Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C[O-].[Na+]>[Cu].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cn1
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(Sc2ccc(Cl)cc2)cn1

Procedure:
2-Amino-5-bromopyridine (7.8 grams), 4-chlorothiophenol (9.2 grams), sodium methoxide (3.5 grams), and copper powder (1.0 gram) were reacted in 100 ml. of methanol, for 12 hours, in a bomb, in accordance with the procedures of J. Med. Chem. 21, 235 (1978). The reaction mixture was filtered, washed with methanol, and methanol removed by evaporation. The methanol washes were combined with ethyl acetate extracts of solids made after refluxing on a steam bath for one hour. Solvents were removed and the solids dissolved in ethyl acetate and filtered to remove insolubles. The liquid was passed over a silica column with ethyl acetate, and the fraction corresponding to the product amine (Rf ≅0.2) collected., yield 6.5 grams, m.p., 161°-163° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][CH:8](O)[C:7]2[CH:11]=[C:12]([Cl:14])[S:13][C:6]=2[S:5]1(=[O:16])=[O:15].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:14][C:12]1[S:13][C:6]2[S:5](=[O:16])(=[O:15])[N:4]([CH2:3][CH2:2][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: C1COCCN1
Reactant: O=S1(=O)c2sc(Cl)cc2C(O)CN1CCBr
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S1(=O)c2sc(Cl)cc2C=CN1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of the product from Step A (0.76 g, 2.20 mmol) in tetrahydrofuran (30 mL) containing triethylamine (0.56 g, 5.5 mmol) was added methanesulfonic anhydride (0.75 g, 4.3 mmol); this mixture was stirred at room temperature for 1 hr and evaporated to dryness. The residue was dissolved in DMF (30 mL), triethylamine (1 mL) was added and the mixture heated at 150° C. for 45 min. Morpholine (3 mL, 34 mmol) was added to the reaction mixture and heating continued at the same temperature for 1 hr followed by heating at 100° C. for an additional hour. The volatiles were evaporated and the residue mixed with ethyl acetate; this mixture was washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 50% ethyl acetate/hexane to ethyl acetate) to give a viscous oil (0.42 g, 58%) which was used in the next step.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)=[CH:7][CH:8]=2)[N:3]=1.[CH3:24][N:25]([CH3:53])[C:26](=[O:52])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)=[O:35])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:24][N:25]([CH3:53])[C:26](=[O:52])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:2]3[N:11]=[C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:9]4[C:4](=[CH:5][C:6]([C:18]5[CH:19]=[N:20][CH:21]=[N:22][CH:23]=5)=[CH:7][CH:8]=4)[N:3]=3)=[CH:41][CH:42]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: Clc1nc(N2CCOCC2)c2ccc(-c3cncnc3)cc2n1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(-c5cncnc5)cc4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-4-morpholin-4-yl-7-pyrimidin-5-yl-quinazoline (150 mg, 0.00046 mol), N,N-Dimethyl-4-{3-[4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (168 mg, 0.00041 mol), cesium carbonate (300 mg, 0.00092 mol), DMF (10 mL) and water (3 mL) were added. The reaction mixture was degassed with N2 for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (16 mg, 0.000023 mol) was added and again degassed with N2 for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 4% MeOH in chloroform) followed by preparative TLC (10% MeOH in chloroform) to yield the title compound [30 mg, 11%]. 1H NMR (400 MHz, DMSO-d6): δ 9.36 (s, 2H), 9.29 (s, 1H), 9.05 (s, 1H), 8.98 (s, 1H), 8.46 (d, J=8.8 Hz, 2H), 8.31 (d, J=2.0 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.93 (dd, J′=8.4 Hz, J″=1.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 3.87 (s, 8H), 2.96 (s, 6H); LC-MS (ESI): Calculated mass: 574.2; Observed mass: 575.1 [M+H]+ (RT: 0.26 min).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH3:15])=[C:10]([C:12](O)=[O:13])[N:11]=2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>CN(C=O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH3:15])=[C:10]([C:12]([NH:28][C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[O:13])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccc(-c2nc(C(=O)O)c(C)s2)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(C(=O)Nc3nnn[nH]3)c(C)s2)s1
Temperature: 70 °C
Yield: 97.1 %

Procedure:
A solution of 2-(5-methyl-2-thienyl)-5-methyl-4-thiazolecarboxylic acid (300 mg) and CDI (304.9 mg) in dry DMF (3 ml) was allowed to react at room temperature for 1 hour. Then a solution of 5-aminotetrazole (128 mg) in dry DMF (2 ml) was added dropwise and the mixture was heated at 70° C. for 3 hours. The solvent was removed from the reaction mixture, and the residue was treated with water and acidified with 2N-HCl under ice-cooling. The produced solids were filtered with suction, washed sufficiently with water and dried to give pale yellow solids of 2-(5-methyl-2-thienyl)-5-methyl-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (372.9 mg, 97%), m.p. 278°-280° C. (from methanol-THF-water).
Reaction SMILES: [H-].[Na+].CC1C=CC(S(/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)(=O)=O)=CC=1.[N+:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])#[C-:25]>O1CCCC1.O.C(OCC)(=O)C>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([C:14]2[CH:13]=[CH:25][NH:24][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Reactant: [C-]#[N+]CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1[nH]ccc1-c1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 111.2 %

Procedure:
To a suspension of 1.62 g (40.63 mmol) of 60% sodium hydride in mineral oil in 100 cm3 of tetrahydrofuran is added dropwise over 25 minutes, at a temperature in the region of 20° C. under an argon atmosphere, a mixture of 5.87 g (19.35 mmol) of 1-[(E)-2-(4-methylphenyl)sulfonylvinyl]-4-nitrobenzene and 3.7 cm3 (38.7 mmol) of methyl isocyanoacetate dissolved in 150 cm3 of tetrahydrofuran. After stirring for 5 hours at a temperature in the region of 20° C., the reaction mixture is taken up in a mixture of 100 cm3 of water and 200 cm3 of ethyl acetate. The organic phase is washed with twice 100 cm3 of water and 150 cm3 of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 5.3 g of a brown oil, which is purified by flash chromatography [eluent: dichloromethane]. After concentrating the fractions under reduced pressure, 2.12 g of methyl 3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate are obtained in the form of a yellow solid; M.W.=246, IE: m/z=246 M+, m/z=214 [M-CH3OH]+.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22]Cl>CCO>[ClH:19].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: Clc1cccc(Cl)c1CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,6-dichlorobenzyl chloride (0.307 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 296 mg of the product 209. 1H NMR (DMSO-d6) δ 11.47 (s, 2 H), 7.75-7.60 (m, 2 H), 7.60-7.40 (m, 1 H), 7.30-6.85 (m, 10 H), 5.90 (s, 2 H), 4.98 (s, 2 H); MS: m/z 413 (M++1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:30])=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([OH:29])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:42][C@H:43]1[O:48][CH2:47][C@@H:46]2[CH2:49][CH2:50][CH2:51][N:45]2[CH2:44]1)(=O)=O>CN(C)C=O>[ClH:8].[Cl:8][C:9]1[C:10]([F:30])=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH2:42][C@H:43]4[O:48][CH2:47][C@@H:46]5[CH2:49][CH2:50][CH2:51][N:45]5[CH2:44]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3F)ncnc2cc1O
Reactant: CS(=O)(=O)OC[C@@H]1CN2CCC[C@H]2CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3F)ncnc2cc1OC[C@@H]1CN2CCC[C@H]2CO1
Product: Cl
Temperature: 70 °C
Reaction time: 41 h
Yield: 38.2 %

Procedure:
4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetic acid salt (307 mg, 0.655 mmol) was dissolved in dimethylformamide (1 mL) and potassium carbonate (452 mg, 3.28 mmol) was added followed by (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl methanesulfonate (250 mg, 1.06 mmol). The mixture was stirred at 70° C. for 41 h and then was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford an orange oil which was purified by column chromatography (ethyl acetate-ethanol 1:1). The purified material was dissolved in methanol and treated with 4M solution of HCl in 1,4-dioxane (0.1 mL) and the mixture was concentrated in vacuo to afford N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride as a pale yellow solid (66 mg, 0.125 mmol, 19% yield). 1H NMR (400 MHz, d6-DMSO): 11.9-11.5 (m, 2H), 8.83 (s, 1H), 8.39-8.35 (m, 1H), 7.69 (dd, 1H), 7.62 (dd, 1H), 7.43 (s, 1H), 4.48-4.24 (m, 4H), 4.04 (s, 3H), 3.97-3.85 (m, 1H), 3.78-2.96 (m, 5H), 2.17-1.90 (m, 3H), 1.72-1.58 (m, 1H); MS (EI) for C23H23N4O3FCl2: 493 (MH+).
Reaction SMILES: C(OOCC[CH2:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)C.[CH3:15][CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:17](Cl)=[O:18].Cl.[O:27]1CCCC1>>[CH3:15][CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:17]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][OH:27])=[CH:9][CH:10]=1)=[O:18]
Reactant: CCCCCCC(C)C(=O)Cl
Reactant: C1CCOC1
Reactant: CCOOCCCc1ccc(Br)cc1
Agent: Cl
Product: CCCCCCC(C)C(=O)c1ccc(CO)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
To this solution was added dropwise 2.61 g (10.1 mmol) of the above 4-bromobenzyl-(1-ethoxy) ethyl ether over 40 minutes. After the completion of the addition, the mixture was heated under reflux for 1 hour and cooled to -78° C., to which was added dropwise 1.70 g (9.6 mmol) of (+)-2-methyl octanoic acid chloride dissolved in 20 ml of tetrahydrofuran over 40 minutes. The mixture was stirred at -78° C. for 3 hours and gradually turned to room temperature. It was added with 10 ml of a normal hydrochloric acid cooled at 0° C. and stirred for 1 hour. The product was extracted with ether and washed with a saturated aqueous solution of sodium hydrogen carbonate and further a saturated aqueous solution of sodium chloride. It was dried on anhydrous magnesium sulfate, and the oily matter after the removal of solvent was purified by a column chromatography of silica gel to obtain 323 mg (yield 14 %) of a colorless and oily 4-(2-methyloctanoyl) benzyl alcohol.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:22]=[CH:21][C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[CH:15][C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25](CO)[N:24]=3)=[N:13]4)[N:10]=2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.S(Cl)([Cl:40])=O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:48]([Cl:50])Cl>>[Cl:40][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:22]=[CH:21][C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[CH:15][C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:48][Cl:50])[N:24]=3)=[N:13]4)[N:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(-c2ccc3ccc4ccc(-c5cccc(CO)n5)nc4c3n2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: ClCc1cccc(-c2ccc3ccc4ccc(-c5cccc(CCl)n5)nc4c3n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
Under a stream of argon, compound (21) (0.7 g; 1.77 mmol) was suspended in methylene chloride (15 mL) in an ice bath. To the reaction mixture, triethylamine (0.54 g; 5.32 mmol) and thionyl chloride (0.51 g; 4.25 mmol) were sequentially added. The resulting reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was made alkaline with a 5% aqueous sodium carbonate, and then evaporated under reduced pressure. The resulting residue was dissolved in chloroform/methanol=3/1, and inorganic matters were removed by membrane filtration. The filtrate was evaporated under reduced pressure to give a residue, and the resulting residue was separated and purified by silica gel column chromatography (SiO2, 200 g) (chloroform/methanol=10/1 to 5/1 to 3/1) to give 0.49 g (yield: 64%) of the title compound (22).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:20])[C@H:6]([CH3:19])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]([CH3:19])[C:5]([O:4][CH3:3])=[O:20])(=[O:9])=[O:10])=[CH:12][CH:13]=1
Reactant: COC(=O)[C@H](C)NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.60 g, 11.0 mmol) in dimethylformamide (20.0 mL), is added N-[4-methoxybenzenesulfonyl]-alanine methyl ester (2.6 g, 10.0 mmol) in dimethylformamide (10.0 mL). After stirring at room temperature for 30 minutes, benzyl bromide (1.22 mL, 10.0 mmol) is added, and the reaction is stirred for two hours at room temperature. The reaction is then partitioned between ether and brine, the organic layer is dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (20% ether/hexanes) to give methyl 2-[[4-methoxybenzenesulfonyl]-(benzyl)amino]-propionoate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:25][C:26]([O:28]C)=[O:27])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]3=[O:24])=[CH:9][C:4]=2[O:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:25][C:26]([OH:28])=[O:27])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]3=[O:24])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCCCN1C(=O)C(CC(=O)OC)(c2ccc3c(c2)OCO3)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(CC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of methyl [3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetate (5.90 g, 15.0 mmol) in THF/water (2/1 v/v, 120 mL) was added lithium hydroxide monohydrate (1.26 g, 28.0 mmol). The mixture was stirred at ambient temperature overnight. Most THF was removed under vacuum and water (150 mL) was added. The solution was extracted with ethyl acetate/hexanes (1/3 v/v, 50.0 mL). The water layer was acidified with 1 N HCl solution until the pH value reached 2 and extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title compound (5.00 g, 88%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.29 (td, 1H), 7.21 (dd, 1H), 7.05 (td, 1H), 6.87 (d, 1H), 6.76 (d, 1H), 6.72-6.64 (m, 2H), 5.90-5.86 (m, 2H), 3.65 (t, 2H), 3.43 (d, 1H), 3.11 (d, 1H), 1.70-1.55 (m, 2H), 1.36-1.22 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 178.2, 174.0, 148.0, 147.1, 143.4, 132.6, 131.4, 128.7, 124.4, 122.7, 119.8, 108.9, 108.2, 107.2, 101.2, 52.6, 41.5, 40.4, 29.0, 26.6, 22.3, 14.0; MS (ES+) m/z 404.0 (M+23), 382.0 (M+1).
Reaction SMILES: C(OC(N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1)=O)(C)(C)C.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH:34]=[C:33]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[N:47]=[CH:46][CH:45]=[CH:44][N:43]=3)=[CH:38][C:37]=2[F:48])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].BrC1C=C([F:56])C(Br)=CC=1F>>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH:32]=[C:33]([C:36]2[CH:41]=[C:40]([F:56])[C:39]([C:42]3[N:47]=[CH:46][CH:45]=[CH:44][N:43]=3)=[CH:38][C:37]=2[F:48])[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3ncccn3)cc2F)CC1
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(F)c(-c3ncccn3)cc2F)CC1

Procedure:
The Compound 12AQ was prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester using the procedure as described for the preparation of Compound 4-(2-fluoro-4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester but using 1,4-dibromo-2,5-difluoro-benzene in place of 4-bromo-2-fluoro-1-iodobenzene.
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[O:22])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[O:20][CH3:21])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.C(OC)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:15]1[C:14]([O:20][CH3:21])=[C:13]([C:7]2([CH2:6][C:5]([OH:22])([C:25]([F:27])([F:26])[F:24])[CH:4]=[O:3])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:18]=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC1(c2cccc(Cl)c2OC)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Cl)cccc1C1(CC(O)(C=O)C(F)(F)F)CCCCC1
Reaction time: 8 h
Yield: 34.5 %

Procedure:
7.07 g (20.87 mmol) of ethyl-3-[1-(3-chloro-2-methoxyphenyl)-cyclohexyl]-2-oxopropionate is dissolved in 33 ml of tetrahydrofuran and mixed with 3.56 g (25.04 mmol) of (trifluoromethyl)-trimethylsilane. After 51.1 mg of tetrabutylammonium fluoride is added, the batch is stirred overnight. The reaction mixture is diluted with methyl tert-butyl ether, washed once with water and then with brine. After the usual working-up, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). The isolated 5.71 g (60.4%) of the product is mixed in 70 ml of tetrahydrofuran with 3.98 g (12.61 mmol) of tetrabutylammonium fluoride and stirred for one hour at room temperature. After the reaction mixture is mixed with water, it is extracted with metyl-tert-butyl ether. After the usual working-up, the residue is chromatographed on a Flashmaster. 2.63 g (51.1%) of the desired compound: ethyl-2-[1-(3-chloro-2-methoxyphenyl)-cyclohexylmethyl]-3,3,3-trifluoro-2-hydroxypropionate is isolated.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([C:17]([CH3:20])([CH3:19])[OH:18])([CH2:10]3)[CH2:8]1)[CH2:14]2.C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:18][C:17]([C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([OH:6])([CH2:14]3)[CH2:8]1)[CH2:10]2)([CH3:20])[CH3:19])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(C)(O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)OC(C)(C)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 23 %

Procedure:
A total of 10 mmole of acrylic chloride was added dropwise to a mixture of 10 mmole of the above-prepared 3-hydroxy-α,α-dimethyl-1-adamantanemethanol, 10 mmole of triethylamine, and 40 ml of tetrahydrofuran ,over about 30 minutes. After the completion of addition, the resulting mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture and the mixture was concentrated, and the concentrate was subjected to column chromatography on a silica gel to yield the title compound in a yield of 23%.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7]([NH2:15])([C:9]2[S:10][CH:11]=[C:12]([Br:14])[CH:13]=2)[CH:6]([CH2:16][OH:17])[CH2:5]1)[CH:2]=[CH2:3].C[Si](N([Si](C)(C)C)C(=[O:28])C(F)(F)F)(C)C.[C:33]([N:41]=[C:42]=S)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[CH2:1]([N:4]1[CH2:5][CH:6]([CH2:16][OH:17])[C:7]([NH:15][C:42]([NH:41][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:28])([C:9]2[S:10][CH:11]=[C:12]([Br:14])[CH:13]=2)[CH2:8]1)[CH:2]=[CH2:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C=CCN1CC(CO)C(N)(c2cc(Br)cs2)C1
Reactant: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: C1CCOC1
Product: C=CCN1CC(CO)C(NC(=O)NC(=O)c2ccccc2)(c2cc(Br)cs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a solution of [1-allyl-4-amino-4-(4-bromo-2-thienyl)pyrrolidin-3-yl]methanol 4 g, 12.6 mmol) in tetrahydrofuran (180 mL) is added bis(trimethylsilyl) trifluoroacetamide (3.2 g, 12.6 mmol) and the reaction is stirred at room temperature for 1 hr. Benzoyl isothiocyanate (2.5 g, 15.1 mmol) is added in one portion, stirred for 1 hour at room temperature, and then quenched with 1 N hydrochloric acid (20 mL). After stirring for 1 hour the pH of the reaction is adjusted to >8 using saturated sodium bicarbonate and extracted with dichloromethane. The organic phases are combined, concentrated under reduced pressure, and triturated with hexane/ethyl acetate (4:1) to give the title compound (5.9 g, >95%). ES/MS (m/e) (79Br/81Br) 480/482 (M+H).