Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[F:16][C:17]([F:27])([F:26])C1C=CC(C=O)=CC=1.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([C:17]([F:27])([F:26])[F:16])=[CH:8][CH:7]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccc(C(F)(F)F)cc1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methylester but using 4-trifluoromethylbenzaldehyde instead 4-fluorobenzaldehyde. 1H-NMR (CDCl3): δ=3.93 (s, 3H); 4.55 (s, 1H); 7.52 (d, 2H); 7.66 (d, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]3[CH:13]=[C:12]([CH3:14])[N:11]=[C:9]3[S:10][C:6]=2[CH:5]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:24]=[O:25]>>[CH:24]([C:13]1[N:8]2[C:9]([S:10][C:6]3[CH:5]=[C:4]([O:3][CH3:2])[CH:16]=[CH:15][C:7]=32)=[N:11][C:12]=1[CH3:14])=[O:25]
Reactant: COc1ccc2c(c1)sc1nc(C)cn12
Reactant: CN(C)C=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)sc1nc(C)c(C=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 100 ml of n-butanol was dissolved 5.0 g of 2-amino-6-methoxybenzothiazole. With heating at 100° C., 25.0 g of propargyl bromide was dropwise added to the solution over 2 hours. The mixture was heated for a further 2 hours. After completion of the reaction, the solvent was evaporated to dryness. After the residue was crystallized with acetone, the crystals were recrystallized from isopropyl alcohol to give 25.1 g of 2-imino-6-methoxy-3-propargylbenzothiazole hydrobromide. The hydrobromide, 24.0 g, was added to sodium ethoxideethanol solution(Na, 2.0 g) followed by refluxing for 1.5 hours. After the reaction mixture was evaporated to dryness, water and ethyl acetate were added to the residue followed by separation. The residue obtained from the ethyl acetate phase was dissolved in ethanol and reacted with hydrochloric acid to convert the same into the hydrochloride. Recrystallization from 95% ethanol gave 17.3 g of 7-methoxy-2-methylimidazo[2,1-b]benzothiazole hydrochloride. The hydrochloride, 17.0 g, was added to a mixture of 10 ml of phosphorus oxychloride and 180 ml of dry dimethylformamide. After stirring at room temperature for one hour, the mixture was heated at 60° C. for 7 hours. The reaction solution was evaporated to dryness and the residue was dissolved in water. The solution was alkalized with potassium carbonate and extracted with chloroform. From the chloroform phase, 14.2 g of 3-formyl-7-methoxy-2-methylimidazo[2,1-b]benzothiazole was obtained. The obtained formyl compound, 3.7 g, was suspended in methanol and treated with 1.0 g of sodium borohydride. The reaction mixture was evaporated to dryness, and the obtained residue was recrystallized from ethanol to give 3.5 g of the title compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH2:10][C:9](=O)[C:8]=2[C:7]([CH3:22])=[CH:6]1)(=[O:4])=[O:3].[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].[ClH:28].Cl.O>C(O)C>[ClH:28].[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][C:13]2[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]([CH3:22])[C:8]=2[C:9](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:10]1
Reactant: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1F)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cn(S(C)(=O)=O)c2c1C(=NNC(=N)N)CC(c1ccccc1F)C2
Yield: 51.8 %

Procedure:
A mixture of 1-methanesulfonyl-3-methyl-6-(2-fluorophenyl)-4,5,6,7-tetrahydroindol-4-one (0.30 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.047 ml), water (0.047 ml) and ethanol (30 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 6-(2-fluorophenyl)-4-guanidinoimino-1-methanesulfonyl-3-methyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 16) (0.2 g) as colorless crystals.
Reaction SMILES: [N:1]1([CH2:15][C:16]2[O:20][C:19]([CH2:21][OH:22])=[N:18][CH:17]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:22][CH2:21][C:19]1[O:20][C:16]([CH2:15][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)=[CH:17][N:18]=1)(=[O:33])=[O:32]
Reactant: OCc1ncc(CN2CCC3(C=Cc4ccccc43)CC2)o1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ncc(CN2CCC3(C=Cc4ccccc43)CC2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a 0° C. stirred solution of [5-(spiro[indene-1,4′-piperidine]-1′-ylmethyl)oxazol-2-yl]methanol (0.15 g, 0.51 mmol) in DCM (10.0 mL) is added triethylamine (0.18 mL, 1.26 mmol) and methane sulphonyl chloride (0.05 mL, 0.61 mmol). The reaction mixture is stirred at 0° C. for 1 hour. The reaction mixture is washed with water (20.0 mL) and brine (10.0 mL), extracted with DCM, dried over Na2SO4, and evaporated to dryness to give the crude product (0.18 g) as a brown liquid.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][CH2:37][C:38]2[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCC>C(Cl)Cl.[Zn]>[Br:1][C:2]([Br:5])=[CH:42][C:41]1[CH:44]=[CH:45][C:38]([CH2:37][CH2:36][C@H:33]2[CH2:32][CH2:31][C@H:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:35][CH2:34]2)=[CH:39][CH:40]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C=O)cc2)CC1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(C=C(Br)Br)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
A mixture of 13.27 g of tetrabromomethane, 10.49 g of triphenylphosphine and 2.62 g of zinc dust in 100 ml of methylene chloride was stirred at room temperature for 24 hours in a sulphonation flask under argon gasification. In so doing, the heterogeneous mixture changed in colour via yellow-green to dark violet and pale violet. A solution of 2.86 g of p-[2-(trans-4-pentylcyclohexyl)ethyl]benzaldehyde in 10 ml of methylene chloride was subsequently added dropwise, the mixture was stirred at room temperature for 4 hours and then poured into 700 ml of pentane. The voluminous precipitate which separated was filtered off (rinsing with pentane), the concentrated filtrate (5.25 g) was digested with 300 ml of pentane, filtered and concentrated. Low-pressure chromatography (0.5 bar) of the residue (4.8 g) on silica gel with 3% ethyl acetate/petroleum ether gave 3.13 g (71%) of β,β-dibromo-p-[2-(trans-4-pentylcyclohexyl)ethyl]styrene as colourless crystals (purity 99.8%); m.p. 47.3° C.
Reaction SMILES: [C:1]([C:9]1[C:10]([O:24][CH2:25][CH3:26])=[C:11]2[CH:17]=[N:16][N:15](CC3OC=CC=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=O>O.COCCOCCOC>[C:1]([C:9]1[C:10]([O:24][CH2:25][CH3:26])=[C:11]2[CH:17]=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1c(C(=O)c2ccccc2)cnc2c1cnn2Cc1ccco1
Agent: O=[Se]=O
Solvent: COCCOCCOC
Solvent: O
Product: CCOc1c(C(=O)c2ccccc2)cnc2[nH]ncc12

Procedure:
1.7 g. of 5-Benzoyl-4-ethoxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine (0.005 mol.) are dissolved in 5 ml. of diethyleneglycol dimethyl ether, 1.1 g. of selenium dioxide are added and the mixture is heated with stirring at 160°. After the addition of 1 drop of water, the temperature is maintained for 1 hour. The mixture is filtered hot and 5-benzoyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine precipitates on cooling. Recrystallization from butanol yields 1 g. (77%). m.p. 195°-197°.
Reaction SMILES: [C:1]([O:4][CH:5]([CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][C:13]=1[Cl:19])[CH2:6][C:7](=[O:9])[CH3:8])(=[O:3])[CH3:2].BrCC(OCC)=O.[Cl-:27].C([Al+]CC)C>C1COCC1.[Zn]>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:27])[C:12]=1/[CH:11]=[CH:10]/[CH:5]1[O:4][C:1](=[O:3])[CH2:2][C:7]([OH:9])([CH3:8])[CH2:6]1
Reactant: CC(=O)CC(C=Cc1ccc(Cl)cc1Cl)OC(C)=O
Reactant: [Cl-]
Agent: CCOC(=O)CBr
Agent: CC[Al+]CC
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC(/C=C/c2c(Cl)cccc2Cl)C1
Reaction time: 5 h
Yield: 92.7 %

Procedure:
A solution of 6-(2,4-dichlorophenyl)-2-oxo-5-hexene-4-yl acetate (1.3 g, 4.3 mmole) and ethyl bromoacetate (0.47 ml, 4.2 mmole) in dry THF (10 ml) was added dropwise to a vigorously stirred slurry of activated zinc dust (490 mg, 7.5 mmole), cuprous bromide (29 mg, 0.2 mmole), diethylaluminum chloride (25% solution in toluene; 1.72 ml, 4.3 mmole) and dry THF (5 ml) under N2 at 20° C. Stirring was continued for 5 hours before quenching with pyridine (3.5 ml). After the addition of water (50 ml) the mixture was extracted with ether (3×80 ml). The combined ether extracts were washed with 1N HCl (2×25 ml), H2O (2×50 ml) and brine, then dried (MgSO4), filtered and evaporated leaving the crude title compound as a pale yellow oil (1.2 g); pmr (CDCl3) δ1.28 (3H, t), 1.33 (3H, t), 2.10 (3H, s).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:36]([C:38]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][N:39]=1)#[N:37]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:29]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:41]3[CH:42]=[CH:43][C:38]([C:36]#[N:37])=[N:39][CH:40]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(C#N)nc2)CC1
Reaction time: 96 h
Yield: 30.6 %

Procedure:
To a mixture of (1,1-dioxo-thiomorpholin-4-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (Example 2, 150 mg, 1.0 eq.), anhydrous copper(II) acetate (131 mg, 2 eq.), pyridine (120 microL, 4 eq.) in dichloromethane (3.5 mL), 2-cyanopyridine-5-boronic acid pinacol ester (247 mg, 3 eq.) was added. The reaction mixture was stirred for 4 days and then concentrated in vacuo. The residue was then purified on silica eluting with dichloromethane/methanol 98:2 v:v. One fraction was isolated and dried in vacuo, to yield 57 mg (23%) of the desired product as light yellow oil. MS (m/e): 522.5 (MH+, 100%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8](Cl)=[O:9])[CH2:3]1.Cl.[CH3:12][NH:13][O:14][CH3:15].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:15][O:14][N:13]([CH3:12])[C:8]([CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1)=[O:9]
Reactant: CNOC
Reactant: CC1CCCC(C(=O)Cl)C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)C1CCCC(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 3-methylcyclohexanecarbonyl chloride (1.13 g, 7.03 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.755 g, 7.74 mmol) in CHCl3 (70 mL) at 0° C. was added pyridine (1.252 mL, 15.48 mmol) dropwise. The ice bath was removed and the mixture was warmed to RT. After 1 h, the reaction was evaporated to dryness, diluted with 1:1 mixture of ether and CH2Cl2 (40 ml) and then washed with brine. The aqueous layer was washed once more with 1:1 mixture of ether and CH2Cl2. The organic layers were combined, dried with MgSO4, filtered, and concentrated to afford the crude N-methoxy-N,3-dimethylcyclohexanecarboxamide (1.1 g, 84% yield) as clear yellowish oil which was used without further purification. MS (ESI) m/z: 186.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.74-3.65 (m, 3H), 3.20-3.14 (m, 3H), 2.71 (m., 1H), 1.85-1.12 (m, 10H), 0.94-0.88 (m, 3H)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31]>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][C:21]=2[N+:30]([O-:32])=[O:31])[CH2:9][CH2:10]1
Reactant: COCCN1CCC(N)CC1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COCCN1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 90 °C

Procedure:
1-(2-Methoxy-ethyl)-piperidin-4-ylamine (2.01 g) and triethylamine (3.24 mL, 2.35 g) were added to 1,4-dioxane (60 mL). 4-Chloro-3-nitrobenzenesulfonamide (2.50 g) was added, and the mixture was heated to 90° C. for 16 hours. The mixture was cooled and the material purified by flash column chromatography on silica gel using 10% methanol in dichloromethane.
Reaction SMILES: CC([O-])(C)C.[K+].S([CH2:17][N+:18]#[C-])(C1C=CC(C)=CC=1)(=O)=O.O[CH:21]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[CH2:23][CH2:22]1>O1CCCC1.C(O)C>[OH:32][CH:29]1[CH2:30][CH2:31][C:24]2([CH2:25][CH2:26][CH:21]([C:17]#[N:18])[CH2:22][CH2:23]2)[CH2:27][CH2:28]1
Reactant: O=C1CCC2(CC1)CCC(O)CC2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#CC1CCC2(CCC(O)CC2)CC1
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Potassium tert-butylate (1.44 g) was added in small portions, at 0° C. under nitrogen atmosphere, to a solution of 1.40 g of tosylmethylisocyanide and 1.00 g of 3-hydroxy-9-oxo-spiro[5.5]undecane (II-a, Prep. 1) dissolved in 7 ml of anhydrous tetrahydrofuran and 0.53 ml of absolute ethanol. After 0.5 hrs at room temperature, the mixture was filtered on an alumina cake. The cake was washed with dichloromethane and the filtrates, dried over anhydrous sodium sulfate, were evaporated under reduced pressure to give 0.52 g of crude 9-hydroxy-3-cyano-spiro[5.5]undecane as a light oil. [TLC: Rf=0.52 (SiO2 plates, diethylether). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 3.63 (1H, hept), 2.57 (1H, m), 1.90-1.05 (16H, m)].
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:22]=[C:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[C:8]1=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1CN
Reactant: O=C1C(=Cc2ccccc2)N2CCC1CC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1ccccc1CN=C1C(=Cc2ccccc2)N2CCC1CC2
Temperature: 116 °C

Procedure:
To a 12 L three neck round bottom flask (3 nrbf) fitted with mechanical stirrer, thermometer, condenser, and Dean Stark trap, was charged 5.9 L toluene, 79I.8 g (3.7 moles) of 2-phenylmethylene-1-azabicyclo[2.2.2]octan-3-one, 764 g (5.6 moles, 1.5 equivalents) 2-methoxybenzylamine, and 8.8 g (0.039 moles) (+)camphor sulfonic acid. The solution was heated to reflux (116° C.) and refluxed for 42 hours. A total of 75 ml water was collected in the Dean Stark trap showing that the reaction was proceeding. The solution containing the title product was cooled to room temperature.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.ClCCl>[C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(NCCCCCCO)OCc1ccccc1
Reaction time: 8 h

Procedure:
6-Aminohexan-1-ol (11.7 g, 100 mmol) and potassium carbonate (16.58 g, 120 mmol) were dissolved in 100 mL water and 70 mL dichloromethane. Benzylchloroformate (14.27 mL, 100 mmol) was added dropwise over 30 minutes at a temperature of 25°-30° C. The resulting mixture stood overnight, then the dichloromethane layer was separated, washed with water (3×200 mL), 2N HCl (3×50 mL) and finally with water (3×100 mL), dried, and evaporated to give a white solid. The solid was recrystallized in hexane-ethylacetate (8:2) to give a solid, which was collected and dried under vacuum at room temperature. Yield: 23 g (91%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]([C:28]([OH:30])=O)=[CH:7][C:8]1[CH:9]=[C:10]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])[CH:11]=[CH:12][C:13]=1[Cl:14].CN(C)C=O>C1(C)C=CC=CC=1>[Br:5][C:6]([C:28]([Cl:3])=[O:30])=[CH:7][C:8]1[CH:9]=[C:10]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[N:17]([CH3:26])[C:16]2=[O:27])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=C(Br)C(=O)O)c2)c1=O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=C(Br)C(=O)Cl)c2)c1=O

Procedure:
1.6 g of thionyl chloride were added to a solution of 4.5 g of 3-[3-(2-bromo-2-carboxyethenyl)-4-chlorophenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine and 0.1 ml of dimethylformamide in 100 ml of toluene. The reaction mixture was heated slowly to the reflux temperature, stirred under reflux for 5 hours and evaporated down, and the residue was dried under greatly reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Sn](C)(C)C)[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[Cl:17].Br[C:19]1[C:27]([F:28])=[CH:26][C:22]2=[N:23][O:24][N:25]=[C:21]2[CH:20]=1.C(OCC)(=O)C.[Na+].[Cl-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:19]2[C:27]([F:28])=[CH:26][C:22]3=[N:23][O:24][N:25]=[C:21]3[CH:20]=2)[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[Cl:17]
Reactant: COC(=O)c1nc([Sn](C)(C)C)c(F)c(N)c1Cl
Reactant: Fc1cc2nonc2cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cc3nonc3cc2F)c(F)c(N)c1Cl
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 18.8 %

Procedure:
Methyl 4-amino-3-chloro-5-fluoro-6-(trimethylstannyl)picolinate (320 mg, 0.86 mmol) and 5-bromo-6-fluorobenzo[c][1,2,5]oxadiazole (170 mg, 0.78 mmol) were combined in 5 mL dry N,N-dimethylformamide, deaerated with a stream of nitrogen for 15 min. Bis(triphenylphosphine)palladium(II) chloride (55 mg, 0.078 mmol) and cuprous iodide (15 mg, 0.078 mmol) were added and the mixture was heated to 70° C. for 4 h. The mixture was shaken with 20 mL ethyl acetate, 10 mL saturated NaCl, dried (Na2SO4) and the residue was chromatographed on silica with a 5-30% ethyl acetate-hexane gradient to give 50 mg of the title compound as a white solid (50 mg, 19%): mp 180-182° C.; 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J=6.2, 0.5 Hz, 1H), 7.54 (dd, J=8.7, 0.5 Hz, 1H), 5.07 (s, 2H), 4.00 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −105.64, −105.72, −137.68, −137.76; ESIMS m/z 341 ([M+H]+), 339 ([M−H]−).
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH3:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1>C(#N)C>[CH:38]1([N:30]2[C:31]3[C:26](=[C:25]([CH3:24])[C:34]([F:35])=[C:33]([N:9]4[CH2:10][CH2:11][CH2:12][CH:7]([N:2]5[CH:6]=[CH:5][N:4]=[N:3]5)[CH2:8]4)[C:32]=3[F:37])[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29]2)[CH2:39][CH2:40]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1cn(C2CCCNC2)nn1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(F)c(N2CCCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reaction time: 66 h
Yield: 47.9 %

Procedure:
3-(1,2,3-triazol-1-yl)piperidine hydrochloride (63 mg, 0.33 mmol) and DBU (77 mg, 0.5 mmol) were added to a suspension of 5-methyl-1-cyclopropyl-6,7,8-trifluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.17 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed under stirring for 66 hrs and then concentrated. The residue was diluted with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 35 mg of desired product. m.p. 227°-228.5° C.; 1H NMR (TFA) δ: 9.35 (s, 1H), 8.53 (s, 1H), 8.65 (s, 1H), 5.30 (m, 1H), 4.60 (m, 1H), 3.55-4.35 (m, 4H), 2.90 (s, 3H), 2.08-2.75 (m, 4H), 1.30-1.55 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=[O:5].[CH3:15][Mg]Br.CO.[NH4+].[Cl-]>C1COCC1>[OH:5][CH:4]([C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:2]([CH3:14])[CH3:1])[CH3:15]
Reactant: CC(C)[C@H](C=O)NC(=O)OC(C)(C)C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(C)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
(R)-tert-butyl 3-methyl-1-oxobutan-2-ylcarbamate (2.5 g, 12.42 mmol) was dissolved in THF (50 mL) and cooled to 0° C. Methyl magnesium bromide (17.0 mL, 51.0 mmol, 3.0 M in diethyl ether) was carefully added via syringe. The reaction was allowed to warm to ambient temperature and left stirring overnight. The cloudy mixture was chilled to 0° C., quenched with methanol (3.0 mL, 74.0 mmol), followed by the addition of 200 mL saturated NH4Cl solution, and extracted twice with 200 mL MTBE. The organic phase was washed with 200 mL brine, dried over Na2SO4, filtered, and concentrated to provide the title compound (2.484 g, 11.43 mmol, 92% yield) as a yellow oil. MS (DCI+) m/z 218.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH2:32](Br)C#C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][C:29]#[CH:32])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: C#CCBr
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: C#CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting propargylbromide and making non-critical variations provided the title compound as a white solid. IR (diffuse reflectance) 3451, 3293, 2964, 2932, 1563, 1493, 1469, 1390, 1204, 1184, 1087, 1076, 820, 742, 646 cm−1; OAMS supporting ions at: ESI+ 465.8; MS (EI) m/z 465 (M+); HRMS (FAB) calcd for C26H25CL2N3O+H1 466.1453, found 466.1455. [α]25D=−56 (c 0.83, methylene chloride). Anal. Calcd for C26H25Cl2N3O: C, 66.96; H, 5.40; N, 9.01. Found: C, 66.96; H, 5.49 N, 8.93.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.CCN(CC)CC.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
2-(4-Bromo-phenoxy)-ethanol (125 g, 0.576 mol) was dissolved in CH2Cl2 (650 mL), and the sol. was cooled to 0° C. Et3N (110 mL, 0.864 mol), then mesyl chloride (67.1 mL, 0.864 mol) were dropped at such a speed that the temperature did not raise above 10° C. (about 60 min). The mixture was stirred at 0° C. for 1 h, then at rt overnight. The mixture was diluted with CH2Cl2, and washed with brine (2×). The aq. phase was extracted back with CH2Cl2. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (174 g, quantitative yield) that was used further without purification. LC-MS: tR=0.92 min.