Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([CH2:17][C:18](=O)[CH3:19])/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10].[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[C:21]([CH:23]([CH:18]([CH3:19])[CH2:17][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22]
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)C(C)CC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
In 200 ml. of benzene was dissolved 50 g. of geranyl acetone, and then 42 g. of ethyl cyanoacetate, 6 g. of ammonium acetate and 6 g. of acetic acid were added to the solution. The mixture was then refluxed for 8 hours while removing the produced water. The reaction mixture was washed with water and dried. To this was added dropwise a solution of 5.7 g. of sodium borohydride in 40 ml. of ethanol, under stirring and at 10°-20° C. The stirring was continued for 1 hour. Then, 60 ml. of 10% acetic acid was added to the reaction mixture, and the mixture was subsequently washed with water and dried. The solvent was then removed by evaporation and the residue was purified by silica gel column chromatography to obtain 59 g. of the desired oily product.
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:9])[S:6][C:7]=1[CH3:8].N1C=CC=CC=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+]>C(OC(=O)C)(=O)C>[C:16]([NH:2][C:3]1[N:4]=[C:5]([Br:9])[S:6][C:7]=1[CH3:8])(=[O:18])[CH3:17]
Reactant: Cc1sc(Br)nc1N
Reactant: CC(=O)[O-]
Agent: Br
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(Br)sc1C
Reaction time: 1 h
Yield: 50 %

Procedure:
A suspension of 4-amino-2-bromo-5-methylthiazole hydrobromide (50 mM, 13.7 g) in acetic anhydride (100 ml) was treated dropwise with pyridine (10 ml) while cooling in an ice bath. After stirring for 1 hour the reaction mixture was poured onto 20% aqueous sodium acetate (1 l) and the aqueous solution extracted with dichloromethane (3×500 ml.). The combined organic layers were dried and evaporated under reduced pressure to give an oil which crystallised on trituration with ether. The crude product was recrystallised from ethanol to give the 4-acetamido-2-bromo-5-methylthiazole (11.7 g, 50%). mp 129°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][NH:29][CH3:30])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:31]([OH:35])(=O)[CH2:32][OH:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:30])[C:31](=[O:35])[CH2:32][OH:33])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(O)CO
Reactant: CNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN(CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 100 %

Procedure:
The procedure described in Example 85 was repeated using N-[3-chloro-4-(pyridiN-2-ylmethoxy)phenyl]-3-[2-(methylamino)ethoxy]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 24) and glycolic acid to give the title compound in 100% yield; Mass Spectrum: 483.8 (M+/retention time 1.30 minutes).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C)C=O>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=[C:15]2[N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
Alternately, combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.7 g, 5.37 mmol) and dimethylformamide (40 mL). Add sodium hydride (0.23 g, 60% n in oil, 5.75 mmol). After 15 minutes, add 4-fluorobenzyl bromide (0.73 mL, 5.86 mmol). After 18 hours, partition the reaction mixture between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer five times with water and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(4-fluorobenzyl-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.42 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.C1COCC1.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Yield: 47.3 %

Procedure:
3.3 g (12 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester were dissolved in 15 ml of ethanol and 5 ml of THF. Over this solution, 3.3 g of Pd over carbon at 10% were added. The crude mixture was hydrogenated at 30 psi for 48 hours. The catalyst was filtered off and the solvent removed under reduced pressure affording 1.55 g (54%) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester.
Reaction SMILES: [CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[C:15](I)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:37])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[CH:40]1([Zn+])[CH2:43][CH2:42][CH2:41]1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:40]1([C:15]2[C:14]3[CH:13]=[C:12]([O:11][CH2:10][C:9]4[CH:33]=[CH:34][C:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[C:7]([C:35]([F:38])([F:37])[F:36])[CH:8]=4)[CH:20]=[CH:19][C:18]=3[N:17]3[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C:16]=23)[CH2:43][CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reactant: [Zn+]C1CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CCn2c1c(C1CCC1)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 70 °C
Yield: 39.1 %

Procedure:
tert-Butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (50 mg, 0.078 mmol) was dissolved in THF (1.0 mL) in a heavy walled sealed microwave tube (0.5-2.0 mL) under N2. Cyclobutylzinc(II) bromide (0.156 mL, 0.078 mmol) and bis(tri-t-butylphosphine)palladium(0) (3.60 mg, 7.04 μmol) were added. The reaction mixture was heated to 70° C. for 2 h, quenched with saturated NaHCO3 and filtered through Celite®. The filtrate was then extracted with EtOAc (3×5 mL). The organic layers were combined and washed with saturated NaCl (10 mL), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to provide the title compound as an amber oil (17.3 mg). LCMS m/z=568.8 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH:2]=[CH2:3].[Br:10][C:11]1[C:12](Cl)=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH2:1]([N:4]([C:12]1[C:11]([Br:10])=[CH:16][N:15]=[C:14]([Cl:17])[N:13]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH:2]=[CH2:3]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C=CCNC(CC)CC
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(c1nc(Cl)ncc1Br)C(CC)CC
Reaction time: 8 h

Procedure:
To a solution of allyl-(1-ethyl-propyl)-amine (10 mmol) is added anhydrous isopropanol (50 ml) and 5-bromo-2,4-dichloropyrimidine (2.979 g, 5 mmol) followed by diisopropylethylamine (2.61 ml, 15 mmol) at ambient temperature. The reaction is stirred overnight and concentrated in vacuo. The residue is purified with column chromatography (SiO2, 1:5 EtOAC/Hexane) to give the desired product.
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]>C1COCC1>[C:9]1([PH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Product: c1ccc(Pc2ccccc2)cc1
Reaction time: 18 h

Procedure:
A THF solution (150 ml) containing chlorodiphenylphosphine (60 g, 0.34 mole) was added dropwise from a dropping flask, and under nitrogen atmosphere to a stirred THF (75 ml) suspension of lithium metal (5 g, 0.7 moles) in a 500 ml round bottom flask. Formation of lithiodiphenylphosphide was indicated by the appearance of a bright red color. After stirring 18 hours, unreacted lithium was removed and the solution was added slowly to a rapidly stirred THF slurry of the brominated resin beads (32 g, 35 percent Br, 131.3 mmol Br). This slurry was allowed to stir two days under nitrogen (longer if high percent Br content resin used). The slurry was then hydrolyzed by adding it to two liters of nitrogen-saturated acetone/water (3:1) and stirring for one hour. The beads were then filtered and washed by stirring successively in one liter each of the following nitrogen-saturated solvents: water (2 hours), acetone (2 hours), benzene/methanol (9:1) (18-24 hours), and methanol (4-5 hours). The beads were then vacuum dried (80° C., 0.05 torr) for 24 hours, and analyzed for 6.44 percent P which corresponds to 35.0 percent of the polystyryl rings substituted with the diphenylphosphide moiety.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:16]([O:18]CC)=O)=[C:5]([C:11](OCC)=[O:12])[NH:6]2.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[C:3]2[C:4]3[C:16](=[O:18])[N:23]=[N:22][C:11](=[O:12])[C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1[nH]c2cccc(Br)c2c1C(=O)OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1N=NC(=O)c2c1[nH]c1cccc(Br)c21
Temperature: 25 °C
Yield: 88 %

Procedure:
To a stirred solution of diethyl 4-bromoindole-2,3-dicarboxylate (0.4 g, 1.2 mM) in ethanol (3 mL) was added hydrazine hydrate (2.0 mL, 40 mM). The mixture was heated to reflux for 2 hours, cooled to room temperature, and the resulting solid was filtered. This was then suspended in glacial acetic acid (3 mL), heated to reflux for several minutes, and cooled to room temperature. The solid was then filtered and dried. This afforded the titled compound as a white solid (0.3 g, 88%), mp >260° C. NMR (d6 -DMSO): 12.8 (br s, 1H), 11.52 (br s, 2H), 7.60 (d, J=8 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.32 (t, J=8 Hz, 1H). MS(CI): 280(M+1).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](=[O:29])[CH3:28]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:10]([N:4]1[CH2:3][CH:25]([C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])[CH:26]([C:27](=[O:29])[CH3:28])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)/C=C/c1ccc(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.8 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (7.82 g, 32.9 mmol) in CH2Cl2 (40 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-4-(2,4-difluoro-phenyl)-but-3-en-2-one (4.0 g, 21.9 mmol) and trifluoroacetic acid (0.17 mL, 0.21 mmol) in CH2Cl2 (10 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, CH2Cl2/MeOH 98:2) afforded 6.2 g (89%) of the title compound as a yellow oil. ES-MS m/e: 316.1 (M+H+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH:19][CH2:20][C:21]1[CH:42]=[CH:41][C:24]([C:25]([O:27][N:28]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:33][CH:32]=2)[NH2:30])=O)=[CH:23][CH:22]=1.C1COCC1>C(OCC)(=O)C>[CH2:37]([C:34]1[CH:35]=[CH:36][C:31]([C:29]2[N:30]=[C:25]([C:24]3[CH:41]=[CH:42][C:21]([CH2:20][OH:19])=[CH:22][CH:23]=3)[O:27][N:28]=2)=[CH:32][CH:33]=1)[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)Cc1ccc(C(N)=NOC(=O)c2ccc(CO)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(-c2noc(-c3ccc(CO)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.8 %

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in THF, 10 mL) was added to a solution of N′-{[4-(hydroxymethyl)benzoyl]oxy}-4-isobutylbenzenecarboximidamide (3.07 g, 9.42 mmol) and THF (50 mL) and stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.33 g, 46% yield) as a crude solid.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35]N)=[CH:31][CH:30]=1>>[CH3:24][CH:23]([CH3:25])[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]3[C:33]4[C:32](=[CH:31][CH:30]=[C:29]([CH3:28])[CH:34]=4)[NH:35][CH:2]=3)[CH2:14][CH2:13]2)[CH:16]=1)=[O:26]
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCCO3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]cc(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 404.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[C:17](OC)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O1CCCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:21])[C:18]([CH3:20])=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3
Reactant: COc1ccc2[nH]c3cc(Br)ccc3c2c1
Reactant: C=C(C)C(=O)OC
Solvent: C1CCOC1
Product: COc1cc2c(=O)c(C)cn3c4cc(Br)ccc4c(c1)c23
Yield: 95 %

Procedure:
2-bromo-6-methoxycarbazole (4 g) produced in Example 101, step 4 was dissolved in anhydrous tetrahydrofuran (32 ml), and to the solution were added methyl methacrylate (12.4 ml) and then Triton B (1.12 ml). The mixture was heated under reflux in an argon atmosphere for 1 hour, and the solvent was evaporated under reduced pressure. The resulting residue was suspended in methanol (40 ml), and sodium hydroxide (1 g) dissolved in water (13 ml) was added dropwise to the solution at room temperature, and the mixture was heated under reflux for 4 hours. The solvent was evaporated under reduced pressure, and water and ether were added for phase separation. The aqueous layer was rendered acidic by addition of 1N hydrochloric acid, and ethyl acetate was added for extraction. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane and recovered by filtration to obtain the title compound (4.0 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[C:14]([F:13])([F:23])[F:24])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: COC(=O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(F)ccc1OCc1ccccc1C(F)(F)F
Yield: 56 %

Procedure:
A solution of 7.50 g (44.08 mmol) of methyl 5-fluoro-2-hydroxybenzoate in 40 ml of dry acetonitrile is mixed with 9.44 g (48.49 mmol) of 2-trifluoromethylbenzyl chloride and 18.28 g (132.25 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then cooled, filtered, washed with dichloromethane and concentrated, and the residue is purified by chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 5:1). 9.18 g (28 mmol, 89% purity, 56% yield) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.[F:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1>C1COCC1>[Cl:22][C:5]1[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)=[CH:7][C:2]([NH:1][C:33]([NH:32][C:27]2[CH:28]=[C:29]([F:31])[CH:30]=[C:25]([F:24])[CH:26]=2)=[O:34])=[C:3]([F:23])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: O=C=Nc1cc(F)cc(F)c1
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2Cl)cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A solution of Example A3 (0.20 g, 0.568 mmol) in THF (6 mL) was treated with TEA (0.098 mL, 0.710 mmol) followed by 3,5-difluorophenyl isocyanate (0.092 g, 0.596 mmol) and stirred at RT for 2 h. Additional 3,5-difluorophenyl isocyanate (0.14 g, 0.903 mmol) was added and the mixture stirred at RT overnight. More 3,5-difluorophenyl isocyanate (0.25 g, 1.61 mmol) was added and the mixture stirred at RT for 24 h. The mixture was cooled to 0° C. and the solids collected via filtration and dried. The filtrate was concentrated to dryness and purified via silica gel chromatography (THF/Hex) and combined with the isolated solid to afford 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea (177 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.27 (br s, 2H), 8.79 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.57 (d, J=10.9 Hz, 1H), 7.16 (m, 2H), 6.77 (m, 1H), 4.27 (q, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 507.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].I.[CH3:10][S:11][C:12](=[NH:18])[NH:13][N:14]=[C:15]([CH3:17])[CH3:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[NH:18][CH:12]([S:11][CH3:10])[N:13]([N:14]=[C:15]([CH3:17])[CH3:16])[C:3]1=[O:4]
Reactant: CSC(=N)NN=C(C)C
Reactant: CN(C(=O)Cl)C(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CSC1NC(=O)N(C)C(=O)N1N=C(C)C
Yield: 75.1 %

Procedure:
15.6 g (0.1 mole) of N-methyl-bis-(chlorocarbonyl)-amine were dissolved in 100 ml of benzene and added dropwise, whilst stirring, to 27.3 g (0.1 mole) of acetone-S-methyliso-thio-semicarbazone hydroiodide suspended in 100 ml of benzene. Thereafter, 30.3 g (0.3 mole) of triethylamine in 50 ml of benzene were slowly added dropwise. The mixture was stirred for a further hour and the precipitate was filtered off. The precipitate was introduced into 100 ml of chloroform and 100 ml of water and extracted by shaking. The chloroform phase was separated off, dried over calcium chloride and evaporated in vacuo, together with the benzene filtrate. The resudue was recrystallized from isopropanol. 17.3 g (76%) of 1-methyl-3-isopropylideneamino-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione were obtained as a colorless powder; melting point 130-132° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Br:13]Br>C(Cl)(Cl)Cl>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([C:2](=[O:3])[CH2:1][Br:13])=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Yield: 65.9 %

Procedure:
In 200 ml of chloroform was dissolved 8.25 g of 4-nitroacetophenone, and 20 ml of a chloroform solution containing 8 g of bromine was added dropwise thereto under cooling. The resulting reaction mixture was concentrated, and the residue (concentrate) was recrystallized from chloroform/ether, collected by filtration, washed, and dried to obtain 8.03 g of p-nitrophenacyl bromide.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1>>[Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ncccc2Br)cc1
Reactant: Cc1cccnc1Br
Product: Cc1cccnc1Nc1ccc(Oc2ncccc2Br)cc1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
To a 35 ml pressure vessel was added 4-(3-bromopyridin-2-yloxy)aniline (0.7095 g, 2.68 mmol) and 2-bromo-3-methylpyridine (0.575 mL, 3.35 mmol) to stir at 160° C. for 3 hours. Upon completion, the crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-bromopyridin-2-yloxy)phenyl)-3-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 356.0.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][C@H:13]3[C:18]([O:19][CH3:20])=N[C@H](C(C)C)C(OC)=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=[O:27].C([O-])(O)=O.[Na+]>C(#N)C>[CH3:20][O:19][C:18](=[O:27])[C@@H:13]([NH2:14])[CH2:12][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:11][N:10]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](N)Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 1 (3.25 g, 8.51 mmol) in acetonitrile (183 ml) was treated with TFA (90 ml, 2 M in water) and stirred at RT overnight. After complete conversion the mixture was neutralized with sat. aq. NaHCO3-solution, the majority of the acetonitrile was evaporated and the remainder extracted with ethyl acetate. The combined organic phases were washed with brine, dried with MgSO4, filtered and evaporated to dryness. The resulting crude oil (2.5 g) was used in the next steps without further purification.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29]>O>[Br:1][C:2]1[N:10]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reaction time: 3 h

Procedure:
50 g of 8-bromo-3-methyl-3,7-dihydropurine-2,6-dione are introduced into 900 ml of DMF, and 14.1 g of potassium carbonate are added. The suspension is heated to an internal temperature of 60° C., and 31.7 g of 1-bromo-3-methyl-2-butene are slowly added. The mixture is stirred at this temperature for 3 hours and then 1.2 l of water are added. The solid is filtered off with suction, thoroughly washed with water and dried in vacuo at 45° C.