml), treated with lithium hydroxide (24.5 mmol, 0.59 g), and heated to reflux for 30 minutes. After cooling to room temperature, the solution was acidified with saturated aqueous citric acid (20 ml), then extracted with ethyl acetate (2×50 ml). The combined organics were concentrated under reduced pressure. Purification of the resulting solid by silica gel chromatography provided 1.15 g (68%) of 5-(3,3,3-trifluoropropyl)-1H-pyrrole-2-carboxylic acid. 1H NMR (CDCl3) δ 9.33 (1H, br s), 6.99 (1H, dd, J=3.7, 2.5), 6.07 (1H, t, J=3.3), 2.96-2.89 (2H, m), 2.55-2.39 (2H, m).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:16]([N:17]=2)=[CH:15][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=2[CH:7]=3)[CH2:3][CH2:2]1.[Cl:18][CH2:19][CH2:20][CH2:21][S:22][C:23]1[N:24]([CH3:39])[C:25]([C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]3)=[N:26][N:27]=1>>[ClH:18].[CH:1]1([C:4]2[O:5][C:6]3[C:16]([N:17]=2)=[CH:15][C:9]2[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][CH2:21][S:22][C:23]4[N:24]([CH3:39])[C:25]([C:28]5[CH:37]=[CH:36][CH:35]=[C:34]6[C:29]=5[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]6)=[N:26][N:27]=4)[CH2:13][CH2:14][C:8]=2[CH:7]=3)[CH2:3][CH2:2]1
Reactant: c1c2c(cc3oc(C4CC4)nc13)CCNCC2
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(C7CC7)oc6cc5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-cyclopropyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.46 mmol) and 5-{5-[(3 chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (0.544 mmol) and was obtained as a yellow solid (0.19 mmol).