Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([C@H:14]([OH:23])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[Li].O>C1COCC1.O>[OH:23][C@@H:14]([C@@H:4]([CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:3]([OH:24])=[O:2])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.2 %

Procedure:
A solution of (R)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester (230 mg, 0.69 mmol) and LiOH.H2O (57.5 mg, 1.37 mmol) in a mixture of THF and water (2:1, 6 ml) was stirred at room temperature for 2.5 hrs. The reaction was diluted with water and THF removed under reduced pressure. The pH of the aqueous solution was adjusted to pH5 with 1N HCl and extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and evaporated under reduced pressure to give the title compound as white solid (180 mg); 1H NMR (CDCl3) δ 1.92–1.60 (m, 4H), 2.75–2.60 (m, 3H), 3.78–3.45 (m, 9H), 4.5 (d, J=8 Hz, 1H), 7.35–7.18 (m, 5H); MS: 322(MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH2:23])[N:16]=3)=[C:9]([F:30])[CH:8]=1.[I-].[CH3:32][S+](C)(C)=O.CC(C)([O-])C.[K+]>C1COCC1.CS(C)=O>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:32][CH2:23]2)[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCOCC1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CCOCC4)CC3)nc2s1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)vinyl)thiazolo[5,4-b]pyridine (0.201 g, 0.471 mmol) in 2.5 mL THF was added a solution of trimethylsulfoxonium iodide (0.207 g, 0.943 mmol) and potassium tert-butoxide (0.106 g, 0.943 mmol) in 2.5 mL DMSO. The yellow slurry was sealed and heated to 60° C. After 6 h, the reaction mixture was cooled, quenched with ice and sat'd aq. NH4Cl. The reaction mixture was partitioned between satd aq NH4Cl and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was purified by silica gel chromatography, 0-50% EA/hexanes, to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)thiazolo[5,4-b]pyridine as a solid. MS (ESI) m/z: Calculated: 440.2; Observed: 441.1 (M++1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[CH3:23]>CN1CCCC1=O>[CH3:23][C:14]1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[C:18]([CH3:19])[C:13]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (NaH; 60% dispersion in mineral oil; 64.11 g, 1.603 mol) in 350 mL of N-methylpyrrolidone (NMP) is cooled to 0° C. and treated with a solution of 4-methoxyphenol (208.4 g, 1.679 mol) over 30 min. The mixture is warmed to room temperature (RT) and after 30 min, 4-chloro-3,5-dimethylnitrobenzene (283.2 g, 1.526 mol; prepared by the method described by Yokoyama et. al. in EP580550) is added in one portion and the reaction is heated at 120° C. for 2 h. The reaction is cooled to room temperature (RT) and quenched with water (1500 mL). The suspension is cooled to 0° C., stirred for 30 min, then filtered and the filtercake is washed with water and dried in vacuo. The crude product, ethyl acetate (EtOAc; 2100 mL) and charcoal (42.6 g) were heated to reflux and the solids were removed by filtration through celite while hot. The filtrate is concentrated under reduced pressure to ca. 800 mL and the resulting suspension is cooled to 0° C. and stirred for 30 min. The product is collected by vacuum filtration, washed with cold EtOAc and dried in vacuo to afford 3,5-dimethyl-4-(4′-methoxyphenoxy)nitrobenzene: NMR (CDCl3) 2.22 (s, 6H), 3.78 (s, 3H), 6.68 (d, 2H, J=8.7) 6.82 (d, 2H, J=8.7), 8.02 (s, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[C:8]2[N:9]([CH:13]=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH3:4].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:19]=1[CH2:20]Br>O>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:19]=1[CH2:20][N:6]([C:7]1[C:8]2[N:9]([CH:13]=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1)[C:3](=[O:5])[CH3:4]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CC(=O)Nc1cccn2cc(C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N(Cc1c(Cl)cccc1Cl)c1cccn2cc(C)nc12
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 17 mg) was added 8-acetylamino-2-methylimidazo[1,2-a]pyridine (73 mg), and the mixture was stirred for 30 minutes, 2,6-dichlorobenzyl bromide (97 mg) was added thereto, and the mixture was stirred for 1 hour. Water was added thereto, and the mixture was extracted with methylene chloride three times. The combined organic layer was washed with water four times and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was crystallized with diethyl ether to give 8-[N-(2,6-dichlorophenyl)methyl-N-acetylamino]-2-methylimidazo[1,2-a]pyridine (85 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)C.C([O-])(=O)C.[NH4+].[N+:22]([CH3:25])([O-:24])=[O:23]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:25][N+:22]([O-:24])=[O:23])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(C=C[N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 53.7 %

Procedure:
In a 250 mL flask was placed 42.45 g of 3,4-dimethoxybenzaldehyde (0.255 mole, 1 eq.), 64 mL of glacial acetic acid (4.0 M), 9.83 g of ammonium acetate (0.128 mole, 0.5 eq), and 15.2 mL of nitromethane (0.281 mole, 1.1 eq.). The mixture was stirred well and heated to reflux for 1.5 hour and allowed to cool to room temperature. The reaction mass solidified and was dissolved in methylene chloride (500 mL) and washed with water (2×400 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator to provide 56.33 g of crude product. Crystallization of the product from ethanol (240 mL) and acetone (100 mL) provided 28.66 g of 2-(3,4-dimethoxypheny)-nitroethene (0.137 mole), 53.7% yield.
Reaction SMILES: [CH:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:15])(=O)=O>C(Cl)Cl>[Cl:15][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:1]=[O:11]
Reactant: CCCCCCCCCC=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCC(Cl)C=O
Reaction time: 2 h
Yield: 47.9 %

Procedure:
A mixture of 59 g of caprinaldehyde, 15 ml of methylene chloride and 52 g of sulfuryl chloride was stirred for 2 hours, refluxed for 1 hour and was then rectified to obtain 34.5 g of α-chlorocaprinaldehyde with a boiling point of 115°C at 12 mm Hg and a refractive index of nD27 = 1.4460. A mixture of 11.6 g of the said product, 10 g of ethyl γ-propargyl-β -ethoxy-crotonate and 42.2 ml of butyl lithium were reacted as in Step A of Example 2 to obtain 4.75 g of ethyl 3-oxo-8-hydroxy-9-chloro-6-heptadecynoate with a refractive index of nD22 = 1.4780.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:20])=[C:4]([F:23])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32](=[O:34])[CH3:33]>C1COCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:31][C:32](=[O:34])[CH3:33])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:20])=[C:4]([F:23])[CH:3]=1
Reactant: O=c1ccc(-c2ccc(O)cc2)cn1Cc1ccc(Cl)cc1F
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Temperature: 110 °C
Yield: 19.7 %

Procedure:
According to Scheme 14 Method A: A suspension of 1-(4-chloro-2-fluorobenzyl)-5-(4-hydroxyphenyl)pyridin-2(1H)-one (1 eq, 0.61 mmol, 0.20 g, Example 20 Step 2), K2CO3 (10 eq, 6.10 mmol, 0.84 g) and chloroacetone (4 eq, 2.43 mmol, 0.20 mL) in THF (10 mL) was heated in a microwave at 110° C. during 30 min. After filtration and evaporation, the resulting crude oil was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 80/20 then washed with Et2O and was dried to afford 1-(4-chloro-2-fluorobenzyl)-5-(4-(2-oxopropoxy)phenyl)pyridin-2(1H)-one (0.12 mmol, 46 mg, 20%) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:14][C:15]1[CH:36]=[CH:35][C:18]2/[C:19](=[C:29](/[CH:32]3[CH2:34][CH2:33]3)\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[CH:32]1(/[C:29](=[C:19]2\[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]3[CH:16]=[C:15]([CH2:14][N:8]4[C:7]5[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=5[N:5]=[C:4]4[CH2:1][CH2:2][CH3:3])[CH:36]=[CH:35][C:18]\2=3)/[C:30]#[N:31])[CH2:34][CH2:33]1
Reactant: N#C/C(=C1\c2ccc(CBr)cc2COc2cc(F)ccc21)C1CC1
Reactant: CCCc1nc2ccccc2[nH]1
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(/C#N)C1CC1
Yield: 91.9 %

Procedure:
Using 2-propyl-1H-benzo[d]imidazole (Synthetic Communication, 2002, vol. 32, p 3703, 55 mg, 0.33 mmol) and (E)-2-(8-bromomethyl-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)-2-cyclopropylacetonitrile (120 mg, 0.31 mmol) obtained in Reference Example 6, and in the same manner as in Reference Example 1A, the title compound (132 mg, 92%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:7]=1)[CH3:2].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:17][C:16]=2[CH2:22][S:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSC(C)(C)C)c1
Reactant: CC(C)(C)C(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CSC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 6, using the following starting materials: [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and pivaloyl chloride.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.CS(C)=O.[C-:22]#[N:23].[Na+]>O>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH3:17])=[CH:4][C:3]=2[CH2:2][C:22]#[N:23])=[CH:11][CH:12]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(C)cc2CC#N)cc1
Temperature: 36 °C
Reaction time: 4 h

Procedure:
A solution of 108 g. of 3-chloromethyl-4-(4-methyl-phenoxy)-toluene in 70 ml. of dimethylsulfoxide is added dropwise at 20°-25° C. to a suspension of 23 g. of sodium cyanide in 35 ml. of dimethylsulfoxide. The mixture is subsequently stirred for 4 hours at 36° C., then diluted with 1 Liter of water and extracted three times with benzene. The benzene extracts are washed three times with water, then dried over sodium sulfate and evaporated in vacuo, and there is obtained crude 2-(4-methyl-phenoxy)-5-methyl-phenylacetonitrile as a brown oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])O)[CH3:2].[H-].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23]Cl)=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]=2[CH:31]=1.[Cl-].[Na+]>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:14]=2[CH:31]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CCN(O)CC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 0 °C
Reaction time: 0.92 h

Procedure:
A stirred, ice cold solution of N,N-diethylhydroxylamine (50 ml.) in dimethylformamide (50 ml.) under nitrogen, was treated with a 57% suspension of sodium hydride in mineral oil (1.39 g., 0.033 mole). The mixture was kept at ambient temperature for 55 minutes, cooled in an ice bath and treated with 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo [4,3-a][1,4]benzodiazepine (10.3 g., 0.03 mole). This mixture was kept at ambient temperature for 18 hours and poured into ice water. The resulting mixture was saturated with sodium chloride and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was mixed with xylene and concentrated in vacuo, the resulting material was crystallized from wet methanol-ethyl acetate to give 8-chloro-1-[(diethylamino)-methyl]-6-phenyl-4H-s-triazolo [4,3-a][1,4]benzodiazepine, N1 -oxide dihydrate in two crops: 5.91 g., of melting point 137.5°-139.5° C. dec. and 1.16 g., of melting point 135°-137.5° C. The analytical sample had a melting point of 135°-137.5° C. dec.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.Cl.Cl.[N:16]1([C:22]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[C:1]1([S:7]([N:19]2[CH2:20][CH2:21][N:16]([C:22]([O:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[CH2:17][CH2:18]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Oc1cccnc1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Oc1cccnc1)N1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (0.23 ml) and benzenesulfonyl chloride (0.075 ml) were added to a dichloromethane (5 ml) solution containing 3-pyridyl 1-piperazinecarboxylate dihydrochloride (150 mg), followed by stirring overnight at room temperature. The reaction solution was diluted with chloroform, the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform), and the resulting solid was recrystallized from 2-propanol to obtain 3-pyridyl 4-(phenylsulfonyl)-1-piperazinecarboxylate (130 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:29])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH2:22]>C(O)C>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9]([CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])=[O:29])[CH:10]=1
Reactant: COC(=O)CCc1c[nH]cn1
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Solvent: CCO
Product: COC(=O)CCc1cn(CC(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1
Temperature: 20 °C
Yield: 107.2 %

Procedure:
3-(Imidazol-4-yl)propanoic acid methyl ester (4 g) was added to a solution of 1-(2,4-dichlorophenyl)-2- phenylpropen-1one (7.5 g) in ethanol (50 ml) and the resulting solution maintained at 20° C. for 12 hours. The solvent was removed under reduced pressure to yield 3-[1-[3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]imidazol-4-yl]propanoic acid methyl ester (12 g) as an oil. A portion of the oil (3 g) was dissolved in dimethylformamide (50 ml) and copper-II-chloride dihydrate (10 g) added to the solution. The resulting solution was heated at 80° C. for 18 hours and then cooled to room temperature. Water was added to the reaction mixture and the aqueous phase extracted twice with ethyl acetate. The organic phases were combined, washed with dilute aqueous ammonia, water, and brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield a gum (2.75 g). The gum was chromatographed on silica gel eluting with a mixture of methanol:dichloromethane (1.5:98.5) to yield an oil upon treatment with ethereal hydrogen chloride yielded the hydrochloride salt of 3-[ 1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]imidazol-4-yl]propanoic acid methyl ester (1.56 g), m.p. 144-7° C., (Found: C, 52.75; H, 4.13; N, 5.57%; C22H20Cl4N2O3 requires C, 52.61; H, 4.01; N, 5.58%), having the formula: ##STR31##
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[NH:21][C:20]=2[CH3:32])[CH2:13][CH2:12]1.C(Cl)Cl>CCOCC>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[NH:21][C:20]([CH3:32])=[C:19]2[CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:16][CH2:15]1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2[nH]c(C)c(CCN3CCN(N)CC3)c2cc1OC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2[nH]c(C)c(CCN3CCN(NC(=O)Nc4ccccc4)CC3)c2cc1OC
Reaction time: 2 h

Procedure:
3.5 g of phenylisocyanate are added dropwise to a stirred solution of 7.78 g of 3-[2-(4-aminopiperazin-1-yl)ethyl]-5,6-dimethoxy-2-methylindole in 100 ml. of dry methylene chloride while maintaining the reaction temperature below 35° C. After 2 hours, 50 ml. of ether are added, the product is filtered and washed with ether. The product is recrystallized from ethyl acetate to give a white solid, m.p. 170°-173° C. of 1-[1-(5,6-dimethoxy-2-methylindol-3-ylethyl)piperazin-4-yl]-3-phenylurea.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].CCN(C(C)C)C(C)C.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:23]([CH:20]1[CH2:22][CH2:21]1)=[O:24]
Reactant: NCc1cccc(Br)c1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc(Br)c1)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-Bromo-benzylamine hydrochloride (437.3 mg, 2.0 mmol) was dissolved in dichloromethane (15 mL), and the solution was cooled to 0° C. DIEA (688.0 μL, 3.9 mmol) was then added, and the reaction was stirred at 0° C. for 5 minutes. Then cyclopropanecarbonyl chloride (180.0 μL, 2.3 mmol) was added, and the reaction was stirred at 0° C. for 20 minutes. The reaction was quenched with distilled water, and the solvents were removed. The resulting mixture was redissolved in DMF (10 mL) and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[C:7](/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)\[CH:8]=[O:9])(=[O:3])[CH3:2].CC(=CC)C.[O-:31]Cl=O.[Na+]>CC(O)(C)C.O>[C:1]([O:4][CH2:5]/[C:6](/[C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1)=[C:7](/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)\[C:8]([OH:31])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\C=O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of the aldehyde from Example 3 (160 mg) and 2-methyl-2-butene (6 mL) in 2-methyl-2-propanol (35 mL) was added a solution of NaClO2 (1 g) and NaH2PO4 (1 g) in 10 mL of H2O. The mixture was stirred for 2 h at r.t., and concentrated. The residue was then taken into 50 mL of pH 7 buffer solution (1M) and extracted with EtOAc (50 mL). The extract was dried over MgSO4 and concentrated. The residue was purified by flash chromatography, eluting with 3:1 EtOAc/hexane containing 1% HOAc to give 150 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.[C:34]1([C@H:40]([NH2:42])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([C@H:40]([NH:42][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:20]=[CH:19][C:18]([C@@H:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH3:17])[CH2:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[O:33])=[CH:23][CH:22]=3)=[CH:29][CH:28]=2)=[O:31])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)ccn1
Reactant: C[C@@H](N)c1ccccc1
Product: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)N[C@H](C)c4ccccc4)cc3)cc2)c2ccccc2C)ccn1

Procedure:
In analogy to example 89, step 2, from 4′-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid (example 95, step 1) and (R)-(+)-1-phenylethylamine was prepared the title compound as a white foam, MS (ESI+): m/z=539.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([CH3:25])[N:17]=1>C(OCC)(=O)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:21])=[C:18]([CH3:25])[N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Stoichiometric amounts (0.04 mol) of methyl proplolate and ethyl 3-aminocrotonate were heated to 140° C. for 1 h. 1 g of the crude (2E,4Z)-methyl-4-(1-aminoethylidene)-5-oxooct-2-enoate in 4 mL of DMF was heated to 230° C. in a sealed microwave reactor for 40 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford crude ethyl 6-hydroxy-2-methylnicotinate. A mixture of 800 mg of crude ethyl 6-hydroxy-2-methylnicotinate in 4 mL of phosphorus oxychloride was heated to 150° C. in a sealed microwave reactor for 15 min. The reaction mixture was poured into ice/water, extracted with diethyl ether. The combined organic layers were dried (MgSO4) and evaporated. Purified by silica gel chromatograph (0-20% ethyl acetate/hexane) to yield ethyl 6-chloro-2-methylnicotinate. 400 mg of ethyl 6-chloro-2-methylnicotinate was hydrolyzed via Procedure M to give 6-chloro-2-methylnicotinic acid. 300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-chloro-2-methylnicotinic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 128 mg of 2,6-dimethylpiperazine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-methylnicotinamide. MS (Q1) 436.3 (M)+.