Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([CH:41]=O)[CH:35]=[CH:34]2>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:41][C:36]3[CH:35]=[CH:34][C:33]4[C:38](=[CH:39][CH:40]=[C:31]([O:30][CH3:29])[CH:32]=4)[CH:37]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc2cc(C=O)ccc2c1
Product: COc1ccc2cc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)ccc2c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 6-methoxy-naphthalene-2-carbaldehyde. MS (ESI) m/z 549.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:12][C@@H:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15].FC1C=CC(N[C@H](CC)C(O)=O)=C([N+]([O-])=O)C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C@@H:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: CC[C@@H](Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Product: CC[C@H](Nc1ccc(Br)cc1[N+](=O)[O-])C(=O)O

Procedure:
5-Bromo-2-fluoronitrobenzene was treated with (S)-2-aminobutyric acid according to the procedure for the preparation of (R)-2-(4-fluoro-2-nitrophenylamino)-butyric acid (see Example 1) to yield (2S)-2-[(4-bromo-2-nitrophenyl)amino]butanoic acid. MS (ESI) m/z 303/305 ([M+H]+); MS (ESI) m/z 301/303 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(SCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-aminothiophenol (6.0 g) was dissolved in methanol (120 ml), aqueous solution of sodium hydroxide (2.7 g, 36 ml) was added to the mixture, benzyl bromide (6.8 ml) was added to the mixture at 0° C., and the mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure, and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 4-(benzylsulfanyl)aniline (7.0 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[C:22]([F:24])[C:21]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][N:34]=3)[CH2:29][CH2:28]2)=[O:26])=[C:20]([F:41])[CH:19]=1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]1[C:18]1[CH:19]=[C:20]([F:41])[C:21]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][N:34]=3)[CH2:29][CH2:28]2)=[O:26])=[C:22]([F:24])[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4[C@H](COCc5ccccc5)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 60 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (536 mg) described in Preparation Example 1 and (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (911 mg) described in Preparation Example 111 and by the reaction and treatment in the same manner as in Example 4, the title compound (760 mg) was obtained.
Reaction SMILES: [S:1]1[C:5]([C:6](=O)[C:7]([OH:9])=[O:8])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.Cl.[C:16]([O:20][NH2:21])([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+]>C(O)C>[C:16]([O:20][N:21]=[C:6]([C:5]1[S:1][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[CH:4]=1)[C:7]([OH:9])=[O:8])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)C(=O)c1cc2ccccc2s1
Reactant: CC(C)(C)ON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)ON=C(C(=O)O)c1cc2ccccc2s1
Reaction time: 8 h
Yield: 38.5 %

Procedure:
Benzo[b]-thien-2-ylglyoxylic acid (3.09 g) and t-butoxyamine hydrochloride (1.98 g) were dissolved in 50% aqueous ethanol (100 ml). The solution was adjusted to pH 4.5 with sodium hydroxide solution and maintained at such for 4 hr. at room temperature. Thin-layer chromatography showed incomplete reaction. t-Butoxyamine hydrochloride (500 mg.) was added and the solution kept at room temperature overnight. The alcohol was removed by evaporation and the aqueous phase adjusted to pH 8 and washed with ether. The aqueous phase was then acidified to pH 1.5 under ether. The ether solution was washed with water and dried. Evaporation gave a cream solid (4.05 g.). Fractional crystallisation from cyclohexane gave the anti-isomer of the title compound (1.6 g.). The mother liquors were combined and evaporated to give a cream solid (2.11 g.) that was treated in ether with excess diazomethane in ether at 0°-5°. The excess reagent was destroyed by acetic acid and the ether solution washed with sodium bicarbonate, water and dried. Evaporation gave an oil (1.75 g.). This was dissolved in methanol (70 ml) and treated with sodium hydroxide solution (N: 7 ml.) at room temperature for 3 hr. Hydrochloric acid (2N: 3.5 ml) was added and the methanol was removed by evaporation. The aqueous residue was partitioned between ether and sodium bicarbonate solution. The ether layer was washed with water and dried. Evaporation gave an oil (0.92 g.) that was dissolved in methanol (20 ml.) and treated with sodium hydroxide (N: 7 ml) at reflux temperature for 3hr. Sodium hydroxide (N: 5ml) was added and the solution refluxed for 6 hr. The methanol was removed by evaporation and the residue partitioned between ether and water. The aqueous phase was acidified (pH 1.5) under ether and the ether layer washed with water, dried and evaporated to give a pale orange crystalline solid (760 mg. 18%). Crystallisation from benzene containing cyclohexane gave syn-2-t-butoxyimino-2-(benzo[b]-thien-2-yl)acetic acid (430 mg.) m.p. 108°-9°, λmax. (EtOH) 231, 253, 297 nm (ε17,000, 7,240, 24,500).
Reaction SMILES: FC(F)(F)C1C=CC([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=NC=1.Br[C:19]1[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=1.C(OC(=O)N[C@@H]1CCN(C2C(C(F)(F)F)=CC=CN=2)C1)(C)(C)C.FC(F)(F)C1C(N2CC[C@@H](N)C2)=NC=CC=1>>[F:25][C:24]([F:27])([F:26])[C:22]1[N:23]=[C:19]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[S:20][CH:21]=1
Reactant: NC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Reactant: FC(F)(F)c1csc(Br)n1
Agent: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Agent: N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Product: NC1CCN(c2nc(C(F)(F)F)cs2)CC1

Procedure:
Prepared from D8 and 2-bromo4-trifluoromethylthiazole (J. A. Edwards Ger. Offen., 2252070, 1973) in a manner similar to that described in D1 and D2. The following were prepared using methods described above and in a manner similar to that of D18:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: COCC#Cc1cc(C(=O)O)ccc1-c1ccccc1C
Agent: [Pd]
Solvent: CO
Product: COCCCc1cc(C(=O)O)ccc1-c1ccccc1C

Procedure:
Intermediate 41 (625.12 mg; 2.23 mmol; 1 eq.) was dissolved in MeOH (50 mL). The solution was injected on a flow hydrogenation reactor (H-cube), adapted with 10% Pd/C cartridge, a flow of 0.5 mL/min, a temperature of 60° C. and the full H2 option enabled. Evaporation of the solvent afforded the title compound as a yellow oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.99 (d, J=1.5 Hz, 1H), 7.92 (dd, J=7.9, 1.7 Hz, 1H), 7.23-7.14 (m, 4H), 7.02 (d, J=7.1 Hz, 1H), 3.25 (t, J=6.5 Hz, 2H), 3.20 (s, 3H), 2.56-2.47 (m, 1H), 2.41-2.31 (m, 1H), 1.97 (s, 3H), 1.65 (quintuplet, J=7.2 Hz, 2H). LC/MS (Method B): 281.2 (M−H)−. HPLC (Method A) Rt 4.25 min (Purity: 97.7%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12]([NH:15][CH2:16][CH2:17][NH2:18])(=[O:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CCO>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:18][CH2:17][CH2:16][NH:15][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)NCCN
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: CC(=O)NCCNc1ccc2ccccc2n1
Yield: 116.5 %

Procedure:
A mixture of 2-chloroquinoline (10.00 g, 0.061 mol), N-acetylethylenediamine (6.24 g, 0.061 mol), sodium carbonate (6.48 g, 0.061 mol), and 3-methyl-1-butanol (125 mL) was heated under reflux for 3 days. The mixture was cooled, filtered, and the filtrate was concentrated to give 16.3 g (>100%) of a yellow oil. Purification by flash chromatography (eluent 5% MeOH/CHCl3 ; 10% MeOH/1% Et3N/CHCl3) gave 6.8 g (49%) of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([NH2:18])([CH3:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.ClCCl>CO>[CH3:1][O:2][C:3]([C:4]1([CH3:17])[CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[NH:8][C:7]=2[CH:24]([C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([OH:20])[CH:22]=2)[NH:18]1)=[O:19]
Reactant: COC(=O)C(C)(N)Cc1c[nH]c2ccc(OC)cc12
Reactant: O=Cc1cccc(O)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(C)Cc2c([nH]c3ccc(OC)cc23)C(c2cccc(O)c2)N1
Temperature: 25 °C
Yield: 15 %

Procedure:
To a solution of (+/−)-2-amino-3-(5-methoxy-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (5.178 g, 19.5 mmol) and 3-hydroxybenzaldehyde (2.85 g, 23.4 mmol, 1.2 equiv.) in dry dichloromethane (80 ml) trifluoroacetic acid (1.5 ml, 19.5 mol, 1 equiv.) is added and the mixture is stirred under argon at room temperature. When TLC indicates the disappearance of (+/−)-2-amino-3-(5-methoxy-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (1 day), a little methanol is added to dissolve the product precipitated during the reaction. The mixture is then diluted with dichloromethane (750 ml) and is washed with 2 M aqueous HCl, aqueous NaHCO3 and water, is dried and concentrated. Column chromatography (dichloromethane-ethyl acetate 9:17:1) of the residue gives 5.22 g (73%) of (1RS,3SR)-1-(3-hydroxy-phenyl)-6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (m.p. 183-184° C. from ethyl acetate-light petroleum) and 1.07 g (15%) of (1RS,3RS)-1-(3-hydroxy-phenyl)-6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (m.p. 175-177° C. from ethyl acetate-light petroleum).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1.[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][O:1][C:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:4][N:3]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CCCCCc1c(O)noc1-c1ccccc1
Product: CCCCCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 81.5 %

Procedure:
3-Hydroxy-4-pentyl-5-phenylisoxazole (231 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (305 mg, 82%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:21]=[CH:22]/[CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(/C=C/CO)cc2c1O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(/C=C/CO)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N-(4-Chlorobenzyl)-6-[(1E)-3-hydroxy-1-propenyl]-4-hydroxy-3-quinolinecarboxamide from Preparation No. 12 (0.184 g), K2CO3 (0.276 g) and iodomethane (0.062 mL) in DMF (2 mL) is heated in a stoppered flask at 90° C. for 1 h. Water is added and the mixture is allowed to cool and stir at room temperature for 16 h during which a precipitate formed. The precipitate is filtered and dried in vacuo at 60° C. for 48 h to give 0.164 g of the title compound as a solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.CC(C)=O.S(=O)(=O)(O)O>O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(COc1ccc(F)cc1)OCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=CCOc1ccc(F)cc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A mixture of 4-fluorophenoxyacetaldehyde diethyl acetal (30.0 g., 0.131 mole) acetone (150 ml.), water (150 ml.), and concentrated sulfuric acid (0.8 ml.) is refluxed overnight (ca. 16 hours). The mixture is allowed to cool to room temperature, and is then extracted with methylenechloride four times. The combined extracts are washed with aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is stripped off on a rotary evaporator and the oil residue is subsequently distilled in vacuo at 70°/0.05 mm to give the title compound (19.0 g., 0.123 mole, 94%). ir (neat) 3.23, 3.50, 3.63, 5.71, 6.62, 7.00, 8.00, 8.24, 9.07, 9.38, 12.03, 12.51, 13.12μ; pmr (CCl4) δ 4.37 (2H, d, J=1Hz), 6.6-7.1 (4H, m), 9.68 (1H, t, J=1Hz).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH2:11](Br)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:2][P:1]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: CCOP([O-])OCC
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCc1ccccc1)OCC
Temperature: -15 °C
Yield: 51.6 %

Procedure:
Diethyl phosphite (27.64 g, 200 m mole) was dissolved in DMF (200 ml), and to the solution at nitrogen atmosphere while stirring and -15° C., sodium hydride (60% in oil, 9.6 g, 220 m mole) was added. The mixture was stirred for 1 hour at not more than 0° C. To the solution phenethyl bromide (37.0 g, 200 m mole) was dropwise added and further the mixture was stirred overnight at room temperature. The DMF solution was distilled under reduced pressure leaving a residue, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated and the thus obtained oily product was distilled under reduced pressure to obtain diethylphenethylphosphonate (25.0 g, yield: 51.6%) of boiling point 136.5°~137.5° C./3 mmHg.
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]([OH:29])[C@H:21]1[O:26][C:24](=[O:25])[C:23]([OH:27])=[C:22]1[OH:28])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:30](Cl)(=[O:36])/[CH:31]=[CH:32]/[CH:33]=[CH:34]/[CH3:35]>N1C=CC=CC=1.ClCCl>[C:1]([O:18][CH2:19][C@H:20]([OH:29])[C@H:21]1[O:26][C:24](=[O:25])[C:23]([O:27][C:30](=[O:36])/[CH:31]=[CH:32]/[CH:33]=[CH:34]/[CH3:35])=[C:22]1[OH:28])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O
Reactant: C/C=C/C=C/C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C/C=C/C=C/C(=O)OC1=C(O)[C@@H]([C@@H](O)COC(=O)CCCCCCCCCCCCCCC)OC1=O
Reaction time: 2 h

Procedure:
50 g (120 mmol; 1 eq.) of 6-O-palmitoyl-L-ascorbic acid were dissolved in 400 ml of pyridine in a 1 l 4-necked flask. 23.40 g (130 mmol; 1.1 eq.) of sorboyl chloride, dissolved in 30 ml of dichloromethane, were slowly added dropwise at an internal temperature of -15° C. Care was taken here that the internal temperature did not exceed -10° C. The mixture was brought to room temperature and additionally stirred for 2 hours. The reaction solution was concentrated on a rotary evaporator and then codistilled with toluene. The residue was taken up in a little dichloromethane and extracted with 1 M HCl. The organic phase was concentrated somewhat and treated with an excess of n-hexane. A white precipitate was deposited, which was dried in an oil pump vacuum.
Reaction SMILES: FC1C(C)=NC2C(N=1)=C([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)C=CC=2.CC(N)(C)CN>CS(C)=O>[NH:20]1[C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=[CH:12]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: CC(C)(N)CN
Solvent: CS(C)=O
Product: O=C1NCCc2[nH]ccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), 2-methylpropane-1,2-diamine (35.7 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(34(2-amino-2-methylpropyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 12.79-12.88 (m, 1H), 7.82-7.88 (m, 1H), 7.52-7.57 (m, 1H), 7.25-7.32 (m, 1H), 7.11-7.23 (m, 1H), 6.96-7.01 (m, 1H), 6.89-6.95 (m, 1H), 4.31-4.37 (m, 1H), 3.44-3.48 (m, 5H), 2.91-2.97 (m, 2H), 2.54-2.60 (m, 3H), 1.20 (s, 6H). m/z (ESI, +ve) 365.1 (M+H)+.
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].O.[C:8]1([C:14]([CH:16]=O)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:16]=[C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: CSC(=N)NN
Solvent: O
Product: CSc1nncc(-c2ccccc2)n1
Yield: 73.2 %

Procedure:
3-(Methylsulfanyl)-5-phenyl-1,2,4-triazine (2.93 g, 73%) was prepared from methyl hydrazinecarbimidothioate (2.07 g, 19.7 mmol) and phenylglyoxal monohydrate (2.89 g, 19.7 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3)[CH3:2].[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CS(C)=O.[NH4+].[OH-]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:25][CH2:24][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCn1ncc2c(Cl)c3cc(Br)ccc3nc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(Br)ccc3nc21
Temperature: 110 °C
Yield: 98.4 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-bromo-1H-pyrazolo[3,4-b]quinoline (6.5 g, 0.021 mol), cyclohexanemethylamine (5.46 g, 0.042 mol) and DMSO (20 ml) is heated at 110° C. overnight. The reaction mixture is cooled, poured into water and basified with NH4OH. The mixture is extracted with CH2Cl2 (2×100 ml), and the combined CH2Cl2 extracts are washed with brine, then evaporated to about 20 ml. The solution is purified by column chromatography on silica gel eluting with ethyl acetate to afford 8.0 g (98.8%) of 1-ethyl-6-bromo-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 158°-160° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@H:10]2[O:19][C@@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]3[C@@H:11]2[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@H:10]3[O:19][C@@H:13]4[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]4[C@@H:11]3[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C[C@H]1[C@H]2OC(C)(C)O[C@H]2O[C@@H]1/C=C/c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H]1[C@H]2OC(C)(C)O[C@H]2O[C@@H]1/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 110 °C

Procedure:
A mixture of the compound obtained from step f above (1.0 g) (4-chlorophenyl)boronic acid (0.76 g), tetrakis(triphenylphosphine)palladium (0) (0.14 g), and potassium carbonate (1.0 g) in dry dimethylformamide (10 mL) was heated at 110° C. for 4 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 12% ethyl acetate in hexane as eluant to afford the title compound (0.9 g).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@@H:20](O)[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4].[F:26]C(N(CC)CC)(F)C(F)F>ClCCCl>[Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([F:26])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4]
Reactant: O=C1[C@H]2C[C@@H](O)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Reactant: CCN(CC)C(F)(F)C(F)F
Solvent: ClCCCl
Product: O=C1[C@H]2C[C@H](F)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In a Teflon® flask, a suspension of (6R-trans)-1-chloro-N-[2-chloro4-fluoro-5-(tetrahydro-6-hydroxy-1,3-dioxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)phenyl]methanesulfonamide (8.24 g, assay 94.5% pure, 18.9 mmol) in 1,2-dichloroethane (40 mL) was heated to reflux and then 1,1,2,2-tetrafluoroethyldiethylamine (3.8 g, 26 mmol) was added over 1-2 minutes. Refluxing was continued for 1 hour, then 20 mL of the solvent was distilled out of the reaction mixture at atmospheric pressure. The reaction mixture was cooled to 50° C., 1-propanol (1 mL) was added, the pressure was reduced to about 20 kPa (150 mm Hg) for 10 minutes, and then the remaining solvent was distilled off at 55-60° C. at 20 kPa (150 mm Hg). More l-propanol (15 mL) was added at 60° C., then the mixture was cooled slowly to room temperature, and stirred overnight at room temperature to complete the crystallization. The mixture was filtered and the solids were rinsed with several portions of 1-propanol (10 mL total) and dried to afford 6.57 g (79.3% crude yield) of the title compound as a white powder melting at 166-168° C. (purity: 97.3% by HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]([NH:16][C:17]1[C:25]([Br:26])=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=1)(=[O:15])[CH3:14]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([Br:26])[C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:18][C:19]=2[O:27][CH3:28])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(NC(C)=O)c(Br)cc1C(=O)O
Product: COc1cc(NC(C)=O)c(Br)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-acetylamino-5-bromo-2-methoxybenzoic acid.