Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14](F)[CH:13]=2)=[O:9])=[C:6]([CH3:20])[CH:5]=[C:4]([Cl:21])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([SH:30])[CH3:29].O>CN(C=O)C>[Cl:21][C:4]1[N:3]=[C:2]([S:30][CH2:28][CH3:29])[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[O:9])=[C:6]([CH3:20])[CH:5]=1
Reactant: CCS
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A solution of 4.0 g (12.8 mmol) 2,6-dichloro-N-(3,5-difluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide in DMF (30 ml) was treated with 2.6 g (19.2 mmol) K2CO3 and 1.2 ml (16.0 mmol) ethanethiol, followed by stirring in a closed vessel at RT for 16 h. Then water (35 ml) was added and the mixture was extracted with EtOAc (2×70 ml). The combined organic layers were washed with water, a 2M aq. NaOH sol. and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 3.3 g (9.7 mmol, 76%) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCN(S(C)(=O)=O)CC2)cc1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 8-methoxy-9-[4-(piperazin-1-yl)phenyl]thieno[2,3-c]quinolin-4(5H)-one (89 mg, 0.23 mmol) in methylene chloride (2 mL) was added N,N-diisopropylethylamine (0.42 mL, 0.68 mmol) and methanesulfonyl chloride (45 μL, 0.27 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with water and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered, concentrated and the residue was purified by preparatory HPLC (C18 silica, acetonitrile/water w/0.05% TFA gradient) to afford the desired product (72 mg, 68%) as a brown solid: ESI MS m/z 470 [C23H23N3O4S2+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][N:15]=[N+]=[N-])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([CH2:14][NH2:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(CN=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CN)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-azidomethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.97 mmol, 0.25 g) in THF (4 mL) was added triphenylphosphine (1.1 mmol, 0.3 g) and stirred for 12 h at room temperature. Water (2 mL) was added to the reaction mixture and stirred for 4 h. The reaction mixture was diluted with EtOAc (10 mL), and the organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 4-aminomethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[CH:10]=[CH:9][C:8]=2[CH3:20])(=[O:3])[CH3:2].[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]2[C:12]([C:13]=1[NH:25][CH:22]([CH3:24])[CH3:23])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)ccc(C)c2[nH]c1=O
Reactant: CC(C)N
Product: CC(=O)c1c(NC(C)C)c2cccc(C)c2[nH]c1=O
Yield: 100.3 %

Procedure:
3-Acetyl-8-methyl-4-methylsulfoxy-2-quinolinone (2.63g, 0.01 mol) and isopropylamine (0.6g, 0.01 mol) were used, but the reaction was carded out as the above process of example 37 to obtain the desired product (2.59g, yield: 68%).
Reaction SMILES: C(O)C.[CH2:4]([N:6]([CH2:32][CH3:33])[C:7](=[O:31])[CH:8]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=2[F:30])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:5].O.O.Cl[Sn]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([CH:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:7]([N:6]([CH2:4][CH3:5])[CH2:32][CH3:33])=[O:31])[CH2:16][CH2:17]2)=[C:22]([F:30])[CH:23]=1
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
A 500 mL, round-bottomed flask under a positive pressure of nitrogen was equipped with a magnetic stirrer and charged with absolute ethanol (150 mL) followed by N,N-diethyl-2-[4-(2-fluoro-4-nitro-phenyl)piperazin-1-yl]-2-phenyl-acetamide (5.6 g, 13.5 mmol). To this stirred solution was added in one portion, SnCl2.2H2O (9.1 g, 40.3 mmol) and the reaction mixture was placed in a pre-heated oil bath maintained at ˜85° C. for 8 h. The reaction mixture was cooled to ambient temperature and then concentrated on the rotary evaporator to yield a viscous orange-brown oil. To this oil was added saturated aqueous sodium carbonate solution (100 mL) and EtOAc (150 mL). The resulting biphasic suspension was stirred at ambient temperature for 0.5 h, then filtered through a pad of Celite®. The Celite® pad was washed with EtOAc (2×50 mL). The filtrates were combined and phases were separated. The aqueous layer was extracted with EtOAc (1×50 mL). The organic layers were pooled, and dried over anhydrous sodium sulfate, filtered and concentrated to yield the title compound as a reddish-brown oil, which was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([CH3:10])=[C:5]([Cl:11])[C:4]=1[OH:12].C(N(CC)C1C=CC=CC=1)C.[CH3:24][C:25](C)=[O:26].C(Cl)(=O)C>O>[C:25]([NH:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([CH3:10])=[C:5]([Cl:11])[C:4]=1[OH:12])(=[O:26])[CH3:24]
Reactant: CC(C)=O
Reactant: Cc1c(Cl)cc(N)c(O)c1Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)Cl
Solvent: CCN(CC)c1ccccc1
Product: CC(=O)Nc1cc(Cl)c(C)c(Cl)c1O

Procedure:
To a mixture of 68.4 g. of 2-amino-5-methyl-4,6-dichloro-phenol hydrochloride and 96 ml. of N,N-diethylaniline in 750 ml. of acetone, 23.4 ml. of acetyl chloride were added slowly by keeping the temperature under 20° C. At the end, the reaction mixture was heated to reflux for an hour. After cooling, the solution was poured into water; the solid product, thus obtained, was collected on a buckner, washed with water until the washings were neutral and dried in a desicator at 50° C. The raw product obtained was purified by crystallization from ethyl alcohol, yielding 44 g. of a pure product with M.P. = 175°-176.5° C.
Reaction SMILES: Br[C:2]1[C:3]([O:37][CH3:38])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:31])[N:16]([CH:28]([CH3:30])[CH3:29])[CH2:17][CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C:13]=4[C:12]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)=[C:9]3[C:10]=2[CH:11]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41](B(O)O)[CH:40]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH:28]([N:16]1[C:15](=[O:31])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:37][CH3:38])[C:2]([C:41]5[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:13]=2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:17]1)([CH3:30])[CH3:29]
Reactant: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Yield: 93.6 %

Procedure:
A mixture of 60 mg of 10l, 22 mg of 3-pyridylboronic acid, 12 mg of Pd(PPh3)4 and 40 mg of K2CO3 in 3 ml of degassed 90% aq. DME was heated under N2 for 16 h. The reaction mixture was poured onto 1M K2CO3 solution and the product was extracted with ethyl acetate. The organic extract was washed once with sat. NaCl, dried and concentrated. The crude material thus obtained was chromatographed over silica gel, using heptane/acetone in a gradient. The isolated product was triturated with diethyl ether, to give 56 mg of 10m, Mp: 207-208° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.C(N(CC)CC)C.[O:24](C(OC(C)(C)C)=O)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:25](=[O:24])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
To a mixture of Example 260a (2.60 g, 7.39 mmol) and triethylamine (1.340 mL, 9.61 mmol) in tetrahydrofuran (50 mL) was added BOC2O (1.78 g, 8.13 mmol) at 0° C. The ice bath was removed and the reaction was stirred at room temperature for 90 minutes. The reaction was diluted with EtOAc and washed with brine and sat. NaHCO3. The organic layer was dried over MgSO4, filtered, concentrated, and purified on an 80 g column using the ISCO Companion flash system eluting with hexane/EtOAc (8:2 to 6:4) to give 1.78 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:21])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (120 mg, 0.48 mmol) in N,N-dimethylformamide (6 ml) was added sodium hydride (23 mg, 0.57 mmol, 60% dispersion in oil) and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was then cooled to 0° C. and methyl iodide 0.04 ml, 0.64 mmol) was added dropwise. After stirring for 16 hours at room temperature, the mixture was quenched by addition of water (10 ml) and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over sodium sulphate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: heptane/ethyl acetate gradient) to yield the title compound as a colorless oil (52 mg, 41%); MS (ISP): 264.0 ([M+H]+), 208.1 ([M+H-Me2C═CH2]+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2Br)[C:35]([F:38])([F:37])[F:36])[N:3]=1.O1CCOCC1.[C:53]1(B(O)O)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>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].C(Cl)Cl.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.13 mmol) in 10:1 dioxane:water (5 mL) was phenyl boronic acid (33 mg, 0.27 mmol), KHCO3 (27 mg, 0.3 mmol), and PdCl2(dppf)-CH2Cl2 (6 mg, 0.007 mmol). The reaction was heated to 100° C. for 15 h, cooled to RT, and concentrated in vacuo. The residue was diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [Br-:1].C([O:5][C:6]1[C:15]2[N+:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Br:16])(=O)C.[CH2:17]([O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[CH:18]=[CH2:19].CCOCC>C(O)(C)C>[CH2:17]([O:20][C:21]1[CH:27]=[CH:26][C:24]([NH3+:25])=[CH:23][CH:22]=1)[CH:18]=[CH2:19].[Br-:16].[Br:16][C:7]1[CH:8]=[CH:9][N+:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[OH:5].[Br-:1]
Reactant: C=CCOc1ccc(N)cc1
Reactant: CC(=O)Oc1c(Br)cc[n+]2ccccc12
Agent: [Br-]
Solvent: CC(C)O
Solvent: CCOCC
Product: C=CCOc1ccc([NH3+])cc1
Product: Oc1c(Br)cc[n+]2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 1-acetoxy-2-bromoquinolizinium bromide (10.0 g., 0.029 mole) in isopropanol (200 ml.) was added p-allyloxyaniline (11.0 g., 0.068 mole). The stirred mixture was boiled under reflux for 4.5 hours. The reaction mixture was cooled at room temperature overnight, and the solid was removed by filtration and washed with ether, providing 5.0 g. of product. The supernatant solution was treated with ether and refrigerated, providing another 5.0 g. of product, making the total yield 10.0 g. (77%). Recrystallization from isopropanol produced a light yellow powder melting at 125°-127°.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH2:15])[CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH3:3].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28](O)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28]([NH:15][C:10]3[CH:9]=[CH:8][C:7]4[CH2:6][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:14][CH2:13][C:12]=4[CH:11]=3)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: CN(C)CC1CCc2cc(N)ccc2C1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Product: CN(C)CC1CCc2cc(NC(=O)c3cc(-c4ccc(Cl)cc4)c[nH]3)ccc2C1

Procedure:
Following preparation as described in WO 03/087046, 6-((dimethylamino)-methyl)-5,6,7,8-tetrahydronaphthalen-2-amine was converted to the title compound (8 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (25 mg) following the procedure described in step C of Example 1. MS (ESI) 408 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1(N)[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:3]1[C:4](O)=[O:5].[CH:14]([NH2:16])=O>C(O)C>[CH3:12][O:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:14][NH:16][C:4]2=[O:5]
Reactant: COC1=CC(C(=O)O)C(N)(N)C=C1
Reactant: NC=O
Solvent: CCO
Product: COc1ccc2nc[nH]c(=O)c2c1
Yield: 50 %

Procedure:
To 1.025 mmoles of 2-amino-5-methoxy anthranilic acid add 6.14 mmoles of formamide and microwave reaction mixture for 20 mins at 160° C. After cooling the solid was diluted with 10 mL ethanol, the mixture was heated to reflux and allowed to cool slowly. The solid obtained was filtered and washed with cold ethanol and vacuum dried to give the title compound in 50% yield.
Reaction SMILES: NC1C=CC=CC=1.C1(C)C=CC=CC=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:26])C(O)=O)=[CH:18][C:17]=1[Br:27]>ClC1C=CC=CC=1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:26])=[CH:18][C:17]=1[Br:27]
Reactant: O=C(O)C(=O)c1ccc(F)c(Br)c1
Solvent: Cc1ccccc1
Solvent: Nc1ccccc1
Solvent: Clc1ccccc1
Product: O=Cc1ccc(F)c(Br)c1

Procedure:
102.3 g (1.1 moles) of freshly distilled aniline were added dropwise to a mixture of 1,300 ml of toluene or chlorobenzene and 247 g of 4-fluoro-3-bromophenylglyoxylic acid at 70° to 80° C. The reaction mixture was then heated to the reflux temperature, and was stirred under reflux for a further 4 hours in order to bring the decarboxylation to completion. Thereafter, the solvent was stripped off in vacuo. 270 g (97% of theory) of the anil remained in the form of a colorless powder with a melting point of 45° to 47° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 67.8 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 13.04 mmol) with 2-methoxyphenylboronic acid (3.96 g, 26.09 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.532 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 3.63 g (68%) of (±)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. mp 151-153° C.; Anal. calcd. for C23H22O5S: C, 67.3; H, 5.4. Found: C, 66.95; H, 5.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([C:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=3)=[N:9]2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[C:53](=[O:54])[C:52]([C:55](O)=[O:56])=[CH:51][CH:50]=[N:49]2)=[CH:44][CH:43]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:55]([C:52]2[C:53](=[O:54])[N:48]([C:45]3[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=3)[N:49]=[CH:50][CH:51]=2)=[O:56])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=3)[N:9]=[C:10]([C:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:28][CH:27]=3)[C:11]=12
Reactant: COc1ccc(Cn2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A 50 mL round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (50.0 mg, 0.0916 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (42.9 mg, 0.183 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (52.7 mg, 0.275 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (37.1 mg, 0.275 mmol), N-ethyl-N-isopropylpropan-2-amine (0.0818 ml, 0.458 mmol) and DMF (5 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (2 days). The reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (38.3 mg, 54.9%). LRMS (APCI pos) m/e 662 (M−99).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCOC(=O)CCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of 1.42 g of 2,4-dihydroxy-3-propylacetophenone, 2 g of ethyl 4-bromobutyrate, 1.5 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred overnight at room temperature. After addition of 100 ml of water to the reaction mixture, the product was extracted with 30 ml of toluene. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue thus formed was applied to silica gel column chromatography and eluted with toluene to provide 1.5 g of ethyl 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyrate as an oily product. In a solution of 2 g of potassium hydroxide dissolved in 40 ml of 80% methanol was dissolved 1.3 g of the oily product and the solution was allowed to stand for one hour. To the reaction mixture was added 20 ml of water and methanol was distilled off under reduced pressure. The aqueous solution thus obtained was acidified by 5% hydrochloric acid and extracted by ethyl acetate. The extract thus formed was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off to provided 1.1 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyric acid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC([O:24][CH2:25][CH3:26])=O.O[C@H:33]([CH3:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36].[S:40]1C=CC=C1CC(O)=O>C1COCC1>[C:25]([S:40][C@@H:33]([CH3:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:24])[CH3:26]
Reactant: O=C(O)Cc1cccs1
Reactant: COC(=O)C[C@@H](C)O
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C[C@H](C)SC(C)=O
Temperature: -23 °C
Reaction time: 16 h

Procedure:
To a -23° C. solution of PPh3 (40 mmol, 10.48 g) in THF (100 mL) was added diethyl azodicarboxylate (40 mmol, 6.28 mL) dropwise and the mixture was stirred at -23° C. for 16 hours, during which time a white precipitate was obtained. A THF (30 mL) solution of methyl 3(R)-hydroxybutanoate (20 mm, 2.36 g) and thiolacetic acid (20 mmol, 2.85 mL) was slowly added and the mixture was allowed to slowly warm to 25° C. and was stirred 16 h at 25° C. Most THF was removed in vacuo and EtOAc (10 mL) and hexanes (100 mL) were added. Insolubles were removed by filtration and the residue was purified by chromatography on silica gel to afford the title compound.