Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:11][CH:12]([CH2:14]O)O>>[CH3:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:14][CH:12]=[CH:11]2
Reactant: Cc1ccc(N)c(Br)c1
Reactant: OCC(O)CO
Product: Cc1cc(Br)c2ncccc2c1

Procedure:
2-bromo-4-methylaniline and glycerol can be combined to form 6-methyl-8-bromoquinoline,
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.C(N(C(C)C)CC)(C)C.Cl.Cl.[CH2:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][C:43]=2[C:51]([F:54])([F:53])[F:52])[CH2:37][CH2:36]1)[CH3:34].O>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:33]([N:35]1[CH2:36][CH2:37][N:38]([CH2:41][C:42]2[CH:50]=[CH:49][C:45]([C:46]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[CH:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:47])=[CH:44][C:43]=2[C:51]([F:54])([F:52])[F:53])[CH2:39][CH2:40]1)[CH3:34]
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cccnc2)ccn1
Reactant: CCN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4cc(-c5cccnc5)ccn4)c3)cc2C(F)(F)F)CC1
Yield: 22.4 %

Procedure:
200 mg of 4-methyl-3-[4-(3-pyridyl)pyridin-2-ylamino]aniline (Reference Example 23) was suspended in 4 ml of acetonitrile, and 78.8 mg of 4-(dimethylamino)pyridine and 484 μl of N,N-diisopropyl-N-ethylamine were added in turn. Under ice-cooling with stirring, 383 mg of 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 5) was added, followed by stirring at room temperature for 2 hours. To the reaction solution was added water and the mixture was subjected to extraction with ethyl acetate three times. The organic layers were washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 93 mg of the objective compound as pale yellow crystals.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[CH2:9][CH:10](C([O-])=O)C([O-])=O)(=O)C.[OH-:20].[Na+].S(=O)(=O)(O)O.[O:27]1[CH2:32]COCC1>>[OH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:9]([CH3:10])[C:32]([OH:27])=[O:20])[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OCc1cccc(CC(C(=O)[O-])C(=O)[O-])c1
Reactant: [OH-]
Reactant: C1COCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C(=O)O)c1cccc(CO)c1

Procedure:
Refer to Chart G. A solution of m-(acetoxymethyl)benzylmalonate, dimethyl ester (Preparation 3, 9.16 g.) in 45 ml. of dioxane is treated with 137 ml. of 10% sodium hydroxide at about 25° C. for 15 min. The mixture is acidified to pH 1.0 with sulfuric acid, treated with an additional 3 ml. of sulfuric acid, and heated at reflux for about 36 hr. The mixture is cooled, diluted with 430 ml. brine and extracted with chloroform. The extract is washed with brine, dried over magnesium sulfate, and concentrated. Yield of title compound: 4.31 g., having NMR peaks at 2.40-3.18, 4.58, 7.17, and 7.53 δ,
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([F:22])[CH:15]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]([OH:19])[C:17]1[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][C:16]=1[F:22]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: OC(c1ccc(Br)cc1F)c1ccccc1C(F)(F)F

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (60 mmol) and 4-bromo-2-fluorobenzaldehyde (54 mmol) using the procedure described for compound (96) (12.3 g, 74%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[NH:18][C:19]([CH:21]=O)=[CH:20][C:12]2=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34](=[O:40])[NH:35]2>N1CCCCC1.C(O)C>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1/[C:33](=[CH:21]/[C:19]1[NH:18][C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:11]([C:9](=[O:10])[CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:12]=3[CH:20]=1)/[C:34](=[O:40])[NH:35]2
Reactant: O=Cc1cc2c([nH]1)CCCCN2C(=O)CCN1CCCCC1
Reactant: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(-c3c(F)cccc3F)c2/C1=C/c1cc2c([nH]1)CCCCN2C(=O)CCN1CCCCC1
Yield: 60.3 %

Procedure:
4-(3-Piperidin-1-yl-propionyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde (80 mg, 0.26 mmol) was condensed with 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one (61 mg, 0.25 mmol) and piperidine (1 drop) in ethanol (3 mL) at rt for over the weekend. The precipitate was filtered, washed with ethanol and dried to give 80 mg of the titled compound as a yellow solid.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][C@@H:9]([C:21]([NH:23][C@H:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:25][O:26][CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30])=[O:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(C)C.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[CH3:32][O:31][CH:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][C@@H:24]([C:33]([O:35][CH3:36])=[O:34])[NH:23][C:21](=[O:22])[C@H:9]([CH2:8][CH2:7][OH:6])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: COC(=O)[C@H](COCC(OC)OC)NC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](COCC(OC)OC)NC(=O)[C@H](CCO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
A solution of N-[O-[(1,1-dimethylethyl)-dimethylsilyl]-N-[(phenylmethoxy)carbonyl]-L-homoseryl]-O-(2,2-dimethoxyethyl)-L-serine, methyl ester [5.56 g, 10 mmol, prepared as described in Example 10(h)] in methanol (65 ml) was cooled to 0° C. (ice salt bath), treated with p toluenesulfonic acid monohydrate (386 mg, 2.0 mmol) and stirred at 0° C. for 1.5 hours. The reaction was quenched with sodium bicarbonate solution (198 mg. in 20 ml water), stirred for 5 minutes then evaporated to remove the methanol. The aqueous phase was extracted with ethyl acetate (2×200 ml) and the combined organic extract was washed with water (110 ml), 5% sodium bicarbonate (80 ml) and brine (80 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude product was chromatographed on silica gel column (Merck), eluting the column with ethyl acetate:hexane (2:1) and ethyl acetate:methanol (98:2) to give 3.975 g of title product as a syrup. TLC (ethyl acetate:hexane, 4:1) Rf =0.17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:9]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:9]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NC(=O)C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 6.0 g. of p-[2,2-bis(p-chlorophenyl)acetamido]benzoic acid, ethyl ester, 920 mg. of potassium hydroxide, and 50 ml. of 95% ethanol is stirred at 75° C. for 9 hours, cooled, diluted with 100 ml. of water, and the pH is adjusted to 2.0 with 37% hydrochloric acid. The precipitate is collected, washed with water, dried and recrystallized from 100 ml. of ethanol, giving 2.78 g. of the desired product as colorless crystals, m.p. 272°-274° C.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][NH2:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC[CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].C(=O)([O-])[O-:27].[Na+].[Na+]>C1C=CC=CC=1.O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][NH:17][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][OH:24])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCC1c2ccccc2CCc2ccccc21
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)CCCCCl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C(CCCO)NCC1c2ccccc2CCc2ccccc21

Procedure:
A mixture of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-methylamine (20.0 g), 5-chlorovaleric acid chloride (19.2 g) and sodium carbonate (35.0 g) in 250 ml of benzene is stirred and subjected to reflux for 16 hours. The reaction mixture is diluted with water. The benzene layer is separated and washed with water, dried and evaporated to dryness The residue is crystallized from benzene-hexane to afford the haloamide N-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyl]-5-chlorovaleramide (III, Alk = CH2CH2CH2CH2 and Y = Cl), m.p.., 98°-99° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+].[Cl-].[NH4+]>CO>[CH3:12][O:13][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A solution of 2-chloro-4-methyl-5-nitropyridine (3.0 g, 17.3 mmol) in methanol (20 mL) was added a solution of sodium methoxide (28% in methanol, 10 mL) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 16 hr. The mixture was neutralized by addition of aqueous ammonium chloride and concentrated in vacuo. The residue was dissolved in water and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (2.84 g, 16.8 mmol, 98%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@@H:5]([C@H:7]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:8]([O:10]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[C:4](=[O:26])[O:3]1.ONC(=O)[C@@H](O)[C@@H](C([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[CH2:41][CH2:40]1)=O)CC(C)C.N1C=CC=CC=1N1CCNCC1>CN(C=O)C>[CH3:27][C:2]1([CH3:1])[O:3][C:4](=[O:26])[C@H:5]([C@@H:7]([C:8]([N:39]2[CH2:44][CH2:43][N:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH2:41][CH2:40]2)=[O:10])[CH2:22][CH:23]([CH3:24])[CH3:25])[O:6]1
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Reactant: CC(C)C[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)[C@@H]1OC(C)(C)OC1=O
Agent: c1ccc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@@H]1OC(C)(C)OC1=O

Procedure:
To a solution of a 55/45 diastereoisomeric mixture of pentafluorophenyl (2S)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate and pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate (Intermediate 1, 792.6 mg; 2.0 mmol; 1.0 eq.) in DMF (15 mL) was added 1-(2-pyridyl)piperazine (326.5 mg; 2.0 mmol; 1.0 eq.). After 14 h of reaction at RT, the solvent was evaporated to give an oil. Purification by chromatography (SiO2) gave the title compound as a colorless oil (as a mixture of 2 diastereoisomers 50/50). This product was dissolved on iPrOH (10 mL) at kept at −20° C. for 48 h. The supernatant was collected and evaporated to give a colorless oil (301 mg, 40%, single diastereoisomer). M+(ESI): 376.3. HPLC (Condition A): Rt: 5.0 min (HPLC purity: 77.1%). 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, J=4.2 Hz, 1H), 7.58-7.47 (m, 1H), 6.74-6.63 (m, 2H), 4.54 (d, J=6.0 Hz, 1H), 3.88-3.41 (m, 8H), 3.33-3.22 (m, 1H), 1.89-1.62 (m, 3H), 1.61 (s, 3H), 1.55 (s, 3H), 0.99-0.88 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(OCC)(OCC)OCC.[N-:19]=[N+:20]=[N-:21].[Na+].[C:23](O)(=O)C.Cl.N([O-])=O.[Na+]>O>[N:1]1([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH:23]=[N:21][N:20]=[N:19]1
Reactant: Nc1cccc(O)c1
Reactant: CC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: O
Product: Oc1cccc(-n2cnnn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
To a 200 ml round bottom flask equipped with a magnetic stir bar containing a solution of 3-aminophenol (5 g, 45.8 mmol, 1.0 eq) in triethyl orthoformate (24.4 ml, 146.5 mmol, 3.2 eq) was added sodium azide (3.73 g, 57.3 mmol, 1.25 eq) and acetic acid (41.95 ml, 732.8 mmol, 16.0 eq). The mixture was stirred for 10 min at room temperature and then heated at 80° C. for 1.5 h. After heating, the mixture was bronze and homogeneous. The mixture was cooled to room temperature. Water (30 mL) and 6 N HCl (17 mL) was added. A 25% aqueous solution of NaNO2 (6 mL) was slowly added while the reaction mixture was cooled in an ice bath. A white solid, 3-tetrazol-1-yl-phenol 29 (5.3 g, 72% yield) was obtained upon filtration and washing with water. LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 163.0 (M+H)+1 1H-NMR, Varian 400 MHz (MeOH-d4) δ 9.71 (s, 1H), 7.41 (t, 1H), 7.28 (d, 2H), 6.96 (d, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[NH:7][C:6]2=O.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([CH3:15])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nc(C)[nH]c(=O)c2cc1OC
Product: COc1cc2nc(C)nc(Cl)c2cc1OC
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A mixture of 6,7-dimethoxy-2-methylquinazolin-4(3H)-one (1.0 mg) and phosphorous oxychloride (20 mL) was refluxed for 3 h. The reaction mixture was attained to rt and poured into ice cold water and stirred for 10 min. The solution was extracted with chloroform (3×100 mL) and the combined CHCl3 layer was washed water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as a yellow color solid (1.0 g, 92%), mp 182-184° C. 1H NMR (400 MHz, CDCl3): δ 7.36 (1H, s), 7.30 (1H, s), 4.06 (6H, s), 2.81 (3H, s); LC-MS (positive ion mode): m/z 239, 241 (M+H)+.
Reaction SMILES: [H-].[Na+].C(O[CH2:7][C:8]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:11])(=O)C.O.C1(C)C=CC=CC=1>CN(C)C=O>[CH3:25][O:24][C:21]1[CH:20]=[C:9]2[C:8]([CH2:7][N:12]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:10]2=[O:11])=[CH:23][CH:22]=1
Reactant: COc1ccc(COC(C)=O)c(C(=O)NCc2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)N(Cc1cccnc1)C2
Temperature: 0 °C
Yield: 58.2 %

Procedure:
To a suspension of 136 mg of sodium hydride (about 60%) in 7 ml of dimethylformamide chilled at 0° C. was added 820 mg of 2-acetoxymethyl-5-methoxy-N-(3-pyridylmethyl) benzamide and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with water and shaken with toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 386 mg of the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][O:6][C:5]2([CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[O:4][CH2:3]1.[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16].N1CCCCC1.C(O)(=O)C>C(O)C>[CH2:21]([O:20][C:18](=[O:19])[C:17]([C:15]#[N:16])=[C:10]1[CH2:11][CH2:12][C:5]2([O:6][CH2:7][C:2]([CH3:14])([CH3:1])[CH2:3][O:4]2)[CH2:8][CH2:9]1)[CH3:22]
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=C1CCC2(CC1)OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-one (10.0 g), ethyl cyanoacetate (5.9 mL), piperidine (0.5 mL), acetic acid (0.3 mL), and ethanol (100 mL) is stirred at room temperature overnight. The mixture is then cooled to −5° C. and the precipitate formed is separated by filtration, washed with ice-cold ethanol, and dried to give the title compound as a colorless solid. Yield: 13.7 g (93% of theory); Mass spectrum (ESI+): m/z=294 [M+H]+.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:23][O:24][C:25](=[O:39])[C@@H:26]1[CH2:30][C@H:29]([NH2:31])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[C:40]([O:44][C:45]([NH:47][CH2:48][C:49](O)=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41]>ClCCl.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:39])[C@@H:26]1[CH2:30][C@H:29]([NH:31][C:49](=[O:50])[CH2:48][NH:47][C:45]([O:44][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:46])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NC(=O)CNC(=O)OC(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 104.7 %

Procedure:
Triethylamine (1.13 mL), 1-hydroxybenzotriazole (1.04 g), and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (1.56 g) were added to a solution of cis-4-amino-N-tert-butoxycarbonyl-L-proline methyl ester (Compound D102 (C), 1.65 g) and N-tert-butoxycarbonylglycine (1.42 g) in dichloromethane (100 mL) at 0° C. The mixture was stirred at room temperature for 19 hr and evaporated in vacuo. The residue was diluted with ethyl acetate and washed with 10% citric acid, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (2.84 g) as a colorless foam.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1[CH:11]=CC=C[CH:7]=1.[N:12]12[CH2:22][CH2:21][CH2:20][N:19]=[C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2.[OH2:23]>ClCCl>[CH:7]1[N:6]=[CH:11][N:19]2[CH2:18][CH2:17][CH2:16][C:15](=[C:14]3[CH2:21][CH2:22][NH:12][C:13]3=[O:23])[C:20]=12
Reactant: O
Reactant: c1ccncc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1NCCC1=C1CCCn2cncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.23 ml of phosphorus oxychloride are added dropwise to a solution of 0.50 g of 3-(8-hydro-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)pyrrolidin-2-one and 7.5 ml of pyridine at 0° C., and the reaction mixture is then warmed to room temperature. After 1 hour, 1.02 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene are added. After 3 hours water is added to the reaction mixture, and it is extra with dichloromethane (3×)—the combined organic phases are washed successively with 1N NaOH and water, dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO2 60F) on the basis of the Rf.
Reaction SMILES: CCN(CC)CC.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29].O>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[S:28]([O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C@H:9]([OH:8])[CH2:10][CH2:11][NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH:21]=1)(=[O:29])=[O:27]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Et3N (1.5 mL, 10.76 mmol) was added to a suspension of Intermediate I (1.00 g, 3.74 mmol) in anhydrous CH2Cl2 (20 mL), and a clear solution resulted. The reaction mixture was cooled to 0° C. under N2 and Tf2O (0.7 mL, 4.14 mmol) was added slowly via syringe. The reaction mixture was stirred for 2 h, water was added and the mixture was extracted with CH2Cl2 twice. Combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography (10%-50% EtOAc-hexanes gradient) gave (R)-3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenyl trifluoromethanesulfonate as a colorless oil. Yield (1.10 g, 74%); 1H NMR (400 MHz, DMSO-d6); δ 7.45-7.52 (m, 1H), 7.39-7.43 (m, 1H), 7.33-7.38 (m, 1H), 7.27-7.32 (m, 1H), 6.72 (br. t, 1H), 5.45 (d, J=4.7 Hz, 1H), 4.56-4.66 (m, 1H), 2.86-3.2 (m, 2H), 1.60-1.70 (m, 2H), 1.33 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@H:7]([O:16][C:17](=[O:19])[CH3:18])[C@@H:8]([O:12][C:13](=[O:15])[CH3:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].[C:21]([C:25]1[CH:34]=[CH:33][C:28]([NH:29][CH2:30][CH2:31][Cl:32])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].Cl.C(N=C=NCCCN(C)C)C.O>C(Cl)Cl>[C:17]([O:16][C@H:7]([C@@H:8]([O:12][C:13](=[O:15])[CH3:14])[C:9]([N:29]([CH2:30][CH2:31][Cl:32])[C:28]1[CH:27]=[CH:26][C:25]([C:21]([CH3:24])([CH3:22])[CH3:23])=[CH:34][CH:33]=1)=[O:11])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])(=[O:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(NCCCl)cc1
Reactant: CC(=O)O[C@@H](C(=O)O)[C@@H](OC(C)=O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@@H](C(=O)OC(C)(C)C)[C@@H](OC(C)=O)C(=O)N(CCCl)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.3 %

Procedure:
To a solution of (R,R)-2,3-bis(acetyloxy)-butanedioic acid mono tert-butyl ester (9 g: Tetrahedron, 45, 3071-3080, 1989) in CH2Cl2 (90 mL), were added compound 11-1 (6.6 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride at 0° C. The reaction mixture was stirred for 5 hours at room temperature. Then water was added into the mixture and it was extracted with CH2Cl2. The organic layer was washed with brine, dried with anhyd. Na2SO4. The solvent was removed under reduced pressure to obtain compound 52-1 (15.8 g) as a brown amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[F:38][C:39]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:38][C:39]1([F:45])[CH2:44][CH2:43][N:42]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: FC1(F)CCNCC1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC(F)(F)CC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 4,4-difluoropiperidine according to conditions described in general procedure C. Mp: 172-174° C.; 1H NMR (400 MHz, CDCl3) δ 1.63-1.71 (m, 6 H), 1.86-1.91 (m, 4 H), 3.28 (t, J=5.8 Hz, 4 H), 3.77 (s, 4 H), 6.07 (d, J=5.8 Hz, 1 H), 6.75-6.79 (m, 1 H), 6.98 (d, J=8.0 Hz, 1 H), 7.29-7.31 (m, 2 H), 7.49-7.60 (m, 2 H), 7.90-7.99 (m, 3 H), 8.12 (s, 1 H), 8.17 (d, J=5.5 Hz, 1 H).
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:5]=1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CC(C)=O>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:5]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1cccc(-n2cncn2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1

Procedure:
The 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert.-butyl ester was prepared from 3-[1,2,4]triazol-1-yl-benzoic acid methyl ester [CAS-No. 167626-27-9] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Prepared from (Example H6) by stirring in TFA/acetone with TFAA according to general procedure J (method b). Obtained as a yellow solid (539 mg).