Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+].Cl>COCCOC.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>[N:20]1([C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:4]3[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=[C:2]([C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:26]([OH:28])=[O:27])[N:3]=3)=[CH:13][CH:14]=2)=[O:19])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=C(c1ccc(Nc2nc(Br)cn3ccnc23)cc1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=C(O)c1cccc(-c2cn3ccnc3c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)c1
Temperature: 95 °C

Procedure:
The bromide (8) (2,46 mmol) is dissolved in 10 mL DME (ethylene glycol, dimethyl ether) in a sealable pressure vessel and N2 is bubbled through for 10 min. Tetrakis(triphenylphosphine)palladium (0.24 mmol) is added and N2 is bubbled through the reaction for another 10 minutes. 3-Carboxyphenyl boronic acid (3.1 mmol) and 1N Na2CO3 solution (10 mL) are then added, the vessel sealed, and the reaction heated to 95° C. for 16 hrs. with vigorous stirring. After cooling to room temperature, the reaction is acidified to pH 3 with 1N HCl and extracted with ethyl acetate (3×25 mL). The pooled ethyl acetate layers are washed with brine, dried over sodium sulfate, and the solvent removed in vacuo. The resulting solid is then dissolved in a minimal volume of CH2Cl2 and precipitated out as a whitish-tan solid by slow addition of ethyl acetate (5 mL) followed by hexanes (30 mL) to yield 3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzoic acid (9).
Reaction SMILES: [OH-].[Li+].C([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])(=O)C.O.Cl>C1COCC1>[OH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(OC(C)=O)c(CC=C(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCc1cc(C(=O)O)ccc1O
Temperature: 25 °C
Yield: 75.4 %

Procedure:
Lithium hydroxide (85 mg, 2.02 mmol) was added to a mixture of methyl ester 7 (106 mg, 0.405 mmol) in 0.5 mL of a 3/1/1 THF/eOH/H2O solution. The reaction mixture was stirred at reflux for 14 hours, cooled to room temperature, and diluted with THF (1 mL). The solution was acidified the solution to pH=3 by the dropwise addition of 6 M HCl. The layers were separated and the organic phase was dried (Na2SO4), filtered, and concentrated to afford acid 8 (63 mg, 75%) as a red oil that was suitable for use without further purification.
Reaction SMILES: C1(CC(O)=O)C2C(=CC=CC=2)CCC1.[CH2:15]([O:17][C:18]([CH2:20][CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH:22]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)CC1CCCc2ccccc21
Agent: O=C(O)CC1CCCc2ccccc21
Product: CCOC(=O)CC1=CCCc2ccccc21

Procedure:
(1,2,3,4-tetrahydronaphthalen-1-yl)-acetic acid was itself prepared from 1-ethoxycarbonylmethyl-1,2,3,4-tetrahydronaphthalene, which was obtained from 1-ethoxycarbonylmethyl-3,4-dihydronaphthalene [cf. J. Chem. Soc. (1960), 4115-4120], which was itself prepared from 1,2,3,4-tetrahydronaphthalen-1-one.
Reaction SMILES: [Br-].C([O:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][N+:9]([CH2:12][CH3:13])([CH3:11])[CH3:10])C>O>[CH2:12]([N+:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]([O-:14])=[O:4])[CH3:13]
Reactant: CCOC(=O)CCC[N+](C)(C)CC
Agent: [Br-]
Solvent: O
Product: CC[N+](C)(C)CCCC(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 417.2 %

Procedure:
A solution of 4-ethoxy-N-ethyl-N,N-dimethyl-4-oxo-1-butanaminium bromide (6b) (12.00 g, 44:7 mmol) in water (10 ml) was passed through Amberlite® IRA-410 (OH) ion exchange resin column (250 ml) eluting slowly (ca. 10 drops/min) with ethanol (TLC control). The eluate was evaporated and the residue (12 g) was dissolved in water (50 ml). To this solution DOWEX® 50WX8 ion exchange resin (5 g) was added and stirred at ambient temperature for 0.5 hours. The reaction mixture was filtered through celite (1 cm) and the eluate was evaporated to dryness. The residue was azeotropically dried with isopropanol, acetonitrile, and acetone. The obtained solid was triturated with acetone (10 ml) and the mixture was kept at 0° C. for 2 h. The precipitate was filtered and dried in vacuo over P205 to give 4.65 g (65%) of 4-[ethyl(dimethyl)ammonio]butanoate.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([C:21]4[CH:22]=[CH:23][C:24]([Cl:30])=[C:25]([S:27]([NH2:29])=[O:28])[CH:26]=4)=[O:20])=[CH:16][CH:17]=3)[C:12]3[CH2:31][CH2:32][N:33]([C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:34][C:11]2=3)(=O)=O)C=CC=CC=1>CO.[OH-].[Na+]>[Cl:30][C:24]1[CH:23]=[CH:22][C:21]([C:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][C:11]2[CH2:34][N:33]([C:35](=[O:40])[C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:32][CH2:31][C:12]3=2)=[O:20])=[CH:26][C:25]=1[S:27]([NH2:29])=[O:28]
Reactant: CC(C)(C)C(=O)N1CCc2c(n(S(=O)(=O)c3ccccc3)c3ccc(C(=O)c4ccc(Cl)c(S(N)=O)c4)cc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(=O)N1CCc2c([nH]c3ccc(C(=O)c4ccc(Cl)c(S(N)=O)c4)cc23)C1
Temperature: 25 °C
Yield: 15 %

Procedure:
5-[9-Benzenesulfonyl-2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carbonyl]-2-chloro-benzenesulfinamide and its isomer (0.12 g, 0.195 mmol) are dissolved in 3 mL of 2:1 (v:v) mixture of methanol and 5 N aqueous sodium hydroxide then heated at reflux for 20 minutes The reaction mixture is allowed to cool to room temperature and the methanol is removed in vacuo. The aqueous solution is acidified with 5 N HCl to pH 3 and then thoroughly extracted with ethyl acetate, the combined organic extracts are washed with water then a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification via preparative HPLC provides 0.014 g (15%) of the title compound as a yellow solid. 1H NMR (DMSO): δ 11.40 (s, 1H), 8.30 (s, 1H), 7.90 (m, 2H), 7.80 (m, 3H), 7.50-7.60 (m, 2H), 4.74 (s, 2H), 4.00 (m, 2H), 2.80 (m, 2H). MS (m/z): 472.1 (M−1).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[O:22][CH3:23].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([O:9][C:10]1[C:11]([O:22][CH3:23])=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][C:19]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCc2ccccc2)c(OC)c1
Yield: 73.2 %

Procedure:
Benzyl chloride (11.04 g, 86.9 mmol) was added to a stirred solution of 121 (19.22 g, 90.8 mmol) over K2CO3 (6.59 g, 47.7 mmol) in anhydrous MeOH (175 mL) and the mixture was heated at reflux for 12 h. Excess solvent was removed under reduced pressure and the residue was extracted with benzene (3×100 mL). The organic layer was washed with H2O (3×100 mL), brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded an orange oil which crystallised on standing. The solid was redissolved in EtOAc, and briefly washed with 1N NaOH (100 mL), H2O (100 mL), brine (100 mL) and dried over MgSO4. Evaporation of excess solvent yielded the product as a yellow solid 122 (19.20 g, 63.6 mmol); 1H NMR (270 MHz, CDCl3) δ3.8 (s, 3H), 3.85 (s, 3H), 3.9 (s, 3H), 5.1 (s, 2H), 7.3-7.5 (m, 7H); 13C NMR (67.8 MHz, CDCl3) δ166.7, 153.2, 140.8, 137.3, 128.7, 128.6, 128.4, 128.4, 128.2, 128.0, 127.7, 125.3, 106.7, 74.9, 56.1, 52.2.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[CH:11][CH:12]=1
Reactant: COCCCCCCOc1ccc(N2CCN(C(C)=O)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COCCCCCCOc1ccc(N2CCNCC2)cc1
Temperature: 75 °C
Yield: 88.5 %

Procedure:
A mixture of 1-acetyl-4-[4-(6-methoxyhexyloxy)phenyl]piperazine (4.87 g) and 6N-hydrochloric acid (50 ml) was heated at 75° C. for 3 hours. After cooling, the solution was adjusted to pH 11 with 25% sodium hydroxide aqueous solution then the resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to give 4-[4-(6-methoxyhexyloxy)phenyl]piperazine (3.77 g) as a pale brown solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:21][OH:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.[CH2:32]([O:39][C:40]1[CH:50]=[CH:49][C:43]([O:44][CH2:45][C@@H:46]2[CH2:48][O:47]2)=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[CH2:32]([O:39][C:40]1[CH:41]=[CH:42][C:43]([O:44][CH2:45][C@@H:46]([OH:47])[CH2:48][NH:2][C@H:3]([CH2:21][OH:22])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:13])=[CH:9][CH:10]=2)=[CH:49][CH:50]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Reactant: N[C@H](CO)Cc1ccc(NC(=O)Nc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a solution of N-[4-[(2S)-2-amino-3-hydroxypropyl]phenyl]-N′-phenylurea hydrochloride (222 mg) in ethanol (5.0 ml) were added successively N,N-diisopropylethylamine (264 μl) and (2S)-2-[[4-(benzyloxy)phenoxy)methyl]oxirane (212 mg) and the solution was refluxed for 13.5 hours. After cooling to room temperature, the precipitates were collected by filtration, washed with ethanol, and dried under reduced pressure to give N-[4-[(2S)-2-[[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea (166 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[C:16](O)(=[O:18])[CH3:17].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:18][C:16](=[C:11]1[C:10](=[O:15])[CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:13][C:12]1=[O:14])[CH3:17]
Reactant: CC(=O)O
Reactant: Cc1ccccc1C1CC(=O)CC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CC(O)=C1C(=O)CC(c2ccccc2C)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.8 %

Procedure:
To a solution of 5-(2-methylphenyl)cyclohexane-1,3-dione (1.0 g), acetic acid (0.27 g) and dimethylaminopyridine (0.60 g) in dimethylformamide (45 ml) was added dicyclohexylcarbodiimide (1.0 g), and the mixture was stirred at room temperature for 12 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with potassium hydrogensulfate aqueous solution, and insoluble materials were filtered, to which was added 1N sodium hydroxide solution. The aqueous layer was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give, the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 2-(1-hydroxyethylidene)-5-(2-methylphenyl)cyclohexane-1,3-dione (0.69 g).
Reaction SMILES: [C:1]([N:5]([CH2:31][CH2:32][O:33][CH2:34][C:35]#[CH:36])[C:6](=[O:30])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH:22]([CH3:24])[CH3:23])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]1[C:25]([O:27]CC)=[O:26])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:31][CH2:32][O:33][CH2:34][C:35]#[CH:36])[C:6](=[O:30])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH:22]([CH3:24])[CH3:23])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]1[C:25]([OH:27])=[O:26])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: C#CCOCCN(C(=O)C(=O)N1CCc2cc(OC)c(OC(C)C)cc2C1C(=O)OCC)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C#CCOCCN(C(=O)C(=O)N1CCc2cc(OC)c(OC(C)C)cc2C1C(=O)O)C(C)(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
A solution of 280 mg of 18a in 4 ml of dioxane was mixed with 140 mg of KOH in 0.8 ml of water and stirred at 60° C. for 5 hr. The reaction mixture was cooled, diluted with 10 ml of water and acidified with cold 0.5N HCl. The product was extracted with ethyl acetate. The extract was washed twice with water, dried and concentrated, to give 264 mg of 18b as a colorless foam.
Reaction SMILES: C([O:3][C:4](=O)[C@:5]([O:11][CH2:12][C:13]([C:28]1[C:33]([F:34])=[CH:32][N:31]=[C:30]([Br:35])[CH:29]=1)([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.[NH3:37].CO>>[Br:35][C:30]1[CH:29]=[C:28]([C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])([CH3:14])[CH2:12][O:11][C@@:5]([CH3:10])([C:6]([F:7])([F:9])[F:8])[C:4]([NH2:37])=[O:3])[C:33]([F:34])=[CH:32][N:31]=1
Reactant: CCOC(=O)[C@@](C)(OCC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F)C(F)(F)F
Reactant: N
Solvent: CO
Product: CC(CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F

Procedure:
A solution of (R)-2-[(RS)-2-(2-Bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl ester (920 mg, 1.527 mmol) in 7N NH3/MeOH (11 ml) was stirred in a sealed glass vial at 55° C. for 44 h. The reaction mixture was evaporated to dryness to leave a yellow solid that was used for the next step without further purification (diastereomer mixture). RtH4=1.03 min; ESIMS: 573, 575 [(M+H)+]; 1H NMR (400 MHz, CDCl3): b 8.00 (m, 1H), 7.97-7.91 (m, 1H), 7.80-7.63 (m, 3H), 7.55 (m, 1H), 6.63 (m, 1H), 6.41 (m, 1H), 5.74 (m, 1H), 4.15 (m, 1H), 3.97 (m, 1H), 1.84 (2s, 3H), 1.69 (2s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][CH:3]1[OH:33].[CH3:34][O:35][C:36]1[CH:45]=[CH:44][C:39]([CH2:40][N:41]=[C:42]=S)=[CH:38][CH:37]=1.CI.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:9]([O:8][CH:7]1[CH:2]2[N:1]=[C:42]([NH:41][CH2:40][C:39]3[CH:44]=[CH:45][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)[O:33][CH:3]2[CH2:4][CH:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: COc1ccc(CN=C=S)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CNC2=NC3C(CC(COCc4ccccc4)C(OCc4ccccc4)C3OCc3ccccc3)O2)cc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 66.6 %

Procedure:
To a solution of Intermediate B (180 mg, 0.403 mmol) in dry THF (3 mL) was added a solution of 4-methoxybenzyl isothiocyanate (94%, 96 mg, 0.50 mmol) in dry THF (2 mL). The mixture was stirred at room temperature for 28 h. Solvents were evaporated under reduced pressure. The residue was dissolved in acetone (3 mL). MeI (114 mg, 0.805 mmol) was added. The mixture was stirred at room temperature for 2 h. Satd. aqueous NaHCO3 (2 mL) was added and stirred at room temperature for 10 min. The mixture was further diluted with satd. aqueous NaHCO3 (20 mL), extracted with EtOAc (2×15 mL). The combined extracts were washed with brine and dried over Na2SO4. Solvents were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 96:3:1 EtOAc-MeOH—NH4OH (28% aqueous) to give rac-(3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-N-(4-methoxybenzyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-2-amine (159 mg, 67%) as a syrup. 1H NMR (400 MHz, CDCl3) δ 7.37-7.25 (m, 15H), 7.21 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 4.80 (m, 1H), 4.79 (d, J=11.3 Hz, 1H), 4.77 (d, J=10.1 Hz, 1H), 4.66 (d, J=11.5 Hz, 1H), 4.45 (s, 2H), 4.44 (d, J=11.2 Hz, 1H), 4.35 (d, J=13.9 Hz, 1H), 4.25 (d, J=13.9 Hz, 1H), 4.07 (dd, J=7.9, 5.4 Hz, 1H), 3.76 (s, 3H), 3.64 (t, J=5.8 Hz, 1H), 3.56 (dd, J=10.2, 5.0 Hz, 1H), 3.51 (dd, J=8.2, 6.5 Hz, 1H), 3.47 (dd, J=9.1, 3.8 Hz, 1H), 2.17 (dt, J=14.7, 3.4 Hz, 1H), 2.06-1.97 (m, 1H), 1.88 (ddd, J=15.2, 12.1, 3.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])C)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrCC(C1C=CC=C2C=1N=C(NCC(F)(F)F)C(C)=N2)=O.C(OC(NCC(=O)CC(OCC)=O)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].C(OC(NCC(=O)C(CC(C1C=CC=C2C=1N=C(NCC(F)(F)F)C(C)=N2)=O)C(OCC)=O)=O)(C)(C)C>CN(C=O)C.CCO.CC(O)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][CH2:33][C:34]([F:35])([F:36])[F:37])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NCC(F)(F)F)nc12)C(=O)CNC(=O)OC(C)(C)C
Agent: CCOC(=O)CC(=O)CNC(=O)OC(C)(C)C
Agent: Cc1nc2cccc(C(=O)CBr)c2nc1NCC(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1CNC(=O)OC(C)(C)C
Yield: 55 %

Procedure:
This compound (380 mg, 0.75 mmol, 55% yield) as a yellow solid was prepared according to the procedure described for 293b, using 2-bromo-1-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)ethanone (616) (492 mg, 1.36 mmol), ethyl 4-((tert-butoxycarbonyl)amino)-3-oxobutanoate (601) (400 mg, 1.63 mmol) and K2CO3 (0.21 mL, 3.40 mmol) in DMF (2.75 mL), followed by subsequent treatment of the resulting ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate (301a) (530 mg, m/z (ESI, +ve) 527.2 (M+H)+) with NH4OAc (838 mg, 10.87 mmol) in 2 mL of EtOH and AcOH (1 mL) at 60° C. overnight. 1H NMR (400 MHz, CDCl3) δ ppm 7.92-7.98 (m, 1H), 7.68-7.74 (m, 1H), 7.44 (t, J=7.92 Hz, 1H), 7.11 (d, J=2.74 Hz, 1H), 5.44 (br. s., 1H), 5.18 (t, J=6.26 Hz, 1H), 4.56-4.65 (m, 2H), 4.54 (d, J=6.46 Hz, 2H), 4.33 (q, J=7.17 Hz, 2H), 2.63 (s, 3H), 1.35-1.43 (m, 12H). 19F NMR (376 MHz, CDCl3) δ ppm −70.89 (s, 3F). m/z (ESI, +ve) 508.1 (M+H)+.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:31][C@H:30]([CH2:32][N:33]4[N:37]=[N:36][CH:35]=[N:34]4)[O:29][C:28]3=[O:38])=[CH:23][C:22]=2[F:39])=[CH:17][CH2:16]1)C1C=CC=CC=1>ClCCl.C(N(CC)C(C)C)(C)C>[NH:15]1[CH2:20][CH2:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:31][C@H:30]([CH2:32][N:33]4[N:37]=[N:36][CH:35]=[N:34]4)[O:29][C:28]3=[O:38])=[CH:23][C:22]=2[F:39])=[CH:17][CH2:16]1
Reactant: O=C1O[C@@H](Cn2ncnn2)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1O[C@@H](Cn2ncnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
1-Chloroethyl chloroformate (1.18 g, 8.3 mM) was added dropwise, under an atmosphere of nitrogen, to a stirred solution of (5R)-3-(4-(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)-3-fluoro-phenyl)-5-(tetrazol-2-ylmethyl)oxazolidin-2-one (2.56 g, 5.90 mM) and N,N-diisopropylethylamine (0.230 mg, 1.77 mM) in dichloromethane (50 ml) with cooling in ice/water. The reaction was stirred for 30 minutes at ice temperature, and the brown solution purified by MPLC on silica, eluting with 75% ethyl acetate in isohexane. The resulting carbamate intermediate was dissolved in methanol (60 ml) and heated at 60° for 30 minutes. Evaporation of the solvent and trituration with diethyl ether gave the title compound (1.76 g) as its hydrochloride salt. MS (ESP): 345 (MH+) for C16H17FN6O2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[CH3:12].Br[C:14]1[CH:19]=[C:18]([CH2:20][O:21][CH2:22][CH3:23])[CH:17]=[C:16]([Br:24])[CH:15]=1.C([Li])CCC>>[Br:24][C:16]1[CH:15]=[C:14]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=2)([OH:11])[CH3:10])[CH:19]=[C:18]([CH2:20][O:21][CH2:22][CH3:23])[CH:17]=1
Reactant: COc1ccc(C(C)=O)cc1C
Reactant: CCOCc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Product: CCOCc1cc(Br)cc(C(C)(O)c2ccc(OC)c(C)c2)c1

Procedure:
In an analogous reaction sequence to that described for Building Block C, the treatment of 1-(4-methoxy-3-methyl-phenyl)-ethanone with 1,3-dibromo-5-ethoxymethyl-benzene beforehand reacted with n-butyllithium, yielded the (RS)-1-(3-bromo-5-ethoxymethyl-phenyl)-1-(4-methoxy-3-methyl-phenyl)-ethanol which was used as crude material in the following elimination reaction with a catalytic amount of p-toluenesulfonic acid to yield the title compound (yield: 86% of theory) as a colourless oil. Mass (calculated) C19H21BrO2 [360]; (found) [M+H]+=361, 363.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[C:27]([C:31]1[CH:36]=[C:35]([CH2:37][OH:38])[C:34]([CH3:39])=[CH:33][C:32]=1[S:40]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:27]([C:31]1[CH:36]=[C:35]([CH2:37][OH:38])[C:34]([CH3:39])=[CH:33][C:32]=1[S:40][C:3]1[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[CH2:7][C:2]=1[OH:1])([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2cccc(O)c2)(CCc2cccc(O)c2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccc(O)c3)(CCc3cccc(O)c3)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The compound was synthesized following General Method 9 and using 172 mg (0.5 mmol) of 4-hydroxy-6,6-bis-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example XX), 179 mg (0.5 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF), 270 mg (2.0 mmol) of K2CO3, and 2 mL of DMF. The reaction was worked up as described and chromatographed on silica get eluting with (1:1 CH2Cl2 :EtOAc+2% MeOH), to yield the title compound, m.p. 92-94° C. 1H NMR (DMSO-d6) δ 1.48 (s, 9 H), 1.80 (s, 3 H), 2,07 (m, 4 H), 2.6 (m, 4 H), 3.0 (s, 2 H), 4.35 (s, 2 H), 6.6 (m, 6 H), 6.65 (s, 1 H), 7.05 (t, 2 H), 7.25 (s, 1 H), 9.25 (s, 2 H).