Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(N(CC)CC)C.Cl[Si:18]([CH3:26])([CH3:25])[CH2:19][CH2:20][Si:21](Cl)([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:6]1[Si:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][Si:18]1([CH3:26])[CH3:25]
Reactant: NCc1cccc(Br)c1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si]1(C)CC[Si](C)(C)N1Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The conversion of Polymer 1 into Polymer 2 was preceded by the preparation of 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine. 3-Bromobenzylamine hydrochloride (25.0 g, 112.3 mmol) was converted to the free base by neutralization with sodium hydroxide and extraction into methylene chloride. Drying and solvent removal resulted in 20.3 g of a brown liquid which was used as such. To the above 3-bromobenzylamine (20.3 g, 109 mmol), in a round bottom flask equipped with a condenser and under argon atmosphere, was added 150 mL of methylene chloride and 30.3 mL (217 mmol) of triethylamine. To this stirred mixture cooled with an ice bath was added slowly 109 mL (109 mmol) of 1 M 1,2-bis(chlorodimethylsilyl)ethane dissolved in methylene chloride. During the addition, considerable precipitate formed. The ice-bath was removed and the mixture was stirred for another 6.5 h at room temperature. The white solid was removed by filtration and washed with methylene chloride (2×30 mL). The filtrate was evaporated using a rotary evaporator resulting in further precipitate formation. Hexanes (100 mL) were added to this mixture. The solid was removed by filtration and washed with hexanes (2×20 mL). After hexane removal from the filtrate, a yellowish liquid was obtained which was distilled to yield 29.0 g (82% yield) of light yellowish liquid (bp. 93-5° C./0.05 mm Hg).
Reaction SMILES: [Si]([O:18][C:19]1[CH:55]=[CH:54][C:22]([O:23][CH2:24][C@@H:25]([OH:53])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=[C:37]3[C:45]3[CH:50]=[CH:49][C:48]([CH2:51][CH3:52])=[CH:47][CH:46]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:51]([C:48]1[CH:47]=[CH:46][C:45]([C:37]2[N:36]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:53])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:55][CH:54]=4)=[CH:31][CH:32]=3)[C:40]3=[N:41][CH:42]=[CH:43][CH:44]=[C:39]3[N:38]=2)=[CH:50][CH:49]=1)[CH3:52]
Reactant: CCc1ccc(-c2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)cc1
Yield: 83.9 %

Procedure:
(2S)-1-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-3-({4-[2-(4-ethylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethyl}amino)-2-propanol (0.13 g, 0.174 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.074 g, 0.146 mmol).
Reaction SMILES: [CH2:1]([C:4]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[O:18][CH:17]([C:22]([O:24]CC)=[O:23])[CH2:16][CH2:15]2)[CH2:2][CH3:3].I[CH3:39]>>[CH2:1]([C:4]1[CH:30]=[C:29]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[O:18][C:17]([CH3:39])([C:22]([OH:24])=[O:23])[CH2:16][CH2:15]2)[CH2:2][CH3:3]
Reactant: CI
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCCOc1ccc2c(c1)CCC(C(=O)OCC)O2
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCCOc1ccc2c(c1)CCC(C)(C(=O)O)O2

Procedure:
The title compound was prepared from ethyl 6-(4-(2-propyl-4-phenoxyphenoxy)butoxy)-chromane carboxylate following the procedures described in Example 2, Step A employing iodomethane instead of iodopropane, and subsequently the procedure in Example 1 Step C.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[O:13][CH:14]=1)=[O:7]>O1CCOCC1.O>[CH3:18][N:8]([C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH:19]([CH3:20])[CH3:21])=[O:7])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[O:13][CH:14]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1coc(C(C)C)n1)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine methyl ester 10 (0.511 g, 0.00164 mol) in p-dioxane (10 mL) and H2O (5 mL) was added LiOH monohydrate (0.103 g, 0.00246 mol). After stirring at room temperature for 1 hr, the p-dioxane was removed by rotary evaporation in vacuo, and the remaining aqueous solution was treated with 1N aq HCl (2.46 mL) and extracted with ethyl acetate (4×100 mL). The combined organic extract was washed with saturated brine and dried for 15 mins over Na2SO4. Concentration in vacuo followed by CH2Cl2 chases (2×) afforded the desired compound as a white solid (0.480 g, 0.00161 mol, 98%):
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:13]=[CH:12][N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccnc(-c3ccc(C(C)C)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(-c2nccc(-c3ccc(C(=O)O)cc3)n2)cc1
Reaction time: 12 h
Yield: 41 %

Procedure:
Part B. A solution of ethyl 4-[2-(4-isopropyl-phenyl)-pyrimidin-4-yl]-benzoate in THF-water-ethanol (2 mL/2 mL/1 mL) is treated with lithium hydroxide hydrate (60 mg) and stirred for 12 h. The solution is evaporated, and the residue is partitioned between 1 M aq. HCl and ethyl acetate. The organic phase is washed with water (20 mL), dried over magnesium sulfate, filtered and evaporated to afford the title compound as a white solid (65 mg, 41%), m.p. 262-264° C. 1H NMR (300 MHz, acetone-d6): δ 8.96 (1H, d, J=6 Hz), 8.48 (2H, d, J=9 Hz), 8.23 (2H, d, J=9 Hz), 8.12 (2H, d, J=9 Hz), 7.98 (1H, d, J=6 Hz), 7.44 (2H, d, J=9 Hz), 3.02 (1H, heptet, J=7 Hz), 1.33 (6H, d, J=7 Hz). MS (ES+): m/e 320 (20), 319 (100). MS (ES−): m/e 318 (20), 317 (100).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[F:20][C:21]([F:31])([F:32])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:25][CH:24]=1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2ccc(OC(F)(F)F)cc2)c(=O)[nH]c1=O
Yield: 53.6 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 4-trifluoromethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (233 mg, yield: 53.6%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:15]([O:19][C:20](=[O:27])[NH:21][C@H:22]1[CH2:25][C@H:24]([NH2:26])[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl.O>[C:15]([O:19][C:20](=[O:27])[NH:21][C@H:22]1[CH2:25][C@H:24]([NH:26][C:10](=[O:12])[C:9]([C:8]2[C:3]([Cl:2])=[N:4][CH:5]=[CH:6][CH:7]=2)([CH3:14])[CH3:13])[CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C(=O)O)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](NC(=O)C(C)(C)c2cccnc2Cl)C1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
2-(2-Chloropyridin-3-yl)-2-methylpropanoic acid hydrochloride (intermediate 25, 992 mg, 4.20 mmol), tert-butyl(trans-3-aminocyclobutyl)carbamate (939 mg, 5.04 mmol), hatu (2077 mg, 5.46 mmol) and triethylamine (2.4 ml, 16.81 mmol) were dissolved in dichloromethane (8.4 mL). The reaction mixture was stirred at room temperature for 21 hours then diluted with water and extracted with dichloromethane. The organic was washed with saturated ammonium chloride and dried over magnesium sulfate. Evaporation under reduced pressure and purification using silica chromatography (0% to 100% ethyl acetate in hexane gradient) gave tert-butyl(trans-3-(2-(2-chloropyridin-3-yl)-2-methylpropanamido)cyclobutyl)carbamate (1327 mg, 3.61 mmol, 86% yield) as white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[O:8][C:9]3[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:2]1.[CH:19](=O)[CH2:20][CH3:21].[H][H]>CO.[Pd]>[CH2:19]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[O:8][C:9]3[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:2]1)[CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCC=O
Reactant: NC(=O)c1cccc2nc(C3CCCNC3)oc12
Agent: [Pd]
Solvent: CO
Product: CCCN1CCCC(c2nc3cccc(C(N)=O)c3o2)C1
Yield: 52.2 %

Procedure:
A mixture of 2-(piperidin-3-yl)benzo[d]oxazole-7-carboxamide (25 mg, 0.1 mmol), propionaldehyde (9 mg, 0.156 mmol) and 10% Pd/C (10 mg) in methanol (5 ml) was stirred at room temperature over 1 atm hydrogen for 3 h. Then the mixture solution was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by prep-HPLC to obtain 2-(1-propylpiperidin-3-yl)benzo[d]oxazole-7-carboxamide (15 mg, yield 41%). 1H-NMR (400 MHz, CDCl3) δ (ppm): 0.88-0.93 (t, J=7.2 Hz, 3H), 1.51-1.61 (m, 2H), 1.72-1.91 (m, 4H), 2.07-2.13 (m, 1H), 2.24-2.27 (m, 1H), 2.38-2.43 (t, J=8 Hz, 2H), 2.91-2.94 (d, J=11.2 Hz, 1H), 3.29-3.35 (m, 2H), 6.26 (s, 1H), 7.0 (s, 1H), 7.41-7.45 (t, J=7.6 Hz, 1H), 7.85-7.87 (d, J=7.6 Hz, 1H), 8.06-8.08 (d, J=8 Hz, 1H). LC-MS (ESI) m/z: 288 (M+1)+.
Reaction SMILES: [C:1]1([N:7]([CH2:9][CH2:10][CH3:11])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].C(O)(C)C.[S:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](Cl)=[O:29])(=[O:24])(=[O:23])[NH2:22]>O>[CH2:9]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:8][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:33]([Cl:34])=[C:25]([S:21](=[O:23])(=[O:24])[NH2:22])[CH:26]=1)[CH2:10][CH3:11]
Reactant: CCCN(N)c1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Temperature: 25 °C

Procedure:
A vigorously stirred mixture of 14.0 g (0.1 mol) 1-phenyl-1-n-propylhydrazine, 8.4 g (0.1 mol) sodium bicarbonate, and 100 ml isopropanol was chilled to 0°-5° C., 23 g (0.09 mol) 3-sulfamoyl-4-chlorobenzoyl chloride was added in one portion, and the reaction mixture was allowed to stir for several hours, gradually warming to room temperature. Dilution with water and refrigeration overnight yielded solid material which was collected and recrystallized from acetone/water, mp. 102° C. (d).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:48][C@H:49]1[CH2:53][CH2:52][N:51]([C@H:54]2[CH2:59][CH2:58][C@@H:57]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:56][C@H:55]2[CH2:68][S:69]([CH3:72])(=[O:71])=[O:70])[C:50]1=[O:73]>CN(C=O)C>[CH3:72][S:69]([CH2:68][C@H:55]1[C@@H:54]([N:51]2[CH2:52][CH2:53][C@H:49]([NH:48][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=3)[C:50]2=[O:73])[CH2:59][CH2:58][C@@H:57]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:65])([CH3:64])[CH3:66])[CH2:56]1)(=[O:71])=[O:70]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(C)(=O)=O)C1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(C)(=O)=O)C1
Reaction time: 0.17 h
Yield: 129.5 %

Procedure:
3-(Trifluoromethyl)benzoic acid (252.4 mg) was dissolved in DMF (5 mL) and 4-methyl morpholine (0.42 mL) was added prior to the addition of BOP (511 mg). After 10 min, tert-butyl (1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-(methylsulfonylmethyl)cyclohexylcarbamate (300 mg) was added. The reaction was stirred for 1 h before it was partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-3-(methylsulfonylmethyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate (560 mg). MS found: (M+H)+=562.2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(O)C.[OH-].[Na+]>O>[ClH:1].[ClH:1].[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:20][CH2:21]1
Reactant: CN1CCN(c2nc(Cl)nc3ccccc23)CC1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(c2nc(N3CCOCC3)nc3ccccc23)CC1
Product: Cl

Procedure:
A mixture of 5 g of 2-chloro-4-(4-methylpiperazinyl)quinazoline, 5 ml of morpholine, and 10 ml of ethanol was refluxed for 16 hours. The reaction mixture was diluted with 200 ml of water, made alkaline with 10 ml of 50 percent aqueous sodium hydroxide solution, and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in 500 ml of ether. The ethereal solution was treated with excess hydrogen chloride and the resulting precipitate was collected by filtration. The crude product was recrystallized twice from 95 percent ethanol, giving 3 g of 2-morpholino-4-(4-methylpiperazinyl)quinazoline dihydrochloride, dihydrate; m.p. 310°-312° with decomposition. The following analytical data were obtained:
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[P:15]([O-:32])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][C:39]([CH3:48])([CH3:47])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CC1C=CC(S(OCCCOCC2C=CC=CC=2)(=O)=O)=CC=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([O:16][P:15]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][C:39]([CH3:48])([CH3:47])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)COCCCO
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cc1ccc(S(=O)(=O)OCCCOCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)COCCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
DIAD (1.36 mL, 6.97 mmol) was added dropwise to a stirred solution of PPh3 (76 mg, 0.30 mmol), dibenzyl phosphite (1.94 g, 6.97 mmol) and tert-butyl 3-(3-hydroxypropoxy)-2,2-dimethylpropanoate (53) (1.08 g, 4.65 mmol) [prepared using the same procedure as Example F1 steps (ii)-(iii) using 3-(benzyloxy)propyl 4-methylbenzenesulfonate in step (ii)] in THF (100 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 16 h, and the volatiles were removed in vacuo. The crude product was purified by silica gel chromatography (120 g, 0-60% EtOAc in isohexane) to afford tert-butyl 3-(3-((bis(benzyloxy)phosphoryl)oxy)propoxy)-2,2-dimethylpropanoate (54) (1.76 g, 54%) as a clear colourless oil: m/z 515 (M+Na)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.40-7.35 (m, 10H), 5.07-4.96 (m, 4H), 4.04-3.92 (m, 2H), 3.39 (t, J=6.2 Hz, 2H), 3.28 (s, 2H), 1.77 (quin, J=6.2 Hz, 2H), 1.35 (s, 9H), 1.02 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].CC(C)([O-])C.[K+].[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH:25][CH3:26])=[O:24])[CH:18]=1>CC(N(C)C)=O.O>[ClH:16].[CH3:26][NH:25][C:23]([C:19]1[CH:18]=[C:17]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([CH3:9])[CH:4]=2)[CH:22]=[CH:21][N:20]=1)=[O:24]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Cc1cc(O)ccc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc(N)c(C)c2)ccn1
Product: Cl
Temperature: 110 °C

Procedure:
A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temp. until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110° C. for 8 h. The mixture was cooled to room temp. and diluted with water (75 mL). The organic layer was extracted with EtOAc (5×100 mL). The combined organic layers were washed with a saturated NaCl solution (200 mL), dried (MgSO4) and concentrated under reduced pressure. The residual black oil was treated with Et2O (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et2O; 100 mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from solution and stored under anaerobic conditions at 0° C. prior to use: 1H NMR (DMSO-d6) δ 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J=8.5, 2.6 Hz, 1H), 7.23 (dd, J=5.5, 2.6 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 8.55 (d, J=5.9 Hz, 1H), 8.99 (q, J=4.8 Hz, 1H).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:32]Br)[CH:28]=2)[CH:23]=1>O1CCCC1.CCCCCC>[C:13]([C:5]([CH3:6])([CH3:7])[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:32][C:14]([CH3:16])([C:13]([O:18][CH3:19])=[O:17])[CH3:15])[CH:28]=2)[CH:23]=1)([O:18][CH3:19])=[O:17]
Reactant: CC(C)NC(C)C
Reactant: BrCc1ccc2cc(CBr)ccc2c1
Reactant: COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C(C)(C)Cc1ccc2cc(CC(C)(C)C(=O)OC)ccc2c1
Reaction time: 0.5 h

Procedure:
To a solution of 56 ml of diisopropylamine in 1200 ml of dry tetrahydrofuran at -78° C was added 260 ml of 1.6 M n-butyllithium in hexane. After 1 hr of stirring 40.4 g of methyl isobutyrate was added dropwise and the solution stirred for another 30 minutes. A 60-g portion of 2,6-bis(bromomethyl)naphthalene was added slowly, and the reaction mixture was stirred overnight and then brought to room temperature. Tetrahydrofuran was removed by evaporation. The residue was dissolved in 300 ml of chloroform, washed 3 times with 400 ml of H2O, dried and evaporated to dryness to obtain 56 g of 2,6-bis(2-carbomethoxy-2-methylpropyl)naphthalene, m.p. 108° C-110° C. The product was recrystallized from benzene.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1.N>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:2][CH2:3]2)=[O:35])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCN2CCN(C(=O)Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a mixture of 9.7 g. (37 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate, 40 ml. methylene chloride and 6.3 g. (80 mmole) anhydrous pyridine is added dropwise at 0° C., in the course of 40 minutes, a solution of 7.0 g. (37 mmole) 4-chlorophenylacetyl chloride in 20 ml. methylene chloride, a cheesy precipitate being formed. After stirring at 20° C. for 4 hours, the reaction mixture is poured into 250 ml. ice water, rendered alkaline with ammonia and extracted several times with methylene chloride. The methylene chloride solution is washed twice with water, dried with anhydrous sodium sulphate and evaporated. After the addition of ligroin, crystallisation occurs. The product is recrystallised from diethyl ether to give 51% of theory of the desired product; m.p. 88°-89° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C(Cl)Cl.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].O>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][N:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)[NH2:20])=[CH:36][CH:35]=1
Reactant: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: NN(Cc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 24 h

Procedure:
A quantity of 10 g of 4-(quinolin-2-ylmethoxy)phenylhydrazine from Step C was added to a solution of 10.5 mL of diisopropylethylamine and 150 mL of CH2Cl2. To the yellow suspension was added 9.11 g of p-chlorobenzyl chloride followed by 3.64 g of Bu4NBr and 50 mL of CH2Cl2. The reaction was stirred for approximately 24 hours. When no starting material remained, the reaction was diluted with H2O and extracted 3 times with CH2Cl2. The combined organic phase was washed once with water and dried (MgSO4), filtered and evaporated to dryness. The solid residue was dried under vacuum overnight prior to being swished in ether/methanol 90/10 to give the title compound as a pale yellow solid. m.p. 130° C.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[CH3:29]>CCO>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([NH:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:34])[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CNc1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Yield: 45.6 %

Procedure:
To a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) in EtOH (8 mL) was added glycine ethyl ester hydrochloride (46 mg, 0.44 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 3 d. The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide ethyl N-(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)glycinate (43 mg, 46%): LCMS RT: 2.16 min, MH+: 429.3.