Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@@H]([C@H](OC(=O)C1C=CC=CC=1)C(O)=O)C(O)=O)(=O)C1C=CC=CC=1.[NH2:27][C@@:28]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[CH2:32][O:31][C@H:30]([C:33]([F:36])([F:35])[F:34])[C@H:29]1[CH2:37][OH:38].CCOC(C)=O.[OH-].[Na+].[C:54]([N:62]=[C:63]=[S:64])(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(Cl)Cl>[F:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C@@:28]1([NH:27][C:63]([NH:62][C:54](=[O:61])[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[S:64])[C@H:29]([CH2:37][OH:38])[C@@H:30]([C:33]([F:36])([F:34])[F:35])[O:31][CH2:32]1
Reactant: N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C(O[C@H](C(=O)O)[C@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Temperature: -3 °C
Reaction time: 0.08 h
Yield: 106.1 %

Procedure:
To chiral salt ((2S,3R,4S)-4-Amino-4-(2-fluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (2S,3S)-2,3-bis(benzoyloxy)succinate (0.361 kg, 0.556 mol) was added EtOAc (1.08 L) and the suspension was cooled to −3° C. 1.0 N aq. NaOH (1.30 L) was added over 20 mins while maintaining T <5° C. After 5 mins, benzoyl isothiocyanate (80.0 mL, 594 mmol) was added over 8 mins while maintaining T <5° C. After 1 h, EtOAc (722 mL) was charged. The aq. layer was removed, and the organics were washed with sat. aq. NaHCO3 (361 mL) and sat. aq. NaCl (361 mL). The organics were filtered over celite (90 g) and rinsed with EtOAc (360 mL). The organics were concentrated under vacuum to afford a residue which was re-dissolved into CH2Cl2 (1.1 L) and concentrated to afford the title compound as yellow foam (261 g, 99% yield accounting for residual solvents) which was used in the following step. 1H NMR (500 MHz, DMSO) δ ppm 12.04 (s, 2H), 11.20 (s, 2H), 7.95 (d, J=7.4 Hz, 2H), 7.69-7.60 (m, 1H), 7.56-7.42 (m, 2H), 7.37-7.28 (m, 1H), 7.24-7.12 (m, 2H). 5.59 (t, J=4.5 Hz, 1H), 5.03 (d, J=9.7 Hz, 1H), 4.92 (d, J=9.7 Hz, 1H), 4.75-4.63 (m, 1H), 3.92-3.74 (m, 2H), 2.77-2.66 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 179.98, 167.85, 159.75 (d, JCF=245.0 Hz), 133.44, 132.58, 129.88, 129.81, 129.04, 128.85, 126.31 (d, JCF=9.8 Hz), 124.36, 116.83 (d, JCF=23.4 Hz), 76.11 (q, JCF=31.0 Hz). 74.37 (d, JCF=6.1 Hz), 68.77 (d, JCF=3.4 Hz), 57.03, 52.23.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH3:21][P:22]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28]([NH2:33])=[CH:27][CH:26]=1)([CH3:24])=[O:23].Cl>COCCO.C(O)C>[CH3:24][P:22]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28]([NH:33][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:5]=[CH:6][N:7]=2)=[CH:27][CH:26]=1)([CH3:21])=[O:23]
Reactant: COc1nc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncn1
Agent: Cl
Solvent: CCO
Solvent: COCCO
Product: COc1nc(P(C)(C)=O)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)ncn1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.250 mmol) in 1 mL of 2-methoxyethanol is added 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (50.0 mg, 0.250 mmol) and 0.15 mL of 2.5 M HCl in ethanol. The mixture is heated in a sealed tube at 90° C. until formation of the desired compound. The mixture is basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers can be combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue can be purified by silica gel chromatography.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>O1CCCC1>[ClH:1].[ClH:1].[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:33]([CH2:34][CH3:35])[CH2:31][CH3:32])=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7])[CH3:32]
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1S2
Reactant: CCNCC
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)CCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCCN(CC)CC)ccc1S2
Product: Cl
Temperature: 106 °C

Procedure:
A mixture of 20 g (0.0046 mole) of 2,7-bis(5-chlorovaleryl)-thioxanthene, 2 g of potassium iodide, 150 ml of diethylamine and 250 ml of tetrahyrofuran was heated to 106°C. in a Paar bomb for 24 hours with stirring. Upon cooling, the solvent was evaporated, and the remaining material was dissolved in heptane and filtered. The solution was acidified with ethereal HCl and the resulting precipitate was recrystallized several times from methanol and ethyl acetate to give the desired product. M.P. 197.5°-199.5°C.
Reaction SMILES: O.NN.C(O)C.[C:7]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH:12]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:11]1)(=[O:9])[CH3:8]>C(OCC)(=O)C>[C:7]([N:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH:12]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:11]1)(=[O:9])[CH3:8]
Reactant: CC(=O)N1CCC(N2C(=O)c3ccccc3C2=O)C(NC(=O)OC(C)(C)C)C1
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCC(N)C(NC(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Hydrazine monohydrate (1 ml) was added to an ethanol (5 ml) solution containing tert-butyl (1-acetyl-4-(1,3-dioxoisoindolin-2-yl)piperidin-3-yl)carbamate (301 mg) obtained in the 3rd step, followed by heating and stirring at 50° C. for 0.5 hours. Ethyl acetate was added to the reaction solution. The reaction solution was washed with water and saturated saline and dried over anhydrous sodium sulfate. Next, the solvent was distilled away under reduced pressure. Colorless oily matter of tert-butyl (1-acetyl-4-aminopiperidin-3-yl)carbamate (147 mg) was thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]([CH3:17])([CH3:16])[CH:9]=2)=[CH:4][C:3]=1[CH3:18].[CH:19](O)=[O:20].O1COCOC1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2[CH:19]=[O:20])=[CH:4][C:3]=1[CH3:18]
Reactant: O=CO
Reactant: Cc1cc(C2=CC(C)(C)CC(C)(C)C2)ccc1F
Agent: C1OCOCO1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(C2=C(C=O)C(C)(C)CC(C)(C)C2)ccc1F
Temperature: 25 °C

Procedure:
To a mixture of 20 kg of 1-fluoro-2-methyl-4-(3,3,5,5-tetramethyl-1-cyclohexen-1-yl)benzene, 72 kg of 96% formic acid and 3.6 kg of 1,3,5-trioxane, 96 g of 70% benzoyl peroxide catalyst was added and the bath was heated to reflux for about 3 hours. The mixture was then cooled to room temperature and 48 kg of heptane was added with stirring. The phases were allowed to separate and the bottom layer was discarded. The top layer was washed with water, then 48 kg of methanol and 7.2 kg of 50% aqueous sodium hydroxide were added. The mixture was stirred for about 10 minutes, washed with water and dried with 10 kg of anhydrous sodium sulfate. The sodium sulfate was filtered off and the filter cake was washed with 10 kg of heptane. To the combined filtrates, 96 kg of dimethyl sulfoxide and 28 kg of triethylamine were added. Sulfur trioxide/pyridine complex (36 kg) was then charged portionwise at 30°-35° C. The batch was agitated for 15 minutes and the reaction was quenched with 96 kg of iced water. The phases were allowed to separate and the bottom layer was discarded. The top layer was washed with dilute hydrochloric acid and with brine. Methanol (48 kg) and 50% sodium hydroxide (4.8 kg) were added and the batch was stirred at 21°-25° C. for one hour. Ice (0.6 kg) was added and the mixture was stirred for 15 minutes. The phases were allowed to separate and the bottom layer was discarded. The top solution was washed with brine and concentrated in vacuo to remove the volatiles. The residue was dissolved in 22 kg of isopropanol and 2.8 kg of water. The mixture was then cooled to about -10° C., seeded and stirred for 16 hours. The crystallized product was filtered off, washed with cold aqueous isopropanol and dried to constant weight. Yield: 8.5 kg of 2-(4-fluoro-3-methylphenyl)- 4,4,6,6-tetramethylcyclohex-1-enecarboxaldehyde; m.p. 50.5°-51.5° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:25]([N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([N:14]2[CH:15]=[CH:16][C:17](=[O:18])[C:12]([C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[CH:9][CH:10]=3)=[N:13]2)[CH2:20]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1ccn(-c2cccnc2)nc1-c1ccnn1-c1ccccc1
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: O=c1ccn(C2CCCN(Cc3ccccc3)C2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(1-phenyl-1H-pyrazol-5-yl)-1-pyridin-3-ylpyridazin-4(1H)-one (500 mg) in acetonitrile (5 mL) was added benzylbromide (0.19 mL) at room temperature, and the mixture was heated under reflux for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The obtained solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 mL), and platinum dioxide (54 mg) was added. The reaction mixture was stirred at room temperature for 24 hr under a hydrogen atmosphere (3 atm) and filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The obtained solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (270 mg).
Reaction SMILES: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41](O)([C:48]2[C:56]([OH:57])=[CH:55][C:51]3[O:52][CH2:53][O:54][C:50]=3[CH:49]=2)[C:40]1=[O:59])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]([C:48]2[C:56]([OH:57])=[CH:55][C:51]3[O:52][CH2:53][O:54][C:50]=3[CH:49]=2)[C:40]1=[O:59])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1N(CCCOCc2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1C(c2cc3c(cc2O)OCO3)c2ccccc2N1CCCOCc1ccccc1

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 1-[3-(benzyloxy)propyl]-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (92%): 1H NMR (300 MHz, CDCl3) δ7.42-6.95 (m, 9H), 6.56 (s, 1H), 6.24 (s, 1H), 5.86 (ABq, 1H), 5.81 (ABq, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.91-3.76 (m, 2H), 3.46 (t, 2H), 2.03-1.93 (m, 2H); MS (ES+) m/z 418.3 (M+1).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=O)[CH3:2].NC1NN=C(C2C=CC(OC3C=CC=CC=3)=CC=2)C=1C#N.NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C#N)=C3N=CC=2)C=CC=1.ClCCC(NC1C=C(C2[N:86]3[N:87]=[C:88]([C:93]4[CH:98]=[CH:97][C:96]([O:99][C:100]5[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=5)=[CH:95][CH:94]=4)[C:89]([C:90]([NH2:92])=[O:91])=[C:85]3[NH:84][CH2:83]C2)C=CC=1)=O>>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][CH:4]([CH:1]2[N:86]3[N:87]=[C:88]([C:93]4[CH:98]=[CH:97][C:96]([O:99][C:100]5[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=5)=[CH:95][CH:94]=4)[C:89]([C:90]([NH2:92])=[O:91])=[C:85]3[NH:84][CH2:83][CH2:2]2)[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3cccc(N)c3)ccnc12
Product: CC(C)(C)OC(=O)N1CCC(C2CCNc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn32)CC1

Procedure:
The desired product was prepared from tert-butyl 4-acetylpiperidine-1-carboxylate and 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile according to the procedures for 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (step 4 to 5) and compound 2 (step 1 and 2) under appropriate conditions recognized by one of ordinary skill in the art. 1H NMR (CD3OD-d4) δ 7.40 (d, J=8.4 Hz, 2H), 7.32-7.25 (m, 2H), 7.06 (t, J=7.6 Hz, 1H), 7.01-6.94 (m, 4H), 4.10-4.00 (m, 2H), 3.98-3.91 (m, 1H), 3.35-3.30 (m, 2H), 2.70-2.58 (m, 2H), 2.18-2.02 (m, 2H), 2.02-1.84 (m, 1H), 1.65-1.45 (m, 2H), 1.39-1.12 (m, 2H), 1.35 (s, 9H). MS (ESI) m/e [M+1]+ 518.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([CH:28]3[CH2:31][CH:30]([C:32]([O:34]CC)=O)[CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:38])[CH:10]=1)#[N:2].[OH-].[Na+].Cl.[CH3:42][Mg]Br>O1CCCC1.C(O)C>[C:32]([CH:30]1[CH2:29][CH:28]([N:18]2[C:17](=[O:37])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][C:11]=3[F:38])=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:31]1)(=[O:34])[CH3:42]
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CC(C(=O)OCC)C2)c2ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CC(C(C)=O)C2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of ethyl 3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate (4.0 g), tetrahydrofuran (40 mL), ethanol (40 mL) and 1 M aqueous sodium hydroxide solution (40 mL) was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was mixed with N,O-dimethylhydroxyamine hydrochloride (1.1 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.2 g), 1-hydroxybenzotriazole (1.6 g), triethylamine (3.3 mL) and N,N-dimethylformaldehyde (40 mL), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was dissolved in tetrahydrofuran (40 mL), methylmagnesium bromide (23 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 2 hr. Methylmagnesium bromide (11 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.8 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[N:17][CH:18]=1)[CH2:6][CH2:5]2.S(Cl)(Cl)=O.[CH3:27]O>>[CH3:27][O:21][C:20](=[O:22])[CH2:19][C:15]1[CH:16]=[N:17][CH:18]=[C:13]([N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[C:8]2=[O:12])[CH:14]=1
Reactant: CO
Reactant: O=C(O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 80 °C

Procedure:
To a solution of [5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-acetic acid (example 263 [B]) (217 mg, 0.68 mmol) in methanol (25 mL) was added thionyl chloride (0.44 mL, 6.0 mmol) slowly at 0° C. After the addition, the reaction mixture was warmed up and heated at 80° C. for 2 hours. After cooling back to room temperature, it was concentrated in vacuo and the residue was dissolved in EtOAc (150 mL) and washed with satd. aq. NaHCO3 solution and then brine. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (224 mg, quant.) as light brown oil. MS: 331.1 (M+H+).
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(N1CCN(C2C=CC=CN=2)CC1)=O)CC(C)C.ONC(=O)[C@@H](O)[C@@H](C([N:64]1[CH2:69][CH2:68][N:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=2)[CH2:66][C@H:65]1[CH3:76])=O)CC(C)C.O>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:64]2[CH2:69][CH2:68][N:67]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=3)[CH2:66][C@@H:65]2[CH3:76])=[O:10])[CH2:22][CH:23]([CH3:24])[CH3:25])[O:6]1
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)C[C@H]1C)[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: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)C[C@@H]1C)[C@@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 22 %

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, 198 mg; 0.50 mmol; 1.0 eq.) in DMF (4 mL) was added (3S)-3-methyl-1-pyridin-2-ylpiperazine (Intermediate 4, 88.6 mg; 0.50 mmol; 1.0 eq.) and the resulting reaction mixture was stirred 48 h at RT. Water was added and the mixture was extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give an oil. Purification by chromatography (SiO2, gradient from 10% EtOAc in c-hex up to 40% EtOAc in c-hex in 15 min) gave the title compound as a colorless oil (43 mg; 22%) (mixture of 2 diastereoisomers). M+(ESI): 390.3.
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][C:14]3=[CH:16][N:17]=[C:18]([CH3:19])[N:13]3[C:12]2=[O:20])[CH2:7][CH2:6]1)=[O:4].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:1][CH:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][C:14]4=[CH:16][N:17]=[C:18]([CH3:19])[N:13]4[C:12]3=[O:20])[CH2:7][CH2:6]2)=[O:4])=[O:36])=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)Nc3ccc(Cl)cc3)c3ccccc3)CC1)C2
Yield: 62.7 %

Procedure:
2-(1-(2-Amino-2-phenylacetyl)-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one (0.10 g) obtained in Example 50b) was dissolved in DMF (3.0 ml), 4-chlorophenyl isocyanate (0.05 g) was added thereto, and mixed at room temperature for 1 hour. The reaction mixture was dissolved in ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to methanol/ethyl acetate=1/10). The product was crystallized from ethyl acetate-diethyl ether to obtain the title compound as colorless powder (0.09 g, 59%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@H:4]([NH2:8])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.C(=O)([O-])O.[Na+].[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19].[CH3:31]N(C)CCN>CO>[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:8][C@@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([O:7][CH3:31])=[O:6])(=[O:29])=[O:28])([O-:20])=[O:19]
Reactant: C=CC[C@H](N)C(=O)O
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: C=CC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC
Temperature: 0 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
L-2-Amino-4-pentenoic acid was added to a solution of 3.18 ml (43.5 mmol) of thionyl chloride in methanol (40 ml) which had been cooled to 0° C., and the mixture was stirred at room temperature for 24 hr. The reaction solution was concentrated under the reduced pressure and was then dried. A solution of this crude product thus obtained in diethyl ether (26 ml) was cooled to 0° C., and a saturated aqueous sodium hydrogencarbonate solution (26 ml) was added thereto. 2-Nitrobenzenesulfonyl chloride (4.24 g, 19.14 mmol) was added thereto, and the mixture was stirred at room temperature for 7 hr. Thereafter, the reaction solution was cooled to 0° C., N,N-dimethylethylenediamine (2 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. The organic layer was separated. The aqueous layer was adjusted to pH 3 by the addition of citric acid and was extracted with diethyl ether. The combined organic layer was washed with a 3% aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution, and saturated brine in that order, was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give 4.52 g (yield 83%) of the title compound.