Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[CH3:11])=[N:3]2)=[N:7][CH:8]=1
Reactant: Cc1ccncc1B(O)O
Reactant: Brc1nn2c(I)cnc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccncc1-c1nn2c(I)cnc2s1
Temperature: 110 °C
Yield: 96.1 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (50 mg, 0.152 mmol), 4-methylpyridine-3-boronic acid (23 mg, 0.167 mmol), PdCl2(dppf) (25 mg, 0.03 mmol) and sat. aq. K2CO3 (0.25 ml) in dioxane (0.5 mL) was heated at 110° C. overnight. The reaction mixture was cooled, diluted with DCM and washed with water. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (MeOH/DCM, 0% to 40%) to give the desired product (50 mg, 96%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=3.75 min, [M+H]+ m/z 343.1.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][N:7]([CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[C:6](=[O:15])[CH2:5]1)[CH2:2][CH3:3].[Cl:16]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C1COCC1>[Cl:16][C:14]1[N:10]([CH2:9][N:7]2[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]2=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCC1CC(=O)N(Cn2cccc2)C1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC1CC(=O)N(Cn2cccc2Cl)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4-propyl-1-(1H-pyrrol-1-ylmethyl)pyrrolidin-2-one x264 (0.182 g, 0.88 mmol) is dissolved in absolute THF (3 ml). A solution of N-chlorosuccinimide (0.118 g, 1 eq) in absolute THF (1 ml) is added dropwise in a flow of argon at 0° C. The obtained solution is allowed to heat up slowly to room temperature in the cooling bath under stirring for 16 h. CCl4 (30 ml) is then added to the obtained solution. A small amount of a precipitate is filtered off, and the filtrate is evaporated. 1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one 299 is isolated from the residue by reverse-phase HPLC (eluent: acetonitrile/water).
Reaction SMILES: C(O[C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)(C)(C)C.Cl.[N:23]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28][C@H:24]1C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CN(C=O)C.C(OCC)(=O)C>[C:34]([O:33][C:31]([N:23]1[CH2:30][CH2:29][CH2:28][CH:24]1[C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Br)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
(4′-Bromo-biphenyl-4-yl)-carbamic acid tert-butyl ester (407 mg, 1.17 mmol) was dissolved in methanol (10 mL) and concentrated HCl (2 mL) was added. The solution was stirred at 60° C. for 1 hour then concentrated. The crude residue was treated with Boc-Pro-OH (302 mg, 1.40 mmol) and HATU (578 mg, 1.52 mmol) and suspended in DMF (6 mL). DIPEA (1.02 mL, 5.85 mmol) was added and the reaction mixture was stirred at RT for 4 hours after which it was diluted with ethyl acetate (200 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica column chromatography (30% to 55% EtOAc/hexanes) to afford 2-(4′-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (496 mg, 95% over 2 steps).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:34]=[CH:33][C:23]([NH:24]C(=O)C2C=CC=CC=2)=[N:22][C:20]1=[O:21])(=O)C.[NH4+].[OH-].C(O)C>CO>[C@@H:6]1([N:19]2[CH:34]=[CH:33][C:23]([NH2:24])=[N:22][C:20]2=[O:21])[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In methanol (50 ml) is dissolved 2',3',5'-tri-O-acetyl-N4 -benzoylcytidine (0.53 g) followed by addition of concentrated NH4OH (5 ml) with stirring at 70° C. The mixture is stirred at 70° C. for 2.5 hours, at the end of which time ethanol is added. The mixture is allowed to stand at room temperature overnight to give colorless needles of cytidine. Yield 0.26 g (95.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:36][C@H:34]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)[CH3:35]
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H](Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccc(F)cc1
Yield: 58.2 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (7.0 g, 16.4 mmol) with (S)-1-(4-fluorophenyl)ethylamine (6.9 g, 49.3 mmol) in toluene (175 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to give 7-chloro-6-[1-(S)-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.96 g, 58%). GC-MS m/z: 414 (M+).
Reaction SMILES: Cl.C1(C[O:6][C:7]2[C:8]([O:27][CH3:28])=[CH:9][CH:10]=[C:11]3[C:16]=2[NH:15][C:14](=[O:17])[CH:13]=[C:12]3[NH:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=2[Cl:26])CC1>CO>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:12]1[C:11]2[C:16](=[C:7]([OH:6])[C:8]([O:27][CH3:28])=[CH:9][CH:10]=2)[NH:15][C:14](=[O:17])[CH:13]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCC1CC1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Temperature: 50 °C

Procedure:
Concentrated HCl (15, ml) was added to a solution of 8-(cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (1.2 g, 2.90 mmol, Example 3) and methanol (8, ml). The reaction mixture was heated at 50° C. for 4 h and then concentrated. The residue was neutralized with saturated NaHCO3, filtered (washed with ethanol and ether), and dried to give 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one: MS (ESI): 352.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:13][CH2:14][S:15][C:16](=[O:18])[CH3:17])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].C1[C@@H](CCC[CH2:27][C:28](O)=[O:29])SSC1.SC(CCS)CCCCC(O)=O>>[C:28]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:13][CH2:14][S:15][C:16](=[O:18])[CH3:17])(=[O:29])[CH3:27]
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Reactant: CC(=O)SCCC(CCCCC(=O)O)SC(C)=O
Agent: O=C(O)CCCCC(S)CCS
Product: CC(=O)OC(=O)CCCCC(CCSC(C)=O)SC(C)=O

Procedure:
6,8-bisacetylmercaptooctanoic (henceforth referred to as bis-acetyl lipoic acid) was prepared from commercially available—lipoic acid using a three step procedure. These steps were as follows: Lipoic acid was first reduced to 6,8-bismercaptooctanoic acid which was then acetylated to produce 6,8-bisacetylmercaptooctanoic acetic anhydride. This 6,8-bisacetylmercaptooctanoic acetic anhydride was then selectively hydrolyzed to produce the 6,8-bisacetylmercaptooctanoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:46])[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:19]4=[O:43])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.C(O)(=O)C>O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:46])[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[NH:20][C:19]4=[O:43])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(Cl)nc21
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Cl)nc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 1.16 g of 5-{4-(5-chloro-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 45) and 16 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. The product was crystallized by trituration with ethyl acetate, to give 0.38 g of the title compound, melting at 222°-223° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH:16]([CH2:18][C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([CH:29]=[O:30])=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH:16]([CH2:18][C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([CH:29]=[O:30])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C=O)c3c2C(Cc2cccc4ccccc24)CCC3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1nn(-c2ccc(O)cc2)c2c1CCCC2Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
1-(4-Methoxyphenyl)-7-[(naphthyl)methyl]-4,5,6,7-tetrahydro-1H-indazole-3-carboxaldehyde (CP 325, 3.44 g, 8.68 mmol) and 26 mL of a 1.0M solution of BBr3 in CH2Cl2 (26 mmol) were combined and stirred at room temperature for 3 h. Additional CH2Cl2 was added and the solution was washed with water and brine. The mixture was concentrated and purified by MPLC using a solvent gradient ranging from 20-25% EtOAc:hexanes to give 0.40 g (12%) of the title compound as a white solid, m.p. >260° C.; 1H NMR (DMSO-d6, 300 MHz) 1.50 (m, 2H), 1.75 (m, 1H), 1.95 (m, 1H), 2.60 (m, 1H), 2.77 (t, 1H, J=12.7), 2.94 (broad d, 1H, J=13.6), 3.06 (broad d, 1H, J=10.8), 3.25 (m, 1H), 6.90 (d, 1H, J=8.5), 7.09 (d, 2H, J=8.7), 7.21 (d, 1H, J=6.5), 7.28 (t, 1H, J= 7.1), 7.4 (t, 1H, J=7.6), 7.47 (t, 1H J=7.4), 7.54 (d, 2H , J=8.7), 7.76 (d, 1H, J=8.2), 7.87 (d, 1H, J=7.9); IR (KBr) 3100 (broad), 1696, 1519 cm-1 ; MS (DCI) m/z 383 (base), 241. Anal. Calcd. for C26H26N2O2 : C, 78.63; H, 6.58; N, 7.03. Found: C, 78.23; H, 6.53; N, 6.99.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([NH:10]/[N:11]=[C:12]1/[CH:13]=[CH:14][C:15]2([CH2:31][CH2:32]/1)[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:17][CH2:16]2)([CH3:9])([CH3:8])[CH3:7].[CH3:33]N(C)C=O>>[C:6]([N:10]1[CH:33]=[C:32]2[C:12]([CH:13]=[CH:14][C:15]3([CH2:31]2)[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:19][CH2:20]3)=[N:11]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)N/N=C1/C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)n1cc2c(n1)C=CC1(CCN(C(=O)OCc3ccccc3)CC1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
(E)-benzyl 9-(2-tert-butylhydrazono)-3-azaspiro[5.5]undec-7-ene-3-carboxylate hydrochloride salt (8.00 g, 19.7 mmol) was dissolved in dichloromethane (100 mL) and treated with sodium bicarbonate (1.70 g, 19.7 mmol). The solution was stirred for 30 minutes and was then filtered and concentrated under reduced pressure to yield (E)-benzyl 9-(2-tert-butylhydrazono)-3-azaspiro[5.5]undec-7-ene-3-carboxylate. A 250 mL round bottom flask was charged with dimethylformamide (80 mL) and cooled to 0° C. Phosphorous oxychloride (5.51 mL, 59.1 mmol) was added dropwise over 2 minutes, and the solution was stirred for 30 minutes at 0° C. To this solution was added the (E)-benzyl 9-(2-tert-butylhydrazono)-3-azaspiro[5.5]undec-7-ene-3-carboxylate in dimethylformamide (15 mL) and the reaction was heated at 80° C. for 18 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The resultant oil was dissolved in ethyl acetate (500 mL) and washed with brine (2×150 mL). The aqueous layer was extracted with an additional 100 mL ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by flash column chromatography (10-80% ethyl acetate/heptane) to yield 4.89 g (65%) of the title compound as a pale yellow oil. +ESI (M+H) 380.0; 1H NMR (400 MHz, CDCl3, δ): 7.25-7.36 (m, 5 H), 7.18 (s, 1 H), 6.57 (d, J=10.0 Hz, 1 H), 5.86 (d, J=10.0 Hz, 1 H), 5.12 (s, 2 H), 3.51-3.69 (m, 2 H), 3.36-3.53 (m, 2 H), 2.58 (s, 2 H), 1.59-1.74 (m, 2 H), 1.52-1.58 (m, 9 H), 1.41-1.53 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH2:16])[CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[Cl:15])[NH:8][CH:7]=1.[CH2:18]=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[NH:16][CH2:18][C:7]2[NH:8][C:9]3[N:10]=[CH:11][CH:12]=[C:13]([Cl:15])[C:14]=3[C:6]=2[CH2:5]1)=[O:17]
Reactant: COC(=O)C(N)Cc1c[nH]c2nccc(Cl)c12
Reactant: C=O
Solvent: c1ccncc1
Product: COC(=O)C1Cc2c([nH]c3nccc(Cl)c23)CN1
Temperature: 100 °C

Procedure:
A suspension of 2-amino-3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid methyl ester (3.5 g, 10 mmol) in pyridine (25 mL) was treated with formaldehyde solution (37% in water, 0.90 mL) and the resulting mixture was heated to 100° C. for 1.25 hours. The mixture was allowed to cool to ambient temperature then evaporated in-vacuo. The resultant residue was treated with saturated aqueous sodium carbonate solution (15 mL) and the resultant solid collected by filtration and washed with water (20 mL). The filtrate was extracted with 20% methanol in dichloromethane (6×25 mL). The combined organic phase was combined with solid and concentrated in-vacuo to afford the title compound as a brown residue (2.1 g, 87%). LCMS (Method B): RT=2.36 min, M+H+=266. 1H NMR (400 MHz, DMSO-d6): 11.66 (s, 1H), 8.02 (d, J=5.2 Hz, 1H), 7.06 (d, J=5.1 Hz, 1H), 4.01-3.71 (m, 3H), 3.69 (s, 3H), 3.19 (dd, J=15.4, 4.7 Hz, 1H), 2.94 (dd, J=15.4, 8.9 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([NH2:10])=O)[NH:6][CH:7]=1)#[N:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:20]2)=CC=1>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:8](=[S:20])[NH2:10])[NH:6][CH:7]=1)#[N:2]
Reactant: N#Cc1c[nH]c(C(N)=O)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1c[nH]c(C(N)=S)c1
Temperature: 100 °C
Yield: 60.1 %

Procedure:
A mixture of 4-cyanopyrrole-2-carboxamide (1.35 g, 10.0 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (4.0 g, 9.9 mmol) in toluene is heated at 100° C. for 41/2 hours, diluted with tetrahydrofuran and heated at reflux for 20 minutes. The reaction mixture is then cooled and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 4:1 hexanes/ethyl acetate mixture gives the title product as a yellow solid (0.9 g, mp 253° C. dec.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4](Cl)[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)C>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:3]=1
Reactant: C1COCCN1
Reactant: Cc1nc(Cl)nc(N)c1[N+](=O)[O-]
Solvent: CCO
Product: Cc1nc(N2CCOCC2)nc(N)c1[N+](=O)[O-]
Temperature: 82 °C
Reaction time: 16 h

Procedure:
To pressure vessel, a mixture of commercially available 4-amino-2-chloro-6-methyl-5-nitropyrimidine (2.00 g, 10.6 mmol) and morpholine (1.85 mL, 21.2 mmol) in absolute ethanol (40 mL) was stirred at 82° C. for 16 hours. Absolute ethanol was evaporated in vacuo and the crude product was dissolved in a mixture of THF:EtOAc and this then subjected on top of a silica gel pad. Elution with EtOAc gave, after evaporation, the title compound as a yellow solid (2.47 g, 97%): IR (KBr, cm−1) 3468, 3307, 1615, 1560, 1247; 1H NMR (400 MHz, DMSO) δ 7.96 (s, 2H), 3.77 (br s, 4H), 3.62-3.60 (m, 4H), 2.53 (s, 3H); LCMS (+ESI, M+H+) m/z 240; HPLC: 100% (220 nm).
Reaction SMILES: [C:1]([O:20][CH2:21][C@@H:22]([OH:31])[CH2:23][CH2:24][C:25]([CH:29]=[CH2:30])(O)[CH:26]=[CH2:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.O>N1C=CC=CC=1>[C:1]([O:20][CH2:21][C@@H:22]1[O:31][C:25]([CH:26]=[CH2:27])([CH:29]=[CH2:30])[CH2:24][CH2:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(O)(C=C)CC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=CC1(C=C)CC[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
13.0 g of (2S)-1-(trityloxy)-5-vinyl-6-heptene-2,5-diol and 57.2 g of toluenesulfonyl chloride were dissolved in 200 ml pyridine, and stirred at 80° C. overnight. After the reaction was completed, water was added thereto, and it was stirred at room temperature for 10 min. After extracting twice with ethyl acetate, washed with brine, and dried over magnesium sulfate. The solvent was removed, and the resulting residue was dissolved in toluene. After the solvent was removed again, the resulting residue was purified by silica gel column chromatography to give 5.88 g of (5R)-5-[(trityloxy)methyl]-2,2-divinyltetrahydrofuran.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH2:39]C)[CH:33]=2)[CH:27]=1)=O)(C)(C)C.[C:43](O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:19])([F:20])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH2:39][CH3:43])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(CC)c3)c2)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(CC)c3)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M230) (282 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (205 mg, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:14])[C@H:11](O)[CH3:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([C@:10]2([OH:14])[O:49][CH2:48][C:47]([CH3:51])([CH3:50])[NH:46][C@H:11]2[CH3:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(N)CO
Reactant: C[C@@H](O)C(=O)c1cccc([N+](=O)[O-])c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1cccc([N+](=O)[O-])c1
Yield: 17.9 %

Procedure:
Compound 4g was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-nitrophenyl)-2-hydroxypropan-1-one (10g, 4.0 g, 0.021 mol), Proton sponge (5.2 g, 0.0246 mol), triflic anhydride (3.7 mL, 0.023 mol), and 2-amino-2-methyl-1-propanol (4.0 g, 0.045 mol) in acetonitrile (45 mL). After purification, 1.0 g (18%) of the free base 4g was isolated and converted to the hemi-D-tartrate salt, which had 94% ee: mp 192-193° C.; [α]20D +6.5° (c 1.0, CH3OH); 1H NMR (methanol-d4) δ 8.47-8.25 (m, 1H), 8.31-8.26 (m, 1H), 8.05-8.01 (m, 1H), 7.73-7.66 (m, 1H), 4.34 (s, 1H), 4.18 (d, 1H, J=12.1 Hz), 3.59 (d, 1H, J=6.6 Hz), 3.50 (q, 1H, J=6.6 Hz), 1.60 (s, 3H), 1.35 (s, 3H), 1.07 (d, 3H, J=6.6 Hz); 13C NMR (methanol-d4) δ 178.3, 149.9, 145.3, 134.4, 131.0, 125.0, 123.0, 96.8, 75.0, 68.1, 54.8, 24.7, 21.7, 14.6; LCMS (ESI) m/z 267.3 [(M-tartrate)', M=C15H21N2O7]; Anal. (C15H21N2O7.0.25H2O) calcd: C, 52.09; H, 6.27; N, 8.10. found: C, 52.13; H, 6.22; N, 8.06.
Reaction SMILES: BrC1C=C2C(=CC=1OCCCCC)C(C)(C)CCC2(C)C.C([Li])(C)(C)C.C(=O)=O.[CH2:30]([O:35][C:36]1[C:37]([C:50]([OH:52])=[O:51])=[CH:38][C:39]2[C:40]([CH3:49])([CH3:48])[CH2:41][CH2:42][C:43]([CH3:47])([CH3:46])[C:44]=2[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH3:34].O[C:54]1[CH:69]=[CH:68][C:57]([C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])=[CH:56][N:55]=1>>[CH2:30]([O:35][C:36]1[C:37]([C:50]([O:52][C:54]2[CH:69]=[CH:68][C:57]([C:58]([O:60][CH2:61][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[O:59])=[CH:56][N:55]=2)=[O:51])=[CH:38][C:39]2[C:40]([CH3:49])([CH3:48])[CH2:41][CH2:42][C:43]([CH3:46])([CH3:47])[C:44]=2[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCOc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(O)nc1
Agent: CCCCCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: O=C=O
Agent: [Li]C(C)(C)C
Product: CCCCCOc1cc2c(cc1C(=O)Oc1ccc(C(=O)OCc3ccccc3)cn1)C(C)(C)CCC2(C)C

Procedure:
In analogy to Example 1, by metallating 6-bromo-7-pentoxy-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene with tert.butyl-lithium and reacting with carbon dioxide gas there was prepared 3-pentoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (m.p. 67-68° C., from hexane). Reaction of this acid with benzyl 6-hydroxy-nicotinate gave benzyl 6-(3-pentoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-carbonyloxy)-nicotinate as a colorless oil. Subsequent hydrogenation yielded the desired end product 6-(3-pentoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-carbonyloxy)-nicotinic acid in white crystals, m.p. 132-133° C. (from diethyl ether/hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-])=O>C(O)(=O)C.O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[NH2:18]
Reactant: COC(=O)c1ccccc1Cc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccccc1Cc1cc(Cl)ccc1N
Temperature: 0 °C
Yield: 47.9 %

Procedure:
To a solution of 2-(2-nitro-5-chlorophenylmethyl) benzoic acid methyl ester (840 mg; prepared in reference example 3) in a mixture of acetic acid-water (5:1; 12 ml) was added steel powder (768 mg) and the mixture was added for 20 minutes at 80° C. The suspension was poured into ice-water and was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, dried, and was concentrated. The residue was purified by column chromatography on silica gel to give the title compound (363 mg) having the following physical data.