Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](OC)=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[C:1]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCCCCCCCOc1ccc(C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(OCCCCCCCCCCCO)cc1

Procedure:
The methyl 11-(p-tert-butylphenoxy)-undecanoate, 3.7 g, 10.6 mmoles, was dissolved in 100 ml dry diethyl ether and added, dropwise, to a stirred slurry of 0.5 g lithium aluminum hydride in 100 ml dry diethyl ether. After one hour the reaction mixture was filtered through Celite and the filtrate was treated with 100 ml 1N hydrochloric acid. The organic layer was removed, dried (MgSO4), and concentrated to a yellow oil, 2.7 g. The oil was chromatographed on 200 g 90 to 200 mesh silica gel (2% MeOH/CH2Cl2 eluent) collecting the product as a white, waxy solid. The solid was recrystallized from warm pentane yielding pure 11-(p-tert-butylphenoxy)-undecanol, 1.1 g, m.p. 39° to 40° C.
Reaction SMILES: Cl.O(CC)CC.[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([CH2:21][CH2:22][CH2:23][O:24]C3CCOCC3)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]>CO>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([CH2:21][CH2:22][CH2:23][OH:24])[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Clc1ccc(C2(CCCOC3CCOCC3)CCCNC2)cc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: OCCCC1(c2ccc(Cl)c(Cl)c2)CCCNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A solution of dry HCl.OEt2 was added to a solution of piperidine (7) (20.2 g, 54.36 mmol) in MeOH (200 mL) until pH˜1. The mixture was stirred at room temperature for 30 minutes. Solvent was evaporated, the residue was dissolved in CH2Cl2 (300 mL) and stirred with 1N NaOH (100 mL) for 15 minutes. The solvent was separated, washed with NaHCO3, and dried over MaSO4. The crude oil was purified by flash chromatography (CH2Cl2-MeOH(saturated with NH3)/95:5) to give a white solid (13.25 g, 84.6%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=4[Cl:28])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.CN.[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23](=[O:24])[NH:35][CH3:34])=[CH:21][C:20]=4[Cl:28])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2ccc(C(=O)O)cc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)ccc21
Agent: CN
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Nc2nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3n2C)c(Cl)c1

Procedure:
Prepared analogously to example 3c from 4-(5-(4-bromophenylcarbamoyl)-1-methyl-1H-benzimidazol-2-ylamino)-3-chlorobenzoic acid, methylamine (solution in THF), TBTU and TEA in THF.
Reaction SMILES: Cl.[C:2]([N:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)N)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1O[C:21]2([CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]2)OC1>C(O)C>[C:2]([N:10]1[C:21]2[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][C:22]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NN(C(=O)c1ccccc1)c1ccccc1
Reactant: OCC1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CCO
Product: O=C(c1ccccc1)n1c2c(c3ccccc31)CC(CO)CC2

Procedure:
1-Benzoyl-1-phenylhydrazine hydrochloride (23.8 g.) and 18 g. of 4-hydroxymethylcyclohexanone ethylene ketal in 450 ml. of absolute ethyl alcohol was heated under reflux for four hours. The chilled mixture was filtered, the filtrate was evaporated to dryness under reduced pressure and the resulting residue was dissolved in ether. The ether solution was washed with water, dilute hydrochloric acid, water, dilute sodium bicarbonate, and water, dried and evaporated to dryness to give, after recrystallization from ethyl acetate-hexane, 9.6 g. of 9-benzoyl-3-hydroxymethyl-1,2,3,4-tetrahydrocarbazole; m.p. 105°-107° C.
Reaction SMILES: [CH2:1]1[CH:10]2[C:4](=[N:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9]2=[O:11])[CH2:3][CH2:2]1.[H-].[Na+].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl)([O-:20])=[O:19]>CN(C=O)C.[Cl-].[NH4+]>[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][N:8]1[C:9](=[O:11])[CH:10]2[CH2:1][CH2:2][CH2:3][C:4]2=[N:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]1=2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: O=C1Nc2ccccc2N=C2CCCC12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1C2CCCC2=Nc2ccccc2N1Cc1cccc([N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
A solution of 2,3,9,10a-tetrahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (4.00 g, 20 mmol) in DMF (40 mL) was cooled to 0° C. and sodium hydride (a 60% dispersion in liquid paraffin, 0.80 g, 20 mmol) was added. This mixture was stirred at the same temperature for 20 minutes. To the resulting solution was added 3-nitrobenzyl chloride (3.77 g, 22 mmol) and the mixture was stirred at room temperature for 20 minutes. This reaction mixture was poured in saturated aqueous ammonium chloride solution (40 mL) and extracted with 3 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to provide 4.81 g (yield 71%) of the title compound. m.p. 123.5°-125.5° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[C:14]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1>O>[CH2:24]([O:31][C:32]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[C:14]2=[O:23])[CH2:10][CH2:9]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1C(=O)C2(CCN(Cc3ccccc3)CC2)c2ccccc21
Reactant: O=C(Cl)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 15.1 g of 1'-benzyl-1-methyl-2-oxoindoline-3-spiro-4'-piperidine, 33.5 g of benzyloxycarbonyl chloride and 530 ml of toluene was refluxed for 6 hours. The resulting mixture was poured into water and extracted with ethylacetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Thus obtained oil was washed with n-hexane to give 1'-benzyloxycarbonyl-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[NH:5][C:4](=[O:12])[N:3]=1.[CH3:13][Si:14]([CH3:21])([CH3:20])[NH:15][Si](C)(C)C>>[CH3:13][Si:14]([NH:15][N:5]1[C:6]2[C:11](=[N:10][CH:9]=[CH:8][N:7]=2)[CH:2]=[N:3][CH:4]1[O:12][Si:14]([CH3:21])([CH3:20])[CH3:13])([CH3:21])[CH3:20]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Nc1nc(=O)[nH]c2nccnc12
Product: C[Si](C)(C)NN1c2nccnc2C=NC1O[Si](C)(C)C

Procedure:
To 20 mL of hexamethyldisilazane (HMDS) is added 2.98 g (0.02 mole) of 4-amino-pteridine-2-one (30). The mixture is heated for 24 hours under reflux, with moisture excluded, to obtain a clear solution. The excess HMDS is removed under high vacuum to give 1-trimethylsilylamino-2-trimethylsilyloxy-pteridine as a viscous oil. The residue is dissolved in 200 mL of benzene and then 9.37 g (0.022 mole) of 2-deoxy-3,5-di-O-p-toluoyl-α-D-ribofuranosyl chloride, 4 g HgO, and 4 g HgBr2 are added and the mixture is refluxed for 5 hours. After cooling, the precipitate is filtered off, the filtrate evaporated to dryness and the residue dissolved in 100 mL of CHCl3. The solution is extracted twice with 100 mL of 20% KI. The organic layer is then dried over Na2SO4, again evaporated and the residue dissolved in a little ethyl acetate for silica-gel column chromatography with ethyl acetate / acetone 7:3. The first fraction contains excess sugar, the second fraction the α-anomer and last eluting fraction the β-deoxyriboside. Evaporation and recrystallization of the residue from ethanol gives 31.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[O:9]C.B(Br)(Br)Br.C(=O)([O-])O.[Na+].Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[OH:9]
Reactant: COc1cc(I)ccc1Cl
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: Oc1cc(I)ccc1Cl
Reaction time: 72 h
Yield: 87.2 %

Procedure:
To a solution of 1-chloro-4-iodo-2-methoxybenzene (1.34 g, 5 mmol) in dichloromethane was dropped under ice cooling a solution of 0.91M boron tribromide in dichloromethane (6.6 ml, 6.00 mmol) and the mixture was reacted for 1 hour under ice cooling and then for 3 days at room temperature. To the mixture was added an aqueous sodium hydrogencarbonate solution and then the mixture was acidified with concentrated hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed and purified with silica gel chromatography (hexane:ethyl acetate, 10:1) to give the subject compound (1.11 g, 87%) as white crystals.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:20]=[CH:19][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:26]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[N+:3]([C:6]1[CH:20]=[CH:19][C:9]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][CH2:26][C:25]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(COC2CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc(OC)c1OC
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 0.8 g of 50% aqueous sodium hydroxide solution, 5 ml of methylene chloride, 1 g (0.004 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine, 1.30 g (0.006 mol) of 3,4,5-trimethoxybenzyl chloride and 0.08 g (2×10-4 mol) of tetrabutylammonium iodide is stirred for 5 hours at 50° C. After dilution with 10 ml of water and 15 ml of methylene chloride, the organic phase is decanted, washed with water until the washings are neutral, dried (MgSO4) and evaporated in vacuo. The residual oil obtained crystallises on stirring in diethyl ether. This yields 1.36 g (79%) of a product which is purified by dissolving it in 7 ml of DMF and slowly reprecipitating it with 7 ml of water. After washing with water and drying in vacuo, 1-(4-nitrobenzoyl)-4-(3,4,5-trimethoxybenzyloxy)-piperidine, m.p. 124° C., is obtained.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:11][C:12]1[N:16]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:15]([C:22]([O:24][CH3:25])=[O:23])=[C:14]([CH:26]=[O:27])[N:13]=1.C(O)(=O)C>CO.C(Cl)Cl>[Br:11][C:12]1[N:16]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:15]([C:22]([O:24][CH3:25])=[O:23])=[C:14]([CH:26]([OH:27])[CH2:4][N+:1]([O-:3])=[O:2])[N:13]=1
Reactant: COC(=O)c1c(C=O)nc(Br)n1CC=C(C)C
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1c(C(O)C[N+](=O)[O-])nc(Br)n1CC=C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
35 ml nitromethane are added to 1.14 g caesium carbonate in 15 ml of methanol at ambient temperature. Then the mixture is combined with a solution of 3.50 g methyl 2-bromo-3-(3-methyl-2-buten-1-yl)-5-formyl-3H-imidazole-4-carboxylate in 20 ml of methanol and 5 ml methylene chloride and stirred for 15 minutes at ambient temperature. Then 0.5 ml acetic acid are added and the solution is evaporated down in vacuo. The flask residue is combined with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.O1CC[CH2:19][CH2:18]1.CC(C)([O-])C.[Na+].BrCC>C(OCC)(=O)C.O.ClCCl>[Cl:1][C:2]1[C:6]([N:7]([CH2:18][CH3:19])[C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(C(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 35 °C
Reaction time: 168 h
Yield: 74 %

Procedure:
To a 3-neck, 100-mL round bottom flask was charged N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (5.00 g, 21.1 mmol) and tetrahydrofuran (50 mL). Sodium tert-butoxide (3.05 g, 31.7 mmol) was added (causing a temperature rise from 22° C. to 27.9° C.), followed by bromoethane (4.70 mL, 63.4 mmol). The reaction was stirred at 35° C. for 168 hours, at which point HPLC analysis indicated that only 2.9% (area under the curve, AUC) starting material remained. The reaction mixture was concentrated to give a brown residue, which was diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (4×50 mL) and the combined organics were concentrated to give a brown residue. The residue was dissolved in dichloromethane (2×10 mL) and purified by flash column chromatography using 60-100% ethyl acetate/hexanes as eluent. The fractions containing pure product were combined and concentrated to afford the title product as a yellow solid (4.20 g, 74%): 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J=2.7, 0.8 Hz, 1H), 8.62 (dd, J=4.8, 1.4 Hz, 1H), 8.06 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 8.00 (s, 1H), 7.47 (dd, J=8.3, 4.7 Hz, 1H), 3.71 (q, J=7.1 Hz, 2H), 1.97 (s, 3H), 1.16 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.69, 148.56, 140.89, 139.95, 135.64, 126.22, 126.08, 124.86, 124.09, 43.77, 22.27, 13.15; mp: 87-91° C.; ESIMS m/z 265 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:62][CH2:63][C:64]1[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:62][CH2:63][C:64]2[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=2)=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)c(NCCc2cccc(F)c2)n1
Reactant: NCc1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc(C(=O)NCc2cccnc2)c(NCCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (2.8 g, 7.76 mmol) in DMF (28 mL) was added HBTU (5.88 g, 15.51 mmol), HOBt (2.1 g, 15.51 mmol), then 3-aminomethylpyridine (1.68 g, 15.51 mmol). The reaction mixture was stirred at room temperature for 1 hr. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide as a pale yellow solid (3.0 g, 86%). LRMS (M+H+) m/z 452.2.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:8](Cl)=[O:9])[CH2:7][CH2:6]1.[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12]>C(=S)=S>[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:8]([CH:5]2[CH2:7][CH2:6]2)=[O:9])=[CH:16][CH:15]=1)[CH3:12]
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOc1ccc(C(=O)C2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere a stirred suspension of 36.7 grams (0.275 mole) of aluminum chloride in 225 mL of carbon disulfide was cooled to 0° C., and 22.7 mL (0.25 mole) of cyclopropanecarboxylic acid chloride was added dropwise during a 15 minute period. During the addition and for 30 minutes after its completion the reaction mixture temperature was maintained at 0°-15° C. Then 34.8 mL of ethoxybenzene was added dropwise during a one hour period. The reaction mixture temperature was maintained at 5°-10° C. during this addition. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for one hour. Petroleum ether, 250 mL, was added to the reaction mixture, and the suspension was stirred for ten minutes. The solid was collected by filtration and washed with petroleum ether. The solid was returned to the reaction vessel and, with stirring, was cooled to 0°-10° C. while 50 mL of water was added dropwise during a 30 minute period. Upon completion of addition, the mixture was stirred until the evolution of hydrogen chloride ceased. An additional 250 mL of water was then added, and the mixture was stirred at ambient temperature for 30 minutes. It was then warmed to 80° C. where it stirred for an additional 30 minutes. The mixture was cooled, and a solid was collected by filtration. The solid was dissolved in methylene chloride, and the solution was dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual solid. The solid was recrystallized from heptane, yielding, in two crops, 44.0 grams of cyclopropyl (4-ethoxyphenyl) ketone, m.p. 67°-70° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].O1CCCC1>C(O)C.[C].[Pd]>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COC(=O)c1cccc(C=CC#N)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CCC#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of the above-mentioned crude product of methyl 3-(2-cyanoethenyl)benzoate in ethanol (45 mL)/tetrahydrofuran (15 mL) was added 10% palladium-carbon (648 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 2 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→75/25), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (2.03 g, 88%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[N:7]=[C:6]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([O:14][CH2:13][CH2:12][O:11][CH3:10])[CH:16]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COCCOc1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COCCOc1cccc(Nc2ncc(F)c(Nc3cccc(OCCOC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-(2-methoxyethoxy)aniline were reacted to produce N2,N4-bis[3-(2-methoxyethyl)oxyphenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.96 (d, 1H, J=2.9 Hz), 7.36 (t, 1H, J=1.7 Hz), 7.28 (t, 1H J=1.7 Hz), 7.25-7.06 (m, 4H), 6.98 (br s, 1H), 6.75 (d, 1H, J=2.3 Hz), 6.70 (dd, 1H, J=1.7 and 8.2 Hz), 6.58 (dd, 1H, J=1.7 and 8.2 Hz), 4.08-4.03 (m, 4H), 3.74-3.69 (m, 4H), 3.44 (s, 3H), 3.43 (s, 3H); LCMS: ret. time: 21.01 min.; purity: 97%; MS (m/e): 429 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.[N:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[C:15](OCC)(=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.O>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15](=[O:24])[CH2:14][C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(OC)cc1
Reactant: Cc1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(C(=O)Cc2ccncc2)cc1
Temperature: -5 °C
Yield: 66.2 %

Procedure:
A solution of diisopropylamine (33.2 mL) in anhydrous tetrahydrofuran (300 mL) was cooled to −78° C. and 1.6 M n-butyllithium-hexane solution (148 mL) was added dropwise with stirring. After completion of dropwise addition, the mixture was stirred for 10 min at the same temperature, then γ-picoline (20 g) was added dropwise. The temperature was raised to −10-0° C., and after stirring for 20 min, a solution of ethyl p-anisate (19.4 g) in anhydrous tetrahydrofuran (40 mL) was added dropwise. After completion of dropwise addition, the mixture was stirred at room temperature for 1 h, and water (100 mL) was added. The organic solvent was evaporated under reduced pressure and an oily product was extracted with ethyl acetate. The extract was washed with water, and after drying, the solvent was evaporated. the remaining crude crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound (16.2 g, yield 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:34][C:35]1[C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=[CH:37][N:36]=1>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:41]([C:40]4[C:35]([CH3:34])=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:42])=[CH:3][C:4]=3[Cl:24])=[O:7])[CH2:9][C:10]=12
Reactant: Cc1ncccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.1 g of 10,11-dihydro-10-(4-amino-2-chlorobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 3 ml of N,N-diisopropylethylamine in 100 ml of methylene chloride is stirred while a solution of 600 mg of 2-methylpyridine-3-carbonyl chloride in 15 ml of methylene chloride is added slowly. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with water and the organic layer washed with water, dried(MgSO4), filtered and evaporated in vacuo to a residue. The product is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane to give the desired product as a pale yellow residue. M+ =456.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[N:26][C:21]=1[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: Clc1ncccn1
Reactant: Cc1ccc(COC(=O)N2CCC(CN)CC2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(COC(=O)N2CCC(CNc3ncccn3)CC2)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 4-methylbenzyl 4-(aminomethyl)-1-piperidinecarboxylate (INTERMEDIATE 2A) (20.00 g, 76.23 mmol), 2-chloro-pyrimidine (8.73 g, 76.23 mmol) and triethylamine (21.25 mL, 152.46 mmol) in DMF (40 mL) was heated at 100° C. for 6 h. The reaction solution was cooled to rt, then diluted with ethyl acetate (800 mL), washed with sat. aq. NaHCO3 (100 mL), water (3×100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-methylbenzyl 4-[(2-pyrimidinylamino)methyl]-1-piperidinecarboxylate. M.S.(M+1): 341.30.