Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5](=[NH:10])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH3:2][C:1]([CH3:4])([CH:5]([NH2:10])[C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:3]
Reactant: CC(C)(C)C(=N)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C(N)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The imine (14 g.) in dry ether (50 ml.) was added to a suspension of lithium aluminum hydride (1.7 g.) in dry ether (50 ml.). The mixture was stirred at room temperature for 24 hours, refluxed two hours and cooled. Water (1.7 ml.), 15% sodium hydroxide solution (5 ml.) and water (5 ml.) were added cautiously in succession, the mixture filtered, concentrated and the residue distilled to afford the desired amine, b.p. 79°-81° C./40 mm.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)(C(C)(C)C)(C)C.C(N(CC)CC)C.[CH2:37]([S:41](Cl)(=[O:43])=[O:42])[CH2:38][CH2:39][CH3:40].[OH-].[Na+].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C1C=CN=CC=1.C(O)(=O)C.O.C(OCC)(=O)C.ClCCCl>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][S:41]([CH2:37][CH2:38][CH2:39][CH3:40])(=[O:43])=[O:42])[CH2:27][CH2:28]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCCCS(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: [F-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCCCS(=O)(=O)N[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1
Reaction time: 17 h
Yield: 35.9 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer charged with cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine (150 mg, 0.34 mmol) and 1,2-dichloroethane (8 ml), was added triethylamine (96 μl, 0.70 mmol) and n-butylsulfonyl chloride (55 μl, 0.40 mmol) at room temperature. 4-Dimethylaminopyridine (3 crystals) was added and the mixture stirred for 17 hr. Aqueous sodium hydroxide solution (15 ml, 0.40M) was added and the mixture stirred for 10 min. The layers were partitioned and the aqueous layer was extracted with dichloromethane (15 ml). The combined organic layers were washed with brine (15 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was then dissolved in tetrahydrofuran (10 ml) and acetic acid (0.15 ml), then tetra-n-butylammonium fluoride hydrate (360 mg, 1.4 mmol) was added. The mixture was stirred at room temperature for 1 hr, then ethyl acetate (10 ml) and water (15 ml) were added. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (10 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to leave an oil. Purification via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:10 then 1:1, v/v) furnished the title compound (40 mg, 35%) as a white solid. m/z (ES−) 326 (M−H+); δH(CD3OD) 0.95 (3H, t), 1.45-1.55 (2H, m), 1.55-1.95 (10H, m), 2.80-2.90 (1H, m), 3.00-3.20 (2H, m), 3.65 (1H, m), 6.22-6.26 (2H, m), 6.96 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>>[CH3:11][S:12]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(CO)c1
Product: COc1cccc(COS(C)(=O)=O)c1

Procedure:
The title compound was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (292 mg, 93%) from 3-methoxybenzyl alcohol (200 mg, 1.45 mmol) and methanesulfonyl chloride (249 mg, 2.17 mmol). 1H NMR (CDCl3, 300 MHz) δ2.92 (s, 3H), 3.83 (s, 3H), 5.22 (s, 2H), 6.90-7.03 (m, 3H), 7.32 (t, 1H, J=7.7 Hz) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[N:11]=[C:12]([CH3:14])[S:13][C:7]2=[N:6][C:5]=1[CH3:15].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH:21]=[CH:20]2.N1(C2CCN(CCC3C(=O)N4C=CSC4=NC=3C)CC2)C2C(=CC=CC=2)C=C1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C(=O)([O-])O.[Na+]>CC(C)CC(=O)C.C(OCCO)C>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[N:11]=[C:12]([CH3:14])[S:13][C:7]4=[N:6][C:5]=3[CH3:15])[CH2:28][CH2:27]1)[CH:21]=[CH:20]2
Reactant: Fc1ccc2c(ccn2C2CCNCC2)c1
Reactant: Cc1nn2c(=O)c(CCCl)c(C)nc2s1
Agent: Cc1nc2sccn2c(=O)c1CCN1CCC(n2ccc3ccccc32)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOCCO
Solvent: CC(=O)CC(C)C
Product: Cc1nn2c(=O)c(CCN3CCC(n4ccc5cc(F)ccc54)CC3)c(C)nc2s1
Yield: 21.8 %

Procedure:
A mixture of 6-(2-chloroethyl)-2,7-dimethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one (3.6 g), prepared as described in EP-A-0,353,821, 5-fluoro-1-(4-piperidinyl)-1H-indole (3.3 g), prepared according to the procedure described in Synthetic Communications, 18 (3), 265-273 (1988), sodium carbonate (1 g), potassium iodide (catalytic quantity) and sodium hydrogen carbonate (2 g) in 4-methyl-2-pentanone (150 ml) and 2-ethoxyethanol (50 ml) was stirred and refluxed overnight. The mixture was filtered and the filtrate was washed with water. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE/CH3CN. The precipitate was filtered off, dried and purified by high-performance liquid chromatography over RP-18 (eluent: (0.5% NH4OAc in H2O)/CH3OH/THF 50/40/10). The pure fractions were collected and the solvent was evaporated, yielding 1.37 g (20%) 6-[2-[4-(5-fluoro-1H-indol-1-yl)-1-piperidinyl]-ethyl]-2,7-dimethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one (compound 8; mp. 194.1° C.).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1>CO>[CH3:1][O:2][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1C(=O)O
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A stainless steel stirred autoclave was charged sequentially with methanol (2.8 1.), sodium methoxide (259 g.) (in portions, keeping the temperature less than 35° C.), and 2-chloro-3-pyridinecarboxylic acid (190 g.). The autoclave was sealed and the reaction mixture heated at 110° C. (50 psig) for 48 hours. The reaction mixture was cooled to 25° C. and discharged from the autoclave. Solids were recovered by filtration. Concentration of the filtrate gave a second crop. These process steps were repeated until virtually all of the methanol had been removed. The several crops of solids were combined, taken up in 2.5 liters of water and acidified with conc. hydrochloric acid to pH 2.7 keeping the temperature below 20° C. The precipitated product was granulated for 30 minutes at 15° C. and recovered by filtration (141 g.). Purified title product was obtained by recrystallization from ethyl acetate-hexane (120.5 g., m.p. 148°-150° C.).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]>>[CH2:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[C:9]([C:7]#[N:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCCC1
Product: CCOC(=O)C(C#N)=C1CCCC1
Yield: 69 %

Procedure:
The sub-title compound was prepared in a 69% yield analogously to the method described in Organic Synthesis, 39, 25 (1959) from cyclopentanone and ethyl cyanoacetate.
Reaction SMILES: C(C1CC(=O)NN=1)CC.ClC1C2C(=CC=C(OC)C=2)[N+]([O-])=CC=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[NH:28]/[C:27](=[C:37]2/[C:38]([CH2:43][CH2:44][CH3:45])=[N:39][NH:40][C:41]/2=[O:42])/[CH:26]=1.[C:46]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([SH:56])=[CH:52][CH:51]=1)(=[O:48])[CH3:47]>C(OC(=O)C)(=O)C.C(O)C>[CH3:36][O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28]/[C:27](=[C:37]1/[C:38]([CH2:43][CH2:44][CH3:45])=[N:39][NH:40][C:41]/1=[O:42])/[CH:26]=[C:25]2[S:56][C:53]1[CH:52]=[CH:51][C:50]([NH:49][C:46](=[O:48])[CH3:47])=[CH:55][CH:54]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Cl)c2cc(OC)ccc2N1
Agent: CCCC1=NNC(=O)C1
Agent: COc1ccc2c(c1)c(Cl)cc[n+]2[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(C)=O)cc2)c2cc(OC)ccc2N1
Temperature: 180 °C

Procedure:
3-Propyl-1H-pyrazol-5(4H)-one (1.16 mmol) and 4-chloro-6-methoxyquinoline 1-oxide (0.15 g, 1.16 mmol) were stirred in acetic anhydride (3 mL) at ambient temperature for 30-40 minutes. The reaction mixture was concentrated and the resulting solid was filtered off and washed with a minimum amount of ether. (Z)-4-(4-chloro-6-methoxyquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one (0.06 g, 0.016 mmol) was dissolved in ethanol (1.5 mL) and 4-acetamidothiophenol (0.028 g, 0.016 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The mixture was then concentrated and the resulting solid filtered and washed with ether to give Example 45. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71 (t, J=7.33 Hz, 3H) 1.27-1.37 (m, J=7.48, 7.48, 7.48, 7.48, 7.48 Hz, 2H) 2.11 (s, 3H) 2.31 (t, J=7.45 Hz, 2H) 3.96 (s, 3H) 6.83 (s, 1H) 7.42 (d, J=2.78 Hz, 1H) 7.57 (dd, J=9.09, 2.27 Hz, 1H) 7.68 (d, J=8.59 Hz, 2H) 7.87 (d, J=8.59 Hz, 2H) 8.00 (d, J=9.35 Hz, 1H) 10.36 (s, 1H); ESI-MS: m/z calc'd for C24H24N4O3S 448.54. found 449.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][O-:13].[Na+].Cl>CO>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:13][CH3:12])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCC(=O)c1ccc(O)cc1
Reaction time: 0.75 h

Procedure:
3.0 g of 2-bromo-1-(4-hydroxy-phenyl)-ethanone in 25 ml of methanol are added dropwise in the course of 10 minutes to a solution of 7.5 g of sodium methanolate in 80 ml of methanol. Stirring is then carried out at 60° C. for 45 minutes. The reaction mixture is cooled, poured into dilute hydrochloric acid and extracted with ethyl acetate. After concentration of the organic phases and crystallisation from diethyl ether, 1-(4-hydroxy-phenyl)-2-methoxyethanone is obtained. 1H-NMR (CDCl3) 300 MHz: 3.50 (s, 3H), 4.70 (s, 2H), 6.62 (s, 1H), 6.91 (d, 2H), 7.89 (d, 2H)
Reaction SMILES: [F:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]=2[N+:22]([O-:24])=[O:23])[CH:7]=1.[CH3:28][O:29][CH2:30][C@H:31]([NH2:34])[CH2:32][CH3:33].Cl>>[F:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:34][C@@H:31]([CH2:30][O:29][CH3:28])[CH2:32][CH3:33])[C:9]=2[N+:22]([O-:24])=[O:23])[CH:7]=1
Reactant: COc1cc(C)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Reactant: CC[C@@H](N)COC
Agent: Cl
Product: CC[C@H](COC)Nc1nccc(-c2cc(F)c(OC)cc2C)c1[N+](=O)[O-]
Yield: 37 %

Procedure:
Trifluoro-methanesulfonic acid 4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.5 g, 1.2 mmol), prepared substantially as described in Part C of Example 19a, and (R)-1-methoxymethyl-propylamine.HCl (0.34 g, 2.4 mmol) were treated substantially as described in Part C of Example 19a to produce 0.16 g (37%) of crude (R)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl>CO>[CH3:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Cl)cc1C
Agent: Cl
Solvent: CO
Product: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Reaction time: 2 h

Procedure:
10 g of methyl 2-methyl-4-chloro-5-methylsulphonylbenzoate are added, while cooling with ice, to a mixture of 30 ml of conc. HCl and 200 ml of methanol, and the whole is then stirred for 2 h. The resulting precipitate is filtered off with suction and recrystallized from methanol. 2-Methyl-4-chloro-5-methylsulphonylbenzoic acid is obtained, m.p. 217°-218°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:19][CH:20]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1[CH:31]=O)=[O:24].N1CCCCC1>C(O)C>[OH:19][CH:20]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1/[CH:31]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH:17]=[CH:16][CH:15]=2)=[O:24]
Reactant: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cc(F)cc(F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4cc(F)cc(F)c4)c32)[nH]1

Procedure:
4-(3,5-Difluoro-phenyl)-1,3-dihydro-indol-2-one (73.5 mg, 0.3 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide (excess) and piperidine in ethanol to give 40 mg of the titled compound as a yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:13][C:14]1[C:15]([C:35]2[CH:36]=[N:37][C:38](F)=[CH:39][CH:40]=2)=[CH:16][C:17]2[C:18]3[N:26]([CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:25](=[O:33])[N:24]([CH3:34])[C:19]=3[CH:20]=[N:21][C:22]=2[CH:23]=1>C1COCC1>[F:13][C:14]1[C:15]([C:35]2[CH:36]=[N:37][C:38]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:39][CH:40]=2)=[CH:16][C:17]2[C:18]3[N:26]([CH:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[C:25](=[O:33])[N:24]([CH3:34])[C:19]=3[CH:20]=[N:21][C:22]=2[CH:23]=1
Reactant: Cn1c(=O)n(C2CCOCC2)c2c3cc(-c4ccc(F)nc4)c(F)cc3ncc21
Reactant: OCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(C2CCOCC2)c2c3cc(-c4ccc(OCCCN5CCCCC5)nc4)c(F)cc3ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
3-(Piperidin-1-yl)propan-1-ol (0.053 mL, 0.35 mmol) was added slowly to a slurry of sodium hydride (31.5 mg, 0.79 mmol) in THF (7 mL) and the solution stirred at ambient temperature for 30 minutes. 7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinolin-2-one (125 mg, 0.32 mmol) in THF (3 mL) was added to the reaction mixture via syringe over a period of 1 minute and the reaction stirred for 24 h. The reaction was quenched with water then extracted into DCM, the organic phase separated and concentrated in vacuo. The crude product was purified by FCC, elation gradient 0 to 10% 1M methanolic ammonia in DCM, and the resultant oil triturated with Et2O to afford the desired material as a white solid (92 mg, 56%). NMR Spectrum: 1H NMR (500 MHz, CDCl3) δ 1.38-1.52 (2H, m), 1.61 (4H, p), 1.92 (2H, dd), 2.03 (2H, dt), 2.43 (4H, s), 2.47-2.58 (2H, m), 2.94 (2H, d), 3.53-3.63 (5H, m), 4.22 (2H, dd), 4.42 (2H, t), 5.01 (1H, s), 6.89 (1H, dd), 7.85-7.96 (2H, m), 8.26 (1H, s), 8.44 (1H, s), 8.71 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=520.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.Cl.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.Cl>>[CH3:15][N:16]1[CH2:21][CH2:20][C:19]2[NH:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([O:3][CH3:2])=[O:13])=[CH:10][C:9]=3[C:18]=2[CH2:17]1
Reactant: COC(=O)c1ccc(NN)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Product: COC(=O)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Temperature: 100 °C

Procedure:
Methyl-4-hydrazinylbenzoate hydrochloride (1 equiv.) and 1-methylpiperidin-4-one HCl (0.76-1.4 equiv.) are taken aqueous HCl and heated at 100° C. overnight (the product was detected by LCMS). The reaction mixture is concentrated and refluxed (90° C.) in methanolic HCl overnight (product was detected by LCMS and TLC). The reaction mixture is concentrated and basified with aqueous NaHCO3 solution and extracted with EtOAc. The crude product is crystallized in DCM and ether and hexane.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[I:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](=[N:12]O)[NH2:11])=[CH:8][CH:7]=1>N1C=CC=CC=1>[I:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]2[N:12]=[C:1]([CH3:2])[O:3][N:11]=2)=[CH:8][CH:7]=1
Reactant: NC(=NO)c1ccc(I)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(I)cc2)no1
Temperature: 25 °C

Procedure:
Acetyl chloride (1.62 ml) was added to a solution of 4-iodobenzamidoxime (5.24 g) in pyridine (35 ml) at ambient temperature. The reaction mixture was heated at reflux for 3 hours. The mixture was cooled to ambient temperature, evaporated and ice-water was added to the residue. The solid was collected by filtration, washed with water and recrystallised from acetonitrile to give 3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole (4.43 g), m.p. 121°-122° C.; microanalysis found: C, 37.6; H, 2.4; N, 9.7%; C9H7IN2O requires: C, 37.8; H, 2.47; N, 9.79%; NMR: 2.66(3H,s), 7.77(2H,dd) and 7.94(2H,dd); m/z 287(M+H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:14]([O:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C1CC[C@@H](CO)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (30.0 g, 261 mmol) and imidazole (23.1 g, 340 mmol) in DCM (900 mL) was added TBS-Cl (42.9 g, 288 mmol). The reaction mixture was stirred at RT for 30 min and filtered. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (50 g, 83.7%). LRMS (M+H+) m/z 230.2.
Reaction SMILES: O[C:2]1[C:11]2[CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[N:3]=1.P(Cl)(Cl)([Cl:31])=O>C(Cl)(Cl)Cl>[Cl:31][C:2]1[C:11]2[CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)CCc2nc([C@H]3CCCN3C(=O)OCc3ccccc3)nc(O)c2C1
Solvent: ClC(Cl)Cl
Product: CC1(C)CCc2nc([C@H]3CCCN3C(=O)OCc3ccccc3)nc(Cl)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A mixture phenylmethyl(2R)-2-(4-hydroxy-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.39 mmol) and phosphorous oxychloride (1 mL) in chloroform (3 mL) was stirred at 80° C. for one hour. After cooling to room temperature the reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate (20 mL) and ethyl acetate (20 mL). The mixture was stirred for 15 minutes and pH was maintained above 7 by the addition of solid sodium bicarbonate. The organic layer was separated and washed with water (10 mL) and brine, dried over sodium sulfate, filtered and concentrated to give phenylmethyl(2R)-2-(4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-1-carboxylate (117 mg, 74%). MS (EI) for C22H26ClN3O2: 400 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[CH:3]=1.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]2[CH3:26])=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][CH:17]=2)=[O:8])=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[CH:3]=1
Reactant: CN1C(=O)CCc2ccc(N)cc21
Reactant: O=C(O)c1ccc(Cl)cc1NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCO)cc21

Procedure:
In dichloromethane, a mixture of 4-chloro-2-[(2-hydroxyethyl)amino]benzoic acid and 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one was treated with 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide hydrochloride at room temperature to obtain 4-chloro-2-[(2-hydroxyethyl)amino]-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=1.[I-].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Fc1ccc(CCCl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(O)c1ccc(NCCc2ccc(F)cc2)cc1

Procedure:
A mixture of 15.8 g. of 1-(2-chloroethyl)-4-fluorobenzene, 33 g. of ethyl p-aminobenzoate, 16.6 g. of potassium iodide and 100 ml. of hexamethylphosphoramide is heated at 95° C. for 15 hours. The mixture is poured into water and extracted with ether. The ether extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. To the oil is added 200 ml. of ethanol-water (9:1) and 21 g. of potassium hydroxide and the mixture is refluxed for 3.5 hours. The mixture is acidified with concentrated hydrochloric acid, diluted with water, cooled and filtered to give gray crystals. Recrystallization from ethanol gives light gray crystals, m.p. 161°-163° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)S(O[C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([C:30]2[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si](C)(C)C)[N:33]=[N:32][N:31]=2)[CH:29]=1)[C:23]([O:25][CH3:26])=[O:24])(=O)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[CH2:37]([O:36][CH2:35][N:34]1[C:30]([C:28]2[CH:27]=[C:22]([CH:21]=[C:20]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])=[N:31][N:32]=[N:33]1)[CH3:38]
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2nnnn2COCC[Si](C)(C)C)c1
Reactant: C1CCNC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: CCOCn1nnnc1-c1cc(C(=O)OC)cc(N2CCCC2)c1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
Pyrrolidine (41 mg), Pd2(dba)3 (35 mg), tBu2-P-Ph-Ph (23 mg) and potassium phosphate (241 mg) were added in that order to a DME (5 mL) solution of methyl 3-{[(trifluoromethyl)-sulfonyl]oxy}-5-[({[2-(trimethylsilyl)ethyl]oxy}methyl)tetrazol-5-yl]benzoate (183 mg), and stirred at 85° C. for 4 hours. The reaction liquid was filtered through Celite, the solvent was evaporated away, the residue was diluted with ethyl acetate, water was added thereto, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated away. The residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a red oil.