Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[OH:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)ccn1
Solvent: C1CCOC1
Product: COc1cc(C[C@@H](CO)NC(=O)OC(C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-methoxypyridin-4-yl)propanoic acid (1.3 g, 4.4 mmol) in tetrahydrofuran (5.0 mL) with stirring, 1.0 M borane-THF complex in THF (13 mL) was added dropwise to keep the internal temperature at 0° C. (about 15 min). After addition, the mixture was stirred at rt for 3 h, cooled with an ice-bath, quenched with AcOH:MeOH (1:5, 5 mL), partitioned between saturated aqueous NaHCO3 and DCM, dried over Na2SO4, filtered, and evaporated under reduced pressure to give 0.5 g (40% yield) of the desired product. LC-MS found: 283.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:23]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH2:30][O:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: C=CC(=O)NC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)CCON(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of 21.33 g of dibenzylhydroxylamine in 100 ml of dry tetrahydrofuran is admixed with 1.12 g of potassium-tert-butoxide followed by 12.70 g of N-tert-butylacrylamide. The solution is heated under reflux for 24 hours under N2. The crude reaction mixture is concentrated under reduced pressure and the residue is partitioned between water and methylene chloride. The organic layer is washed with water, brine dried (MgSO4) and evaporated under reduced pressure. Purification by liquid chromatography affords the title compound as an oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:22])[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:6]2=[O:31])[CH2:3][CH2:2]1.[CH3:32][C:33]([CH3:35])=O.C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1.ClCCl>[CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([NH:21][CH:33]([CH3:35])[CH3:32])=[CH:19][CH:20]=4)[NH:10][C:9]=3[C:8](=[O:22])[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:6]2=[O:31])[CH2:3][CH2:2]1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 25 °C
Yield: 23.8 %

Procedure:
To a solution of 3-cyclopropylmethyl-8-[4-aminobenzyl]-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione (0.21 g, 0.50 mmol) in tetrahydrofuran (tetrahydrofuran) (5 mL) was added acetone (36.7 μL, 5.0 mmol) and sodium cyanoborohydride (Aldrich, catalog number 15,615-9) (94.3 mg, 1.5 mmol). Stirred vigorously at ambient temperature and glacial acetic acid (J. T. Baker, catalog number 9508-5) (50 μL, 0.87 mmol) added. After 3 h additional glacial acetic acid (50 μL, 0.87 mmol) was added and the mixture stirred at ambient temperature for an additional 1 h. The reaction mixture was diluted with dichloromethane and washed with 1M aqueous sodium hydroxide (2×), brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by chromatography using silica eluted with 1:2 hexanes/ethyl acetate. Concentration of the appropriate fractions gave the product as a colorless solid (0.055 g, 23%). 1H NMR, δH(DMSO-d6, 300 MHz) 13.29 (br s, 1H), 7.30–6.85 (m, 6H), 6.40 (d, J=8.8 Hz, 2H), 5.16 (d, J=8.4 Hz, 1H), 5.04 (s, 2H), 3.78 (s, 2H), 3.42 (sept, J=6.4 Hz, 1H), 1.25–1.10 (m, 1H), 1.01 (d, J=6.2 Hz, 6H) and 0.45–0.30 (m, 4H)
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]([C:10](=[O:15])[CH2:11][CH2:12][CH:13]=[CH2:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6]>CO>[OH:15][CH:10]([CH2:11][CH2:12][CH:13]=[CH2:14])[CH:4]([CH3:3])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=CCCC(=O)C(C)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCCC(O)C(C)C(=O)OCC
Yield: 49.9 %

Procedure:
Sodium borohydride (2.48 g, 65.7 mmol) was added to a methanol (200 mL) solution of ethyl 2-methyl-3-oxohept-6-enoate (12.1 g, 65.7 mmol) with stirring under ice cooling. The mixture was stirred for 30 minutes in this bath, further stirred at room temperature for 2 hours, and then concentrated under reduced pressure to remove the solvent. The residue was diluted with dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated saline, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil (6.11 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[C:19](OC)=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccsc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2sccc2CO)CC1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A solution of 4-(3-methoxycarbonylthiophen-2-yl)piperidine-1-carboxylic acid t-butyl ester (3.8 g, 12 mmol, 1.0 eq.) in THF (70 mL) was degassed and purged with nitrogen (2×). Borane dimethyl sulfide complex (45 mL, 90 mmol, 110 eq.) was added at room temperature and the mixture was heated to reflux for 3 hours. The mixture was allowed to cool to room temperature and MeOH (20 mL) was slowly added. The mixture was then concentrated under vacuum. The addition of MeOH (20 mL) and concentrating was repeated two additional times. The crude material was applied onto a silica gel column and purified by chromatography with PE/EtOAc (10:1). The product was then purified by preparative HPLC to yield the title compound (1.8 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][F:12])=[CH:6][CH:5]=1.O.[NH2:15][NH2:16]>C(O)C>[F:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:15][NH2:16])=[O:2])=[CH:5][CH:6]=1
Reactant: NN
Reactant: COC(=O)c1ccc(OCF)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(OCF)cc1
Yield: 1010.6 %

Procedure:
4-Fluoromethoxy-benzoic acid methyl ester (573 mg, 0.31 mmol) was dissolved in ethanol (10 ml) and heated under reflux with hydrazine monohydrate (0.8 ml, 1.55 mmol, 5 eq.) for 60 hrs. The volatiles were completely evaporated and the product was dried overnight under high vacuum at 40° C., to afford the title compound (577 mg, 100% yield) as a light brown solid. MS: m/e=184 (M+).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].C([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])C>O1CCCC1>[CH:20]1[C:27]2[CH2:7][C:6]3[CH:5]=[CH:4][CH:9]=[CH:8][C:25]=3[CH2:24][N:23]([C:16]([C:15]3[CH:19]=[CH:20][C:12]([N:2]([CH3:1])[C:3](=[O:11])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[CH3:10])=[CH:13][CH:14]=3)=[O:17])[C:26]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.4 %

Procedure:
A mixture of 0.291 g of 6,11-dihydro-5-dibenz[b,e]azepine, 0.518 g of 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoyl chloride and 0.182 g of triethylamine in 10 ml of tetrahydrofuran is stirred at room temperature for 2 hours. The solvent is removed, the residue diluted with water and extracted with dichloromethane. The extract is washed with 1N HCl water, 1M NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and chilled to give 0.52 g of crystals, m.p. 160°-170° C.
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:9]([O:8][P:4]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)([O:5][CH2:6][CH3:7])=[O:3])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: O=C(O)c1ccc(CBr)cc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
Triethylphosphite (9.28 mL, 53.3 mmol) and α-bromo-p-toluic acid (10.4 g, 48.4 mmol) were suspended in toluene (25 mL) and the mixture was heated to reflux for 18 h. The mixture was cooled to room temperature. After 12 h, the resulting white solid was collected by suction filtration, washed with petroleum ether and dried to yield 4-(diethoxyphosphorylmethyl)benzoic acid as a white solid (10.2 g, 77%): mp 117-120° C.; 1H NMR δ 1.26 (t, J=6.8 Hz, 6H), 3.24 (d, J=25.6 Hz, 2H), 4.06 (m, 4H), 7.38-7.40 (m, 2H), 8.02 (d, J=7.6 Hz, 2H), 11.4 (br s, 1H); 13C NMR δ 16.5, 16.6, 33.4, 34.8, 62.8, 62.9, 129.1, 129.2, 130.00, 130.05, 130.10, 130.48, 130.51, 137.3, 137.4, 170.1; FABMS obsd 273.0896, calcd 273.0892; Anal. Calcd. for C12H17O5P: C, 52.94; H, 6.29. Found: C, 52.92; H, 6.28. A suspension of 4-(diethoxyphosphorylmethyl)benzoic acid (9.99 g, 36.7 mmol) in anhydrous THF (40 mL) at 0° C. was treated dropwise over 10 min with borane-THF complex (40.3 mL, 40.3 mmol, 1.0 M in THF). The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched by slow addition of water. The mixture was concentrated and the residue was partitioned between water (100 mL) and CH2Cl2 (100 mL). The aqueous layer was washed with CH2Cl2. The combined organic layers were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Analysis by TLC and 1H NMR spectroscopy showed starting material (˜10%) and the desired benzyl alcohol. The latter (9.56 g) was dissolved in CH2Cl2 and rapidly added to a sample of PCC (10.8 g, 50.1 mmol) in CH2Cl2 (50 mL) with rapid stirring. After 2 h, ethyl ether (150 mL) was added and the organic solution was decanted from the tarry residue. The residue was washed with ethyl ether (3×50 mL). The combined organic solution was filtered through Florisil and concentrated to a brown oil. Kugelrohr distillation (190° C. @ 0.05 Ton) afforded a clear, colorless oil (6.54 g, 77%): 1H NMR δ 1.24 (t, J=7.2 Hz, 6H), 3.21 (d, J=22.4 Hz, 2H), 4.03 (m, 4H), 7.45-7.48 (m, 2H), 7.83 (d, J=7.6 Hz, 2H), 9.99 (s, 1H); 13C NMR δ 16.1, 16.2, 33.0, 34.9, 62.1, 62.2, 77.2, 129.49, 129.53, 129.6, 129.66, 129.71, 130.2, 130.2, 138.8, 138.9, 191.61, 191.63; 31P NMR δ 25.4, 25.9; FABMS obsd 257.0949, calcd 257.0943 (C12H17PO4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].Cl[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[Ca+2]>CN(C)C=O>[CH3:16][O:15][C:13](=[O:14])[CH2:12][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](=[O:6])[NH2:7])[CH:3]=1
Reactant: COC(=O)CCl
Reactant: NC(=O)c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: COC(=O)CNc1cccc(C(N)=O)c1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
To a mixture of 6.8 g of 3-aminobenzamide, 5.5 g of methyl monochloroacetate and 10.0 g of calcium carbonate was added 30 ml of dimethylformamide and the mixture was stirred at 110° to 120° C. for 2 hours. The inorganic salt precipitated was filtered off and the filtrate was concentrated under reduced pressure. 50 ml of water was added to the resulting residue and the mixture was stirred to precipitate crystals. The crystals were collected by filtration, dried and recrystallized from a mixture of methanol and diethyl ether to obtain 5.7 g of N-(3-carbamoylphenyl)glycine methyl ester as colorless needles having a melting point of 146°-147° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:3]1.Cl[CH2:39][CH2:40][N:41]=[C:42]=[O:43].CC(C)([O-])C.[K+]>C1COCC1.O>[C:21]([C:18]1[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])[C:15]([C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@H:6]2[CH2:7][C@@H:2]([N:1]3[CH2:39][CH2:40][NH:41][C:42]3=[O:43])[CH2:3][N:4]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:5]2)=[O:14])=[CH:20][N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C=NCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N2CCNC2=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3R,5S)-3-amino-5-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1-carboxylate (124 mg) was dissolved in THF (4 ml), chloroethyl isocyanate (24 μl) was added, and the mixture was stirred at room temperature for 1 hr. Potassium tert-butoxide (40 mg) was added and the reaction mixture was stirred at room temperature for 7 hr and further at 60° C. for 5 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (10:90-100:0) and concentrated under reduced pressure to give the object compound (70.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([I:26])[CH:21]=4)=[O:19])[CH:16]=3)[N:11]=[C:10]([O:27]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>Cl.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:19])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([I:26])[CH:21]=4)[CH:16]=3)[NH:11][C:10](=[O:27])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3cccc(I)c3)ccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(c1cccc(I)c1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Temperature: 0 °C
Yield: 88 %

Procedure:
A solution of intermediate (73) (0.0304 mol) in HCl 3N (150 ml) and THF (70 ml) was stirred and refluxed overnight, brought to room temperature, poured out into ice water and basified with potassium carbonate. The precipitate was filtered, washed with 2-propanone and dried, yielding 13 g (88%) of 4-(3-chlorophenyl)-6-(3-iodobenzoyl)-2(1H)-quinolinone (intermediate 74).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1.[C:32]1([C@H:38]([CH3:42])[C:39]([O-:41])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cs+].[I-].[Na+].O>C(#N)C>[C:28]([N:5]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)[C:4]([O:3][CH2:2][O:41][C:39](=[O:40])[C@H:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:42])=[O:31])(=[O:30])[CH3:29]
Reactant: C[C@H](C(=O)[O-])c1ccccc1
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@@H](C)c1ccccc1
Temperature: 25 °C
Yield: 75 %

Procedure:
(R)-acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid chloromethyl ester (10) (0.40 g, 0.84 mmol), cesium 2(S)-phenyl-propionate (0.37 g, 1.31 mmol) and sodium iodide (0.13 g, 0.86 mmol) in acetonitrile (25 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 75%. 1H NMR (400 MHz, DMSO-d6): δ 7.43-7.39 (m, 1H), 7.33 (t, 1H), 7.27-7.15 (m, 6H), 5.78-5.72 (m, 2H), 4.63-4.57 (m, 1H0, 4.02-3.95 (m, 2H), 3.84 (q, 1H), 3.76-3.69 (m, 2H), 3.36-3.26 (m, partially obscured by water, 2H), 3.18-3.12 (m, 1H), 3.07-3.04 (m, 2H), 2.30 (d, 3H), 2.11 (q, 2H), 2.01-1.97 (m, 2H), 1.35 (d, 3H); MS-APCI (m/z+): 341, 385, 517, 591.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]([NH:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22]>C(#N)C.O.Cl>[CH2:19]([NH:23][CH2:24][CH2:25][C:6]1[C:5]([CH2:9][CH3:10])=[C:4]([Cl:11])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCNCC
Reactant: CCc1c(Cl)nc(C)nc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCNCCc1nc(C)nc(Cl)c1CC
Yield: 88.3 %

Procedure:
A mixture of 2-methyl-5-ethyl-4,6-dichloro-pyrimidine (1.009 g, 5.28 mmol) in 5 ml of acetonitrile was treated with triethylamine (0.571 g, 5.65 mmol) and N-butyl-ethyl-amine (0.540 g, 5.31 mmol) and heated at reflux overnight. The mixture was diluted with water and dilute hydrogen chloride, and extracted with ethyl acetate. The organic layer was neutralized with saturated potassium carbonate and washed with brine, dried and concentrated to give 1.193 g of yellow oil which was purified through silica gel column chromatography to give 1.157 g (86%) of title compound as a yellow oil. 1H NMR (CDCl3) δ 0.90 (t, 3H), 1.13 (t, 3H), 1.18 (t, 3H), 1.1-1.33 (m, 2H), 1.4-1.6 (m, 2h), 2.41 (s, 3H), 2.62 (q, 2H), 3.25-3.48 (m, 4H) ppm.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:15]>>[CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][NH2:15])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1csc(Cc2ccccc2)n1
Reactant: N
Product: NCc1csc(Cc2ccccc2)n1
Yield: 50 %

Procedure:
2-Benzyl-4-chloromethylthiazole [Pharmazie 1972, 27, 146] (223.7 g, 1 mol) was stirred with liquid ammonia (600 ml) in an autoclave for 24 hours. The ammonia was removed and the product was distilled in vacuo [bp (0.02 mmHg) 141-144° C.] to give the title compound (102 g, 50%).
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:10]2[CH2:11][CH2:12][S:13][CH2:14][CH:15]=2)[S:6][C:7]=1[CH2:8][CH3:9].[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C(=O)C>[CH:16]1([CH:2]([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[C:3]2[CH:4]=[C:5]([C:10]3[CH2:11][CH2:12][S:13][CH2:14][CH:15]=3)[S:6][C:7]=2[CH2:8][CH3:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCc1sc(C2=CCSCC2)cc1C(Cl)C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCc1sc(C2=CCSCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To a mixture of 4-{4-[chloro(cyclohexyl)methyl]-5-ethylthiophen-2-yl}-3,6-dihydro-2H-thiopyran (1.37 g) synthesized above, methyl 4-aminobenzoate (1.15 g), sodium iodide (1.15 g) and N,N-dimethylacetamide (20 mL) was added sodium carbonate (810 mg), and the mixture was stirred overnight at 100° C. under an argon atmosphere. To the reaction mixture was added 1N hydrochloric acid to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give a pale-brown solid. To a mixture of the obtained solid, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred overnight at 50° C. To the reaction mixture was added 1N hydrochloric acid (10 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3, volume ratio) to give the title compound (554 mg, 31%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]([CH3:16])[C:13](O)=[O:14].B.C1COCC1>C1COCC1>[OH:14][CH2:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH3:16]
Reactant: Cc1c(C(C)C(=O)O)ccc2c1COC2=O
Agent: B
Solvent: C1CCOC1
Product: Cc1c(C(C)CO)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoic acid (300 mg, 1.4 mmol) in 18 mL of anhydrous THF was added BH3.THF (2 mL, 2 mmol) dropwise at 0° C. Then the mixture was warmed to room temperature slowly and then stirred for 3 hours. Then the mixture was quenched with MeOH and the solvent was removed under vacuum. The residue was the purified via prep-TLC to give 5-(2-hydroxy-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.73 (d, J=7.8 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 5.23 (s, 2H), 3.77 (d, J=7.0 Hz, 2H), 3.36˜3.42 (m, 1H), 2.30 (s, 3H), 1.27 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].[NH2:22][C:23]1[CH:24]=[C:25]([N:29]([CH3:39])[S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=1>C1COCC1.CCOC(C)=O>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:39])[S:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])[CH:24]=2)[N:20]=1
Reactant: CN(c1cccc(N)c1)S(=O)(=O)c1ccccc1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cccc(Nc2nc(Cl)ccc2C(N)=O)c1)S(=O)(=O)c1ccccc1
Reaction time: 18 h
Yield: 79.8 %

Procedure:
A 1 M THF solution of LiHMDS (2.302 mL, 2.302 mmol) was added dropwise to a suspension of 2,6-dichloronicotinamide (163 mg, 0.855 mmol) and N-(3-aminophenyl)-N-methylbenzenesulfonamide (172.5 mg, 0.658 mmol) in THF (3 mL) at room temperature. After 18 h at room temperature, the mixture was diluted with EtOAc and washed with saturated NH4Cl (5 mL). The EtOAc phase was concentrated and purified by silica gel chromatography, eluting with 20-100% EtOAc in hexanes, to give a yellow solid (218.8 mg, 51% yield). LCMS: (M+H)+=417.0.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30]>>[F:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[F:26])[O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:28][CH:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:7])[N:9]=[CH:10]2)=[CH:15][CH:14]=1
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccc(F)c(F)c3)ccc2c1O
Reactant: C[C@H](N)C(=O)O
Product: CC(NC(=O)c1ncc2cc(Oc3ccc(F)c(F)c3)ccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-50 by reacting 7-(3,4-Difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (compound of Example A-62 a) with L-alanine in a pressure tube for 3 days at 85° C. MS-(+)-ion: M−1=389.2.