Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])O.N1C(C)=CC=CC=1C.FC(F)(F)S(O)(=O)=O.[F:24][C:25]1[C:31]([F:32])=[C:30]([F:33])[CH:29]=[CH:28][C:26]=1[NH2:27].Cl>ClCCl>[F:24][C:25]1[C:31]([F:32])=[C:30]([F:33])[CH:29]=[CH:28][C:26]=1[NH:27][C@@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: COC(=O)[C@@H](C)O
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Under ice-cooling, methyl D-lactate (8.5 g) and 2,6-lutidine (11.4 g) were dissolved in dichloromethane (100 ml). After dropping anhydrous trifluoromethanesulfonic acid (25.4 g), the mixture was heated to room temperature and stirred for 30 minutes. Then it was cooled to 0° C. again and a solution (30 ml) of 2,3,4-trifluoroaniline (12.0 g) in dichloromethane was dropped therein to. The mixture was stirred at the same temperature for 17 hours. To the resultant solution, hydrochloric acid (0.5 mol/l) was added and the mixture was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered. After evaporating the solvent, the residue thus obtained was subjected to silica gel column chromatography. Thus, 17.1 g (90%) of the title compound was obtained as an oily substance. The optical purity determined by HPLC was 97% ee.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]1>>[CH3:6][N:7]1[C:11]([CH3:12])=[C:10]([S:2]([Cl:1])(=[O:5])=[O:3])[C:9]([C:13]([F:14])([F:16])[F:15])=[N:8]1
Reactant: Cc1cc(C(F)(F)F)nn1C
Reactant: O=S(=O)(O)Cl
Product: Cc1c(S(=O)(=O)Cl)c(C(F)(F)F)nn1C
Reaction time: 3 h

Procedure:
To 53 mls of chlorosulfonic acid at 10 C. was added dropwise over fifteen minutes 1,5-dimethyl-3-(trifluoromethyl)pyrazole (24.0 grams). No significant exotherm resulted and after 15 minutes the cooling bath was removed and the reaction was heated to 110 C. for three hours. After standing overnight, the reaction was heated to 110 C. for an additional four hours and allowed to cool to 50 C. Then 19.0 g of thionyl chloride was dropwise over fifteen minutes. The reaction was then heated to 80 C. for twenty minutes and 110 C. for one hour. After cooling, the reaction was cautiously added to 600 g of ice. The aqueous phase was extracted with two 250 ml portions of ether. The combined organic extracts were dried with MgSO4 and concentrated under reduced pressure to yield 7.8 g of the desired product as a tan oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][CH2:12][C:13](=O)[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=1.[C:22]([S-:24])#[N:23].[K+].O.[OH-].[Na+]>CC(O)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:12]=[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:23]=[C:22]2[SH:24])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(NCC(=O)c2cccnc2)c1
Reactant: N#C[S-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2cc(-c3cccnc3)nc2S)c1
Temperature: 100 °C
Yield: 94.3 %

Procedure:
A mixture of 4-methyl-3-(2-oxo-2-pyridin-3-yl-ethylamino)-benzoic acid methyl ester (84.5 mg, 0.297 mmol) and KSCN (58 mg; 0.59 mmol) in 1.5 mL of HOAc were heated to 100° C. for 2 h. The mixture was then poured into water and carefully brought to pH 8 with NaOH. The mixture was immediately extracted with EtOAc, and the extract washed with brine. The washes were extracted once more with EtOAc, and the combined extracts were dried with Na2SO4, filtered, and concentrated to provide 3-(2-mercapto-4-pyridin-3-yl-imidazol-1-yl)-4-methyl-benzoic acid methyl ester (90 mg, 0.28 mmol; 93%). ESI MS m/z 326 [C17H15N3O2S+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=O.C([BH3-])#N.[Na+]>CO.CC(O)=O>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: CCOC(=O)C=O
Reactant: COc1cc(Cl)c(I)cc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CNc1cc(I)c(Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.8 %

Procedure:
To a solution of 4-chloro-5-iodo-2-methoxybenzenamine (6 g, 21.2 mmol) in MeOH (50 mL) at room temperature, AcOH (3 drops) and ethyl glyoxalate (5.6 g, 27.5 mmol, 50% in toluene) were added. The mixture was stirred at room temperature for 2 h and then sodium cyanoborohydride (5.32 g, 84.8 mmol) was added to the mixture. The resulting mixture was stirred at 50° C. for 16 h. The mixture was allowed to cool to room temperature, and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product (8.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:5][CH:4]=1.[CH2:17]=O.Cl.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>C(O)(C)C>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:16])[CH:14]([CH3:17])[CH2:15][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: CCC(=O)c1ccc(OC)c2c1CCCC2
Reactant: C1CCNC1
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(C(=O)C(C)CN2CCCC2)c2c1CCCC2
Yield: 83.9 %

Procedure:
A mixture of 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-1-propanone (4.37g), paraformaldehyde (1.80g), pyrrolidine hydrochloride (3.23g), and hydrochloric acid (0.2 ml) in isopropyl alcohol (50 ml) was refluxed for 8 hours. The reaction mixture was evaporated in vacuo to give the residue. The residue was partitioned into water and ethyl ether. The aqueous layer was extracted, neutralized with ammonia water, and then extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was evaporated in vacuo to give 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-2-methyl-3-pyrrolidino -1-propanone. (5.06; yield: 83.9%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[CH:12]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[CH:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cnc2[nH]ccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
Benzenesulfonyl chloride (1b) (98.7 g) was added dropwise into a solution of 7-azaindole (1a) (60.0 g) and triethylamine (56.6 g) in DCM (500 mL) at 0° C. The mixture was warmed to rt and stirred for 2 days to produce a white crystalline product. The white crystals were filtered off and the solution was washed with a saturated aqueous NaHCO3 solution and brine, then dried over MgSO4 and concentrated. The residue was recrystallized in ethyl acetate (200 mL) to provide N-phenylsulfonyl-7-azaindole (1c) (121.31 g, 94%) as white crystals. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=4.8 Hz, 1H), 8.18 (d, J=8.0 Hz, 2H), 7.85 (d, J=8.0 Hz, 1H), 7.73 (d, J=4.8 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.48 (t, J=7.6 HZ, 2H), 7.15 (dd, J=8.0 Hz, 4.8 Hz, 1H), 6.58 (d, J=4.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[C:21]3[O:23][CH2:24][O:25][C:20]3=[CH:19][C:18]=2[N+:26]([O-])=O)[CH2:12]1)=[O:9])=[O:5]>[Pd].CO>[NH2:26][C:18]1[CH:19]=[C:20]2[O:25][CH2:24][O:23][C:21]2=[CH:22][C:17]=1[CH2:16][N:13]1[CH2:14][CH2:15][C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][NH:6][C:4](=[O:5])[C:3]2[CH:29]=[C:30]([C:33]([F:35])([F:34])[F:36])[CH:31]=[CH:32][C:2]=2[NH2:1])[CH2:12]1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2cc3c(cc2[N+](=O)[O-])OCO3)C1
Agent: [Pd]
Solvent: CO
Product: Nc1cc2c(cc1CN1CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C1)OCO2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine (30.5 mg), 10% Pd-activated carbone (6 mg), and methanol (3 mL) was stirred under a hydrogen atmosphere at room temperature for 10 h. The Pd catalyst was filtered off through Celite, and the filtrate was concentrated. Solid phase extraction (Bond Elut™ SI, 20% methanol/AcOEt) afforded (R)-1-(2-amino-4,5-methylenedioxybenzyl)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 2127) (21.9 mg, 76%): The purity was determined by RPLC/MS (95%); ESI/MS m/e 480.1 (M++H, C22H24F3N5N4).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1([CH2:29][CH2:30]Cl)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:30][CH2:29][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(-n2c(-c3ccc(OCCN4CCCCC4)cc3)nc3ccccc32)cc1

Procedure:
The title compound was prepared by reacting the compound of Example 29 with 2-(piperdin-1-yl)ethyl chloride in acetone and potassium carbonate as previously described. mp 107° C., NMR, MS 397.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Cl[C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH2:24][OH:25])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:26])[CH2:7]1.[Li].N.C(O)C>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[OH:25][CH2:24][C@@:21]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:26])[CH2:14][CH2:13]4)[CH2:10][CH:9]=[C:8]1[CH2:7][CH2:6][CH2:23][CH2:22]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](Cl)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H](CC=C4CCCC[C@@]43CO)[C@@H]1CCC2=O
Reaction time: 2 h

Procedure:
A solution of 3β-chloro-19-hydroxy-5-androsten-17-one acetate in anhydrous tetrahydrofuran is added with stirring to a solution of lithium in liquid ammonia. After approximately two hours of stirring, 95% ethanol is added via dropwise addition. The residue obtained after evaporation of the ammonia is treated with water and ether. The ether extract is washed with water, dried over magnesium sulfate and concentrated under vacuum. The residue which remains is crystallized from an acetone-hexane solution to yield 19-hyroxy-5-androsten-17-one acetate.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[CH:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[C:27][C:2]3[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=3)=[N:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CC(O)COc1ccc(I)cc1
Product: CC(O)COc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
Prepared according to general working method I from 1-(4-iodo-phenoxy)-propan-2-ol (2.00 g, 7.19 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (1.54 g, 7.20 mmol).
Reaction SMILES: C([CH:3]([C:7]([NH2:9])=[O:8])[C:4]([O-:6])=[O:5])C.C(O[CH:13]=[C:14]([C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.[C:27]([O-])(=O)[CH3:28].[Na+]>C(O)C>[CH2:25]([O:24][C:22]([C:20]1[NH:9][C:7](=[O:8])[C:3]([C:4]([O:6][CH2:27][CH3:28])=[O:5])=[CH:13][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:23])[CH3:26]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Reactant: CCC(C(N)=O)C(=O)[O-]
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(C(=O)OCC)c(=O)[nH]c1C(=O)OCC
Temperature: 0 °C
Yield: 80.3 %

Procedure:
A solution of ethylmalonamate (23.6 g, 0.18 mol) in absolute ethanol (300 mL) is added to a stirred solution of diethyl ethoxymethyleneoxalacetate (44.0 g, 0.18 mol) in ethanol (200 mL) at 0° C., followed by the addition, of solid sodium acetate (14.72 g, 0.18 mol). After stirring for ten minutes at 0° C., the mixture is heated to reflux and stirred for 13.5 hours. After cooling, the ethanol is removed under vacuum, and the residue diluted with water and acidified to pH 2 with concentrated hydrochloric acid. The aqueous solution is extracted with methylene chloride (2×200 mL) and the organic layer washed with 300 mL saturated sodium chloride, then dried over anhydrous magnesium sulfate and concentrated in vacuum to give 45.0 g of the title product as an orange oil.
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)(=O)=O.[CH3:19][C:20]1[C:25](O)=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(C(F)(F)F)=O>ClCCCl.CN(C=O)C>[CH3:19][C:20]1[C:25]([O:5][CH:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Cc1ncccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ncccc1OC1CCNCC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.1 g), 2-methylpyridin-3-ol (500 mg), potassium carbonate (1.7 g), and DMF (10 ml) were mixed, followed by stirring at 100° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with DCE (10 ml), and TFA (4.5 g) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a 1M aqueous NaOH solution were the added thereto, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain 2-methyl-3-(piperidin-4-yloxy)pyridine (355 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[F:10].P(Br)(Br)[Br:12].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[CH:4][C:3]=1[F:10]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(CBr)ccc1Br
Temperature: 20 °C
Yield: 61 %

Procedure:
To a solution of (4-bromo-3-fluorophenyl)methanol (5 g, 24.39 mmol) in DCM (100 mL) was added PBr3 (2.76 mL, 29.3 mmol) dropwise. The resulting mixture was stirred at 20° C. After LCMS analysis showed the starting material had disappeared, the mixture was adjusted to pH=8 by aqueous Na2CO3. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography (PE/EA=10/1) to yield a white solid of 1-bromo-4-(bromomethyl)-2-fluorobenzene (4.2 g, 14.89 mmol, 61.1% yield): 1H NMR (400 MHz, CD3OD) δ 7.57 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.16 (d, J=6.4 Hz, 1H), 4.53 (s, 2H); ES-LCMS m/z 186.9 (M−79).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][C@@H:39]([OH:41])[CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][C@@H:39]([OH:41])[CH3:40])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Product: C[C@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-1-amino-2-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.08-1.13 (m, 3 H), 1.55 (d, J=2.74 Hz, 4 H), 1.63 (s, 2 H), 1.65-1.78 (m, 2 H), 2.41 (d, J=10.11 Hz, 2 H), 3.19 (s, 1 H), 3.38 (d, J=6.95 Hz, 5 H), 3.81 (s, 1 H), 4.16-4.25 (m, 4 H), 4.96 (d, J=4.63 Hz, 1 H), 7.11-7.17 (m, 2 H), 7.38-7.44 (m, 2 H), 8.00 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.44 (t, J=6.21 Hz, 1 H), 17.21 (s, 1 H); ES+ MS: 525 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[ClH:27].[C:28]([Cl:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[OH2:8].[ClH:36].[ClH:27].[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:28]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:35])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O
Product: O=C(NCCN1CCC(c2noc3cc(F)ccc23)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (1.17 g, 4.34 mmol) and triethylamine (1.08 g, 10.8 mmol) in chloroform (30 ml) was added nicotinoyl chloride hydrochloride (0.96 g, 5.4 mmol) in one portion. The mixture was stirred for 1 hour at room temperature. The solution was diluted with methylene chloride (DCM) and washed with brine and dried over anhydrous MgSO4. The solution was concentrated and the crude product was purified by flash chromatography over a silica gel column (SiO2, 25 g; eluted with DCM and 1-3% MeOH in DCM). The free base thus purified weighed 1.7 g. This product was treated with 1M.HCl in ethanol and recrystallized twice from methanol:isiproply ether to yield white crystals, 1.19 g, m.p. 243°-245° C. as a dihydrochloride hydrate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2F)cc1
Yield: 86 %

Procedure:
Prepared in analogy to example 8 from 4-nitrophenol and 2,4-difluoro-benzylbromide. Colorless solid. Yield=86%. MS: m/e=265.1 (M+).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15]Br>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:15][C:14]2[CH:17]=[CH:18][C:19]([F:20])=[C:12]([F:11])[CH:13]=2)[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: Nc1cc(O)nc(S)n1
Solvent: O
Product: Nc1cc(O)nc(SCc2ccc(F)c(F)c2)n1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step 1) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (2.0 g) with 3,4-difluorobenzyl bromide (2.66 g) to afford the subtitle compound as a white solid. Yield: 3.35 g. 1H NMR. δ(DMSO) 7.54 (1H, m), 7.32 (2H, m), 6.58 (2H, bs), 4.96 (1H, bs), 4.29 (2H, s).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.Cl>C(Cl)Cl.O1CCOCC1>[NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(N)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)[C@@H](N)Cc1cccnc1

Procedure:
Suspend Boc-(L)-Pal-NH2 (0.98 g) in methylene chloride (15 mL) with light heating and add a solution of hydrochloric acid (4M, 10 mL) in dioxane. After 30 minutes evaporate methylene chloride and dioxane. Dissolve the solid in methanol, precipitate by addition of ether and filtrate to give H-(L)-Pal-NH2. 2HCl (0.86 g, 98%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[C:15](Cl)(=[O:17])[CH3:16].B(Cl)(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:15]([C:4]1[CH:5]=[C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:8][C:3]=1[OH:2])(=[O:17])[CH3:16]
Reactant: COC(=O)C(C)c1ccc(OC)cc1
Reactant: CC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)c1ccc(O)c(C(C)=O)c1
Reaction time: 0.17 h

Procedure:
Titanium tetrachloride (82.3 mls) was added dropwise to a stirred solution of methyl 2-(4-methoxyphenyl)propionate (25 g) in dry dichloromethane (250 mls), cooled in an ice/salt-bath, at a rate sufficient to maintain the temperature between -10° C. and -5° C. The mixture was stirred for 10 minutes and acetyl chloride (10 g) was added dropwise at a rate sufficient to maintain the temperature below 0° C. The solution was stirred at -5° C. for 11/2 hours when boron trichloride (15 mls) was added. Stirring was continued for 1/2 hour at +3° C. before pouring on to crushed ice/concentrated hydrochloric acid and separating the two phases. The aqueous phase was extracted with ether (3x) and the combined organic extracts were washed with saturated sodium bicarbonate solution, saturated brine solution, and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded the crude product as a pale yellow oil. Vacuum distillation furnished a pale yellow oil bp 120°-125° C./0.15 mm (16.2 g; 59%)
Reaction SMILES: [O:1]1[O:3][CH2:2]1.[C:4]([N:12]=[C:13]=[O:14])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C[OH:16]>>[NH2:12][CH:4]([CH2:2][OH:3])[CH2:5][OH:16].[C:4]([NH:12][C:13](=[O:1])[O-:14])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CO
Reactant: C1OO1
Reactant: O=C=NC(=O)c1ccccc1
Product: NC(CO)CO
Product: O=C([O-])NC(=O)c1ccccc1

Procedure:
Alternatively, an enantiomeric 2-aminopropane-1,3-diol of the present invention is prepared by reducing a trans-propenoate 83, prepared from an appropriate aldehyde and a (carbalkoxymethylene)triphenylphosphorane in a conventional Wittig reaction, is reduced to a carbinol 84 and epoxidized under asymmetric conditions to an epoxycarbinol 85, which in turn, is condensed with a benzoylisocyanate to provide a benzoylcarbamate, 86 cyclized to an oxazolidinone 87, and cleaved to an aminopropanediol 88.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]([Cl:16])([CH3:15])[CH:13]=O.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:13]([NH:9][C:7](=[O:8])[C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[C:12]([Cl:16])([Cl:11])[CH3:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1ccc(C(N)=O)cc1
Reactant: CC(Cl)(Cl)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1ccc(C(=O)NC(n2nnc3ccccc32)C(C)(Cl)Cl)cc1

Procedure:
A suspension of p-toluamide, 2,2-dichloropropionaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 53A to provide the desired product.