Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][CH3:19])[CH2:12][CH2:11]1.[CH2:27]([N:29](CC)CC)C.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41].CN.CO>C(Cl)Cl.O>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][NH:29][CH3:27])[CH2:12][CH2:11]1
Reactant: O=C(Cl)CCCCCBr
Reactant: CCN(CC)CC
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CNCCCCCC(=O)N(C)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
1-[2-(Methylamino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamate (500 mg, 1.41 mmol) was dissolved in methylene chloride (5 mL), triethylamine (0.236 mL, 1.70 mmol) and 6-bromohexanoyl chloride (0.232 mL, 1.56 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (×3) and washed with saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, the resulting residue was dissolved in methylene chloride (5 mL), a 40% methyl amine-methanol solution (5.76 mL, 56.4 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 7.5 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=100:0→10:1, v/v) to give the title compound (574 mg; yield, 85%) as a light yellow oily substance.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]2[O:18][C:14]([CH3:13])=[CH:15][CH:16]=2)=[N:7]3)=[CH:24][CH:23]=1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: Cc1ccc(CN)o1
Reactant: Fc1ccc(S)cc1
Product: Cc1ccc(CNc2ccc3c(Sc4ccc(F)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=365.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline (CAS 455955-26-7), 5-methyl-2-furanmethanamine and 4-fluorothiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:20])[CH2:15][C:16]([CH2:18]Cl)=O)[CH3:12].O>CCO>[CH2:11]([O:13][C:14](=[O:20])[CH2:15][C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:7][CH:18]=1)[CH3:12]
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Dissolve 4-chlorothiobenzamide (74.0 g, 431.1 mmol) in EtOH (470 mL) and treat with ethyl-4-chloroacetoacetate (58.0 mL, 70.1 g, 426.0 mmol). Stir the resulting solution mechanically at reflux for 2 h. Cool to room temperature, add water (1000 mL), and extract with Et2O (2000 mL, then 2×500 mL). Combine the organic solutions and wash with brine (950 mL). Concentrate in vacuo to give an oil that solidifies upon standing (121.8 g). Recrystallize the crude material from isopropanol/water to give the title compound (107.3 g, 89% yield). ES/MS m/z (35Cl) 282.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ncccn2)CC1
Yield: 71 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 71%). 1H NMR (200 MHz, CDCl3): δ 3.68 (s, 4H), 3.96 (s, 3H), 4.12 (s, 4H), 6.23 (t, J=4.4 Hz, 1H), 7.02 (s, 1H), 6.89-7.00 (m, 1H), 7.36-7.43 (m, 1H), 7.67 (m, 1H), 8.32 (d, J=4.4 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([N+:12]([O-])=O)[CH:7]=[CH:8]2)=[N:3]1.[Sn](Cl)(Cl)(Cl)Cl.Cl.CCOCC>COCCOCCOC>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH2:12])[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1c2ccc([N+](=O)[O-])cc2nn1C
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: COCCOCCOC
Solvent: CCOCC
Product: Cc1c2ccc(N)cc2nn1C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2,3-dimethyl-6-nitro-2H-indazole (0.48 g, 2.5 mmol, 1 equiv) was dissolved in 2-methoxyethylether (4.3 ml) with heating then cooled down to 0° C. Tin chloride (1.6 g, 7.1 mmol, 2.8 equiv) was added under nitrogen. Concentrated HCl (3.2 ml) was added dropwise keeping the temperature below 5° C. When all the HCl was added, the reaction was allowed to warm up to room temperature and stirred for 45 min. Ether (14 ml) was added and a precipitate was collected too yield the desired product as an hydrochloride salt (0.35 g, 86.8%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:22](=[O:45])[NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([N:30]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:28][OH:29])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C.C(OC(=O)N[C@H](C(=O)NCCCC[C@H](N(S(C1C=CC(N)=CC=1)(=O)=O)CC(C)C)CO)CC1C=CC2C(=CC=CC=2)C=1)(C)(C)C>>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]([NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([N:30]([S:35]([C:38]1[CH:39]=[CH:40][C:41]([NH2:44])=[CH:42][CH:43]=1)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:28][OH:29])=[O:45]
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1ccccc1-c1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N)cc1
Agent: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1ccccc1-c1ccccc1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (1S,4S)-(1-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentylcarbamoyl}-2-biphenyl-2-yl-ethyl)-carbamic acid tert-butyl ester as described for the acid hydrolysis of (1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexylcarbamoyl}-2-naphthalen-2-yl-ethyl)-carbamic acid tert-butyl ester (see example 49). The final product was obtained in 90% yield.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+].[N+](C1C=C(S(O[CH2:42][C@H:43]2[O:45][CH2:44]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:42][C@@H:43]2[CH2:44][O:45]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OC[C@@H]3CO3)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of the foregoing product from Step 1 in DMF (0.04 M) were added cesium fluoride (3 eq) and (S)-glycidyl 3-nitrobenzenesulfonate (1.1 eq). The resulting mixture was stirred at RT overnight, then diluted with EtOAc and washed with water and brine. Drying over Na2SO4, filtration and concentration in vacuo gave the crude product, which was purified by flash chromatography on silica gel (1:5 EtOAc/PE) to afford the title compound as a colourless foam (74%); MS (ES+) m/z 406 (M+H)+; [α]D20=+22 (c=0.5, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH:35]([OH:38])([CH3:37])[CH3:36]>C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:36][CH:35]([OH:38])[CH2:37][N:18]4[CH2:19][CH2:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:17]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(C)O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCc2ccccc2C1

Procedure:
A mixture of N-13-(2,3-epoxy)propyl]-4-(6-fluoro-1,2-benzisoxaz-3-yl)piperidine (3.56 g, 12.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.06 g, 15.4 mmol) in isopropyl alcohol (150 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was removed. The residual oil was purified by flash chromatography over a silica gel column (SiO2, 45 g, eluted with 1% CH3OH: 99% methylene chloride). The product thus purified as a light oil, weighed 4.15 g. The oil was treated with a solution of fumaric acid (1.98 gm, 17 mmol) in ethanol. The white crystals so obtained were recrystallized in a large volume of hot ethanol (˜150 ml). The recrystallized crystals weighed 2.75 g, m.p. 179-181° C.
Reaction SMILES: [C:1]([CH:4]([C:11](=[O:13])[CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].Cl.[NH2:15]O.CC([O-])=O.[Na+].C(O)(=O)C>C(O)C>[CH3:2][C:1]1[C:4]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([CH3:12])[O:13][N:15]=1
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)noc1C
Yield: 3.4 %

Procedure:
A mixture of ethyl 3-acetyl-4-oxopentanoate (37.24 g, 0.2 mol), hydroxylamine hydrochloride (14.6 g, 0.21 mol), NaOAc (17.23 g, 0.21 mol) and ethanol (500 mL) was refluxed for 4 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was heated in acetic acid (12.61 g, 0.21 mol) and toluene (300 mL) for 6 to 6.5 hours with the removal of water. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford a tan oil which crystallized on cooling. The product was collected by filtration and washed with ether to afford 1.26 g of ethyl 3,5-dimethyl-4-isoxazolylacetate, m.p. 180-182° C. Additional product was obtained by concentration of the ether filtrate and distillation of the residue at 69-81.5° C. and 0.05 mm Hg to afford a total of 31.18 g (85%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][C:20](O)=O)C1C=CC=CC=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[OH:44][C:45]1[CH:46]=[CH:47][C:48]2[O:53][CH2:52][CH:51]([CH2:54][NH2:55])[O:50][C:49]=2[CH:56]=1>CN(C=O)C>[OH:44][C:45]1[CH:46]=[CH:47][C:48]2[O:53][CH2:52][CH:51]([CH2:54][NH:55][CH2:20][CH2:19][CH2:18][C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=4)[NH:14][CH:13]=3)[O:50][C:49]=2[CH:56]=1
Reactant: NCC1COc2ccc(O)cc2O1
Reactant: O=C(O)CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2c(c1)OC(CNCCCc1c[nH]c3ccc(O)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
5-Benzyloxyindole-3-propionic acid (1.5 g, 5.0 mmole), 1-hydroxybenzotriazole hydrate (0.8 g, 6.0 mmole) and 1,3-diisopropylcarbodiimide (1.9 ml, 12.0 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.1 g, 5.0 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on silica gel using ethyl acetate as eluant. Fractions containing product were concentrated and recrystallized from ethyl acetate to give 1.6 g (68%) of the desired product, (7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-(5-hydroxy-1H-indol-3-yl)-propanamide, as a white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15](=O)[CH2:16][CH3:17].[CH3:19][O:20][CH2:21][CH2:22][C@@H:23]1[NH:28][CH2:27][CH2:26][N:25]([C:29]2[C:38]3[N:37]=[C:36]([C:39]([F:42])([F:41])[F:40])[S:35][C:34]=3[NH:33][C:32]3[CH:43]=[CH:44][CH:45]=[CH:46][C:31]=3[N:30]=2)[CH2:24]1>ClC(Cl)C>[CH3:19][O:20][CH2:21][CH2:22][C@@H:23]1[N:28]([CH2:15][CH2:16][CH3:17])[CH2:27][CH2:26][N:25]([C:29]2[C:38]3[N:37]=[C:36]([C:39]([F:41])([F:42])[F:40])[S:35][C:34]=3[NH:33][C:32]3[CH:43]=[CH:44][CH:45]=[CH:46][C:31]=3[N:30]=2)[CH2:24]1
Reactant: CCC=O
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN1CCN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)C[C@@H]1CCOC
Yield: 73.8 %

Procedure:
Add sodium triacetoxyborohydride (0.273 g, 1.29 mmol), and then propionaldehyde (0.083 mL, 1.15 mmol) to (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.353 g, 0.858 mmol) in anhydrous dichloroethane (15 mL) and stir at ambient temperature overnight. Add saturated aqueous sodium bicarbonate and extract aqueous phase with dichloromethane. Wash organics with saturated aqueous sodium chloride, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue (0.29 g). Purify the residue by flash chromatography, eluting with a gradient of a 3% solution of 2M ammonia in methanol, in dichloromethane, (0-100%) to give the title compound (0.287 g, 74%): mass spectrum (APCI, m/e): 454 (M+1); NMR (1H, 300 MHz, DMSO-d6): δ 8.46 (s, 1H), 6.96-6.82 (m, 3H), 6.71 (m, 1H), 3.46 (br. m, 3H), 3.31-3.17 (m, 3H), 3.15 (s, 3H), 2.73 (m, 1H), 2.58-2.44 (m, 2H), 2.31 (m, 2H), 1.67 (m, 2H), 1.40 (m, 2H), 0.83 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.[Mg].O1CCOC1.[CH3:20][C:21]([CH3:25])([CH3:24])[CH:22]=[O:23]>O1CCCC1>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([CH:22]([OH:23])[C:21]([CH3:25])([CH3:24])[CH3:20])=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC1(c2ccc(Br)cc2)OCCO1
Reactant: CC(C)(C)C=O
Agent: [Mg]
Solvent: C1COCO1
Solvent: C1CCOC1
Product: CC1(c2ccc(C(O)C(C)(C)C)cc2)OCCO1
Reaction time: 8 h

Procedure:
In 250 milliliters of tetrahydrofuran, 118 grams of the above dioxolane is dissolved. One quarter of this solution is then added to 12 grams of magnesium previously washed with chloroform, and refluxed with tetrahydrofuran for 20 minutes; and this mixture is refluxed 4 hours to initiate reaction. Additional dioxolane solution is thereafter added to maintain the refluxing without further heating. After the addition has been completed, 35 grams of 2,2-dimethylpropanal is added and the mixture is refluxed for 2 hours. The reactants are allowed to stand overnight and then poured onto ice-cold ammonium chloride solution. Tetrahydrofuran is added and the two layers formed are allowed to separate. The solvent layer is decanted off and the aqueous layer is extracted twice with 100 milliliters of tetrahydrofuran which are decanted off and combined with the remaining solvent layer. The organic phase is dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to yield a yellow oil which is distilled at 120° to 150°C. at 30M and recrystallized from pentane/ether to yield 2-methyl- 2-(4-[1-hydroxy-2,2-dimethylpropyl]-phenyl)-1,3-dioxolane (m.p. 75°-80°C.).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1.C(=O)=O>CO>[CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C@:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1
Reactant: CC(C)(C)CCc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: O=C=O
Solvent: CO
Product: CC(C)(C)CCc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Yield: 42.9 %

Procedure:
Racemic 2′-(3,3-dimethylbutyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (490 mg) from step 1 was subjected to chromatography using 20:80:0.1 MeOH:CO2:DEA at 70 ml/min on a 20×150 mm ChiralPak AD-H column and 100-bar system pressure. The first peak (RT=1.97 min) provided (4S)-2′-(3,3-dimethylbutyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (210 mg, 99% ee), and the second peak (RT=4.43 min) provided (4R)-2′-(3,3-dimethylbutyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (>99% ee).
Reaction SMILES: C(OC([C:6]1([OH:22])[C:14]2[C:9](=[CH:10][C:11]([CH3:20])=[C:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH:13]=2)[NH:8]C1=O)=O)C.[OH-:23].[Na+]>CO>[C:15]([C:12]1[CH:13]=[C:14]([C:6]([OH:22])=[O:23])[C:9]([NH2:8])=[CH:10][C:11]=1[CH3:20])(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)c1cc2c(cc1C)NC(=O)C2(O)C(=O)OCC
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCCC(=O)c1cc(C(=O)O)c(N)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
13.0 g of 5-butyryl-3-hydroxy-6-methyloxindole-3-carboxylic acid ethyl ester are suspended in 200 ml of methanol and 85 ml of 2N sodium hydroxide solution are added. The mixture is stirred at room temperature for 90 minutes, the methanol is removed under reduced pressure, the mixture is acidified to pH 3-4 with 2N hydrochloric acid, filtered with suction, then the residue is washed with water, dissolved in ethyl acetate, dried over magnesium sulphate, concentrated to dryness by evaporation under reduced pressure, digested with a little methylene chloride and filtered with suction. 5-Butyryl-4-methylanthranilic acid having a melting point of 184°-186° is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:25]=1[CH3:26])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18]C(=O)CC)[C:10]=1[O:23][CH3:24])=[O:8].C(=O)([O-])[O-].[K+].[K+].CO>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:25]=1[CH3:26])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([OH:18])[C:10]=1[O:23][CH3:24])=[O:8]
Reactant: CCC(=O)Oc1c(OC)cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c(OC)c1O

Procedure:
A mixture of 66A (6.65 g), potassium carbonate (7.0 g), water (50 ml) and methanol (100 ml) is heated to reflux for 3 hours. Upon cooling to room temperature water is added. The reaction mixture is filtered and the filtrate is acidified with concentrated hydrochloric acid. The solid material is collected and used without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.Cl.[CH3:12][NH:13][O:14][CH3:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.O>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([N:13]([O:14][CH3:15])[CH3:12])=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CCC(O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)C1CCC(O)CC1
Yield: 69.8 %

Procedure:
4-Hydroxycyclohexanecarboxylic acid (10.0 g, 69.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (8.80 g, 90.2 mmol) in dichloromethane (500 mL) was stirred with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.3 g, 90.2 mmol), 1-hydroxybenzotriazole (12.2 g, 90.2 mmol) and N,N-diisopropylethylamine (24.2 mL, 139 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)→ethyl acetate) to give the title compound as a yellow oil (9.07 g, yield 70%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.[Cl-].[Na+].O>[CH2:14]([O:11][CH2:10][C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[NH2:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@H](COCc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of L-phenylalaninol (11.78 g) in THF (200 ml) was gradually added 60% sodium hydride (3.43 g) in oil at room temperature. Twenty minutes later, the reaction mixture was refluxed under heating for 1 hour. Then, the mixture was allowed to cool, followed by gradual addition of benzyl bromide (9.27 ml) under ice-cooling, and stirred at room temperature for 16 hours. The reaction mixture was added to saturated brine, and extracted with ether. The organic layer was extracted with 10% hydrochloric acid. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution, and extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (14.5 g, yield 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:13]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:14]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)[C@H](C)N
Product: CCOC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure BG and using 3,5-difluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93°-95° C. The reaction was monitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1-chlorobutane.