Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:24])[CH2:15][C:16]2[C:21](Br)=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:24][C:21]3=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)Cc2cc(Cl)ncc2Br)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Temperature: 110 °C

Procedure:
A mixture of 4-[2-(5-bromo-2-chloro-pyridin-4-yl)-1-hydroxy-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (11.60 g), palladium acetate (500 mg), racemic 2-(di-tert-butylphosphino)-1,1′-binapthyl (1.00 g), and cesium carbonate (14.00 g) in toluene (150 mL) is heated in an oil bath at 110° C. under an argon atmosphere for 5 h. After cooling to room temperature ethyl acetate and water are added and the organic phase is separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30→50:50) to give the title compound. LC (method 7): tR=1.44 min; Mass spectrum (ESI+): m/z=339 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[CH2:14][CH:13]([C:18]([O:20][CH3:21])=[O:19])[O:12][C:11]=2[C:10]([CH2:22][CH2:23][CH3:24])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8]2.BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[CH:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[O:12][C:11]=2[C:10]([CH2:22][CH2:23][CH3:24])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: CCCc1c2c(c(OC)c3c1OC(C(=O)OC)CC3=O)CCCC2
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1c2c(c(OC)c3c(=O)cc(C(=O)OC)oc13)CCCC2

Procedure:
A mixture of methyl 2,3-dihydro-5-methoxy-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylate (3.4 g) and N-bromosuccinimide (1.78 g) was heated at reflux in carbon tetrachloride (150 ml) for 6 hours. The solution was cooled, washed with water, dried (Na2SO4) and evaporated. The residue was crystallised from petroleum ether (60°-80°) giving the title compound as a fawn solid, mp 92°-3°.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CCO>[CH2:1]([C:5]1[C:6]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)OCC)cc2)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccc(OC)cc1
Yield: 89.2 %

Procedure:
Ethyl ester (162) (0.25 g, 0.52 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.21 g (88%) of compound 163 as a white solid. mp 186-187° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.78 (t, J=7.3 Hz, 3H), 1.15-1.29 (m, 2H), 1.40-1.50 (m, 2H), 2.62 (t, J=7.3 Hz, 2H), 3.75 (s, 3H), 6.26 (d, J=15.9 Hz, 1H), 6.56 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.6 Hz, 2H), 7.30-7.40 (m, 3H), 7.47 (t, J=7.5 Hz, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.50-7.56 (m, 2H), 7.89 (d, J=8.2 Hz, 1H). LCMS (ESI): m/z 453 (M+H)+, m/z 451 (M−H)−.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:22]([S:12][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Sc1nnc(-c2ccccc2)o1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1ccc(CSc2nnc(-c3ccccc3)o2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 5-phenyl-[1,3,4]oxadiazole-2-thiol (3.1 g, 17.4 mmol; Aldrich) in ethanol (30 mL) was cooled to 0° C. and treated with diisopropylethylamine (3.1 mL, 17.4 mmol; Aldrich). The suspension cleared. Benzyl bromide (2.08 mL, 17.4 mmol; Aldrich) was then added, and the mixture was allowed to warm to room temperature. After 45 minutes, the resulting precipitate was collected by filtration and dried to afford the title compound.
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[NH:18][C:17]2[C:12](=[CH:13][C:14]([Br:19])=[CH:15][CH:16]=2)[C:8]=1[CH2:9][CH2:10][NH2:11])=[O:6])C.C(O)C.[OH-].[Na+]>C(O)(=O)C>[Br:19][C:14]1[CH:13]=[C:12]2[C:17]([NH:18][C:7]([C:5]([OH:6])=[O:4])=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NCCc1c(C(=O)O)[nH]c2ccc(Br)cc12
Yield: 91 %

Procedure:
1.00 g. (2.87 mmoles) of ethyl-5-bromo-tryptamine-2-carboxylate hydrochloride are boiled for 2 hours in a mixture of 10 ml. of ethanol and 10 ml. of 4 n aqueous sodium hydroxide solution. The mixture is cooled with ice, acidified to pH 6 with glacial acetic acid, and the separated crystals are collected by filtration. 0.75 g. (91%) of 5-bromo-tryptamine-2-carboxylic acid are obtained; m.p.; 248°-249° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[N+:21]([C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:29]([C:27]2[S:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[O:30])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])s1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 5-nitrothiophene-2-carboxylic acid. MS (m/e): 428.3 (MH−, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[CH:11]=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 248.8 %

Procedure:
To a solution of 5-bromoindole-3-carboxaldehyde (10 g) in dry tetrahydrofuran (75 ml), cooled to -78° C., was added with 2M lithium diisopropylamide/tetrahydrofuran (22.5 ml). After 30 min., the mixture was treated with a solution of tosyl chloride (9.5 g) in dry tetrahydrofuran (75 ml). The mixture was allowed to warm to room temperature overnight and evaporated. The residue was dissolved in dimethylformamide, filtered, and the filtrate was diluted with water. The precipitate was collected and recrystallized from ethanol to give 42 g (25%) of product.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[C:13](=[O:35])[N:14]([CH3:34])[CH:15]=[C:16]([C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[N:19]=2)[CH:17]=1>>[CH2:23]([N:22]1[C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=2[N:19]=[C:18]1[C:16]1[CH:17]=[C:12]([NH:11][CH:8]=[O:10])[C:13](=[O:35])[N:14]([CH3:34])[CH:15]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=CO
Reactant: Cn1cc(-c2nc3ccccc3n2Cc2ccccc2)cc(N)c1=O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc(-c2nc3ccccc3n2Cc2ccccc2)cc(NC=O)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Acetic anhydride (0.050 ml; 0.518 mmol) is added to formic acid (1.000 ml; 25.974 mmol), the mixture is stirred at 50° C. for 1 h. The reaction is then cooled to RT and 3-amino-5-(1-benzyl-1H-benzoimidazol-2-yl)-1-methyl-1H-pyridin-2-one V-2 (97.000 mg; 0.294 mmol) is added in one portion. The reaction is stirred at RT for 16 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in water/dcm (20 ml) and extracted 3 times with DCM (10 ml). The combined organic layers are dried with Na2SO4, filtered and concentrated under reduced pressure. The residue is used in the next step without further purification (yield: 88%; 93 mg; 0.259 mmol).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[N:9]2[CH:24]=[CH:25][CH:26]=[C:8]2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[OH:27][C:7]1[C:8]2[N:9]([CH:24]=[CH:25][CH:26]=2)[N:10]([CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:11](=[O:12])[C:6]=1[C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc3ccccc3c2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccc3ccccc3c2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 4-hydroxy-1-naphthalen-2-ylmethyl-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 392 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([NH2:19])=O.OS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[N:19]=[CH:17][O:10][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC=O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Product: c1ccc(-c2ncoc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of benzoin (2.65 g, 12.5 mmol), formamide (10 mL), xylene (40 mL) and conc. H2SO4 (1 mL) was refluxed for 14 h with a dean-stark trap attached to remove water. After cooling to room temperature, water was added to the mixture. The organic layer was separated, washed, dried (with MgSO4), and then distilled under reduced pressure to give 4,5-diphenyloxazole (1.93 g) as a yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:18])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O>[C:5]([Cl:3])(=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCC(=O)Cl
Temperature: 45 °C
Reaction time: 0.83 h

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 5.85 ml (80 mmol) of thionyl chloride, and a water condenser, is placed 10.02 g (50 mmol) of dodecanoic acid. Addition of the thionyl chloride is completed with heating to about 45° C. over the course of about 40 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 50 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, dodecanoyl chloride.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=O.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:45]([O:48]CC)(=[O:47])[CH3:46]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:46][C:45]([OH:48])=[O:47]
Reactant: CCOC(C)=O
Reactant: O=CCCCCCCCCCCCBr
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(O)C=CCCCCCCCCCCCBr
Reaction time: 4 h

Procedure:
To 12-bromododecanol (5 g) dissolved in methylene chloride (30 ml) were added Celite (5.0 g) and pyridinium chlorochromate (5.2 g), and the mixture was stirred at room temperature for 12 hours. Then, .the reaction mixture was filtered and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (30:1) to give 12-bromododecanal (4.4 g). To 12-bromododecanal (4.4 g) dissolved in methylene chloride (50 ml) was added (carbomethoxymethylene)triphenylphosphorane (6.75 g), and the mixture was stirred for 4 hours. Then, the reaction mixture was concentrated, and the residue thus obtained was subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (30:1) to give the methyl ester of 14-bromo-2-tetradecenoic acid (4.91 g). The product was dissolved in acetonitrile (30 ml), and 1M tetra-n-butylammonium chloride in THF (27 ml) and potassium fluoride (7.6 g) were added. The mixture was heated under reflux for 12 hours. The reaction mixture was concentrated and subjected to chromatography on a silica gel column with an eluent system of n-hexaneethylacetate 100:1 to give the methyl ester of 14-fluoro-3-tetradecenoic acid (3.3 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[N:8]2[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1Nc2cc(F)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A solution of 6-fluoroindoline-2,3-dione (2 g, 12.11 mmol) in dry DMF (100 ml) was cooled to 0° C., and NaH (60% w/w dispersion in mineral oil; 0.484 g, 12.11 mmol) was added portion wise over 10 minutes. The mixture was stirred at the same temperature for 10 minutes, then tert-butyl 2-bromoacetate (1.788 ml, 12.11 mmol) was added drop wise. The mixture was left warm to room temperature and stirred for 2 hours. DMF was evaporated under vacuum, and the crude was portioned between ethyl acetate (50 ml) and aqueous 1N HCl (40 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml), and the combined organic layers were dried over sodium sulfate, filtered and concentrate under vacuum. The crude was purified by flash chromatography on silica gel cartridge (petroleum ether:ethyl acetate=80:20) affording tert-butyl 2-(6-fluoro-2,3-dioxoindolin-1-yl)acetate
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:35]=[O:36])[CH2:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:37])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:35]=[O:36])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:37])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCC(C=O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CC(CCC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A solution of t-butyl ester 234e (179 mg, 0.35 mmol) in dry CH2Cl2 (3 ml) was cooled to 0° C. and treated with trifluoroacetic acid (2 ml). The resulting solution was stirred at 0° C. for 30 min and then at room temperature for 2 h. The solution was concentrated, the residue taken up in dry CH2Cl2 (5 ml) and the mixture again concentrated. This process was repeated once again with more CH2Cl2 (5 ml). The residue obtained was crystallized in diethyl ether. The precipitate was collected and purified on silica gel column (5% methanol in CH2Cl2) which afforded compound 235e as a white solid (111 mg, 70%): mp 142° C. (dec); [α]D20 -85.5° (c 0.062, MeOH); IR (KBr) 3409, 3075, 2952, 1651, 1541, 1424, 1280, 1198, 1136, 717; 1H NMR (D6 -DMSO) δ 9.40 (1H, s), 8.62 (2H, m), 7.96-7.38 (5H, m), 5.19-5.02 (1H, m), 4.98-4.79 (1H, m), 4.48-4.19 (1H, m), 3.51-3.11 (2H, m), 3.04-2.90 (2H, m), 2.38-1.46 (10H, m).
Reaction SMILES: [O:1]([C:8]1[C:13]([NH2:14])=[C:12]([C:15]#[C:16][CH3:17])[N:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>O1CCCC1>[CH3:17][C:16]1[NH:14][C:13]2[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][CH:10]=[N:11][C:12]=2[CH:15]=1
Reactant: CC#Cc1ncnc(Oc2ccccc2)c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2ncnc(Oc3ccccc3)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
4-Phenoxy-6-prop-1-yn-1-ylpyrimidin-5-amine (776.0 mg) was dissolved in tetrahydrofuran (30 mL) and cooled to 0° C. To this solution was added dropwise a 1.0 M solution (4 mL) of potassium tert-butoxide in tetrahydrofuran, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33→20:80) to give the title compound (578.6 mg) as a white solid.
Reaction SMILES: C([O:4][CH:5]([C:7]1[C:16]([C:17]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])=[C:15]([OH:25])[C:14]2[C:9](=[C:10]([C:26]([F:29])([F:28])[F:27])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)[CH3:6])(=O)C.Cl>C(O)C>[OH:25][C:15]1[C:14]2[C:9](=[C:10]([C:26]([F:27])([F:29])[F:28])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH:5]([OH:4])[CH3:6])[C:16]=1[C:17]([NH:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1)=[O:18]
Reactant: CC(=O)OC(C)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Agent: Cl
Solvent: CCO
Product: CC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of 4.3 g of the product of Example 1, 50 ml of ethanol and 25 ml of concentrated hydrochloric acid was refluxed with stirring for one hour and was then cooled and iced and vacuum filtered. The product was washed and dried under reduced pressure at 60° C. The said product was added to 300 ml of water and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was crystallized from ethyl acetate. The mixture was iced and vacuum filtered and the recovered product was washed and dried under reduced pressure at 60° C. to obtain 2.45 g of 4-hydroxy-2-(1-hydroxyethyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 205° C. and then at 235° C.
Reaction SMILES: F[C@H:2]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1.N[C:27]1[S:31][C:30]([C:32]2[C:37](F)=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])=[N:29][C:28]=1[C:40]([NH:42][C:43]1[CH:44]=[N:45][N:46]([CH3:57])[C:47]=1[CH:48]1[CH2:54][CH2:53][C@H:52]([NH2:55])[C@H:51]([F:56])[CH2:50][O:49]1)=[O:41]>>[NH2:55][C@H:52]1[C@H:51]([F:56])[CH2:50][O:49][C@H:48]([C:47]2[N:46]([CH3:57])[N:45]=[CH:44][C:43]=2[NH:42][C:40]([C:28]2[N:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH3:2])=[CH:34][C:33]=3[F:39])[S:31][CH:27]=2)=[O:41])[CH2:54][CH2:53]1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC[C@H](N)[C@H](F)CO1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cc1ccc(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)cs2)c(F)c1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2-fluoro-4-methylphenyl)thiazole-4-carboxylic acid (Intermediate 131) gave 316. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.48 (s, 1H), 8.36 (t, J=8.1 Hz, 1H), 7.89 (s, 1H), 7.34-7.18 (m, 2H), 4.87 (dd, J=10.6, 3.6 Hz, 1H), 4.57-4.39 (m, 1H), 4.38-4.25 (m, 1H), 4.19-4.01 (m, 1H), 3.78 (s, 3H), 2.40 (s, 3H), 2.12-2.03 (m, 1H), 1.88-1.78 (m, 1H), 1.77-1.66 (m, 3H). LCMS (ES+) m/z 448 (M+1).
Reaction SMILES: C(O)=O.C([O:8][C:9](=[O:46])[CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[C:16]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:15]2[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)=[CH:37][CH:36]=1)(C)(C)C>ClCCl>[CH:43]1([CH2:42][O:41][C:38]2[CH:37]=[CH:36][C:35]([C:15]3[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([O:11][CH2:10][C:9]([OH:46])=[O:8])[CH:13]=4)[N:17]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:16]=3[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:40][CH:39]=2)[CH2:44][CH2:45]1
Reactant: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(OCC(=O)OC(C)(C)C)ccc2n1Cc1cccc(OC)c1
Solvent: ClCCl
Solvent: O=CO
Product: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(OCC(=O)O)ccc2n1Cc1cccc(OC)c1
Reaction time: 1 h
Yield: 53 %

Procedure:
Formic acid (1 mL) was added to a stirred solution of ethyl 5-(2-tert-butoxy-2-oxoethoxy)-3-[4-(cyclopropylmethoxy)phenyl]-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 150, 20 mg, 0.035 mmol) in dichloromethane (1 mL). The reaction was stirred for 1 h and then concentrated in vacuo. Flash chromatography of the residue over silica gel using (1:1 ethyl acetate/hexane) gave 10 mg (53% of the desired product. The product had: 1H NMR (300 MHz, CD3OD) δ 7.30-7.48 (m, 3 H), 6.92-7.19 (m, 4 H), 6.77 (dd, 1 H), 6.54-6.68 (m, 3 H), 5.79 (s, 2 H), 4.61 (s, 2 H), 4.13 (q, 2 H), 3.95 (d, 2 H), 3.74 (s, 3 H), 1.29-1.41 (m, 1 H), 1.25 (t, 3 H), 0.61-0.71 (m, 2 H), 0.39-0.49 (m, 2 H); mass spectroscopy gave MH+ of 530.2 (calc'd exact mass for C31H31NO7=529.21).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].[CH2:9]([O:16][C:17](ON1C(=O)CCC1=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([O:16][C:17]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCO)C(=O)O
Solvent: CN(C)C=O
Product: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6 g (50.4 mmol) of L-homoserine were largely dissolved in 50 ml of DMF and treated at 0° C. in portions with 12.56 9 (50.4 mmol) of N-(benzyloxycarbonyloxy)succinimide. The mixture was stirred at 0° C. for 1 h, then at RT for 48 h. The solvent was distilled off and the residue was partitioned between EA and a saturated NaCl solution. The organic phase was washed with saturated NaCl solution, with 5% strength citric acid and again with saturated NaCl solution, dried, filtered and concentrated. The crystalline residue was stirred in ether, filtered off with suction, and washed with ether and pentane. Yield: 9.55 g (75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)o1
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(-c3cccc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (65) (67 mg, 0.3 mmol) was coupled to ethyl ester (64) (58 mg, 0.25 mmol) using Method C. The crude residue was purified by column chromatography eluting with a stepped gradient of 10-20% EtOAc in heptane to give the title compound.