Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[C:8]([N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])(=[O:10])[CH3:9].CN1CCOCC1.[NH2:24][C:25]1[C:26]([Cl:44])=[C:27]([C:40]([Cl:43])=[CH:41][CH:42]=1)[CH2:28][O:29][C:30]1[C:31]2[N:32]([CH:36]=[C:37]([CH3:39])[N:38]=2)[CH:33]=[CH:34][CH:35]=1>CN1CCCC1=O>[C:8]([N:11]([CH2:13][C:14]([NH:24][C:25]1[C:26]([Cl:44])=[C:27]([C:40]([Cl:43])=[CH:41][CH:42]=1)[CH2:28][O:29][C:30]1[C:31]2[N:32]([CH:36]=[C:37]([CH3:39])[N:38]=2)[CH:33]=[CH:34][CH:35]=1)=[O:16])[CH3:12])(=[O:10])[CH3:9]
Reactant: CC(=O)N(C)CC(=O)O
Reactant: Cc1cn2cccc(OCc3c(Cl)ccc(N)c3Cl)c2n1
Agent: CC(C)(C)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CC(=O)N(C)CC(=O)Nc1ccc(Cl)c(COc2cccn3cc(C)nc23)c1Cl
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
Pivaloyl chloride (0.22 ml) was added dropwise to a mixture of acetylsarcosine (264 mg), N-methylmorpholine (0.22 ml) and N-methylpyrrolidone (30 ml) under a dry ice-tetrachloromethane bath cooling. This mixture was stirred for 10 minutes under ice-cooling, and 8-[3-amino-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (500 mg) was added thereto under a dry ice-tetrachloromethane bath cooling. The mixture was stirred for 22 hours at ambient temperature. The mixture was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo, and the residue was purified by flash column chromatography (methylene chloride:methanol=50:1, V/V) to give 8-[3-(acetylsarcosylamino)-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (260 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[B-](F)(F)(F)[CH2:84][N:85]1[CH2:90][CH2:89][N:88]([CH3:91])[CH2:87][CH2:86]1.[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:19]2[N:18]=[C:17]([C:4]3[C:5]([NH:8][C:9]4[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=4)=[N:6][CH:7]=[C:2]([CH2:84][N:85]4[CH2:90][CH2:89][N:88]([CH3:91])[CH2:87][CH2:86]4)[CH:3]=3)[N:22]=[C:21]([CH3:23])[N:20]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CN1CCN(C[B-](F)(F)F)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 140 °C
Yield: 88.7 %

Procedure:
A mixture of 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (160 mg, 0.274 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (X-Phos, 13.06 mg, 0.027 mmol), cesium carbonate (268 mg, 0.822 mmol), potassium 1-methyl-4-trifluoroboratomethylpiperazine (Frontier Scientific Co., 66.3 mg, 0.301 mmol) and palladium acetate (3.08 mg, 0.014 mmol) was purged with argon. The mixture was then treated with THF (1.0 mL) and water (0.1 mL) and heated under microwave irradiation at 140° C. for 30 min. The mixture was filtered through a short path of Celite® (diatomaceous earth), washed with EtOAc (×3), and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (pure DCM to 5% MeOH in DCM) to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (161 mg, 0.243 mmol, 89% yield) as a yellow syrup. m/z (ESI, +ve ion) 662.0 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:21][CH2:20][CH2:19]1)=[O:17])[CH3:14].[CH3:22][S:23]([O:26][C@H:27]([CH2:29][CH2:30]I)[CH3:28])(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:26][C@@H:27]([CH3:28])[CH2:29][CH2:30][C:18]1([C:16]([O:15][CH2:13][CH3:14])=[O:17])[CH2:21][CH2:20][CH2:19]1)(=[O:25])=[O:24]
Reactant: C[C@@H](CCI)OS(C)(=O)=O
Reactant: CCOC(=O)C1CCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC[C@H](C)OS(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
To a solution of diisopropylamine (9.1 mL, 65 mmol) in 43 mL of THF was added n-BuLi (26 mL, 65 mmol) at 0° C. slowly (5 min). The mixture was stirred at 0˜5° C. for 30 min. After the mixture was cooled to −78° C. (10 min), Ethylcyclobutanecarboxylate (8 mL, 59.6 mmol, 1.1 eq.) was added dropwise and stirred at −78° C. for 30 min. The enolate was added into the solution of (S)-4-iodobutan-2-yl methanesulfonate 96 (15 g, 54 mmol) in 100 mL of THF at −78° C. Cooling bath was removed to allow the reaction to warm up to RT. After 30 min at RT, reaction was quenched by addition of water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4, filtered and concentrated down. The residue was purified by silica gel chromatography first with (5% to 30% EtOAc in hexanes) then 100% DCM to (98% DCM/2% EtOAc) to provide 5.3 g (36% isolated yield) of (S)-ethyl 1-(3-(methylsulfonyloxy)butyl)cyclobutanecarboxylate 97.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[S:13][C:14]([CH3:16])=[CH:15][C:8]=2[C:7]1=[O:17])C.Cl.O>O1CCCC1>[CH3:16][C:14]1[S:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH:4]=[O:3])[C:7](=[O:17])[C:8]=2[CH:15]=1
Reactant: CCOC(CN1CCCc2sc(C)cc2C1=O)OCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(s1)CCCN(CC=O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 5.0 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one in 70 ml of dimethylformamide was added 4.4 g of potassium t-butoxide with stirring under ice-cooling and the mixture was stirred for an hour at room temperature. To the mixture was added 7.1 g of bromoacetaldehyde (2-bromo-1,1-diethoxyethane) dropwise under ice-cooling. The mixture was stirred at 60° C. for 5 hours and poured into chilled water and then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was chromatographed on a silica gel using chloroform as an eluent to give 2.5 g of 5-(2,2-diethoxyethyl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]-azepin-4-one as a pale yellow oil. To the solution of 2.1 g of 5-(2,2-diethoxyethyl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one in 30 ml of tetrahydrofuran was added 10 ml of 10% hydrochloric acid solution, and the mixture was stirred for 2 hours at room temperature, poured into water and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1.39 g of 2-methyl-5,6,7,8-tetrahydro-4-oxo-4H-thieno[3,2-c]azepin-5-acetoaldehyde. To the solution of 1.39 g of 2-methyl-5,6,7,8-tetrahydro-4-oxo-4H-thieno[3,2-c]azepin-5-acetoaldehyde in 20 ml of ethanol were added 2.4 g of 4-[bis(4-fluorophenyl)methylene]piperidine and 0.39 g of sodium cyanoborohydride. The mixture was stirred for 2.5 hours at room temperature, poured into chilled water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting orange oil was chromatographed on a silica gel using chloroform as an eluent and the eluate was concentrated under reduced pressure. The resulting residue was dissolved in ethanol and to the solution of the residue was added ethanolic hydrochloric acid to produce its hydrochloride. The precipitated crystals were collected by filtration and recrystallized from methanol to give 5-[2-(4-(bis(4-fluorophenyl)methylene)piperidino)ethyl]-2-methyl-5,6,7,8-tetrahydro-4H -thieno[3,2-c]azepin-4-one hydrochloride as white crystals, melting at 228°-229° C.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Br.[Br:13][CH2:14][CH2:15][NH2:16]>O1CCOCC1.[OH-].[Na+].O1CCOCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:16][CH2:15][CH2:14][Br:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NCCBr)OCc1ccccc1
Yield: 92 %

Procedure:
A solution of CBz-Cl (7.7 mL; 54 mmol) in dioxane (5 mL) was added to a cold (0° C.) stirred solution of 2-bromoethylamine hydrobromide (10.0 g; 49 mmol) in 40 mL 1M NaOH:dioxane (3:1) under Schotten-Bauman conditions. The reaction mixture was allowed to attain rt. and extracted with CHCl3. The organic layer was separated, concentrated and purified by column chromatography (CHCl3) to give the sub-title compound in a 92% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]1[C:11]2[C:12]([OH:16])=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8]1.CS(O[CH:22]1[CH2:25][N:24]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23]1)(=O)=O.C(OCC)(=O)C>CN(C=O)C.O>[CH:26]([N:24]1[CH2:25][CH:22]([O:16][C:12]2[C:11]3[O:7][CH:8]=[CH:9][C:10]=3[CH:15]=[CH:14][CH:13]=2)[CH2:23]1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Oc1cccc2ccoc12
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)N2CC(Oc3cccc4ccoc34)C2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (348 mg, 2.52 mmol) and benzofuran-7-ol (169 mg, 1.26 mmol) were successively added to a solution of 1-benzhydrylazetidin-3-yl methanesulfonate (400 mg, 1.26 mmol) in DMF (8 mL). The reaction mixture was stirred overnight at 90° C. and then diluted by addition of ethyl acetate (20 mL) and water (20 mL). The aqueous phase was separated and extracted with ethyl acetate (4×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (5×50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using petroleum ether/dichloromethane (1:0 to 2:8 to 0:1) as eluent. The title product was obtained as a yellow oil (350 mg, 69%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][C:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[N:23]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:29][O:28][C:24]1[N:23]=[C:22]([C:20]([C:12]2[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[S:15][C:11]=2[CH2:10][CH2:9][N:8]([CH3:30])[CH3:7])=[CH2:1])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1cccc(C(=O)c2c(CCN(C)C)sc3ccccc23)n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(c1cccc(OC)n1)c1c(CCN(C)C)sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Anhydrous THF (8 mL) was added to a mixture of potassium t-butoxide (140 mg, 1.27 mmol) and methyltriphenylphosphonium bromide (0.45 g, 1.27 mmol) under N2 atmosphere. The reaction was stirred for 30 min at room temperature. A solution of [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-(6-methoxy-pyridin-2-yl)-methanone (0.29 g, 0.85 mmol) in THF (8 mL) was added and the reaction was stirred for 1 hour at room temperature. The reaction was quenched by the addition of 0.1N HCl until the pH was <3 and extracted with 0.1N HCl. The aqueous layers were made basic with NH4OH and extracted with EtOAc. The organic layers were washed with water and concentrated in vacuo. Mass triggered preparative HPLC afforded 190 mg of (2-{3-[1-(6-methoxy-pyridin-2-yl)-vinyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (Compound 15-1) as a TFA salt.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[N:26]=2)=[CH:21][CH:20]=1)=[C:17]=S>>[F:40][C:37]([F:38])([F:39])[O:36][C:33]1[CH:32]=[CH:31][C:30]([N:27]2[CH:28]=[N:29][C:25]([C:22]3[CH:23]=[CH:24][C:19]([NH:16][C:17]4[O:5][CH2:4][CH2:3][CH:2]([C:6]5[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=5)[N:1]=4)=[CH:20][CH:21]=3)=[N:26]2)=[CH:35][CH:34]=1
Reactant: NC(CCO)c1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(NC4=NC(c5ccc(C(F)(F)F)cc5)CCO4)cc3)n2)cc1

Procedure:
The title compound was prepared with 3-amino-3-(4-(trifluoromethyl)phenyl)propan-1-ol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.10 g, 43%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([C:15](=O)[CH3:16])=[CH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1)[CH2:2][CH3:3].Cl.[NH2:19][OH:20].N1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:1]([O:4][C:5]1[C:6]([C:15](=[N:19][OH:20])[CH3:16])=[CH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cc2c(cc1C(C)=O)CCCC2
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCOc1cc2c(cc1C(C)=NO)CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
1-(3-Propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone (8.88 g, 38.2 mmol) was dissolved in a mixed solvent of chloroform (20 ml) and methanol (80 ml). Hydroxylamine hydrochloride (4.05 g, 58.2 mmol) and pyridine (9.46 ml, 117 mmol) were added to the solution and stirred for 16 hours while heating under reflux. The reaction mixture was cooled to room temperature, and then concentrated to dryness under reduced pressure. 2N hydrochloric acid (30 ml) and water were added to the residue, followed by extraction using dichloromethane. The thus-obtained organic layer was concentrated to dryness under reduced pressure, and the residue was then purified using silica gel column chromatography (n-hexane:ethyl acetate=5:1). The purified product was concentrated to dryness under reduced pressure, giving a pale yellow powder of 1-(3-propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone oxime (8.87 g, yield: 94%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[CH:14]=[N:13]2)=[C:4]([F:21])[CH:3]=1>C(O)(=O)C.O.[Zn]>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[CH2:14][NH:13]2)=[C:4]([F:21])[CH:3]=1
Reactant: C#CCOc1cc(-n2ncc(=O)n(C)c2=O)c(F)cc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: C#CCOc1cc(N2NCC(=O)N(C)C2=O)c(F)cc1Cl
Temperature: 60 °C
Yield: 74 %

Procedure:
A solution of 1.6 g (0.0052 mole) of 2-(4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-4-methyl-1,2,4-triazine-3.5(2H,4H)-dione (compound 21) dissolved in 5 mL of glacial acetic acid was added dropwise to a stirred suspension of 1.5 g (0.023 mole) of zinc dust in 10 mL of glacial acetic acid and 5 mL of water. After complete addition the mixture was heated at 60° C. for 1.5 hours. The mixture was filtered and the filtrate was partitioned between 50 mL of water and 50 mL of diethyl ether. The organic phase was washed first with water followed by a saturated aqueous sodium bicarbonate solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.2 g of 2-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-1,6-dihydro-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione as an oil, compound A-3 of Table A-1.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].ClC(Cl)(Cl)C[O:19][C:20](=[O:41])[CH:21]([S:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=1>>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][S:31][CH:21]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][O:13][C:12](=[O:14])[CH:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=3)[CH3:15])=[CH:27][CH:28]=2)[C:20]([OH:41])=[O:19])=[CH:35][CH:36]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Product: CC(C)Cc1ccc(C(C)C(=O)OCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared starting from 2-(4-isobutyl-phenyl)-propionic acid and 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2-trichloro-ethyl ester in the same manner as described for example 7 (yield: 5.6 mg, 17%). 1H-NMR (300 MHz, CDCl3): δ 0.90 (d, 6H), 1.50 (d, 3H), 1.77-1.92 (m, 1H), 2.45 (d, 2H), 2.75-2.96 (m, 5H), 3.12-3.23 (m, 1H), 3.41-3.50 (m, 1H), 3.74 (q, 1H), 5.00-5.13 (m, 2H), 6.91-6.99 (m, 2H), 7.04-7.23 (m, 10H); Mass Spectrum: M−H+ 521.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH3:12][O:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[O:15]>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:20]2[CH:19]=[CH:18][S:17][C:16]=2[C:14]([O:13][CH3:12])=[O:15])(=[O:22])=[O:23])=[O:26])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C

Procedure:
To 1.5 g of 2-amino-4,6-dimethoxypyrimidine in 30 ml of anhydrous acetonitrile was added 2.7 g of 2-methoxycarbonyl-3-thiophenesulfonyl isocyanate with stirring at ambient temperature. All of the solid reactant dissolved and after twenty minutes of stirring a precipitate started to form. After two hours the mixture was filtered and the solid which was washed with anhydrous ethyl ether, melted at 191°-193°. The solid showed peaks by nuclear magnetic resonance spectroscopy at 4.0 ppm and 3.8 ppm for the methoxy groups, 6.0 ppm for the H of pyrimidine and 7.6 ppm for the hydrogens on thiophene. The infrared absorption spectrum showed absorption peaks at 1730 and 1700 cm-1 consistent for the two carbonyl peaks in the desired product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])[CH3:11].C(O)(=O)C.C(O[BH3-])(=O)C.[Na+]>C(Cl)Cl>[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[I:9])[CH2:17][CH2:16]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Nc1ccc(F)cc1I
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC(Nc2ccc(F)cc2I)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-fluoro-2-iodoaniline and (18 g) 4-oxo-cyclohexanecarboxylic acid ethyl ester (20 g) in DCM (200 ml) is added acetic acid (4.4 ml) and 4 Å molecular sieves (5 g). After 2 h at rt, sodium acetoxyborohydride (50 g) is added and the suspension stirred overnight. The reaction is made slightly alkaline with KHCO3/NaHCO3(aq) and extracted with DCM to give crude 4-(4-fluoro-2-iodo-phenylamino)-cyclohexanecarboxylic acid ethyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[C:20]([C:38]([F:41])([F:40])[F:39])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:43]>C(O)C>[ClH:43].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:36])[F:37])=[C:20]([C:38]([F:39])([F:40])[F:41])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccccc3C(F)(F)F)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccccc2C(F)(F)F)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 24-3 (800 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (600 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2](=[CH2:29])/[CH:3]=[CH:4]/[C:5](/[NH:8][C:9]1[C:18]2[CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:15](=[O:28])[NH:14][C:13]=2[N:12]=[CH:11][CH:10]=1)=[CH:6]/C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][C:32]=1[F:40]>>[F:40][C:32]1[CH:33]=[C:34]([NH:37][C:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]3[C:18]4[CH2:17][N:16]([CH2:19][C:20]5[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)[C:15](=[O:28])[NH:14][C:13]=4[N:12]=[CH:11][CH:10]=3)=[CH:6][CH:29]=2)=[O:39])[CH:35]=[CH:36][C:31]=1[F:30]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: C=C(N)/C=C/C(=C/C)Nc1ccnc2c1CN(Cc1ccc(OC)cc1)C(=O)N2
Product: COc1ccc(CN2Cc3c(Nc4ccc(NC(=O)Nc5ccc(F)c(F)c5)cc4)ccnc3NC2=O)cc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 63 using 5-[(Z)-4-amino-1-eth-(E)-ylidene-penta-2,4-dienylamino]-3-(4-methoxy-benzyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one and 1,2-difluoro-4-isocyanato-benzene. LC-MS (M+H=531, obsd.=531).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][OH:22])[CH:15]=[CH:14]2)#[CH:10].C(NC(C)C)(C)C>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[C:9][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH2:21][OH:22])[CH:15]=[CH:14]3)=[N:3][CH:4]=1
Reactant: C#Cc1ccc2c(ccn2CCO)c1
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OCCn1ccc2cc(C#Cc3ccc(Br)cn3)ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere 29.4 g (124 mmol) 2,5-dibromo-pyridine, 241 mg (1.3 mmol) CuI and 888 mg (1.3 mmol) Pd(PPh3)2Cl2 are added to a solution of 23.0 g (124 mmol) 2-(5-ethynyl-indol-1-yl)-ethanol and 35 mL (248 mmol) diisopropylamine in 1150 mL THF and the reaction mixture is heated to 50° C. for 3.5 h. Another 241 mg CuI and 888 mg Pd(PPh3)2Cl2 and 9 g (38 mmol) 2,5-dibromo-pyridine are added, the mixture is stirred for a further 2.5 h at 50° C., 64 h at RT and a further 8 h at 60° C. The mixture is evaporated down i. vac., the residue is combined with 500 mL 3% NH3 solution and 800 mL EtOAc. The precipitate formed is filtered off, washed with water and dried at 50° C. The two phases of the filtrate are separated and the organic phase is evaporated down i.vac. The residue is stirred vigorously with 500 mL PE/diisopropylether (1:1) and suction filtered. The two product fractions are then combined.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5](=[CH:9][C:10]=1[Cl:11])[C:6]([OH:8])=O>C(OC(=O)C)(=O)C>[Cl:11][C:10]1[CH:9]=[C:5]2[C:6](=[O:8])[O:14][C:12](=[O:13])[C:4]2=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A suspension of 4,5-dichlorophthalic acid [(XVII), X=4--Cl, Y=5--Cl, 50.0 g, 0.213 mol] and acetic anhydride (70 mL) was heated to reflux until dissolution occurred. A distilling head was then attached and 30 mL of distillate was removed. The solution was cooled to room temperature whereupon a precipitate appeared. This solid was filtered, washed with anhydrous ether and dried in vacuo to provide the product (40.4 g, 87%) as a tan solid, m.p. 189°-192° C.