Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[NH:25]C(=O)OC(C)(C)C)[CH2:13]2)=[CH:8][CH:7]=1.O1C=CN=C1C1C=CC(N2CCCC2CN[C@@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[NH2:25])[CH2:13]2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc(-c3ncco3)cc2)C1
Agent: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NCC1CCCN1c1ccc(-c2ncco2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc(-c3ncco3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (1R,2R)-2-(1-(4-(oxazol-2-yl)phenyl)piperidin-3-ylamino)cyclohexylcarbamate (32 mg, 0.073 mmol) and tert-butyl (1R,2R)-2-((1-(4-(oxazol-2-yl)phenyl)pyrrolidin-2-yl)methylamino)cyclohexylcarbamate (134.0 mg, 0.304 mmol) in CH2Cl2 (1.5 mL) was added trifluoroacetic acid (1.5 mL, 19.47 mmol). The reaction was stirred at rt for 1 h. After this time, LC/MS showed no starting material remained and the desired product formed. The reaction was concentrated, and the resulting residue was reconcentrated from CH2Cl2 (2×5 mL). The residue was dried under high vacuum for 1 h to afford the desired product (1R,2R)—N1-(1-(4-(oxazol-2-yl)phenyl)piperidin-3-yl)cyclohexane-1,2-diamine bis-trifluoroacetate (41 mg, 0.072 mmol, 99% yield) and (1R,2S)—N1-((1-(4-(oxazol-2-yl)phenyl)pyrrolidin-2-yl)methyl)cyclohexane-1,2-diamine bis-trifluoroacetate (35 mg, 0.073 mmol, 100% yield) as an oil.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].C(N(CC)CC)C.[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>C1COCC1.O>[C:7]([C:6]1[C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=[CH:10][C:9]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:31]([NH:30][CH2:28][CH3:29])=[O:32])#[N:8]
Reactant: CCN=C=O
Reactant: N#Cc1c(OCC2CCCCN2)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCCCC1COc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a solution of 2-nitro-6-(piperidin-2-ylmethoxy)benzonitrile hydrochloride (Example 26d, 0.5 g, 1.68 mmol) in THF were added triethylamine (0.514 mL, 3.7 mmol) and ethylisocyanate (0.2 mL, 2.52 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 3 hours. The solution was then diluted with water and extracted with EtOAc, the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated to give 2-((2-cyano-3-nitrophenoxy)methyl)-N-ethylpiperidine-1-carboxamide (0.485 g, 87%) which was used in the next step without further purification. MS 333 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[CH:9][C:8]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
(4-Amino-2-phenylbenzoyl)methionine methyl ester (1.15 g, 3.21 mmol), prepared as in Example 192B, and 3-pyridine carboxaldehyde (361 mg, 3.37 mmol) were combined in 15 mL methanol and sodium cyanoborohydride (302 mg, 4.81 mmol) was added followed by crushed molecular sieves. The reaction was adjusted to pH=6 with acetic acid and stirred at 25° C. for 3 hours. The reaction was concentrated and transferred directly to a column of silica gel and purified by flash chromatography (5%methanol-ethyl acetate) to give [4(3-pyridylmethylamino)-2-phenylbenzoyl]methionine methyl ester (1.38 g, 95%) as an oil that solidified after standing. 1H NMR (300 mHz, CDCl3) δ 8.6 (d, 1H), 8.52 (dd, 1H), 7.72-7.65 (m, 2H), 7.45-7.30 (m, 6H), 6.62 (dd, 1H), 6.48 (d, 1H), 5.72 (bd, 1H), 4.64 (dq, 1H), 4.42 (bs, 2H), 3.64 (s, 3H), 2.25-2.05 (m, 3H), 2.00 (s, 3H), 1.95-1.80 (m, 1H), 1.72-1.60 (m, 1H); CIMS MH+ 450.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:28](=[O:30])[CH3:29])[CH2:13][CH:12]1[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC(O)CC1Cc1c[nH]c2cc(F)ccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1CC(Cc2c[nH]c3cc(F)ccc23)N(C(=O)OCc2ccccc2)C1
Reaction time: 16 h
Yield: 62.4 %

Procedure:
To a solution containing 7 (4.7 g, 12.8 mmol) and DMAP (81 mg, 0.66 mmol) in DCM (100 mL) was added acetic anhydride (2.6 g, 25.5 mmol) at ambient temperature. After 16 h, the reaction mixture was quenched with a MeOH (ca. 3 mL) and washed successively with 10% aq. Na2CO3 (50 mL), dilute HCl (50 mL), and 10% aq. Na2CO3 (50 mL). The organic solution was concentrated in vacuo and filtered through a short column of silica gel (ca. 25 g) [eluant: DCM (200 mL) to 0.5% (v/v) MeOH/DCM (80 mL) to 2% MeOH/DCM (100 mL) to 5% MeOH/DCM (100 mL)]. The product-containing fractions were combined and concentrated to provide 3.28 g (63%) of 8 as a white foam [Note: 94.3 A % by HPLC analysis]. 1H NMR (300 MHz, CDCl3), ˜1:1 mixture of rotomers: δ7.99 (m, 1H), 7.75-6.61 (m, 9H), 5.28 (m, 1H), 5.20 (m, 2H), 4.23 (m, 1H), 3.82 (dt, J=5.4, 13.5 Hz, 1H), 3.60 (app. t, J=13.2 Hz, 1H), 3.50 (d, J=11.7 Hz, 0.5H), 3.31 (d, J=12.9 Hz, 0.5H), 2.87 (dt, J=5.1, 13.5 Hz, 1H), 2.13 (s, 3H), 2.01 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3), ˜1:1 mixture of rotomers: δ170.8, 160.2 (JCF=236.4 Hz), 155.2, 136.8, 136.6, 136.4, 128.9, 128.8, 128.5 (JCF=24.3 Hz), 124.5 (JCF=21.4 Hz), 123.0, 123.0, 120.0 (JCF=27.1 Hz), 119.9 (JCF=26.0 Hz), 112.8 (JCF=10.5 Hz), 108.2 (JCF=24.3 Hz), 97.7 (JCF=25.7 Hz), 74.0, 73.2, 67.9, 67.2, 58.5, 57.6, 53.4, 53.0, 35.4, 34.6, 30.8, 29.7, 21.5 ppm. Mass spectrum (ESI), m/z 410.6 [(M)+; calcd for C23H23FN2O4: 410.4].
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@@H:46]([C:48]([NH:50][CH2:51][C:52]([NH:54][C@H:55]([C:58]([NH:60][C@H:61]([C:66]([O:68]C(C)(C)C)=[O:67])[CH2:62][C:63](=[O:65])[NH2:64])=[O:59])[CH2:56][OH:57])=[O:53])=[O:49])[CH3:47])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])[CH3:11])=[O:8]>FC(F)(F)C(O)=O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@@H:46]([C:48]([NH:50][CH2:51][C:52]([NH:54][C@H:55]([C:58]([NH:60][C@H:61]([C:66]([OH:68])=[O:67])[CH2:62][C:63](=[O:65])[NH2:64])=[O:59])[CH2:56][OH:57])=[O:53])=[O:49])[CH3:47])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:13])[CH3:11])=[O:8]
Reactant: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reaction time: 0.67 h

Procedure:
In 5 ml of trifluoroacetic acid is dissolved 500 mg of pGlu-Ala-Lys(Boc)-Ser-Gln-(D)-Ala-Gly-Ser-Asn-OBut and the solution is allowed to stand at room temperature for 40 minutes. The trifluoroacetic acid is distilled off and the residue is precipitated with ether and recovered by filtration. The powdery product is dissolved in 50 ml of water and the solution is passed through a column of Amberlite IRA-410 (acetate-form) (2×5 cm). The effluent is combined with washings and lyophilized. The powdery lyophilizate is dissolved in a small amount of 0.1 N-acetic acid and put onto a column of Sephadex LH-20 (2.5×125 cm), elution being carried out with 0.1 N-acetic acid. The fractions from 185 ml through 202 ml are pooled and lyophilized. Yield 170 mg (34%); [α]D27 -50.6° (c=0.42, H2O); Rf4 (Avicel)=0.25; amino acid analysis (acid hydrolyzate); Lys, 1.00(1); Asp, 0.96(1); Ser, 1.77(2), Glu, 2.02(2); Gly, 1.04(1); Ala, 1.95(2); average recovery 75%.
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22]C#N)[CH2:16]1>>[OH:14][CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:13]2[NH:2][C:3](=[O:12])[C:4]3[C:5]([CH:11]=2)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=3)[CH2:16]1
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Reactant: N#CCCCN1CCC(O)C1
Product: Cc1cccc2c(=O)[nH]c(CCCN3CCC(O)C3)cc12
Yield: 10.6 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (2.00 g) and 4-(3-hydroxypyrrolidin-1-yl)butyronitrile (0.8 g), 3-[3-(3-hydroxypyrrolidin-1-yl)propyl]-5-methyl-2H-isoquinolin-1-one (157.5 mg) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][OH:11])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].S(O[C@@H:23]1[CH2:28][CH2:27][O:26][C:24]1=[O:25])(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[C:3]([NH:10][O:11][C@H:23]1[CH2:28][CH2:27][O:26][C:24]1=[O:25])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2=O)cc1
Reactant: CC(C)(C)OC(=O)NO
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NO[C@H]1CCOC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A suspension of 60% NaH (350 mg, 8.8 mmol) in dry CH2Cl2 under N2 at 0° C. was added a solution of BocNHOH in CH2Cl2 (5 mL). The reaction mixture was stirred at 0° C. for 30 minutes, where after a solution of (R)-α-tosyloxy-γ-butyrolactone (2 g, 7.8 mmol) in CH2Cl2 (5 mL) was added. The reaction mixture was allowed to warm up to room temperature, and left with stirring overnight. The reaction mixture was quenched with 1M phosphate buffer pH=6.3 (20 mL) and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (2×20 mL), and the combined organic fractions extracted with NaCl (aq., sat.) (15 mL). The organic fraction was dried with Na2SO4, filtered and evaporated to dryness. Column chromatography (150 g SiO2, eluent: EtOAc:PE60/80=1:2) gave 1.5 g (89%) of (S)-α-N-Boc-aminoxy-γ-butyrolactone. [α]D25=−42°; [α]36525=−127°.
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[NH:11][N:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][C:16]=3[CH:26]=2)[NH:8]1.[OH-].[Na+].Cl>CO>[CH3:6][N:7]1[NH:11][N:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:16]=3[CH:26]=2)[NH:8]1
Reactant: COC(=O)C1=Cc2cc(C3=NNN(C)N3)ccc2OCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1NN=C(c2ccc3c(c2)C=C(C(=O)O)CCO3)N1
Temperature: 5 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
In methanol (7 ml) and THF (7 ml) was suspended methyl 7-(2-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (324 mg, 1.13 mmol), and to the mixture was added 1N sodium hydroxide solution (3.4 ml). The mixture was stirred at 5° C. for 4 hours, and to the mixture was added, under ice-cooling, 1N hydrochloric acid (3.4 ml). The mixture was concentrated under reduced pressure, and to the residue was added water. Insoluble materials were filtered, which were washed with water and dried under reduced pressure to give 7-(2-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (295 mg, 1.08 mmol, 96%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C@@H:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]2)[CH:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:33][C@H:29]2[CH2:30][CH2:31][CH2:32][C@@H:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: N[C@H]1CCC[C@@H](c2cccnc2)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COc2c(N[C@H]3CCC[C@@H](c4cccnc4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 93 °C
Reaction time: 9 h
Yield: 13.4 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (457 mg, 1.65 mmol), cis-3-(3-pyridyl)cyclohexylamine (348 mg, 1.97 mmol) and diisopropylethylamine (0.63 mL, 3.63 mmol) in anhydrous DMSO (8 mL) was stirred at 93° C. for 9 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[cis-3-(3-pyridyl)cyclohexylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (96.0 mg, 13%) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:7]=[C:6]([CH2:8]O)[O:5][N:4]=1.[Br:12]P(Br)Br>CN(C)C=O>[Br:12][CH2:8][C:6]1[O:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:7]=1
Reactant: OCc1cc(C(F)(F)F)no1
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CBr)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of (3-(trifluoromethyl)isoxazol-5-yl)methanol (2.5 g, 15 mmol) in dimethylformamide (25 mL) was added drop wise tribromophosphine (4.64 g 17.1 mmol, 1.15 eq) and the mixture was stirred at 0° C. for 15 min and at ambient temperature for 2 h. The reaction mixture was partitioned between 10% sodium bicarbonate and dichloromethane. The phases were separated and the organic phase was washed with water and passed over a plug of silica eluting with dichloromethane. The UV active product fractions were collected and evaporated to yield the title compound as colorless oil (2.04 g 59.3%), MS 229 and 231 (M.)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1.[H-].[Na+].[CH2:13]([O:20][C:21]([N:23]([C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[S:35](Cl)(=[O:37])=[O:36])[CH3:24])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(COC)OC>[CH2:13]([O:20][C:21]([N:23]([C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[S:35]([NH:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1)(=[O:36])=[O:37])[CH3:24])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1nc(Br)cnc1N
Reactant: CN(C(=O)OCc1ccccc1)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C(=O)OCc3ccccc3)cccc12
Reaction time: 0.17 h
Yield: 61 %

Procedure:
2-Amino-5-bromo-3-methoxypyrazine (0.3 g) was added to a stirred suspension of sodium hydride (60% dispersion in oil; 0.15 g) in dimethoxyethane (5 ml). After 10 minutes, 5-(N-benzyloxycarbonyl-N-methylamino)-1-naphthalenesulphonyl chloride (0.6 g) in dimethoxyethane (2 ml) was added and stirring was continued for 2 hours. The mixture was poured into water (20 ml) and washed with ethyl acetate (20 ml). The aqueous layer was acidified with concentrated hydrochloric acid to pH2 and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (25 g), eluting with a gradient of 20-50% ethyl acetate in hexane to give 5-(N-benzyloxycarbonyl-N-methylamino)-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.50 g) as a white foam; 1H NMR (d6 -DHSO): 3.34 (s,3H), 3.90 (s,3H), 5.08 (br,2H), 6.95 (br,1H), 7.19 (br,2H), 7.22-7.56 (m,2H), 7.6-7.77 (m,3H), 7.79 (s,1H), 8.07 (d,1H), 8.37 (dd,1H), 8.80 (d,1H), 11.58 (br,1H); mass spectrum (+ve FAB, DMSO/NBA): 557(M+H)+.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:36])[C@@H:15]([O:33][CH2:34][CH3:35])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[Cl:32])[OH:17])C1C=CC=CC=1.[CH3:37][O-:38].[Na+]>CO>[CH3:37][O:38][C:14](=[O:36])[C@@H:15]([O:33][CH2:34][CH3:35])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][C:19]=1[Cl:32])[OH:17]
Reactant: C[O-]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1Cl
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1Cl

Procedure:
In analogy to the procedure described in example 1 b], (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one was treated with sodium methoxide in methanol to give (2S,3R)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(F)ccc2c1Cl
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1sc2cc(F)ccc2c1Cl

Procedure:
Following the 4a synthetic method, using B1 (110.65 mg, 0.5 mmol) instead of A1 gave 4b as a white powder; (175.31 mg, 92.8%). [α]D25: +15.5 (c=0.38, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 8.03-7.77 (m, 3H), 7.44-7.25 (m, 6H), 5.03-4.97 (m, 1H), 3.45-3.26 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 163.90, 160.62, 159.50, 139.01, 136.65, 133.57, 129.50, 128.40, 126.88, 124.94, 115.15, 114.82, 109.31, 108.96, 54.06, 36.79; HRMS (ESI): calcd for: C18H13ClFNO3S [M+H]+=378.0361, obsd [M+H]+=378.0352.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[CH:4][CH:3]=1.I[CH:26]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1.[H-].[Na+].[OH-].[Na+]>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH:26]4[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29]4)[CH:21]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2cc(-c3c[nH]c4cc(F)ccc34)cn2)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 346 mg; 1.0 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (283 mg; 1.0 mmol) and NaH (100 mg; 2.5 mmol; 60% w/w) in DMF (5 mL) was heated to 120° C. for 0.5 hour in a microwave reactor. The reaction mixture was added NaOH (100 mg; 2.50 mmol) in water (0.5 mL) and stirred for 0.5 hour at 85° C. The mixture was concentrated and purified by a silica gel chromatography (petroleum ether/EtOAc=1/1) to afford 220 mg (62%) of the title compound as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH:7]1[CH2:16][CH2:15][CH2:14][CH:8]12.[C-:24]#[N:25].[K+].C1OCCOCCOCCOCCOCCOC1>>[OH:13][C:11]1[CH:10]=[C:9]2[C:4]([CH2:5][CH:6]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)[CH:7]3[CH2:16][CH2:15][CH2:14][CH:8]32)=[C:3]([CH2:2][C:24]#[N:25])[CH:12]=1
Reactant: Oc1ccc(C2Cc3c(CBr)cc(O)cc3C3CCCC23)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Product: N#CCc1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21

Procedure:
Combine 6-Bromomethyl-4-(4-hydroxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-8-ol (0.037 g, 0.1 mmol), KCN (0.010 g, 0.15 mmol), and 18-crown-6 (0.043 g, 0.16 mmol) and heat at 80° C. for 2 hours. Cool, add ice and extract with ethyl acetate. Wash organic layer with sodium bicarbonate solution sat., then water. Dry over anhydrous sodium sulfate and concentrate to a residue which yields, after separation on silica gel with 33% EtOAC/hexanes, the titled compound (0.022 g, 70%). 1H NMR (DMSO-d6) 9.27(s, 1H), 9.18 (s, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.73 (d, J=7.9 Hz, 2H), 6.66 (s, 1H), 6.59 (s, 1H), 3.95 (s, 2H), 3.4 (m, 1H presumed), 3.0 (m, 1H), 2.76 (m, 1H), 2.65 (m, 1H), 2.45(m, 1H) 2.15 (m, 1H), 1.6-1.2 (m, 5H). MS m/z 318 (M−1).
Reaction SMILES: C(N=C(N(C)C)N(C)C)(C)(C)C.[I:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:23]([O-:25])=[O:24])[NH:16][N:15]=1.Br.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>CC#N.O>[I:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:23]([O-:25])=[O:24])[N:16]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:15]=1
Reactant: BrCCc1ccccn1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: Br
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cccc2c1c(I)nn2CCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
2-Tert-butyl-1,1,3,3-tetramethyl-guanidine (0.48 mL, 2.4 mmol) was added to a mixture of 3-iodo-4-nitro-1H-indazole (0.30 g, 1.0 mmol) and 2-(2-bromoethyl)pyridine hydrobromide (0.30 g, 1.1 mmol) in CH3CN (4 mL). The mixture was stirred at ambient temperature overnight, diluted with H2O (35 mL), stirred for 30 minutes, and then extracted with CHCl3. The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography, eluting with EtOAc, to provide 3-iodo-4-nitro-1-(2-(pyridin-2-yl)ethyl)-1H-indazole (0.14 mg, 34%) as a solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:12]1([C:18]2[CH:33]=[CH:32][C:21]([O:22][CH:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:24](Cl)=[O:25])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>O1CCCC1>[CH:1]([NH:4][C:24](=[O:25])[CH:23]([O:22][C:21]1[CH:32]=[CH:33][C:18]([C:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=2)=[CH:19][CH:20]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH3:3])[CH3:2]
Reactant: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)Cl
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)NC(C)C
Reaction time: 5 h

Procedure:
To a solution of 5 g of isopropylamine and 5 ml of triethylamine in 100 ml of absolute tetrahydrofuran is slowly added dropwise with stirring at -5° C a solution of 13 g of α-[p-(1-cyclohexenyl)-phenoxy]-heptanoic acid chloride in 25 ml of absolute tetrahydrofuran. The reaction mixture is left to stand for 5 hours at room temperature, then evaporated in vacuo to dryness. The residue is partitioned between methylene chloride and 2N hydrochloric acid. The organic phase is washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated in vacuo. The residue yields the crude α-[p-(1-cyclohexenyl)-phenoxy]-heptanoic acid isopropylamide of the formula ##STR23## (m.p. 86°-88° C after recrystallisation from petroleum ether).