Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.Cl[S:16]([CH2:19][C@H:20]([CH3:31])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])(=[O:18])=[O:17]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:16]([CH2:19][C@H:20]([CH3:31])[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])(=[O:18])=[O:17])[CH2:4][CH2:3]1
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CS(=O)(=O)N1CCN(C)CC1)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 0.42 mL (1.05 eq) N-methyl-piperazine, 1 mL NEt3 and 20 mL CH2Cl2. The solution was cooled to 0° C. and 1.0 g of benzyl 3-chlorosulfonyl-2(R)-methylpropionate from Example 3 in 5 mL CH2Cl2 was added. After 1 hour reaction was concentrated in vacuo. The residue was partioned between EA/H2O and the organic phase was washed with saturated aqueous bicarb., brine, dried, and concentrated in vacuo to yield benzyl 3-[(4-methylpiperizin-1-yl)sulfonyl]-2(R)-methylpropionate which was used without further purification.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:18]=[C:17]([F:19])[C:16]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([CH3:27])[N:22]([CH3:28])[C:21]2=[O:29])=[CH:15][C:8]=1[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]>C(O)(=O)C>[Cl:6][C:7]1[CH:18]=[C:17]([F:19])[C:16]([N:20]2[C:25](=[O:26])[C:24]([Cl:4])=[C:23]([CH3:27])[N:22]([CH3:28])[C:21]2=[O:29])=[CH:15][C:8]=1[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1c(Cl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.3 g of sulphuryl chloride are added dropwise with stirring to a solution of 15.0 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 100 ml of acetic acid at room temperature during 1 minute, during which the temperature rises to approx. 30° C. Then the reaction mixture is stirred for a further 15 minutes at room temperature and evaporated to dryness under reduced pressure. The residue is dissolved in ethyl acetate and the solution washed in turn with aqueous sodium bicarbonate solution and water. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is recrystallized from methylene chloride/diethyl ether. Isopropyl 2-chloro-4-fluoro-5-[5-chloro-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 150°-153° C., is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([NH2:14])[CH3:13].CN1C(=O)CCC1>O>[CH2:12]([NH:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1)[CH3:13]
Reactant: CCN
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCNc1ccc(C(F)(F)F)cn1
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine (12 g), 70% of aqueous ethylamine solution (16 ml), and NMP (7 ml) was stirred with heating at 70° C. for 1 day. Into the reaction mixture cooled to room temperature, water was poured, and then the precipitated solid was collected by filtration. The obtained solid was washed with water, and dried to give 6.3 g of N-ethyl-(5-trifluoromethylpyridin-2-yl)-amine.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[C:2]=[S:3].[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.CC1C=CC=CC=1>[CH3:15][N:16]([C:2]([NH:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[S:3])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)N1CCC(N=C=S)CC1
Reactant: CNc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(NC(=S)N(C)c2ccccc2)CC1
Yield: 42 %

Procedure:
A mixture of 107 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate, 53.5 parts of N-methylbenzenamine, 1 part of N,N-dimethyl-4-pyridinamine and 450 parts of methylbenzene was stirred and refluxed overnight. After cooling, the reaction mixture was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 68 parts (42%) of ethyl 4-[[(methylphenylamino)thioxomethyl]amino]-1-piperidinecarboxylate; mp. 95.2° C. (14).
Reaction SMILES: CC(C)=O.[OH:5][C@@H:6]1[C@@:13]([CH3:20])([CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C@@H:12]2[C@:21](O)([O:22]C)[C@@:8]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])([C:9]([O:26][CH3:27])=[CH:10][C:11]2=[O:25])[CH2:7]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCCCCC>O.CCOC(C)=O>[OH:5][C@@H:6]1[C@@:13]([CH3:20])([CH2:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])[C@@H:12]2[C:21](=[O:22])[C@@:8]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])([C:9]([O:26][CH3:27])=[CH:10][C:11]2=[O:25])[CH2:7]1
Reactant: COC1=CC(=O)[C@@H]2[C@](C)(CCC=C(C)C)[C@@H](O)C[C@@]1(CC=C(C)C)[C@@]2(O)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC1=CC(=O)[C@H]2C(=O)[C@]1(CC=C(C)C)C[C@H](O)[C@@]2(C)CCC=C(C)C
Yield: 88.2 %

Procedure:
A 1:1 acetone:H2O (4 mL) solution of 19 (65 mg, 0.17 mmol, 1 equiv.) and pyridinium para-toluenesulfonate (208 mg, 0.83 mmol, 5 equiv.) was heated to reflux in a 10-mL recovery flask with an affixed reflux condenser. After stirring at reflux for 15.5 h, the solution was cooled, diluted with H2O, and extracted thrice with 1:1 hexane:EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a faint yellow oil. Flash column chromatography (20 mL SiO2, 7:3 hexane:EtOAc) afforded 54 mg (0.15 mmol, 90% yield) of 20 as a colorless oil. TLC Rf 0.50 (1:1 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.67 (s, 1H), 5.08 (t, J=7.1 Hz, 1H), 4.98 (t, J=7.0 Hz, 1H), 3.82-3.80 (m, 1H), 3.75 (s, 3H), 3.19 (s, 1H), 2.49 (dd, J=14.5, 6.3 Hz, 1H), 2.40 (dd, J=14.6, 7.6 Hz, 1H), 2.34 (tt, J=12.6, 6.3 Hz, 1H), 2.11 (dd, J=13.4, 5.4 Hz, 1H), 1.91 (tt, J=12.4, 6.2 Hz, 1H), 1.75 (dd, J=13.3, 11.6 Hz, 1H), 1.67 (s, 2H), 1.66 (s, 3H), 1.65 (s, 3H), 1.64 (s, 3H), 1.61-1.59 (m, 1H), 1.56 (td, J=12.8, 4.8 Hz, 1H), 1.32 (td, J=12.7, 4.8 Hz, 1H), 0.91 (s, 3H). 13C NMR (126 MHz; CDCl3): δ 205.2, 193.1, 177.5, 134.5, 132.2, 124.3, 119.0, 106.0, 72.1, 69.2, 57.1, 56.0, 45.9, 39.4, 38.1, 29.5, 26.1, 25.9, 21.8, 18.1, 17.9, 15.7. HRMS-ESI (m/z): [M+H]+ calculated for C22H32O4, 361.2373. found, 361.2357.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:24][C:25]([O:27]C(C)(C)C)=O)[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[CH:10]=[CH:9]2.C(O)(C(F)(F)F)=O.[Cl:40][C:41]1[CH:49]=[N:48][CH:47]=[C:46]([Cl:50])[C:42]=1C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:24][C:25](=[O:27])[C:42]1[C:41]([Cl:40])=[CH:49][N:48]=[CH:47][C:46]=1[Cl:50])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=1[Cl:22])[CH:10]=[CH:9]2
Reactant: COC(=O)[C@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(Cl)cncc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cncc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
Methyl-(2S)-2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate (compound No 26, international patent application WO 03/093237) (500 mg, 1.05 mmol) was dissolved in DCM (5 ml) and a solution of TFA (0.8 ml, 10.5 mmol) in DCM (2 ml) was added drop wise over 10 minutes. After addition was complete the reaction was stirred at RT over night. The reaction was cooled to 0° C. and TEA (2.1 ml, 15.8 mmol) in DCM (2 ml) was added drop wise over 10 minutes. The reaction was cooled to −10° C. and 3,5 dichloro-isonicotinoylchloride (Bioorg. Med. Chem. Lett. 2002, 12, 1591-1594), (663 mg, 3.0 mmol) was added drop wise over 10 minutes, before allowing the reaction to warm to RT. After 1 hour the reaction was washed with aqueous HCl (1N, 10 ml), followed by washing with aqueous NaHCO3 solution (saturated, 10 ml). The DCM layer was dried over MgSO4, filtered and the solvent removed in vacuo to yield an off white solid. The solid was purified using flash chromatography (eluent EtAc) to yield the title compound as a white powder (432 mg, 75%) LCMS M+1 (552, 550, 548), Retention Time 3.82 min, 1H NMR, 300 Mz, d6-DMSO-9.50 (1H, d), 8.63 (2H, s), 8.42 (1H, d), 7.98 (1H, d), 7.94 (1H, d), 7.78 (1H, dd), 7.65 (2H, d), 7.55 (2H, m), 4.95 (1H, m), 3.74 (3H, s), 3.45 (1H, dd), 3.20 (1H, dd).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:9][CH:8]([OH:10])[CH2:7]2)=[N:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:9][C:8](=[O:10])[CH2:7]2)=[N:2]1
Reactant: OC1CC(c2ccon2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C1CC(c2ccon2)C1
Reaction time: 2 h
Yield: 82.9 %

Procedure:
3-Isoxazol-3-ylcyclobutanol (0.316 g, 2.27 mmol), as a mixture of cis- and trans-isomers, was dissolved in methylene chloride (10 mL) and Dess-Martin periodinane (0.96 g, 2.3 mmol) was added. After stirring for 2 hours, satd. NaHCO3 solution and brine were added, and the mixture was extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated. Flash column chromatography, eluting with a gradient of 20-50% ethyl acetate in hexanes, afforded product (258 mg, 83%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:4]2[N:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:17]([C:15]1[N:16]=[C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=3)[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][N:5]2[N:14]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1nc2nc(Cl)c(-c3ccccc3)cn2n1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)c1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Temperature: 90 °C

Procedure:
To a mixture of 5.30 g 5-chloro-2-isopropyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine and 3.80 g 4-formylphenylboronic acid in 160 mL 1,2-dimethoxyethane were added 33 mL of a 10% w/w sodium carbonate solution and 0.71 g dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) and the resulting mixture was heated to 90° C. under an inert gas atmosphere for 18 h. The work up was performed by diluting the reaction mixture with water and dichloromethane, separating the phases and extraction of the aqueous phase with dichloromethane. The combined organic layers were dried over sodium sulphate, the solvent was evaporated and the residue suspended in ethyl acetate. The insoluble solid was filtered and the filtrate was evaporated. The residue was purified by chromatography on silica gel (dichloromethane/ethyl acetate) to yield the product.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.Cl.NCCC1C2C(=CC=CC=2)NC=1.C(O)(=O)C=O.C(O)C>C1(C(C)C)C=CC=CC=1.[Pd]>[CH:8]1[CH:9]=[CH:10][C:11]2[NH:12][C:13]3[CH:1]=[N:2][CH:3]=[CH:4][C:5]=3[C:6]=2[CH:7]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: [Pd]
Agent: Cl
Agent: NCCc1c[nH]c2ccccc12
Solvent: CC(C)c1ccccc1
Solvent: CCO
Product: c1ccc2c(c1)[nH]c1cnccc12

Procedure:
A stirred solution of 13 g (0.0756 Mol) 1,2,3,4-tetrahydro-β-carboline, manufactured by tryptamine hydrochloride and glyoxylic acid as described by Ho and Walker (1988), and 2.6 g Pd/C (10%) in 600 ml of cumene were refluxed in a nitrogen atmosphere for 90 min. After addition of 100 ml of ethanol, the hot solution was filtrated, and the coal was extracted thrice by 30 ml of hot ethanol. The combined liquid fractions were concentrated, and the residues was crystallised in toluene to yield 10.5 g (82%) or norharman. Methylation at position 9 was performed as described in the literature (Ho B T, Mcisaac W M, Walker K E, Estevez V, J Pharm Sci 57: 269, 1968) yet with an improved reprocessing. One gram (5.95 mmol) of norharman was dissolved in 10 ml of dried DMF in a nitrogen atmosphere. After that, 0.36 g (14.9 mmol) of sodium hydride were added in form of a 60% dispersion in paraffin at 0° C. After cooling of the reaction mixture down to room temperature, this was cooled down to −10° C., and 0.84 g (5.95 mmol) iodomethane were added. After further stirring for 12 hours, one allowed the mixture to cool down to room temperature once again. All volatile ingredients were removed in reduced pressure. After that, 100 ml of water were added, and the mixture was extracted by 3×50 ml of CHCl3. The combined organic fractions were washed with 5×20 ml of water and were evaporated for drying. The residue was suspended in 100 ml 2 N hydrochloric acid. To separate the educt from the desired methylated product, ion pair exchange extraction of the HCl salt was performed in CHCl3 by a liquid/liquid extractor for two days. After removal of the solvent one yielded 0.7 g (64%) of yellow crystals of 9-methyl-β-carbolinium hydrochloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:21]=2[CH3:36])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17](O)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C1C=[N:41]C2N(O)N=NC=2C=1.[OH-].[NH4+].C(Cl)CCl>C1COCC1>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]([NH:26][C:22]2[C:21]([CH3:36])=[C:20]([C:7]3[C:8]4[C:9]5[C:14](=[CH:13][C:12]([C:17]([NH2:41])=[O:18])=[CH:11][CH:10]=5)[NH:15][C:16]=4[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=3)[CH:25]=[CH:24][CH:23]=2)=[O:35])=[CH:33][CH:32]=1
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)O)ccc3c12
Reactant: On1nnc2cccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(N)=O)ccc3c12
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 32.2 %

Procedure:
A mixture of 8-carbamoyl-5-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-2-carboxylic acid (Example 23-1, 30 mg, 0.062 mmol) and HOAT (12.72 mg, 0.093 mmol) in THF (0.4 mL) was treated with 28% aqueous ammonium hydroxide (0.052 mL, 0.374 mmol) and EDC (23.89 mg, 0.125 mmol) and the mixture was stirred at rt. After 22.5 h, the mixture was concentrated and purified by preparative HPLC. The appropriate effluent fractions were concentrated and the residue was treated with NaHCO3 (aq) and extracted three times with EtOAc. The combined organic phases were dried and concentrated to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-1,7-dicarboxamide as an off-white solid (9.6 mg, 29%). 1H NMR (400 MHz, methanol-d4) δ 8.11 (d, J=1.3 Hz, 1H) 8.03-8.08 (m, 2H) 8.01 (d, J=7.9 Hz, 1H) 7.51-7.55 (m, 1H) 7.41-7.48 (m, 2H) 7.29 (dd, J=7.5, 1.3 Hz, 1H) 7.24 (t, J=8.8 Hz, 2H) 7.08-7.12 (m, 2H) 1.98 (s, 3H). Mass spectrum m/z 481.1 (M+H)+.
Reaction SMILES: CN(C)C=O.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[I:12][C:13]1[CH:14]=C2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=C2O>ClCCCl>[Cl:11][C:6]1[C:7]2[C:20](=[CH:21][CH:22]=[C:13]([I:12])[CH:14]=2)[N:19]=[CH:18][N:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Oc1ncnc2ccc(I)cc12
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.4 %

Procedure:
To a stirred solution of anhydrous dimethyl foramide (DMF) (3.20 ml) in 1,2-dichloroethane (DCE) (10 ml), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (5.2 ml, 60 mmol) in DCE (25 ml). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml). The aqueous layer is further extracted with DCM (2×50 ml). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 5.2 g (99%) of desired product as a tan solid.
Reaction SMILES: C([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[O:16][CH:17]([CH3:19])[CH3:18])(C)C.[Li+].[OH-].Cl>C1COCC1>[CH:17]([O:16][C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:6]=1[C:5]([OH:20])=[O:4])([CH3:19])[CH3:18]
Reactant: CC(C)OC(=O)c1ccc(C(F)(F)F)cc1OC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-isopropoxy-4-trifluoromethyl-benzoic acid isopropyl ester (35 mg, 0.12 mmol) in THF (1 ml) was added a solution of 0.5 N-LiOH (2 eq), and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was acidified with 1N HCl, and then extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was vacuum dried to yield the 2-isopropoxy-4-trifluoromethyl-benzoic acid. To an ice-cold suspension of 2-isopropoxy-4-trifluoromethyl-benzoic acid and N,O-dimethylhydroxylamine hydrochloride (13 mg, 0.132 mmol) in CH2Cl2 (1 mL) was added N-methylmorpholine (0.015 ml, 0.132 mmol), and the resulting mixture was stirred for 5 minutes, to which were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (26 mg, 0.132 mmol). The resulting mixture was stirred for 2 hours at room temperature, and then diluted with EtOAc. The organic layer was washed with 1N HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography (Hex/EtOAc=3/1) to give the title compound (28 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:27]([O:29]C)=[O:28].O[Li].O>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1c(C)sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc12
Agent: [Li]O
Solvent: O
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)O
Yield: 85.1 %

Procedure:
This material was prepared by the reaction of methyl 2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}benzo[b]thiophene-3-carboxylate 117a (200 mg, 0.46 mmole) with LiOH.H2O (192 mg, 4.6 mmole) in a manner as previously described for example 11c to give a yellow solid (165 mg, 85%). 1H NMR (DMSO-d6, 300 MHz): δ 8.57 (1H, d, J=5.46 Hz), 8.45 (1H, d, J=8.85 Hz), 8.00 (2H, s), 7.53 (1H, s), 7.40 (1H, dd, J=2.35, 8.95 Hz), 7.22 (1H, s), 6.79 (1H, d, J=5.46 Hz), 4.00 (3H, s), 2.82 (3H, s).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([N:11](OC)[CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23](N)C.CCO.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([CH2:7][C@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([NH:11][CH2:12][CH3:23])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CON(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Product: CCNC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
To a solution of (S)-tert-butyl 3-cyclohexyl-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.17 g, 4.3 mmol) and TEA (2.4 mL, 17.2 mmol) in anhydrous DMF was added 2.0 M EtNH2 solution in EtOH (6.5 mL, 13 mmol), followed by HBTU (1.96 g, 5.2 mmol). The resulting solution was stirred at rt for 3 h. The reaction was concentrated under reduced pressure and the residue dissolved in EtOAc (50 mL). The mixture was then washed with 1 M NaOH (4 times), 1 M HCl (3 times), sat. aq. NaHCO3, brine, dried over Na2SO4 and filtered. The concentrated residue gave (S)-tert-butyl 3-cyclohexyl-1-(ethylamino)-1-oxopropan-2-ylcarbamate (444 mg, 34%). MS ESI +ve m/z 299 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)=[N:14][CH:15]=1
Reactant: Clc1nccc2cccnc12
Reactant: Nc1ccc(F)cn1
Product: Fc1ccc(Nc2nccc3cccnc23)nc1

Procedure:
The title compound, MS: m/e=241.2 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-[1,7]naphthyridine and 2-amino-5-fluoropyridine.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]([C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:13]=[C:12]([CH3:24])[N:11]=1)[NH:6]C(=O)C.C(=O)([O-])O.[Na+]>Cl.O>[Br:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]([C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[CH:13]=[C:12]([CH3:24])[N:11]=1)[NH2:6]
Reactant: CC(=O)NN(Cc1ccccc1Br)c1nc(C)cc(Nc2ccc(Cl)cc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Nc2ccc(Cl)cc2)nc(N(N)Cc2ccccc2Br)n1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
Acetic acid N′-(2-bromo-benzyl)-N′-[4-(4-chloro-phenylamino)-6-methyl-pyrimidin-2-yl]-hydrazide (0.4 g, 0.87 mmol) was suspended in aqueous hydrochloric acid (6 M, 50 mL) and heated to 100° C. for 3 days. The reaction mixture was diluted with water (50 mL), basified with solid sodium hydrogencarbonate and extracted with chloroform (3×50 mL). The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and evaporated to give {2-[N-(2-bromo-benzyl)-hydrazino]-6-methyl-pyrimidin-4-yl}-(4-chloro-phenyl)-amine (0.3 g, 82%) as a brown solid.