Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[C:7]1=[O:18])[CH3:2]>CCO.C(O)(C(F)(F)F)=O>[O:18]=[C:7]1[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH2:10][CH2:9][NH:8]1
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)C1=O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1CCNC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
tert-Butyl 2-oxopyrrolidine-1-carboxylate (10 g, 54.0 mmol) was dissolved in THF (75 mL) and cooled to −78° C. LDA (1.8 M in THF/heptane, 30.0 mL, 54.0 mmol) was added and the solution was stirred for 1 h. Ethyl 2-bromoacetate (9.02 g, 54.0 mmol) was added and the mixture was stirred for 1 h and allowed to warm to room temperature and stirred for 16 h. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted two times with EtOAc and the combined extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide partially purified tert-butyl 3-(2-ethoxy-2-oxoethyl)-2-oxopyrrolidine-1-carboxylate. tert-Butyl 3-(2-ethoxy-2-oxoethyl)-2-oxopyrrolidine-1-carboxylate (4.72 g, 17.40 mmol) was dissolved in EtOH (30 mL) and TFA (10 mL). The reaction was stirred at room temperature for 2 h and 20 mL of TFA was added. After stirring for an additional 2 h, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to provide the title compound (1.77 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=7.2 Hz, 3H), 1.81-1.93 (m, 1H), 2.35-2.49 (m, 2H), 2.75-2.85 (m, 1H), 2.88 (dd, J=16.4, 3.9 Hz, 1H), 3.31-3.40 (m, 2H), 4.09-4.21 (m, 2H), 5.96 (bs, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[CH3:12][C:13]([CH3:15])=O.[H][H]>C(O)C.[Pd]>[NH:6]1[CH:5]=[C:4]([CH2:3][CH:2]([NH:1][CH:13]([CH3:15])[CH3:12])[C:9]([OH:11])=[O:10])[N:8]=[CH:7]1
Reactant: [H][H]
Reactant: CC(C)=O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)NC(Cc1c[nH]cn1)C(=O)O
Yield: 37.1 %

Procedure:
A mixture of L-histidine (15.51 g, 100 mmol) and acetone (14.7 mL, 200 mmol) was agitated in an atmosphere of hydrogen (pressure, 46-51 psi) at 40° C. in 500 mL ethanol in the presence of Pd/C (20%, 2 g) until the absorption of hydrogen had ceased. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The white solid thus obtained was triturated with ethanol and dried under vacuum to give 7.31 g (37%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][CH2:9][OH:10].[C:11]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25]I)=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[CH2:8][CH2:9][OH:10])=[CH:20][CH:21]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)Oc1ccc(CCCCI)cc1
Reactant: OCCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1ccc(CCCCn2ccnc2CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
65% sodium hydride (1.78 g) was added to a solution of 2-(1H-imidazol-2-yl)ethanol (5.62 g) in DMF (80 ml) at 0° C., and the mixture was stirred at room temperature for 30 min. A solution of 1-tert-butoxy-4-(4-iodobutyl)benzene (13.3 g) in DMF (20 ml) was added to the mixture at 0° C., and the mixture was stirred at the same temperature for 5 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed successively with water (twice), and saturated brine, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex; eluent hexane:ethyl acetate=2:5) to give the titled compound (9.53 g) as a colorless amorphous form.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH2:13][CH2:14][OH:15])[C:11]=1[NH2:12].C(N(CC)CC)C.[C:23]([O:27][C:28]([NH:30][C:31]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=NS(C(F)(F)F)(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:12][C:11]1[N:10]([CH2:13][CH2:14][OH:15])[N:9]=[CH:8][C:7]=1[NH:6][C:31]([NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[N:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: Nc1cnn(CCO)c1N
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn(CCO)c1N
Yield: 62.5 %

Procedure:
To a suspension of 4,5-diamino-1-(2-hydroxyethyl)pyrazole sulfuric acid salt (50.0 g) in chloroform (500 ml) were added 4-(dimethylamino)pyridine (2.54 g), triethylamine (116 ml) and 1,3-bis(tert-butoxycarbonyl)-2-(trifluoromethanesulfonyl)guanidine (106 g). The mixture was stirred under reflux for 2 hours. After cooling on an ice bath, the reaction mixture was washed successively with water, 4% aqueous citric acid solution, water and aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixed solvent of ethyl acetate (50 ml) and diethyl ether (200 ml) to give 5-amino-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-1-(2-hydroxyethyl)pyrazole (50 g) as a solid.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:16][CH2:17]OC)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH3:14])[C:8](=[O:15])[CH2:7]1)=[O:5])C.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.[Cl-].C[Al+]C.O>C1(C)C=CC=CC=1.CCCCCC>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:27]([C:26]3[CH:28]=[CH:29][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=3)[CH2:17][CH2:16]2)[CH2:7][C:8]1=[O:15])[CH2:13][CH3:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCCN1CCC(CCOC)(C(=O)OCC)CC1=O
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: CCCN1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.7 %

Procedure:
4-(2-Methoxy-ethyl)-2-oxo-1-propyl-piperidine-4-carboxylic acid ethyl ester (0.205 g) and 4-(trifluormethoxy)aniline (0.268 g) were dissolved in toluene (15 ml) under an argon atmosphere at RT. Dimethylaluminium chloride in hexane (1 molar in hexane, 3.02 ml) was added and the mixture was refluxed over night. The reaction mixture was then cooled to RT, water (1 ml) was added and the mixture was stirred at RT for 15 minutes. The solvent was removed in vacuo, the residue adsorbed on silica gel and purified by flash chromatography on silica gel (eluents: AcOEt/CH2Cl2, gradient from 0 to 50% then with AcOEt/heptane: 70%) to give the desired material (0.072 g) as a viscous light yellow oil. MS (ESI): 371.2 (MH−).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8](Cl)(=O)[C:9](Cl)=O.C(O)C>CN(C=O)C.ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCBr
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.7 %

Procedure:
A solution of 4-bromobutanoic acid (25.0 g, 150 mmol), DMF (5 drops) and oxalyl chloride (17.0 mL, 195.0 mmol) in dichloromethane (250 mL) was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, dichloromethane (200 mL) and ethanol (9.0 mL, 170 mmol) were added to the residue, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, and the organic layer was dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (0-5% ethyl acetate/hexane) to give ethyl 4-bromobutanoate as a colorless oil (24.5 g, 84%).
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[S:44]1[CH:48]=[CH:47][CH:46]=[C:45]1[S:49]([NH:52][C@H:53](C(O)=O)[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)(=[O:51])=[O:50]>>[CH3:4][CH:2]([CH2:1][N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)(=[O:33])=[O:34])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:53]([NH:52][S:49]([C:45]1[S:44][CH:48]=[CH:47][CH:46]=1)(=[O:51])=[O:50])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:13])[CH3:3]
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1
Reactant: CC(C)CN([C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CN([C@@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-(2-thiophenesulfonyl)-L-phenylalanine (300 mg, 1.2 mmol) which was prepared in step A of example 24. The final product was purified by preparative HPLC to yield 46 mg (54%) of the desired material.
Reaction SMILES: [Cl:1]C1C=C(OC)C(OC)=CC=1C1N=C(C2C=C(C(OC)=S)SC=2C)SC=1.[Cl:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:29]=1[C:30](O)=[O:31].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:29]=1[C:30]([Cl:1])=[O:31]
Reactant: COc1cc(Cl)c(C(=O)O)cc1OC
Reactant: COC(=S)c1cc(-c2nc(-c3cc(OC)c(OC)cc3Cl)cs2)c(C)s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cc(Cl)c(C(=O)Cl)cc1OC
Temperature: 120 °C
Yield: 96 %

Procedure:
Methyl 4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 2-Chloro-4,5-dimethoxybenzoic acid (0.5 g, 2.3 mmol) and PCl5 (0.54 g, 2.6 mmol) were placed in a round bottomed flask fitted with a reflux condenser. The mixture was heated in an oil bath at 120° C. for 70 min. The mixture was allowed to cool and the formed phosphorus oxychloride was removed under vacuum to give 0.52 g (96%) of 2-chloro-4,5-dimethoxybenzoyl chloride as a solid. 2-Chloro-4,5-dimethoxybenzoyl chloride (0.52 g, 2.2 mmol) was treated in a manner similar to that for Example 32 step (a) to give 2-bromo-1-(2-chloro-4,5-dimethoxyphenyl) ethan-1-one. The dry solid (0.65 g, 2.2 mmol) was dissolved in acetone (25 ml). To this solution 5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (0.55 g, 2.2 mmol) was added and heated at reflux for 5 h. At this point the solid that precipitated was filtered off and washed with acetone and dried under vacuum to give 0.53 g (54%) of methyl 4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate. 1H-NMR (DMSO-d6; 300 MHz) δ 2.73 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 7.13 (s, 1H), 7.69 (s, 1H), 8.13 (s, 1H), 8.17 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].CN(C)C=O.[CH2:25](I)[CH3:26]>O>[CH2:25]([N:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1)[C:15](=[O:17])[CH3:16])[CH3:26]
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 1 h

Procedure:
A mixture of 4.0 g of N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide, 0.85 g of sodium hydride (50% in oil) and 300 ml of dry dimethylformamide, under argon, was stirred for 1 hour then 1.42 ml of ethyl iodide was added. After stirring for 2.5 hours, 0.5 equivalent of sodium hydride and 1.1 equivalent of ethyl iodide were added. This mixture was stirred overnight, poured into 1 liter of water and extracted with five 100 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo, giving 3.6 g of the desired compound as tan crystals, mp 105°-110° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:32])[C:5]2[N:6]=[CH:7][N:8]([C@@H:11]3[O:15][C@H:14]([CH2:16][CH:17]([P:26](=[O:29])([OH:28])[OH:27])S(C4C=CC=CC=4)=O)[C@@H:13]([F:30])[C@H:12]3[OH:31])[C:9]=2[N:10]=1.C(N(CCCC)CCCC)CCC.C[Si](Cl)(C)C>CN(C=O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:32])[C:5]2[N:6]=[CH:7][N:8]([C@@H:11]3[O:15][C@H:14](/[CH:16]=[CH:17]/[P:26](=[O:27])([OH:29])[OH:28])[C@@H:13]([F:30])[C@H:12]3[OH:31])[C:9]=2[N:10]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CC(S(=O)c3ccccc3)P(=O)(O)O)[C@@H](F)[C@H]2O)c(=O)[nH]1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](/C=C/P(=O)(O)O)[C@@H](F)[C@H]2O)c(=O)[nH]1
Temperature: 130 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
Compound 35.18 (12 mg, 0.025 mmol) was dissolved in anhydrous DMF (4 mL), treated with tributylamine (0.12 mL, 0.5 mmol) and TMSCl (0.063 mL, 0.5 mmol). The mixture was heated to 130° C. for 4 h, cooled to r.t., and then quenched with 2 mL water. The mixture was stirred at r.t for another 2 h and then the solvent was removed under reduced pressure. The residue was washed with 3×20 mL acetonitrile to remove TBA and TMSOH. The acetonitrile washes were discarded and the solid was dissolved in water, subjected to a reverse phase HPLC to give compound 35.19 (6.6 mg, 73% yield). 1HNMR (D2O, 300 MHz) δ 8.40 (s, 1H), 6.57 (m, 1H), 6.13 (t, 1H), 5.92 (d, 1H), 4.90-5.20(m, 3H). 31PNMR (D2O, 300 MHz): 11.815 ppm. LRMS (ESI) MH+ C11H13FN5O6P requires 362.1. Found 362.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Br)[CH:9]=2)=[CH:6][N:7]=1.[C@@H:21]1([NH2:30])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C(#N)C>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:30][C@@H:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: N[C@H]1CCc2ccccc21
Reactant: CCNC(=O)c1nc(-c2cccc(CBr)c2)cnc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCNC(=O)c1nc(-c2cccc(CN[C@H]3CCc4ccccc43)c2)cnc1N
Reaction time: 7 h
Yield: 38.8 %

Procedure:
The 3-amino-6-[3-(bromomethyl)phenyl]-N-ethylpyrazine-2-carboxamide (112 mg, 1.0 eq) was dissolved in acetonitrile (5 mL) and treated with (1S)-2,3-dihydro-1H-inden-1-amine (133.8 mg, 3.0 eq), diisopropylethylamine (69.3 mg, 1.6 eq) at ambient temperature. After being stirred for 7 h, the white suspension was filtered on Celite and concentrated in vacuo. The resulting residue was purified by flash column chromatography to give the 3-amino-6-(3-{[(1S)-2,3-dihydro-1H-inden-1-ylamino]methyl}phenyl)-N-ethylpyrazine-2-carboxamide (50.2 mg, 39% yield): 1H NMR (400 MHz, CD3OD): δ 8.72 (s, 1H), 8.21 (s, 1H), 8.11 (d, 1H), 7.61 (d, 1H), 7.58 (t, 1H), 7.49 (d, 1H), 7.39 (d, 2H), 7.39 (d, 2H), 7.37 (m, 1H), 4.38 (s, 2H), 3.47 (m 1H), 3.23 (m, 1H), 3.01 (m, 1H), 2.64 (m, 1H), 2.39 (m, 1H); MS (EI) for C23H25N5O: 388.22 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][N:4]=[CH:3]1.S(Cl)([Cl:11])=O>CN(C=O)C>[ClH:11].[Cl:11][CH2:7][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cncc1CO
Solvent: CN(C)C=O
Product: Cl
Product: Cn1cncc1CCl
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 37.9 %

Procedure:
A mixture of (1-methyl-1H-imidazol-5-yl)methanol (500 mg, 4.5 mmol) in DMF (5 mL) at −5° C. was slowly treated with thionyl chloride (0.49 mL, 6.7 mmol), stirred an additional 10 minutes at −5° C., warmed to room temperature, stirred 1.5 hours, cooled to −5° C., quenched with isopropyl alcohol and ethyl acetate, stirred 30 minutes at −5° C., concentrated under vacuum, and filtered to collect the solid. The solid was rinsed with ethyl acetate and dried under vacuum to give (212 mg, 28%) of the desired product as the hydrochloride salt. MS (DCI) m/e 131 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 9.10 (s, 1H), 7.76 (s, 1H), 5.02 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C@H:5]([OH:7])[CH3:6].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.O>CN(C)C=O>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][O:7][C@H:5]([CH3:6])[C:4]([F:9])([F:8])[F:3])[CH:13]=1
Reactant: C[C@@H](O)C(F)(F)F
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OCc1cccc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Under argon atmosphere, a suspension of sodium hydride (77 mg, 60 wt % oil dispersion) in N,N-dimethylformamide (2.0 ml) was cooled to 0° C., a solution of (R)-1,1,1-trifluoropropan-2-ol (213 mg) in N,N-dimethylformamide (2.0 ml) was added thereto, and the mixture was stirred for 15 minutes. Then, a solution of 1-bromomethyl-3-chlorobenzene (311 mg) in N,N-dimethylformamide (2.0 ml) was added thereto, and then the mixture was stirred at room temperature for 2.5 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=1/0 to 19/1) to give the titled compound (307 mg).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([NH2:29])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46].CNC>C(Cl)Cl.C1COCC1>[Cl:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][CH:8]2[N:13]3[C:14](=[O:30])[CH:15]([NH:29][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:16][N:17]([S:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])(=[O:20])=[O:19])[CH:12]3[CH2:11][N:10]([CH:31]([CH3:33])[CH3:32])[C:9]2=[O:34])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Agent: Br
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CC2N(C(=O)C(NS(C)(=O)=O)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reaction time: 2 h

Procedure:
64 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were dissolved in 3 ml of DCM. 0.5 mmol of triethylamine and 1.5 equivalents of methanesulfonyl chloride were added to the solution. After 2 hours, 0.5 ml of dimethylamine in THF was added, and the solvent was evaporated in vacuo. The pure title compound was removed after purification by HPLC. The system and process described under “general processes” was used for this. MW=636.04 (calculated, monoisotopic); measured value (M+H)+: 637.4.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([S:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)=[CH:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([S:21][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:13]1[Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(c1ccccc1)c1cn(Cc2ccccc2)c2ccccc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1c(Sc2ccccc2)c2ccccc2n1Cc1ccccc1
Temperature: 0 °C

Procedure:
A solution of thionyl chloride (0.03 ml, 0.054 g, 0.45 mmol) in dry dichloromethane (5 ml) was added dropwise to a stirred solution of 1-benzyl-3-phenylsulfinylindole (0.150 g, 0.45 mmol) in dry dichloromethane (20 ml), containing suspended sodium bicarbonate (1 g), maintained at 0° C. One half hour after the addition was completed the reaction was quenched with a saturated solution of aqueous sodium bicarbonate. The organic phase was separated, combined with a dichloromethane extract of the aqueous phase and the combined organic phases were dried and evaporated in vacuo. Crystallization of the residue from dichloromethane/hexane gave the title product.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH:20]([C:24]([OH:26])=[O:25])[CH2:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[O:12]=[C:6]1[NH:7][C:8]2[N:9]=[CH:10][CH:11]=[C:2]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][CH:20]([C:24]([OH:26])=[O:25])[CH2:21]4)=[CH:16][CH:15]=3)[C:3]=2[CH:4]=[CH:5]1
Reactant: O=C(O)C1CCc2ccc(O)cc2C1
Reactant: O=c1ccc2c(Cl)ccnc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C1CCc2ccc(Oc3ccnc4[nH]c(=O)ccc34)cc2C1
Temperature: 180 °C
Yield: 70.1 %

Procedure:
A suspension of 5-chloro-1,8-naphthyridin-2(1H)-one (0.050 g, 0.00028 mol), 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.080 g, 0.00042 mol), and cesium carbonate (0.270 g, 0.000829 mol) in DMF (1 mL) was subjected to microwave heating (180° C.) for 15 min. The reaction mixture was dissolved in water and then acidified to pH of 2 with 1N HCl. The mixture was extracted with EtOAc (4×). The combined organic solutions were dried over MgSO4, filtered, and concentrated. The residue was triturated with DCM and hexanes to produce 7-[(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid as a white solid (0.066 g, 71%). LCMS: (FA) ES+ 337.3.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]1[CH2:9][CH2:10][C:11]#[N:12].C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[NH:12][C:16](=[O:25])[C:17]2[C:18]([CH:24]=1)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2
Reactant: C[C@H]1C[C@H](CO)N(CCC#N)C1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@@H](C)C[C@@H]3CO)cc12

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514-522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{2-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one is obtained.