Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH:46]([CH2:50][NH2:51])[CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].CS(C)=O>C(#N)C.ClCCl>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:51][CH2:50][CH:46]4[CH2:47][CH2:48][CH2:49][N:44]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:45]4)=[O:4])=[CH:6][CH2:7][C:8]3=[CH:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1ccccc1-c1ccc(C(=O)N2C=C3CC=C(C(=O)NCC4CCCN(C(=O)OC(C)(C)C)C4)N3Cc3ccccc32)cc1C
Temperature: 80 °C
Yield: 128 %

Procedure:
To a suspension of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 9 (0.54 g, 1.0 mmol) and 3-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.43 g, 2.0 mmol) in dry acetonitrile (5 mL) was added dimethylsulfoxide (0.35 mL, 4.9 mmol) and the reaction mixture heated to 80° C. under nitrogen for 3 days. The cooled reaction mixture was diluted with dichloromethane (25 mL), washed with water (2×25 mL) and brine (25 mL), dried over anhydrous potassium carbonate, filtered and concentrated in vacuo to afford a brown oil (0.81 g). Purification by flash chromatography using a solvent gradient of 3 to 20% ethyl acetate in dichloromethane gave the title compound (0.45 g) as a white foam.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20](=[O:24])[N:19]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:18]=1[CH3:36].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:21]1[C:20](=[O:24])[N:19]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:18]([CH3:36])=[C:17]([Cl:16])[N:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@@H]1COCCN1Cc1ccccc1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NC[C@@H]2COCCN2Cc2ccccc2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 32.9 %

Procedure:
A solution of [(3R)-4-benzylmorpholinyl]methylamine (preparation 95) (4.2 g, 20.4 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (1 g, 3.06 mmol), and triethylamine (0.7 ml, 5.0 mmol) in ethyl acetate (25 ml) was heated under reflux for 18 hrs. The cooled reaction mixture was diluted with ethyl acetate, washed with water, then brine, dried over MgSO4 and concentrated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 100:0) to give the title compound as a white solid, (500 mg, 32%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:24]#[N:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1.B(Br)(Br)Br.CO.O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:24]#[N:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COc1ccc(-c2c(-c3c(C)noc3C)n(C#N)c3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C#N
Temperature: -50 °C
Reaction time: 4.5 h

Procedure:
2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile was dissolved in 3 ml DCM and the mixture was cooled to −50° C. BBr3 (5 eq) was added and the reaction was stirred at −50° C. for 4.5 h and then at −20° C. for 16 h. The mixture was cooled to −78° C. and MeOH (90 μl) was added followed by water. The aqueous layer was extracted with DCM 3× and the combined organic layers were concentrated. The crude product was purified on silica (EtOAc/n-Heptane 2:8-3:7). 4.9 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile was obtained as a white solid. ES/MS m/z: 330.2 (M+H), 328.3 (M−H); 1H NMR (CDCl3, 500 MHz): 7.75 (m, 1H), 7.67 (m, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.20 (m, 2H), 6.88 (m, 2H), 2.28 (s, 3H) and 2.05 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[CH:12]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:11]
Reactant: CCOC(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 1.2 eq oxalyl chloride (12.69 g, 0.10 mol) in dichloromethane (150 mL) was cooled to approximately −78° C. and treated dropwise, under nitrogen, with a solution of 2.4 eq anhydrous dimethylsulfoxide (15.63 g, 0.20 mol) in dichloromethane (50 mL). 15 minutes after the addition was complete, a solution of 1.0 eq ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate (15.60 g, 83.3 mmol) in dichloromethane (50 mL) was added dropwise. 30 minutes after the addition was complete, a solution of 3.0 eq triethylamine (25.30 g, 0.25 mol) in dichloromethane (50 mL) was added dropwise and the reaction warmed to room temperature. The reaction was stirred at room temperature for 1 hour, then quenched with saturated sodium bicarbonate (500 mL). The layers were separated and the aqueous layer extracted once with dichloromethane (200 mL). The pooled organic layers were washed with H2O (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to afford 13.84 g ethyl 4-formylpiperidine-1-carboxylate as a viscous amber oil. 1H-NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 4.00 (br m, 2H), 2.97 (m, 2H), 2.40 (m, 1H), 1.87 (br m, 2H), 1.54 (m, 2H), 1.23 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1([N:7]=C=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:10](=O)(=[O:13])([OH:12])[OH:11]>>[S:10]([OH:13])(=[O:12])([C:4]1[CH:5]=[CH:6][C:1]([NH2:7])=[CH:2][CH:3]=1)=[O:11]
Reactant: O=S(=O)(O)O
Reactant: O=C=Nc1ccccc1
Product: Nc1ccc(S(=O)(=O)O)cc1

Procedure:
The reaction of phenyl isocyanate with sulfuric acid is reported by Bieber [J. Am. Chem. Soc. 75, 1405 (1953)] to give sulfanilic acid. ##SPC1##
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:18]O>>[I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)c(C)cc1C
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 5-iodo-2,4-dimethylbenzoic acid (compound 2.1, 10 g, 32.60 mmol, 1.00 equiv, 90%) and sulfuric acid (10 mL) in methanol (100 mL) was stirred overnight at 80° C. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was diluted with 200 mL of ethyl acetate. The resulting mixture was washed with 3×50 mL of water, 2×50 mL of sodium bicarbonate (aq. sat.), followed by 2×50 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 9.2 g (88%) of the title compound as a yellow oil.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:73])[CH:24]([NH:25][C:26](=[O:72])/[C:27](=[N:53]\[O:54][CH2:55][C:56]([O:58][CH:59]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:57])/[C:28]3[N:29]=[C:30]([NH:33][C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[S:31][CH:32]=3)[C@H:21]2[S:20][CH2:19][C:18]=1[CH2:74][Cl:75])=[O:16])([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.ClC1C=CC=C(C(OO)=[O:84])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH:59]([O:58][C:56]([CH2:55][O:54]/[N:53]=[C:27](/[C:28]1[N:29]=[C:30]([NH:33][C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[S:31][CH:32]=1)\[C:26]([NH:25][CH:24]1[C:23](=[O:73])[N:22]2[C:17]([C:15]([O:14][CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:16])=[C:18]([CH2:74][Cl:75])[CH2:19][S:20](=[O:84])[C@H:21]12)=[O:72])=[O:57])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
23.4 g (22.3 mmol) of Benzhydryl-7-[(Z)-2-(benzhydryloxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate was dissolved in 500 ml of methylene chloride, and 4.8 g (22.3 mmol) of m-chloroperbenzoic acid was added under cooling with ice in 10 minutes. The mixture was further stirred for 20 minutes. To the reaction solution, 150 ml of a 10 % sodium thiosulfate aqueous solution was added for extraction. The organic layer was washed with a 5% sodium hydrogen carbonate aqueous solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a powder of the above-identified compound. The compound thus obtained was employed for the next reaction without purification
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:28])[C@H:5]([NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH3:7])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:5]([CH2:6][CH3:7])[CH:4]([OH:28])[CH:2]([CH3:3])[CH3:1]
Reactant: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(O)C(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of (3RS,4R)-2-methyl-4-(trityl-amino)-hexan-3-ol (0.53 g, 1 eq, 1.41 mmol) in DCM (20 mL) under an argon atmosphere at room temperature, was added CF3COOH (5 mL) dropwise, and the solution was stirred at this temperature for 1 h. The solvent was evaporated in vacuo, the residue was precipitated from Et2O (10 mL) with hexane (90 mL) with stirring to give a yellow oil. The solvent was decanted from the oil, and the oil was washed with hexane (20 mL) and dried in vacuo to afford the title compound as a light yellow oil. Yield: 0.18 g (100%). (50% de 3S,4R: 50% de 3R,4R). 1H-NMR (d6-DMSO, 250 MHz): δ 0.85-0.99 (m, 9H, NH2CH (CH2CH3)CH(CH(CH2)OH;, 1.42-1.79 (m, 2H, NH2CH(CH2CH3)CH (CH(CH3)2) OH), 2.95 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 3.18 (m, 1H, NH2CH (CH2CH3)CH(H(CH(CH3)2)OH), 3.37 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH, 7.58 (bs, 2H, NH2CH(CH2CH3)CH(CH(CH3)2)OH).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[CH3:14].[CH2:15]([N:22]1[C:30]2[C:29](Cl)=[N:28][C:27]([Cl:32])=[N:26][C:25]=2[CH:24]=[CH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1C(=O)CCC1.O>[CH2:15]([N:22]1[C:30]2[C:29]([O:3][C:4]3[C:9]([CH3:10])=[CH:8][C:7]([C:11](=[O:13])[CH3:12])=[CH:6][C:5]=3[CH3:14])=[N:28][C:27]([Cl:32])=[N:26][C:25]=2[CH:24]=[CH:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Reactant: CC(=O)c1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)c1cc(C)c(Oc2nc(Cl)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a stirred solution of NaH (31 mg, 0.78 mmol) in dry NMP (2 mL) was added 1-(4-hydroxy-3,5-dimethylphenyl)ethanone (127 mg, 0.78 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (216 mg, 0.78 mmol) in dry NMP (2.4 mL) and heated at 160° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1-2:1), to give the product as a light yellow solid (111 mg, 35%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[CH3:16].[OH-].[Na+].CN([CH:22]=[O:23])C>O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:22]=[O:23])=[C:8]1[CH3:16]
Reactant: Cc1cc2ccccc2n1C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A solution of POCl3 (7.0 mL, 75 mmole) in DMF (100 mL) was stirred for 5 minutes at 0° C., then 1,2-dimethylindole (10.0 g, 69 mmole) was added in one portion. The reaction was allowed to warm to RT and stirred for 4 h. The thick slurry was poured into ice water (300 mL) and the flask was rinsed with additional water (50 mL). The aqueous mixture was basified with a solution of NaOH (13.2 g, 330 mmole) in H2O (50 mL), and the thick suspension was filtered to collect the solid. This was washed with water and dried under vacuum to give the title compound (11.59 g, 97%) as an off-white solid:
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:7][CH2:8][C:9]([CH2:11]Cl)=O>>[Cl:7][CH2:8][C:9]1[N:6]=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][CH:11]=1
Reactant: O=C(CCl)CCl
Reactant: CC(C)C(N)=O
Product: CC(C)c1nc(CCl)co1
Yield: 6.2 %

Procedure:
In substantially the same manner as in Reference Example 31, isobutyramide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-isopropyl oxazole as an oily product. The yield was 6.2%.
Reaction SMILES: N1SN=C2C(S(NC3C=C(Cl)C(Cl)=CC=3C(N[C@H](CC3C=CC([Cl:30])=CC=3)C(O)=O)=O)(=O)=O)=CC=C[C:2]=12.C(OC([NH:44][C@H:45]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=1)[C:46]([OH:48])=[O:47])=O)(C)(C)C>>[ClH:30].[CH3:2][O:48][C:46](=[O:47])[C@H:45]([NH2:44])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=1
Reactant: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Product: COC(=O)[C@H](N)Cc1ccc(Cl)cc1
Product: Cl

Procedure:
(R)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionic acid. (R)-2-(tert-Butoxycarbonylamino)-3-(4-chloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-(4-chloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This salt was then coupled with 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.35 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 583.95; m/z found, 583/585 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.07 (s, 1H), 8.34 (d, J=7.1, 1H), 8.23 (d, J=8.8, 1H), 7.84 (s, 1H), 7.74-7.70 (m, 1H), 7.30-7.26 (m, 2H), 7.24 (s, 1H), 7.07 (d, J=8.3, 2H), 6.38 (d, J=7.4, 1H), 5.00-4.97 (m, 1H), 3.30 (dd, J=14.1, 5.9, 1H), 3.21 (dd, J=14.1, 5.9, 1H).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10]1)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31].O>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH2:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([CH:11]2[O:12][CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:6]([OH:29])=[O:5])[CH2:10]2)=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OCc3ccccc3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCN1CCOC(c2ccc(OCc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude 3-{2-[4-(benzyloxy)-phenyl]morpholin-4-yl}-propionic acid tert-butyl ester (see §3) was treated with a mixture of TFA, water, and CH2Cl2 (30:3:67; 3 mL) and stirred at RT for 2 h. Subsequently, the volatiles were removed in vacuo, and the crude product was purified by preparative HPLC to afford 3-{2-[4-(benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid trifluoroacetic acid salt; Rt=1.86 min. (System A), [M+H]+ Found: 342.19; Calc: 342.17. Conditions for the preparative LC-MS: Injection of the crude product dissolved in 600 L DMSO/CH3CN 1:2; column Waters Sunfire 19×100 mm 5 μm 45° C., mobile phase water/CH3CN/TFA 0.1% 25 mL/min, run 20 min 10%-90% CH3CN, detection with UV 210-260 nm.
Reaction SMILES: [I:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4](I)[N:3]=1.[Na].[OH2:10].[CH3:11]O>>[CH3:11][O:10][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([I:1])[N:3]=1
Reactant: CO
Reactant: Ic1cncc(I)n1
Reactant: O
Agent: [Na]
Product: COc1cncc(I)n1

Procedure:
2,6-Diiodopyrazine (6.06 g. 18.2 mmol) was added to a solution of sodium (0.42 g, 18.2 mmol) in methanol (45 ml) and heated under reflux for 3.5 h. Water (150 ml) was added and extracted With ether (3×150 ml). The combined extracts were dried (Na2SO4) and the residue remaining after removal of the solvent was chromatographed through silica gel eluting with ether/petroleum ether (50:50) to give 2-methoxy-6-iodopyrazine (4.17 g); δ (360 MHz, CDCl3) 3.95(3H,s,OMe); 8.18(1H,s,pyrazine-H); 8.45(1H,s,pyrazine-H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl.[C:21]1([CH:27](O)[CH:28]([NH2:30])[CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[C:21]1([CH2:27][CH:28]([NH:30][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(N)C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(Cc1ccccc1)NC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Benzoyl chloride in an amount of 349 mg (2.48 mmol) and triethylamine in an amount of 1.0 ml (7.3 mmol) were added into 10 ml of chloroform solution of the above-described 1-phenyl-2-aminopropanol in an amount of 465 mg (2.48 mmol). The resulting solution was stirred for 2 hours in ice bath and added with water to discontinue the reaction. After separation of the solution, the chloroform solution was dried with anhydrous magnesium sulfate and distilled out under reduced pressure to obtain 1-phenyl-2-benzoylaminopropane in crude state. The crude product was purified by means of silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain anti-isomer of 1-phenyl-2-benzoylaminopropanol in an amount of 705 mg (2.42 mmol) at a yield of 97%. The optical purity of said anti-isomer was determined by means of high performance liquid chromatography (ethanol:hexane 1:30, flow rate: 1.0 ml/min., chiralcell OJ) and was found to be 95% ee as the purity of the (1S, 2R)-isomer. The optical purity of the syn-isomer was also determined and the purity was found to be 90% ee as the purity of the (1S, 2S)-isomer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)CN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.1 %

Procedure:
In a sealed tube a mixture of enantiomer E2 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.28 g, 1.45 mmol), acetonitrile (15 mL), potassium carbonate (0.4 g, 2.9 mmol) and 1-bromo-2-methylpropane (0.15 mL, 1.59 mmol) was stirred at ambient temperature for 5 h and then at 60° C. for 2 h. Aqueous sodium carbonate (10%, 5 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 10:1) gave the title compound (0.193 g). [α]D=−22.9° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 162-163° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 2), 212 (bp), 182 (46), 213 (13), 57 (10), 127 (10).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[CH:3]=1.CO.[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[CH:3]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69 %

Procedure:
To a solution of methyl 4,6-dichloronicotinate in a mixture of THF (400 ml), MeOH (100 ml) and H2O (100 ml) was added a solution of NaOH (10 g) in 40 ml H2O. The mixture was stirred for 40 min. at room temp. Then, the solvents were reduced and it was acidified with conc. HCl to a pH of about 2. It was extracted using a mixture of Et2O/EtOAc and the organic layer was dried with Na2SO4. The solvents were removed and the residue dried in vacuo to obtain the title compound as a white solid (12.3 g, 69%). Rf (CHCl3/MeOH 10:1)=0.85. 1H-NMR (300 MHz, DMSO-D6): δ=8.80 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:8]([CH3:62])[CH:7]([OH:63])[CH2:6][C:5]1=[O:64])[CH:2]=[CH2:3].[C:65](OC(=O)C)(=[O:67])[CH3:66]>N1C=CC=CC=1>[C:65]([O:63][CH:7]1[CH2:6][C:5](=[O:64])[CH:4]([CH2:1][CH:2]=[CH2:3])[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:53])[CH3:54])[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:8]1[CH3:62])(=[O:67])[CH3:66]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(OC(C)=O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 17-allyl-12-[2-(4-tert-butyl-dimethylsilyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (39.9 mg) in pyridine (1.5 ml) was added acetic anhydride (0.5 ml), and the mixture was stirred at room temperature for 6 hours. The solvent was removed from the reaction mixture under reduced pressure to give a crude oil, which was purified on silica gel thin layer chromatography (developing solvent: diethyl ether and hexane, 1:1 v/v) to afford 14-acetoxy-17-allyl-12-[2-(4-tert-butyl-dimethylsilyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (26.5 g).