Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]([CH3:29])[CH3:28])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=2)[N:4]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O)C>ClCCl>[CH:27]([O:26][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:32][CH3:33])=[C:8]([O:30][CH3:31])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])([CH3:29])[CH3:28]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC(C)C)c1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1c(CN2CCOCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC(C)C)c1

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3-isopropoxy-4-methoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (3.0 g), morpholine (2.76 g) and ethanol (50 ml)--dichloromethane (5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and dichloromethane (50 ml) was added to the residue. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (1:1, v/v) gave ethyl 4-(3-isopropoxy-4-methoxyphenyl)-6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate as an oil. This oil was dissolved in ethanol (20 ml), and a solution of hydrogen chloride in ethanol (23%, 1.05 g) was added. The mixture was stirred at room temperature for 10 minutes, and the solvent was evaporated under reduced pressure. The crystals were separated by filtration and recrystallized from ethanol-ether to give ethyl 4-(3-isopropoxy-4-methoxyphenyl)-6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate hydrochloride (1.62 g, 45%). Colorless crystals, mp. 185°-188° C.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:4]=2[N:3]=1.[NH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2>CCO>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:3][C:4]=2[CH:10]=1
Reactant: FC(F)(F)c1ccc2[nH]c(Cl)nc2c1
Reactant: Nc1cccc2cccnc12
Solvent: CCO
Product: FC(F)(F)c1ccc2[nH]c(Nc3cccc4cccnc34)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole (66 mg, 0.3 mol, prepared according to the procedure described in WO 2004/035549 A1) and 8-aminoquinoline (29 mg, 0.6 mmol, Aldrich) in EtOH (2 mL) was subjected to microwave irradiation at 170° C. with stirring for 30 min. The reaction mixture was allowed to cool to room temperature, the solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 3% MeOH/DCM to give the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 329 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.[OH-].[Na+].[C:18](=[S:20])=[S:19].[C:21]1([CH2:26]Cl)[S:25][CH:24]=[CH:23][CH:22]=1>CO.C(O)C>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:18]([S:20][CH2:26][C:21]1[S:25][CH:24]=[CH:23][CH:22]=1)=[S:19]
Reactant: S=C=S
Reactant: ClCc1cccs1
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1cccs1
Yield: 49.7 %

Procedure:
In the same manner as described in Example 8 by using (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (2.02 g), 2N NaOH (10 ml), CS2 (1.5 g), 2-Thenyl chloride (2.65 g), and 80% ethanol (50 ml), there is prepared the title compound (1.86 g, 50%) as white powder, [α]D20 +108.4° (c=1.0, methanol). NMR (CDCl3, δ): 4.84 (s, 2H, CSSCH2 -- ##STR8## Mass m/e: 374 (M+), 244 (M+ -- ##STR9##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:22][CH:21]=2)=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@@H:16]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:25]=2)=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCc1ccc(NC(=O)C(Cc2ccc(OCc3ccccc3)cn2)NC(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(OCc2ccccc2)cn1)C(=O)Nc1ccc(CCCC(=O)O)cc1
Temperature: 60 °C
Yield: 89.3 %

Procedure:
A mixture of methyl 4-(4-(3-(5-(benzyloxy)pyridin-2-yl)-2-(tert-butoxycarbonylamino)propanamido)phenyl)butanoate (0.59 g, 1.07 mmol) and lithium hydroxide (0.26 g, 10.7 mmol) in 10 mL THF/H2O (1:1) was heated at 60° C. for 2 h (monitored by TLC). The solution was acidified to PH=2 and extracted with dichloromethane. The dichloromethane was separated, dried over magnesium sulfate, and concentrated in vacao to give 0.51 g of the desired compound (90%): (400 MHz in CDCl3, Bruker AVANCE-400): δ 1.30 (s, 9H, Boc), 1.74 (m, 2H, CH2), 2.17 (t, 2H, CH2—CH2—COOMe, J=7.34 Hz), 2.52 (t, 2H, CH2, J=7.55 Hz), 2.92-3.07 (m, 2H, CH2), 4.44 (m, 1H CH), 5.13 (s, 2H OBn), 7.09 (d, 1H, J=8.47 Hz, Ar—H), 7.21 (d, 1H, Ar—H, J=8.52 Hz), 7.31˜7.48 (m, 9H Ar—H), 8.26 (br, 1H, NH), 9.91 (br, 1H, OH).
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5][C:6](=O)[CH3:7])=[O:4].[C:9]([O-:12])(=O)[CH3:10].[NH4+:13]>C(O)(=O)C>[CH3:10][C:9]1[O:12][C:5]([C:3](=[O:4])[CH3:2])=[C:6]([CH3:7])[N:13]=1
Reactant: CC(=O)[O-]
Reactant: [NH4+]
Reactant: CC(=O)CC(=O)CCl
Solvent: CC(=O)O
Product: CC(=O)c1oc(C)nc1C

Procedure:
Chloroacetylacetone 8 g (59.4 mmol) is dissolved in 70 ml of glacial acetic acid and ammonium acetate 13.7 g (178.2 mmol) is then added and the mixture is refluxed for 4 hours. The solution is cooled, brought to pH 5 and extracted into ether; the organic layer is dried over Na2SO4 and concentrated to dryness in vacuo. The residue is purified by column chromatography on silica gel using 8:2 hexane:ethyl acetate as eluent. The 2,4-dimethyl-5-acetyloxazole is obtained as orange needles (2.2 g, 27%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)[N:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH2:26])=[N:23][CH:24]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:8][C:7]1[C:2]([NH:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)=[N:3][C:4]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=23)=[N:5][CH:6]=1
Reactant: NCc1ccc(F)cn1
Reactant: Clc1cnc(-c2cnn3ccncc23)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Fc1ccc(CNc2nc(-c3cnn4ccncc34)ncc2Cl)nc1
Yield: 40 %

Procedure:
A mixture of 3-(4,5-dichloropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 32, 75 mg, 0.26 mmol), (5-fluoropyridin-2-yl)methanamine (33 mg, 0.26 mmol) and diisopropylethylamine (52 μL, 30 mmol) in tetrahydrofuran (3 mL) was heated to reflux for 72 h. The solvent was then evaporated under reduced pressure and the crude product was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (37 mg, 39%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCl.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15]CBr>>[Br:15][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:1]=[O:8]
Reactant: BrCBr
Reactant: O=Cc1ccccc1
Agent: ClBr
Agent: [Al+3]
Agent: [Cl-]
Product: O=Cc1cccc(Br)c1

Procedure:
A process which comprises reacting one molar proportion of benzaldehyde with about 0.9-1.2 molar proportions of bromine chloride in the presence of about 1.1-2.2 molar proportions of aluminum chloride and about 0.3-0.9 mol of dibromomethane per mol of aluminum chloride under substantially anhydrous conditions at a temperature in the range of about 40°-95° C. so as to form 3-bromobenzaldehyde, the components of the reaction mixture being combined by gradually adding the bromine chloride to a dibromomethane slurry of the benzaldehyde and aluminum chloride.
Reaction SMILES: [H-].[Na+].N1C=[CH:6][N:5]=[N:4]1.Cl[CH2:9][C@:10]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])([OH:21])[C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH3:12].O.[CH3:31][N:32](C=O)C>C(OCC)(=O)C>[Si:14]([O:13][C@@H:11]([CH3:12])[C@:10]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])([OH:21])[CH2:9][N:5]1[CH:6]=[N:32][CH:31]=[N:4]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@](O)(CCl)c1ccc(F)cc1F
Reactant: c1c[nH]nn1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of 0.22 g (5.4 mmol) of sodium hydride (60% content) in 3 mL of DMF was added 0.37 g (5.4 mmol) of triazole. Furthermore, a solution of 0.63 g (1.8 mmol) of (2R,3S)-1-chloro-2-(2,4-difluorophenyl)-3-(tert-butyldimethylsilyloxy)butan-2-ol in 10 mL of DMF was added thereto. The resulting reaction mixture was stirred at room temperature for 2 hours and then at 50° C. for 12 hours. Next, 10 mL of water was added to stop the reaction, and extraction was performed with ethyl acetate (30 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting product was purified by column on silica gel to obtain 0.18 g of the title compound (yield: 25%). 1H-NMR (400 MHz, CDCl3) δ: 0.22 (s, 6H), 0.97 (s, 12H), 4.42 (dq, 1H, J=5.9, 1.2 Hz), 4.54 (d, 1H, J=1.4 Hz), 4.81 (d, 1H, J=1.4 Hz), 6.67-6.78 (m, 2H), 7.32-7.38 (m, 1H), 7.71 (s, 1H), 7.96 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][OH:8].Cl.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9](=[O:11])[C@H:6]([CH2:7][OH:8])[NH:5][CH2:4][C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[OH:1])[CH3:18]
Reactant: CCO
Reactant: O=C(O)[C@H](CO)NCc1ccccc1O
Agent: Cl
Product: CCOC(=O)[C@H](CO)NCc1ccccc1O
Reaction time: 8 h

Procedure:
L-serine (3.6 g) was dissolved in 17 ml of a 2N sodium hydroxide aqueous solution. To the solution were then added 3.6 ml of salicylaldehyde and 0.4 g of sodium boron hydride in this order. After the mixture was stirred for 1 hour, 3.6 ml of salicylaldehyde and 0.4 g of sodium boron hydride were added thereto again. After the resulting mixture was stirred overnight at room temperature, the insoluble matter was separated through filtration, and the filtrate was extracted with diethyl ether. The extract was adjusted to a pH of 7 with hydrochloric acid to obtain 4.8 g of N-(2-hydroxybenzyl)-L-serine. To 300 mg of the resulting N-(2-hydroxybenzyl)-L-serine were added 30 ml of ethanol to which a hydrogen chloride gas had been blown to saturation. The mixture was stirred overnight. The reaction solution was concentrated, and the resulting oil was purified through HPLC using Inertcil ODS-3 column (supplied by GL Science) in a high performance liquid chromatography (supplied by Hitachi) to obtain 114 mg of N-(2-hydroxybenzyl)-L-serine ethyl ester. Various N-(2-hydroxybenzyl) amino acid alkyl esters were obtained in the same manner. With respect to the novel compounds undescribed in the literature among these compounds, the results of the measurement of the mass spectrum are shown in Table 1.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][CH:9]=1
Reactant: Cc1ccc(Br)nc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
n-Butyllithium (12.8 ml, 2.5M in hexanes, 32.6 mmol) was added dropwise to a cooled (−78° C.) solution of 2-bromo5-methylpyridine (5.0 g, 29.1 mmol), and the solution stirred for an hour. Tri-n-butyltin chloride (9.5 ml, 34.9 mmol) was then added and the reaction allowed to warm to room temperature, and stirred for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 90:10) to give the title compound, (6.5 g, 58%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[N:56]1([C:62](=[O:71])[CH2:63][O:64][CH:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:68]1[CH2:69][CH2:70][CH:65]([O:64][CH2:63][C:62](=[O:71])[N:56]2[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]2)[CH2:66][CH2:67]1)=[O:6]
Reactant: O=C(COC1CCNCC1)N1CCCCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)N1CCCCC1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMA (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 1-(piperidin-1-yl)-2-(piperidin-4-yloxy)ethanone (112) (0.152 g, 0.67 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material (0.303 g, 89% yield); 1H NMR (400.132 MHz, DMSO) δ 1.07-1.39 (8H, m), 1.46-1.56 (1H, m), 1.61-1.71 (1H, m), 2.76-2.85 (1H, m), 3.02-3.09 (2H, m), 3.10-3.20 (4H, m), 3.34-3.41 (1H, m), 3.66-3.75 (1H, m), 3.90-3.93 (2H, m), 4.08-4.12 (2H, m), 6.99 (1H, t), 7.09-7.21 (2H, m), 7.57-7.69 (1H, m), 7.72-7.76 (1H, m), 8.02-8.06 (2H, m), 12.34 (1H, s); m/z (LC-MS, ESI+), RT=1.76 (M+H 507.5).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:9]([CH3:10])[C:8]2[S:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:10][N:9]1[C:5]([CH2:3][NH:2][CH3:1])=[CH:6][C:7]2[CH:13]=[CH:12][S:11][C:8]1=2
Reactant: CNC(=O)c1cc2ccsc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cc2ccsc2n1C
Temperature: 25 °C
Yield: 114.2 %

Procedure:
To a solution of N,6-dimethyl-6H-thieno[2,3-b]pyrrole-5-carboxamide (134 mg, 0.69 mmole) in dry THF (5 mL) was added a solution of LiAlH4 in THF (1.0 M, 1.38 mL, 1.38 mmole) slowly at RT. After gas evolution had ceased the mixture was heated to a gentle reflux. After 2 hr the mixture was cooled to RT and quenched by dropwise addition of 2M NaOH until a white solid had formed. The mixture was dried (MgSO4, filtered, and concentrated to give the title compound as a brown oil (142 mg, 100%) which was sufficiently pure for use in the next step: 1H NMR (400 MHz, CDCl3) δ 6.95 (d, J=5.2 Hz, 1H), 6.78 (d, J=5.2 Hz, 1H), 6.27 (s, 1H), 3.78 (s, 2H), 3.72 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CC(C)([O-])C.[K+].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Cl.O>C1COCC1>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1ccccc1S
Reactant: COC(CCl)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(CSc1ccccc1F)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Fluorothiophenol (4.14 g, 32.6 mmol) was dissolved in anhydrous THF (100 mL). Potassium tert-butoxide (1.0 M in THF, 35.8 mL) was added and the suspension was stirred at room temperature for 15 minutes. 2-Chloroacetaldehyde dimethyl acetal was added and the mixture was stirred for 3 days. Water (100 mL) was added and the solution was extracted with diethyl ether (3×100 mL). The extracts were concentrated to a yellow oil and chromatographed (5 to 20% ethyl acetate in hexane) to yield 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene (6.42 g) as a colorless oil. Chlorobenzene (25 mL) was heated to reflux and polyphosphoric acid (1 mL) was added. The 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene was then added slowly turning the solution dark. After 3 hours of heating, the reaction was cooled to room temperature and diluted with water (50 mL). The solution was extracted with benzene (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophenyl (0.77 g). The 7-fluorobenzothiophenyl (0.77 g, 5.1 mmol) and dichloromethyl methyl ether (0.872 g, 7.6 mmol) were dissolved in anhydrous DCM (25 mL). Titanium tetrachloride (1.0 M in DCM, 7.6 mL, 7.6 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g). The 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g, 3.77 mmol) and sulfamide (1.7 g, 18 mmol) were combined in anhydrous ethanol (20 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.148 g, 3.92 mmol) was added. After two hours, water (25 ml) was added and the solution was extracted with chloroform (3×25 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C@H:8]1[CH2:14][S:13][CH2:12][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:9]1=[O:29].BrC(CC[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)C(OCC)=O.[Cl-].[Na+].[C:49]([O:52][CH2:53][CH3:54])(=[O:51])[CH3:50]>CN(C)C=O>[CH2:53]([O:52][C:49]([C@H:50]([NH:7][C@H:8]1[CH2:14][S:13][CH2:12][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:9]1=[O:29])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:51])[CH3:54]
Reactant: CCOC(=O)C(Br)CCCCc1ccccc1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSC[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1CSC[C@@H](c2ccccc2)N(CC(=O)OC(C)(C)C)C1=O
Temperature: 65 °C
Reaction time: 15 h

Procedure:
2.4 g of sodium carbonate were added to a mixture of 1.1 g of t-butyl α-[6(R)-amino-5-oxo-3(R)-phenylperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above]]and 1.4 g of ethyl 2-bromo-4-phenethylbutyrate dissolved in 15 ml of dimethylformamide, and this mixture was stirred for 15 hours at 65° C. The reaction mixture was then dissolved in ethyl acetate and an aqueous sodium chloride solution. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation. The residue was subjected to silica gel column chromatography, using a 1:9 by volume mixture of ethyl acetate and methylene chloride as eluent. t-Butyl α-[6(R)-[1(R)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-3(R)-phenylperhydro-1,4-thiazepin-4-yl]acetate was obtained from the first fraction as an oily substance in a yield of 0.53 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:18]=[C:17]([NH:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=2)[N:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:20]=[C:19]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])[N:18]=[C:17]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=2)[N:16]=1
Reactant: COC(=O)c1ccc(Nc2nc(NCCCOCCCCOCCCN)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: NCCCOCCCCOCCCNc1nc(Nc2ccc(C(=O)O)cc2)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
To a suspension of methyl 4-(4-(3-(4-(3-aminopropoxy)butoxy)propylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.1 g) in acetone (6 mL) was added potassium carbonate in water (6.00 mL). The mixture was heated to reflux for 16 hours. After cooling to r.t., the reaction solution was acidified with 1N HCl to pH=3. All the solvents were removed under vacuum. The residue was purified by prep. HPLC to give 4-(4-(3-(4-(3-aminopropoxy)butoxy)propylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (28 mg, 0.054 mmol).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.OC1C(=O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N2CCN(C(C)C)C(=O)C=12>>[Cl:28][C:24]1[CH:23]=[C:22]([C:17]2([CH2:16][C:12]3[N:11]4[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]4=[C:9]([OH:8])[C:14](=[O:15])[N:13]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)N1CCn2c(CC3(c4cccc(Cl)c4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CC(C)N1CCn2c(CC3(c4ccc(C(F)(F)F)cc4)CCCC3)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4cccc(Cl)c4)CCCC3)nc(=O)c(O)c2C1=O

Procedure:
6-((1-(3-Chlorophenyl)cyclopentyl)methyl)-9-hydroxy-2-isopropyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (505) was synthesized as a white solid from 9-(benzyloxy)-6-((1-(3-chlorophenyl)cyclopentyl)methyl)-2-isopropyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (504) following the procedure described for 6-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (248).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[NH2:10]OS(O)(=O)=O>>[ClH:9].[Cl:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[O:8][NH2:10]
Reactant: NOS(=O)(=O)O
Reactant: Oc1ccc(Br)cc1Cl
Product: Cl
Product: NOc1ccc(Br)cc1Cl
Yield: 39.8 %

Procedure:
4-bromo-2-chlorophenol (110 g, 0.53 mol) was reacted with hydroxylamine-O-sulfonic acid (15 g, 0.13 mol) using the procedure of Example 29, step A to give O-(2-chloro-4-bromophenyl)hydroxylamine hydrochloride (13.4 g, 28%) as a light brown solid: 1H NMR (DMSO, 400 MHz) δ 7.61 (d, J=2.0 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.47 (s, 1H), 5.81 (br s, 3H).