Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9]O2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.C(=O)([O-])[O-].[Na+].[Na+].[C:31]([OH:34])(=[O:33])[CH3:32]>>[C:31]([O:34][CH2:9][CH2:10][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:33])[CH3:32]
Reactant: c1ccc(C2CCOC2(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
30.0 g of 2,2,3-triphenyltetrahydrofuran are dissolved in 125 ml of acetic acid, after which 25 ml of 40% hydrogen-bromide in acetic acid are added. The mixture is stirred for 1 h at 75° C. The solvent is evaporated,and 1M sodium carbonate solution is added in excess. The product is extracted in toluene. The toluene solution is dried over sodium sulfate and the solvent is evaporated. The product is recrystallized from aqueous methanol and then has m.p 81-3° C. The yield is 28.7 g (84%).
Reaction SMILES: [CH:1]([NH:4][C:5](=[NH:7])[CH3:6])([CH3:3])[CH3:2].Br[C:9](=[CH:13]OC)[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH3:6])=[N:7][CH:13]=1)(=[O:12])[CH3:11]
Reactant: COC=C(Br)C(C)=O
Reactant: CC(=N)NC(C)C
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)c1cnc(C)n1C(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 16.2 g (0.162 mol) of N-isopropylacetamidine (which was prepared in the above-mentioned Reference Example 1), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours, for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was distilled under reduced pressure (0.4 kPa, 85° C.) to give 10.9 g (yield: 61%) of 5-acetyl-1-iso-propyl-2-methylimidazole as pale yellow liquid.
Reaction SMILES: [N:1]([CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=2[C:6]2[C:22]([CH3:25])=[N:23][O:24][C:5]1=2)=[N+]=[N-].CP(C)C>[Cl-].[Na+].O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=3[C:6]3[C:22]([CH3:25])=[N:23][O:24][C:5]=3[CH:4]([NH2:1])[N:10]=2)=[CH:12][CH:13]=1
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2N=[N+]=[N-]
Agent: CP(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2N
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A round bottomed flask containing crude 4-azido-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine (1.05 g, 3.0 mmol), was purged with nitrogen and diluted with THF (30 mL) and water (6 mL). Trimethylphosphine (6.03 mL, 6.0 mmol, 1M in toluene) was added dropwise. The solution was stirred at ambient temperature for 2 h. The reaction was poured into half-saturated brine (100 mL), extracted with EtOAc (3×), dried over Na2SO4, filtered, concentrated and purified on a Biotage system (isocratic elution 65% EtOAc: 35% Hexanes) to provide the title compound as an oil (0.44 g). LC/MS m/z 324 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:27])=[CH:25][CH:26]=2)[NH2:23])=[C:13]([CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:12]=1[OH:36])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[C:24]([CH3:27])=[CH:25][CH:26]=2)=[C:13]([CH2:30][CH2:31][C:32]([F:34])([F:33])[F:35])[C:12]=1[OH:36])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(OCCCOc2ccc(C)c(N)c2)c(CCC(F)(F)F)c1O
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1cc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)ccc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1.9 ml (21 mmol) of methyl chlorooxalate in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 7.5 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methylaniline and 3.0 g of triethylamine in 60 ml of methylene chloride in the course of about 5 minutes. The reaction mixture is subsequently stirred at room temperature for 90 minutes and poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether gives methyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methylphenyl}}-oxamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[O:26][CH:25]=[N:24][C:23]=1[C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:23]3[N:24]=[CH:25][O:26][C:22]=3[CH3:21])=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1ocnc1C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1ocnc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-4-oxazolecarboxylic acid as starting materials, MS (LC/MS): 412.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]2[CH3:20])=[N:4][C:5]([Cl:9])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[F:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[F:36])[NH2:32]>C(O)C(O)C.ClCCl>[ClH:9].[CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]2[CH3:20])=[N:4][C:5]([NH:32][C:31]2[CH:33]=[CH:34][C:35]([F:36])=[C:29]([F:28])[CH:30]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: Nc1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CC(O)CO
Solvent: ClCCl
Product: Cc1nc(Nc2ccc(F)c(F)c2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Temperature: 140 °C
Reaction time: 18 h
Yield: 13.8 %

Procedure:
To the solution of 5,6-dimethyl-2-chloro4-(1-methyl- 1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.5 g, 1.74 mmol) prepared in accordance with WO 96/05177 in propylene glycol (2 ml), were added triethylamine (0.3 ml, 2.09 mmol) and 3,4-difluoroaniline (0.2 ml, 2.09 mmol). The reaction mixture was heated to 140° C., stirred for 18 hours, and cooled to room temperature. The resulting solution was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography (eluent: ethyl acetate/hexane =⅓), and then treated with ethyl ether solution saturated with hydrochloric acid to afford 0.1 g (13.8%) of the titled compound.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.[CH2:64]([N:71]1[CH2:76][CH:75]=[C:74]([C:77]([F:80])([F:79])[F:78])[CH2:73][CH2:72]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.C(O)(C)(C)C.[OH2:86]>>[CH2:64]([N:71]1[CH2:72][CH2:73][C@@:74]([C:77]([F:80])([F:78])[F:79])([OH:86])[C@@H:75]([OH:22])[CH2:76]1)[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: O
Reactant: FC(F)(F)C1=CCN(Cc2ccccc2)CC1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Product: O[C@H]1CN(Cc2ccccc2)CC[C@]1(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
43.80 g of AD-Mix-Beta was placed in 3000 mL of tert-butanol/water (1:1) and stirred for 20 minutes at RT. The mixture was cooled to 0° C., 2.97 g (31.25 mmol) of methanesulfonamide and 7.54 g (31.25 mmol) of 1-benzyl-4-trifluoromethyl-1,2,3,6-tetrahydropyridine were added, the cooling bath was removed, and the mixture was stirred for 8 days at RT. Another 22 g of AD-Mix-Beta and 1.5 g of methanesulfonamide were added and the mixture was again stirred for 7 days at RT. 11.2 g of sodium sulfite was added and the mixture was stirred for 1 hour. 200 mL of semisaturated aqueous sodium bicarbonate solution was added and the aqueous phase was exhaustively extracted with DCM. The combined organic phases were dried over sodium sulfate and evaporated down in vacuo. The crude product was purified by MPLC-MS (Grom-Sil 120 ODS 4, 10 μm, gradient 0.15% formic acid in water/acetonitrile 90:10→10:90 in 10 minutes). The eluates were combined, evaporated down in vacuo, and neutralized with 100 mL of semisaturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over sodium sulfate and evaporated down in vacuo. Yield: 1.51 g (17% of theoretical); C13H16F3NO2 (M=275.267); calc.: molpeak (M+H)+: 276; found: molpeak (M+H)+: 276; Rf value: 0.40 (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[CH:23]=[CH:24][CH2:25]Br)#[N:19].CCOCC>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:25][CH:24]=[CH:23][C:22]3[CH:27]=[CH:28][CH:29]=[C:20]([C:18]#[N:19])[CH:21]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: N#Cc1cccc(C=CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1cccc(C=CCN2CCc3nc(N)sc3CC2)c1
Yield: 48 %

Procedure:
Prepared analogously to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 3-cyano-cinnamyl bromide (melting point: 52°-55° C.) in anhydrous dimethylformamide for 2 hours at 20° C. Yield: 48% of theory, Melting point: 136°-140° C. (ether).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)(C)C>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:15]
Reactant: CN=C=S
Reactant: NCCCNc1ccccn1
Solvent: CC(C)O
Product: CNC(=S)NCCCNc1ccccn1
Yield: 60.3 %

Procedure:
A solution of 2-(3-aminopropylamino)pyridine (2.74 g.) and methyl isothiocyanate (1.46 g.) in isopropyl alcohol (50 ml.) was stirred at room temperature for 16 hours. Concentration, followed by trituration of the residue under methyl ethyl ketone gave the crude product which was recrystallised from aqueous ethanol to give N-methyl-N'-[3-(2-pyridylamino)propyl]thiourea (2.45 g.), m.p. 134°-135°. (Found: C, 53.4; H, 7.2; N, 25.0; S, 14.3. C10H16N4S requires: C, 53.5; H, 7.2; N, 25.0; S, 14.3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][C:14]([O-])(C)C.[K+].C(Br)C>CN(C=O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:13][CH3:14])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCBr
Product: CCN1C(=O)CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (750 mg, 3.32 mmol) in 20 ml dry DMF was added potassium tert-butylate (804 mg, 6.64 mmol). After the mixture was stirred for 30 min at room temperature, a solution of ethyl bromide (724 mg, 6.64 mmol) in 10 ml dry DMF was added. Following overnight stirring, the mixture was diluted with 150 ml 1 N HCl. Extraction with ethyl acetate (2×100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 1/1, Rf=0.52) gave 6-bromo-1-ethyl-3,4-dihydro-1H-quinolin-2-one (583 mg, 2.29 mmol, 59%) as a colorless solid.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=1[Cl:19].[CH3:21][S:22]([CH3:24])=[O:23].C1COCC1>C1COCC1>[Cl:19][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3](=[O:20])[CH2:21][S:22]([CH3:24])=[O:23]
Reactant: COC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Reactant: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=O)CS(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
2-[(2,6-Dichloro-3-methylphenyl)amino]benzoic acid methyl ester (3.3 g, 10.6 mmol) is dissolved in 30 ml of dry THF and added to a solution of dimsyl anion (JACS, 84, 866, 1982) (31.9 mmol) in 60 ml of 1:1 DMSO/THF at 0° C. under argon. When addition is complete, the ice bath is removed and the reaction mixture is stirred at room temperature for five hours. The reaction is quenched with 400 ml of 1N hydrochloric acid, and extracted twice with 300 ml of chloroform. The combined chloroform extract is washed with 300 ml of water three times, and once with 300 ml of brine. This chloroform layer is dried over magnesium sulfate and evaporated. The residue solidifies after being dried at room temperature under vacuum for 12 hours. Recrystallization from methylene chloride in hexane gives 1.0 g of 1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-2-(methylsulfinyl)ethanone (26% yield); mp 152°-154 ° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[I-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[C:27]([N+:33]([O-:35])=[O:34])[CH:26]=1>CN(C)C=O>[OH:1][CH2:2][CH:3]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:29][C:28]1[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][C:27]=1[N+:33]([O-:35])=[O:34])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCl
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CO)N(Cc1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 115.5 %

Procedure:
To a solution of 0.289 g (1 mmol) of methyl 3-hydroxy-2-(4-methoxy-benzenesulfonylamino)propionate in 4 ml of N N-dimethylformamide cooled in an ice bath was added 40 mg of NaH (60% in oil) (1 mmol). After the gas evolution ceased, 0.165 g (1.1 mmol) of sodium iodide was added, followed by the addition of 0.226 g (1.1 mmol) of 4-chloro-2-nitrobenzyl chloride in 1 ml of dimethylformamide. The solution became purple and was stirred at room temperature over the weekend. The solvent was removed under vacuum and the residue extracted with CH2Cl2. The extract was washed with H2O, brine and dried with Na2SO4. The solvent was removed to give 0.53 g of solid which was chromatographed on thick layer silica gel plates with hexane-ethyl acetate (2:1) as solvent to give 0.143 g (31%) of product, as crystals, m.p. 112°-114° C. Anal. for C18H19ClN2O8S: Calc'd: C, 47.2; H, 4.2; N, 6.1; Found: C, 47.0; H, 4.1; N, 6.0.
Reaction SMILES: C(O)(=O)C.[CH2:5]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:25]1[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=1)[CH:19]=[CH:18]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Br>O>[CH2:5]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[CH:19]=[CH:18]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCc1ccc2nc(-c3ccc(OC)cc3)ccc2c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCc1ccc2nc(-c3ccc(O)cc3)ccc2c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 70.6 %

Procedure:
To 35 ml of acetic acid, 2.5 g of 6-decyl-2-(4-methoxyphenyl)quinoline and 15 ml of 47%-hydrobromic acid were added, followed by stirring for 12 hours at 100° C. and further stirring overnight at room temperature. After the reaction, the reaction mixture was poured into water and subjected to extraction with chloroform. The organic layer was washed with water and dried with anhydrous sodium sulfate, followed by distilling-off of the solvent and purification by silica gel column chromatography to obtain 1.7 g of 6-decyl-2-(4-hydroxyphenyl)quinoline.
Reaction SMILES: [C:1]1([C:7]2[O:8][N:9]=[C:10]3[CH:15]=[C:14]([CH2:16][C:17]#N)[CH:13]=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:19].[Na+].C(O)C.[OH2:24]>>[C:1]1([C:7]2[O:8][N:9]=[C:10]3[CH:15]=[C:14]([CH2:16][C:17]([OH:24])=[O:19])[CH:13]=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccc2c(-c3ccccc3)onc2c1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1ccc2c(-c3ccccc3)onc2c1
Yield: 66 %

Procedure:
A mixture of 2.9 g (0.012 mole) of crude 3-phenyl-2,1-benzisoxazole-6-acetonitrile, 10 ml of 20% sodium hydroxide, and 75 ml of ethanol was heated at reflux under a nitrogen atmosphere overnight. The dark solution was cooled and poured into 600 ml of water. The mixture was filtered through Celite, treated with charcoal and again filtered. The filtrate was made acidic with concentrated hydrochloric acid and a solid precipitated. The solid was collected by filtration, washed with water, dried, and recrystallized from 2-propanol (charcoal) to give 2.1 g (66%) of brown powder, m.p. 162°-177° C., with decomposition.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34]C)=[O:33])[CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4]>CO.O.O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC(C(=O)O)CC3)ccc2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
NaOH (0.75 mL, 2M, 1.5 mmol) was added to a solution of methyl 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}piperidine-4-carboxylate (173 mg, 0.36 mmol) in 10 mL MeOH—H2O (1:1) at ambient temperature. The reaction mixture was stirred overnight and diluted with water (40 mL). The solvent was concentrated to 40 mL. The resulting solution was neutralized with HCl solution and the product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid. Yield: 60 mg (95%); MS (ESI) (M+H)+=464.0.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25]>CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[CH:3]=[C:4]([NH:8][CH:9]3[CH2:13][CH2:12][NH:11][CH2:10]3)[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ncn2)C1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2cc(NC3CCNC3)ncn2)cc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A neat mixture of tert-butyl 3-(6-chloropyrimidin-4-ylamino)pyrrolidin-1-carboxylate (354 mg, 1.18 mmol) and 3-chloro-4-fluoroaniline (3.03 g, 20.8 mmol) was heated at 140° C. for 21 hours. Upon cooling to ambient temperature, the melt was diluted with EtOAc and the mixture was stirred for 1 hour. A beige, amorphous precipitate was collected, washed with water and dried in vacuo at 50-60° C. giving 292 mg (80%) of N4-(3-chloro-4-fluorophenyl)-N6-(pyrrolidin-3-yl)pyrimidine-4,6-diamine. MS (APCI): (M+1)=308, (M−1)=306.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)=[CH:31][N:30]=1)[CH3:27]>>[CH2:26]([O:28][C:29]1[N:30]=[CH:31][C:32]([CH2:35][N:36]2[CH:40]=[C:39]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:38]=[N:37]2)=[CH:33][CH:34]=1)[CH3:27]
Reactant: CCOc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cn1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CCOc1ccc(Cn2cc(-c3ccc4c(c3)CN(c3cc(N5CCN(C)CC5)nc(N)n3)CC4)cn2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 2-ethoxy-5-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}pyridine. LCMS(M+H)+: m/z=526.4
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=NCC2C=CC=CC=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C(O)=[O:26]>O.C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=[O:26])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=NCc2ccccc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1

Procedure:
A solution of trans-[4-(benzylimino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.50 g, 8.00 mmol) and oxalic acid (0.80 g) in water/THF (50 mL, 1:1) was stirred for 10 h at room temperature. The reaction mixture was concentrated under reduced pressure and methylene chloride (50 mL) was added to the residue. The organic phase was dried and concentrated under reduced pressure to give trans-(4-Formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.3 g, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH:15]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:16]([O:18]CC)=[O:17].Br.[NH:33]1[CH2:37][CH2:36][N:35]=[C:34]1[NH:38][NH2:39]>>[NH:35]1[CH2:36][CH2:37][N:33]=[C:34]1[NH:38][N:39]=[CH:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][CH2:14][C@@H:15]([C:16]([OH:18])=[O:17])[NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[CH:7][CH:6]=1
Reactant: NNC1=NCCN1
Reactant: O=CCCc1ccc(O)cc1
Reactant: CCOC(=O)C(CCBr)NC(=O)OCc1ccccc1
Agent: Br
Product: O=C(N[C@@H](CCOc1ccc(CCC=NNC2=NCCN2)cc1)C(=O)O)OCc1ccccc1
Yield: 8.4 %

Procedure:
The operation is carried out as in Example 1 Stages A, B and C but using 190 mg of 3-(4-hydroxyphenyl)-propanal and 530 mg of ethyl 4-bromo-2-[[(phenylmethoxy)carbonyl]amino]butanoate (Stage A) then, during Sage B, 92 mg of 4,5-dihydro-1H-imidazol-2-yl-hydrazine hydrobromide. 20 mg of expected product is obtained in the form of an E/Z mixture 90/10.