Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[C:12]([O:14][C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:10][C:9]=1[NH:19][C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)=[O:21].ClCCl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:21]=[C:20]1[N:22]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:8]2[CH:13]=[C:12]([O:14][C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:10][C:9]=2[NH:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc(OC(F)(F)F)cc2Br)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccc(OC(F)(F)F)cc32)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of tris(dibenzylideneacetone)dipalladium (0) (0.33 g), 1,1′-bis(diphenylphosphino)ferrocene (0.21 g), sodium tert-butoxide (1.1 g) in 1,4-dioxane (20 mL) was stirred under an atmosphere of argon for 10 minutes. 1,1-Dimethylethyl 4-{[({2-bromo-4-[(trifluoromethyl)oxy]phenyl}amino)carbonyl]amino}-1-piperidinecarboxylate (D30) (2.7 g) was added and the mixture was heated to 90° C. The mixture was stirred at this temperature overnight. The mixture was poured into dichloromethane which was washed with dilute ammonium chloride, brine and dried over sodium sulphate. The solvent was removed and the residue was chromatographed on silica gel eluted with ethyl acetate/hexane 0-50% to give the title compound as a solid foam. (1.54 g)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([SH:12])[CH:6]=[CH:5]2.Br[CH2:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].Cl>N1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12][CH2:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:6]=[CH:5]2
Reactant: COC(=O)CCCC(=O)CBr
Reactant: Oc1ccc2cc(S)ccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)CCCC(=O)CSc1ccc2cc(O)ccc2c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Into 205 ml (1.16 mmol) of 6-hydroxynaphthalene-2-thiol was charged 5 ml of pyridine, and the mixture was stirred under an ice bath. A solution of 315 mg of methyl 6-bromo-5-oxohexanoate in 2 ml of pyridine was added, and the mixture was stirred under an ice bath for 1 hour. Further, the reaction was carried out at room temperature for 4 hours, by heating to 90° C. for 4 hours, and subsequently stirring was continued at room temperature overnight. The reaction mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>C(#N)C.O>[CH3:11][N:12]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CNc1ccc(O)cc1
Solvent: CC#N
Solvent: O
Product: CN(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Yield: 58.7 %

Procedure:
A mixture of 2-chlorobenzimidazole (1.0 g), 4-(N-methylamino)phenol (1.13 g) and acetonitrile/water (1:1) was heated under reflux for a period of 5 hours. The mixture was concentrated, made basic with dilute ammonium hydroxide and the solid was collected. The product was recrystallised from ethanol to give 4-[N-methyl-N-(2-benzimidazolyl)amino]phenol (0.92 g) as colourless crystals, mp>260° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=[C:9]([NH:16][C:17](=[O:25])OC3C=CC=CC=3)[CH:8]=2)[CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[NH:33][CH2:32][CH2:31]2>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=[C:9]([NH:16][C:17]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([O:27][CH3:26])=[C:36]([C:37]([F:39])([F:40])[F:38])[CH:35]=4)[CH2:31][CH2:32]3)=[O:25])[CH:8]=2)[CH:2]=1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: O=C(Nc1cc2c(c(-c3cccnc3)c1)OCC2)Oc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc3c(c(-c4cccnc4)c1)OCC3)CC2
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Phenyl N-[2,3-dihydro-7-(pyrid-3-yl)benzofuran-5-yl]carbamate (D65) (0.20 g, 0.00060 mole) in dry DMF (10 ml) was treated under argon with 5-methoxy-6-trifluoromethyl indoline (D11) (0.13 g, 0.00060 mole) and heated under reflux for 18 hours. The reaction was allowed to cool to ambient temperature and the solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with deionised water and 10% sodium hydroxide solution, dried (Na2SO4) and evaporated in vacuo. The resulting brown oil was purified by flash column chromatography on silica gel eluting with 2% methanol/dichloromethane, followed by recrystallisation from ethyl acetate 60.80° petroleum ether to afford the title compound (0.07 g, 26%) as a beige solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[NH2:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[OH:21].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]3[OH:21])[S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 115 °C
Reaction time: 96 h
Yield: 76.2 %

Procedure:
To the solution of 2-chloro-6-methoxybenzo[d]thiazole (1.0 g, 5 mmol) in 5.5 ml of NMP was added (1R,2R)-2-aminocyclohexanol hydrochloride (910 mg, 6 mmol) and DIPEA (2.44 ml, 14 mmol). The reaction solution was stirred at 115° C. for 96 hours. The crude reaction solution was purified by prep HPLC to give purified fractions that was combined and neutralized with solid NaHCO3. The resulting solution was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with water (60 ml) and brine (60 ml), then dried over Na2SO4 and evaporated in vaccuo to give (1R,2R)-2-(6-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (1.06 g, 3.81 mmol) as an ivory solid. ES/MS m/z 279.1 (MH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=S)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:21](CC)CC)C>CN(C=O)C.C(OCC)(=O)C.Cl[Hg]Cl>[C:6]([NH:8][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[NH:21])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 129.9 %

Procedure:
To a solution of amine 228 (126 mg, 0.42 mmol), N, N'-bis-tert-butoxycarbonylthiourea (127 mg, 0.46 mmol), and triethylamine (123 μL, 0.88 mmol) in DMF (4 mL) at 0° C. was added HgCl2 (125 mg, 0.46 mmol). The mixture was stirred at 0° C. for 30 min and at room temperature for 1.5 h. The reaction was diluted with ethyl acetate and filtered through celite. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated NaCl, dried (MgSO4), filtered and the solvent was evaporated. The crude product was purified on silica gel (2/1, 1/1-hexane/ethyl acetate) to afford bis-Boc-guanidine 251 (155 mg, 69%) as a solid: 1H NMR (CDCl3) δ 11.40 (s, 1H), 8.66 (d, 1H, J=7.9), 6.8 (s, 1H), 6.22 (d, 1H, J=8.9), 4.43-4.34 (m, 1H), 4.19-4.08 (m, 1H), 4.03 (m, 1H), 3.76 (s, 3H), 3.35 (m, 1H), 2.79 (dd, 1H, J=5.4, 17.7), 2.47-2.36 (m, 1H), 1.92 (s, 3H), 1.50, 1.49 (2s, 18H), 0.89 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][CH3:11])=[CH:5][CH:4]=1)#[N:2].[I:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](Cl)=[C:20]([C:26]([O:28]CC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C(O)CC>C(OCC)(=O)C>[I:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:10]([CH3:11])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[C:26](=[O:28])[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:18]=1
Reactant: CNNc1ccc(C#N)cc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(Cl)c1ccc(I)cc1
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(I)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Yield: 55.9 %

Procedure:
A mixture of 29.34 g of 1-(4-cyanophenyl)-2-methylhydrazine, 65.17 g of ethyl 3-(4-iodophenyl)-3-chloro-2-ethoxycarbonylacrylate, 30.9 g of diisopropylethylamine and 300 ml of 1-propanol was refluxed under heating for 17 hours, then cooled and stirred with 200 ml of ethyl acetate at room temperature for 20 hours. The precipitated crystals were collected by filtration and washed with hexane-ethyl acetate to give 42.21 g of the title compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8].II.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH2:12]([C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cnc(Cl)c(Br)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: CN(C)C=O
Product: Oc1cnc(Cl)c(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Starting material (5-bromo-6-chloropyridin-3-ol) is available from a published 3-step procedure: Synthesis, 1990, 499-501. To an oven-dried flask was added zinc (2.45 g, 37.4 mmol) and a crystal of iodine. The mixture was heated with a heat gun for 10 min under vacuum and then allowed to cool under Ar atmosphere. After charging the flask with degassed DMF (10 mL), the mixture was cooled to 0° C., and benzyl bromide (2.96 mL, 24.9 mmol) was added. After stirring the resulting mixture at 0° C. for 30 min, a mixture of Pd2(dba)3 (0.571 g, 0.624 mmol), S-Phos (1.02 g, 2.49 mmol) and 5-bromo-6-chloropyridin-3-ol (2.60 g, 12.5 mmol) was added to the flask quickly, and then the reaction was flushed with Ar and placed in an oil bath at 60° C. for 4 h or until starting material was gone by LCMS. The reaction was cooled to rt and filtered through a fine fritted funnel. The filtrate was concentrated to afford a yellow oil that was adsorbed onto silica and purified by flash chromatography (25% EtOAc/Hex, ramped to 100% EtOAc). The product was further purified after the column by recrystallization from hexane and minimal cold chloroform to afford a white solid. MS (ESI) m/z: Calculated: 219.1; Observed: 220.0 (M++1).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH:14]3[CH:12]([O:13]3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:17]([CH2:19][NH2:20])[OH:18]>C(O)(C)C>[OH:13][C@H:14]1[C@H:12]([NH:20][CH2:19][CH2:17][OH:18])[CH2:11][N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=2)(=[O:8])=[O:9])[CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)N2CC3OC3C2)cc1
Reactant: NCCO
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)N2C[C@@H](O)[C@H](NCCO)C2)cc1
Temperature: 25 °C

Procedure:
643.7 g (2.65 mol) of 3-(toluene-4-sulphonyl)-6-oxa-3-aza-bicyclo[3.1.0]hexane are refluxed for 16 hours with 318.5 ml of ethanolamine in 4 l of isopropanol. After TLC checking, a further 35.1 ml (altogether 5.86 mol) of ethanolamine are added to the mixture and it is boiled again until the next morning. The mixture is filtered off with suction whilst hot and the filtrate is concentrated to 3.5 ltr in a rotary evaporator. After seeding and stirring at room temperature, 3.5 l of diisopropyl ether are added and the mixture is stirred at 0° C. for 6 hours. The precipitated crystallizate is filtered off with suction, washed with 250 ml of a mixture of isopropanol/diisopropyl ether (1:1) and twice with 300 ml each of diisopropyl ether and dried overnight in a high vacuum.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=4)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:34](=O)[CH3:35].C([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH2:34]([N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH:19]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:21]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1)[CH3:35]
Reactant: N#Cc1ccc(-c2cc(COCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)c2)cc1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3′-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (25.0 mg, 0.05 mmol) and acetaldehyde (0.25 mL, 4.31 mmol) were combined in acetonitrile (2.0 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (14.0 mg, 0.23 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 17 mg (79%). 1H-NMR (CDCl3, 500 MHz) δ 7.74-7.75 (m, 2H), 7.66 (s, 1H), 7.59-7.60 (m, 2H), 7.44 (s, 1H), 7.30-7.39 (m, 5H), 7.18-7.21 (m, 1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.76 (s, 2H), 2.39-2.41 (m, 2H), 2.25-2.32 (m, 4H), 2.07-2.11 (m, 2H), 1.09 (t, J=7.0 Hz, 3H). 13C-NMR (CDCl3, 126 MHz) δ 144.0, 141.0, 140.1, 132.8, 131.7 (q, J=32.6 Hz), 129.0, 128.5, 128.0, 127.4, 126.3, 124.0 (q, J=272.6 Hz), 123.9, 123.0, 118.7, 111.9, 72.2, 52.5, 49.5, 41.4, 32.0, 11.8. Mass spec.: 479.15 (MH)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.[F-].[Cs+].C1(P(C2CCCCC2)C2(OC)CC=CC(OC)=C2C2C=CC=CC=2)CCCCC1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][O:13][CH2:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([F:27])([F:26])[F:15]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COCc1cc(C(=O)OC)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC1=C(c2ccccc2)C(OC)(P(C2CCCCC2)C2CCCCC2)CC=C1
Solvent: O
Solvent: C1COCCO1
Product: COCc1cc(C(=O)OC)ccc1-c1ccccc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 1 Step 2, 8.0 g, 30.8 mmol), 2-(trifluoromethyl)phenylboronic acid (8.8 g, 46.3 mmol), cesium fluoride (14.0 g, 92.4 mmol), palladium acetate (0.69 g, 3.1 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (3.16 g, 7.7 mmol) was prepared in a mixture of dioxane (80 mL) and water (80 mL) under nitrogen atmosphere and heated at 100° C. for 12 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with EtOAc (200 mL), and then washed with water (100 mL) and brine (100 mL). The organic layer was dried (Na2SO4) and concentrated under vacuum. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a pale yellow solid (8.0 g, 88%). 1H NMR (CDCl3, 400 MHz) δ 8.22 (1H, s), 7.99 (1H, d, J=6.5 Hz), 7.78 (1H, d, J=7.7 Hz), 7.57 (2H, m), 7.27 (2H, m), 4.19-4.10 (2H, m), 3.95 (3H, s), 3.26 (3H, s).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9](Cl)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:21]1([CH:28]=[CH:27][CH:26]=[C:24]([OH:25])[CH:23]=1)[OH:22].C[O-].[Na+]>C1S(=O)(=O)CCC1.CO.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:26]3[CH:27]=[CH:28][C:21]([OH:22])=[CH:23][C:24]=3[OH:25])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: Oc1cccc(O)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Temperature: 118 °C
Reaction time: 6 h

Procedure:
A 500 mL three-necked, round-bottomed flask equipped with a mechanical stirrer is charged with 60 g of xylene and 55.5 g (0.207) of 4,6-diphenyl-2-chloro-s-triazine. The mixture is warmed to 118° C. and the pressure is reduced to 300 mbar and 2.8 g of hydrogen chloride gas is charged to the system. The mixture is cooled to 80° C. and a solution of resorcinol (88.2 g, 0.802 mol) in 60 g of tetramethylene sulfone is added dropwise over a 7-minute period. The mixture is stirred at 80° C. for six hours and then for one hour at 100° C. The temperature is reduced to 60° C. and a 300 mL portion of methanol is added. The mixture is allowed to cool to room temperature and is stirred overnight. Sodium methoxide (41.3 g) is added portionwise to adjust the pH to 5.0-5.5. The solids are collected by vacuum filtration and are washed with methanol and water. After drying, the title compound is obtained in a yield of 59.2 g as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]([OH:16])=[O:15].[CH3:17]I.O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:17])[CH:8]=[C:7]2[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CI
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(CC(=O)O)c2cc(Br)ccc21
Reaction time: 1 h

Procedure:
500 mg of a 60% dispersion of sodium hydride in mineral oil were added to solution of 1 g of 5-bromoindole-3-acetic acid in 50 ml of tetrahydrofuran and the mixture was stirred under a nitrogen atmosphere for 1 hour. Thereafter, 820 mg (5.8 mmol) of methyl iodide were added and the mixture was stirred under a nitrogen atmosphere for 24 hours. Then, 5 ml of water were added and the solvent was removed under reduced pressure. The residue was treated with 2M hydrochloric acid and the precipitate formed was filtered off, washed with n-hexane and dried. The obtained solid was recrystallized from diethyl ether to give 5-bromo-1-methyl-3-indolylacetic acid of melting point 192°-194° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[S:10])[NH2:9])[CH3:2].Br[CH:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C(#N)C>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:12]2[N:9]=[C:8]([C:4]3[N:3]([CH2:1][CH3:2])[CH:7]=[CH:6][CH:5]=3)[S:10][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:28][CH:27]=1
Reactant: CCn1cccc1C(N)=S
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Solvent: CC#N
Product: CCn1cccc1-c1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 77 %

Procedure:
1-Ethylpyrrole-2-carbothioamide obtained in Reference Example 1 (1.85 g, 12 mmole) and α-bromo-4,4'-dimethoxydeoxybenzoin (cf. Aust. J. Chem., 8, 385, 1955) (4.02 g, 12 mmole) are dissolved in acetonitrile (120 ml), and the mixture is stirred at 60° C. for 50 minutes. After the reaction, the mixture is distilled under reduced pressure to remove the solvent. To the residue are added chloroform and aqueous sodium carbonate, and the mixture is shaken. The chloroform layer is taken, and the aqueous layer is further extracted with chloroform. The chloroform layers are combined, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue is recrystallized from n-hexane to give 4,5-bis(4-methoxyphenyl)-2-(1-ethylpyrrol-2-yl)thiazole (3.6 g, yield: 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(OC)c(F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncccc2-c2nc(C)nc(N)n2)cc1F
Yield: 4.6 %

Procedure:
A solution of 4-(2-(3-fluoro-4-methoxyphenylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.1253 g, 0.221 mmol) in TFA (8.0 mL) (Aldrich) was heated at 80° C. overnight. The TFA was removed in vacuo and the residue was treated with a saturated solution of NaHCO3. The mixture was extracted with DCM (3×15 mL) and concentrated. The crude brown oil was dissolved in 2.5 mL of DMSO and purified by reversed phase chromatography (Gilson, 10-90% CH3CN in water with NH4OH additive: 0.1% v/v in each solvent). The fractions were concentrated in a Genevac Series II System to give 4-(2-(3-fluoro-4-methoxyphenylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (3.3 mg, 10.11 μmol, 4.57% yield) as a yellow amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 11.91 (s, 1H); 8.77 (dd, J=7.8, 2.0 Hz, 1H); 8.35 (dd, J=4.7, 2.0 Hz, 1H); 7.94 (dd, J=14.2, 2.6 Hz, 1H); 7.48-7.53 (m, 1H); 7.11 (t, J=9.4 Hz, 1H); 6.90 (dd, J=7.8, 4.7 Hz, 1H); 3.82 (s, 3H); 2.43 (s, 3H). m/z (ESI, +ve ion) 327.1 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13]1.[Br-].C([NH3+])(C)(C)C.[C:25]([O:29]C(=O)CBr)(C)(C)[CH3:26].[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.[OH-].[Na+].O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][CH2:26][CH2:25][OH:29])[CH2:13]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCC1CCN(CC2COc3ccccc3O2)C1
Agent: CC(C)(C)[NH3+]
Agent: [Al+3]
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: OCCOCC1CCN(CC2COc3ccccc3O2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 50 mg (0.19 mmol) of [1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-pyrrolidin-3-yl]-methanol in dichloromethane (1.5 mL), 1.5 mL of cold aqueous NaOH-solution (50%, w/w) and 6 mg (0.02 mmol) of tert-butylammonium bromide were added at 0° C. The reaction mixture was stirred for ½ h at 0° C. After adding 28 μL (0.19 mmol) of tert-butylbromoacetate the stirring was continued for 3 h at 10° C. Subsequent addition of water (10 mL) and dichloromethane (40 mL) was followed by stirring the mixture for additional 10 min at room temperature. The phases were separated, and the organic phase was washed with 5% NaHCO3 (1×20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was dried under high vacuum and redissolved in dry tetrahydrofuran (4 mL) and reduced with 15 mg (0.40 mmol) of LiAlH4 using the same procedure as above. The crude product was purified by column chromatography (silica gel, methanol/triethylamine/ethyl acetate, 1:1:99).