Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[N:4]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH:34]=O)=[CH:28][CH:27]=1.C(N(CC)CC)C.C([BH3-])#N>CO.C1(C)C=CC=CC=1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][N:21]2[CH2:22][CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15]([NH:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([C:7]4[N:3]([CH3:2])[N:4]=[N:5][N:6]=4)[CH:9]=3)=[O:16])[CH2:20]2)=[CH:28][CH:27]=1
Reactant: O=CCCc1ccc(F)cc1
Reactant: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCNC2)c1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCN(CCCc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 64.2 %

Procedure:
A mixture of 1-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-piperidin-3-ylmethylurea hydrochloride (35 mg, 100 μmol), 3-(4-fluorophenyl)-propionaldehyde (15 mg, 100 μmol), triethylamine (15 μL, 110 μmol), resin-bound cyanoborohydride (prepared according to Ley, S. V., et al., J. Chem. Soc. Perkin Trans. 1, 1998, 2239; 100 mg), toluene (1 mL) and methanol (1 mL) was agitated gently at room temperature for 65 hours. The mixture was filtered, the resin was washed with dichloromethane, and the filtrates were concentrated. The residue was purified by flash chromatography, eluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide, to provide an amorphous white solid (29 mg, 64%). 1H NMR (300 MHz, CDCl3) δ7.88 (s, 1H), 7.79 (d, J=8 Hz, 1H), 7.44 (t, J=8 Hz, 1H), 7.27 (m, 1H), 7.11 (m, 2H), 6.93 (t, J=9 Hz, 2H), 4.18 (s, 3H), 3.2-3.0 (m, 4H), 2.59 (m, 4H), 2.3-1.8 (m, 8H), 1.10 (m, 1H). Mass Spec (ES+) m/z 452.4 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[OH:18])[O:9][C:6]2=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:32](I)([CH3:34])[CH3:33]>O>[CH:32]([O:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=2)([CH3:34])[CH3:33]
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 60 °C
Yield: 53.5 %

Procedure:
To a mixture of 0.26 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.14 g of potassium carbonate and 3 ml of DMF, 0.17 g of isopropyl iodide was added at room temperature and stirred while heating at 60° C. for 1.5 hours. To the reaction solution, 38 mg of potassium carbonate and 47 mg of isopropyl iodide were added, and the reaction solution was stirred while heating at 60° C. for two hours. The reaction solution was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.16 g of 2-(3-isopropoxypyridin-4-yl)-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as “active compound 160”).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[C:3]=1[O:12][C:13]([F:16])([F:15])[F:14].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C@H:25]2[CH3:37])=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C@H:25]3[CH3:37])=[N:22][CH:23]=2)=[O:8])=[C:4]([F:11])[C:3]=1[O:12][C:13]([F:16])([F:15])[F:14]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cn1
Reactant: O=C(O)c1ccc(Br)c(OC(F)(F)F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(NC(=O)c2ccc(Br)c(OC(F)(F)F)c2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 4-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (150 mg, 0.50 mmol, Preparation 52), (R)-tert-butyl 4-(5-aminopyridin-2-yl)-3-methylpiperazine-1-carboxylate (145 mg, 0.50 mmol), and HATU (235 mg, 0.62 mmol) dissolved in DMF (1 mL) was added DIPEA (0.43 mL, 2.48 mmol). The reaction mixture was stirred at RT for 1 h, extracted with EtOAc (80 mL) washed with water (3×20 mL) and brine (20 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (12 g silica gel, 0-40% EtOAc:hexanes over 20 min), to provide the title intermediate (203 mg, 71% yield) as a yellow solid. (m/z): [M+H]+ calcd for C23H25BrF4N4O4 577.10; 579.10. found 579.0.
Reaction SMILES: [CH3:1][C:2]1([CH:5]([O:9][CH2:10][CH:11]=O)[CH2:6][CH:7]=[CH2:8])[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].Cl.[NH2:19][OH:20]>C(O)C.O>[OH:20][NH:19][CH2:11][CH2:10][O:9][CH:5]([C:2]1([CH3:1])[CH2:4][CH2:3]1)[CH2:6][CH:7]=[CH2:8]
Reactant: C=CCC(OCC=O)C1(C)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCC(OCCNO)C1(C)CC1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
{[1-(1-Methylcyclopropyl)but-3-en-1-yl]oxy}acetaldehyde (C54) (27.7 g from the previous step, ≦165 mmol) was dissolved in a 2:1 mixture of ethanol and water (39 mL). Sodium acetate (63.1 g, 770 mmol) was added; after the reaction mixture had been stirred for 15 minutes, hydroxylamine hydrochloride (98%, 32.1 g, 462 mmol) was added. The reaction mixture was heated to 60° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol and extracted with dichloromethane (2×140 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 22° C. Silica gel chromatography (Gradient: 0% to 12% ethyl acetate in petroleum ether) provided the product as a colorless oil. By 1H NMR analysis, this material consisted of a roughly 1:1 mixture of E and Z oxime isomers. Yield: 4.1 g, 22.4 mmol, 48% over two steps. 1H NMR (400 MHz, CDCl3) δ [7.49 (t, J=5.6 Hz) and 6.91 (t, J=3.6 Hz), total 1H], 5.82-5.92 (m, 1H), 5.00-5.10 (m, 2H), {[4.52 (dd, half of ABX pattern, J=16.4, 3.2 Hz) and 4.35 (dd, half of ABX pattern, J=16.4, 3.6 Hz)] and [4.27 (dd, half of ABX pattern, J=13.2, 5.6 Hz) and 4.09 (dd, half of ABX pattern, J=12.8, 6.0 Hz)], total 2H}, 2.59-2.64 (m, 1H), 2.25-2.45 (m, 2H), 1.02 (s, 3H), 0.42-0.56 (m, 2H), 0.18-0.29 (m, 2H).
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13](C)=[C:14]([C:29]([O:31][CH2:32]CO)=[O:30])[CH:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]=1[C:17]([O:19][CH2:20][CH2:21][OH:22])=[O:18]>C(Cl)CCl.N1C=CC=CC=1>[CH3:10][C:11]1[NH:12][C:13]2[CH2:32][O:31][C:29](=[O:30])[C:14]=2[CH:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]=1[C:17]([O:19][CH2:20][CH2:21][OH:22])=[O:18]
Reactant: CC1=C(C(=O)OCCO)C(c2ccccc2)C(C(=O)OCCO)=C(C)N1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC1=C(C(=O)OCCO)C(c2ccccc2)C2=C(COC2=O)N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.33 grams of 80 percent pyridinium bromide perbromide (1.46 millimoles) was added to a solution of 500 milligrams (1.51 millimoles) of bis(2-hydroxyethyl) 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate in 400 milliliters of ethylene dichloride and 1.6 milliliters of pyridine. The resulting mixture was stirred at 0° C. for 1 hour and then heated at reflux temperature for 2 hours. Thereafter, the mixture was cooled to room temperature, the resulting solution washed with 2N hydrochloric acid, sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered, and the filtrate subjected to reduced pressure to vaporize the solvent and to recover as residue a semi-crystalline solid. The solid was not crystallizable from acetonitrile. The acetonitrile was vaporized to obtain an orange oil which on trituration with ethyl acetate produced crystals. The crystals, after recrystallization twice from ethyl acetate, had a melting point of 185°-186° C. 1H NMR and elemental analyses showed the product to have ethyl acetate solvate of crystallization. Elemental analyses were as follows:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([Cl:20])[C:5]2[O:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7](=[O:16])[C:6]=2[C:17]=1[O:18]C.B(Cl)(Cl)Cl.ClCCl.C(OCC)C>CCCCCC>[Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:4]([Cl:20])[C:5]2[O:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7](=[O:16])[C:6]=2[C:17]=1[OH:18]
Reactant: CCOC(=O)COc1c(Cl)c(OC)c2c(c1Cl)OC1(CCCCC1)CC2=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)COc1c(Cl)c(O)c2c(c1Cl)OC1(CCCCC1)CC2=O

Procedure:
According to the procedure of Preparation 66 employing ethyl 2-{(6,8-dichloro-5-methoxy-3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan]-7-yl)oxy}acetate (65-1, prepared in Preparation 65) (0.635 g, 1.52 mmol) and 2M boron trichloride solution in dichloromethane (1.7 ml, 3.4 mmol), the title compound is prepared as a crystalline solid (0.60 g, yield 98%). Recrystallizaton from a mixture of diethyl ether and hexane gives a product having a melting point of 134°-135° C.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[OH:19][CH2:20][CH2:21][NH:22][C:23]1[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.ClC1N=CC(C#N)=CC=1.NC(O)C>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([O:19][CH2:20][CH2:21][NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Reactant: N#Cc1ccc(NCCO)nc1
Agent: CC(N)O
Agent: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NCCOc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1

Procedure:
In analogy to the procedure described for Example 90, 35 mg (48% of theory) of the product are obtained starting from 50 mg (0.17 mmol) of 5-chloro-7-(2,4-dichlorophenyl)imidazo-[1,2-c]pyrimidine (Example 6A) by reaction with 38 mg (0.23 mmol) of 6-[(2-hydroxyethyl)amino]pyridine-3-carbonitrile, which can be prepared in analogy to the synthesis of Example 48A from 6-chloropyridine-3-carbonitrile and aminoethanol, after subsequent purification by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9][C:4]=2[CH:3]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+].[I-].[K+].[CH3:26][C:27]([CH3:29])=[O:28]>>[C:27]([C:29]1[CH:6]=[CH:7][C:8]([O:9][CH2:4][CH2:3][CH2:2][CH2:17][CH2:16][O:1][C:2]2[CH:17]=[CH:16][C:5]3[C:6](=[O:15])[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9][C:4]=3[CH:3]=2)=[CH:10][C:18]=1[OH:21])(=[O:28])[CH3:26]
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)c1cc(=O)c2ccc(OCCCCCOc3ccc(C(C)=O)c(O)c3)cc2o1

Procedure:
A mixture of 3.05 parts of 4-(5-bromopentyloxy)-2-hydroxy acetophenone, 2.34 parts of ethyl 7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate, 1.38 parts of potassium carbonate and 0.5 parts of potassium iodide, in 200 parts of dry acetone, was heated under reflux for 24 hours. The solution was filtered while hot and the inorganic salts washed with hot acetone. The solvent was removed to leave a yellow solid, which was washed with water and ether. The insoluble yellow solid was crystallised from ethyl alcohol to yield 3.3 parts of ethyl 7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-4-oxo-4H-1-benzopyran-2-carboxylate as pale yellow needles, melting point 136°-137° C.
Reaction SMILES: N12CCCN=C1CCCC=C2.[Cl:12][C:13]1[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[N+:25]([O-:27])=[O:26])=[N:15][NH:16][CH:17]=1.[CH2:28]=[O:29]>C1COCC1>[OH:29][CH2:28][N:16]1[CH:17]=[C:13]([Cl:12])[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[N+:25]([O-:27])=[O:26])=[N:15]1
Reactant: O=[N+]([O-])c1c(Cl)cccc1-c1n[nH]cc1Cl
Reactant: C=O
Agent: C1=CN2CCCN=C2CCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(Cl)cccc1-c1nn(CO)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
0.40 ml of 1,8-diazabicyclo[5.4.0]undecen-7-ene is added, at room temperature, to a solution of 7.0 g (0.027 mol) of 4-chloro-3-(2-nitro-3-chlorophenyl)pyrazole and 2.40 g of paraformaldehyde in 100 ml of THF. The reaction mixture is stirred for 4 hours at room temperature, concentrated under reduced pressure and taken up in a mixture of 150 ml of water and 150 ml of methylene chloride. The organic phase is dried over magnesium sulphate and concentrated under vacuum. 7.40 g of 1-hydroxymethyl-4-chloro-3-(2-nitro-3-chlorophenyl)pyrazole melting at 146° C. are obtained (yield: 95.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:11][C:12]([CH2:33][CH3:34])=[C:13]([CH:32]=1)[O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:20]([CH2:29][CH2:30][CH3:31])=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24]C)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CN1CCCC1=O.O.COC(C)(C)C>[CH2:1]([O:8][C:9]1[C:10]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[CH:11][C:12]([CH2:33][CH3:34])=[C:13]([CH:32]=1)[O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:20]([CH2:29][CH2:30][CH3:31])=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([OH:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)cccc1C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)cccc1C(=O)O
Temperature: 120 °C
Reaction time: 0.42 h

Procedure:
To a solution of methyl 3-[3-[5-benzyloxy-2-ethyl-4-(4-fluorophenyl)phenoxy]propoxy]-2-propyl-benzoate (119 g, 181 mmol) in N-methylpyrrolidone (476 mL), add potassium hydroxide (21.2 g, 378 mmol) and stir 25 min at 120° C. Allow the mixture to cool and then dilute with water (240 mL) and methyl-tert-butylether (100 mL). Adjust to pH=2.5 with 12 N hydrochloric acid. Separate the phases and wash the aqueous phase with methyl-tert-butylether (3×35 mL). Wash the combined organic extracts twice with water and once with brine. Concentrate the organic extracts in vacuo. Recrystallize the resultant residue from acetonitrile, filter, and dry to yield (78 g, 67%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.60-7.47 (m, 3H); 7.37-7.20 (m, 6H); 7.12-7.02 (m, 4H); 6.60 (s, 1 H); 5.00 (s, 2H); 4.20 (m, 4H); 3.00 (m, 2H); 2.61 (q, J=7.7 Hz, 2H); 2.33 (m, 2H); 1.59 (m, 2H); 1.18 (t, J=7.7 Hz, 3H); 0.98 (t, J=7.7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18]C)=[O:17])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CO.O1CCOCC1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([OH:18])=[O:17])[CH3:13])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccccc1N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CN(c1ccccc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(3,4-dichloro-N-methylphenylsulfonamido)benzoate (21.0 g, 56.1 mmol) was dissolved in a mixture of methanol/dioxane/4 M NaOH (15/4/1, 420 ml, 84 mmol NaOH, 1.5 eq.), and further 4 M NaOH (63 ml, 252 mmol, 4.5 eq.) was added. The solution was stirred overnight at room temperature and then concentrated using a rotary evaporator. Ethyl acetate (800 ml) was added to the residue, and the mixture was washed with 0.5 M KHSO4 (1000 ml). The aqueous phase was then extracted three times with ethyl acetate (350 ml each time), and the combined organic phases were washed with saturated NaCl solution (500 ml). The organic phase was dried (sodium sulfate) and concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].C(O)(=O)C>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])([CH3:9])[CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[CH:4][CH:3]=1.[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:9])=[CH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccn1
Reactant: CC(=O)c1ccc(Br)cc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=Cc1ccccn1)c1ccc(Br)cc1
Product: CC(O)(Cc1ccccn1)c1ccc(Br)cc1
Yield: 26 %
Yield: 63 %

Procedure:
2-(p-Bromophenyl)-1-(2-pyridyl)-2-propanol is prepared from p-bromoacetophenone and 2-picoline according to the method of Villani, et al., J. Med. Chem., 13, 359 (1970) in 63% yield. This alcohol (129.1 g.) is dehydrated by heating in 1150 ml. of acetic acid-12 N hydrochloric acid (3:1) at reflux temperature for 4 hr. The mixture is evaporated in vacuo, made basic with concentrated ammonium hydroxide, and extracted with ethyl acetate. The ethyl acetate extract is washed with water and brine, dried over sodium sulfate, and evaporated to give a dark brown oil. A solution of the oil in benzene is passed through a column of silica gel. Evaporation of the eluate gave 46.4 g (26% yield) of crystalline 2-(p-bromophenyl)-1-(2-pyridyl)propene, m.p. 71.5°-73.5° C. (corr.).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].Cl.[NH2:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([NH:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CC(=O)SCC(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)C(C)CSC(C)=O

Procedure:
3-Acetylthio-2-methylpropanoyl chloride (3.78 ml., 25 mmole) is added dropwise over six minutes to a cold (-5°), stirred suspension of (L)-methionine, methyl ester, hydrochloride salt (4.99, 25 mmole) and triethylamine (13.94 g.) in methylene chloride (100 ml.). The mixture is stirred in the cold for three hours and then diluted with methylene chloride (100 ml.). The resulting yellow solution is washed sequentially with 10% aqueous HCl (70 ml.), saturated sodium bicarbonate (70 ml.) and brine (100 ml.), dried over sodium sulfate, and concentrated in vacuo to give (±)-N-[3-(acetylthio)-2-methyl-1-oxopropyl]-L-methionine, methyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1ccc(C=O)cn1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1ccc(C=CC(=O)O)cn1
Reaction time: 3 h
Yield: 59.4 %

Procedure:
A mixture of 6-methylpyridine-3-carboxaldehyde (51.57 g), malonic acid (44.30 g), piperidine (6 ml) and pyridine (300 ml) was stirred at 100° for 3 hours and was allowed to cool. The mixture was evaporated to dryness, water was added to the residue and the solid was filtered off and recrystallised from ethanol-acetic acid to give 3-(6-methyl-3-pyridyl)acrylic acid (41.25 g) m.p. 213.5°-215.5°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[C:42]1([CH2:48][CH2:49][CH2:50][NH2:51])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:42]1([CH2:48][CH2:49][CH2:50][NH:51][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=2)=[O:10])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCc1ccccc1)c1ccc(O)cn1
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
To a solution of 5-hydroxypyridine-2-carboxylic acid (0.103 g, 0.74 mmol) in dichloromethane was added diisopropylethylamine (0.279 mL, 1.6 mmol), followed by 1-hydroxybenzotriazole monohydrate (0.012 g, 0.8 mmol) and EDCI (0.153 g, 0.8 mmol). The resulting mixture was stirred for 15 minutes and 3-phenyl-1-propylamine (0.108 g, 0.8 mmol) was added. After stirring for 22 h, the reaction mixture was diluted with dichloromethane (80 mL), washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by column chromatography afforded 5-hydroxypyridine-2-carboxylic acid (3-phenylpropyl)amide as white crystals (0.116 g, 61% yield). MS (ES+) m/z 257.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[N:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:22][N:23]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)cc2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Reaction time: 2 h

Procedure:
To the solution of tert-butyl 4-(6-(2-(4-(2-methylpyridin-4-yl)phenyl)acetamido)pyridin-3-yl)piperazine-1-carboxylate (125) (1.5 g, 3 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction was stirred for 2 hours. The excess TFA and solvent was removed by rotary evaporation to give 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1. The compound was used for next step without further purification. MS m/z 388.2 (M+1).
Reaction SMILES: [O:1]=[C:2]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)[CH:26]=2)[CH2:21][CH2:20]1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>ClCCl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[CH:33]=[N:32][CH:31]=[N:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3cncnc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3cncnc3)cc21
Reaction time: 3 h
Yield: 75.7 %

Procedure:
The (S)-tert-butyl 1-oxo-3-phenyl-1-(6-(pyrimidin-5-yl)indolin-1-yl)propan-2-ylcarbamate (64 mg, 144 μmol) was dissolved in dichloromethane (1.0 mL) and TFA (1.0 mL, 13 mmol) was added. The resulting solution was stirred for three hours then concentrated. The residue was taken up in ethyl acetate and filtered and washed with hexanes to give the desired product (S)-2-amino-3-phenyl-1-(6-pyrimidin-5-yl-2,3-dihydro-indol-1-yl)-propan-1-one trifluoroacetate (50 mg, 76% yield) as the mono-trifluoroacetic acid salt. MS ESI (pos.) m/e: 345.1 (M+H).