Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:37][CH2:36][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]4[C:18]([F:34])=[CH:19][CH:20]=[CH:21][C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:7]2)=[C:4]([C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42]C)=[O:41])[C:3]=1[CH3:49].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[Br:1][C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:7][CH2:8][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]4[C:18]([F:34])=[CH:19][CH:20]=[CH:21][C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:36][CH2:37]2)=[C:4]([C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([OH:42])=[O:41])[C:3]=1[CH3:49]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1Br)-c1cccc(c1)-c1cccc(F)c1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 5 %

Procedure:
Prepared in 5% yield from methyl(2S)-2-[(22S)-5-bromo-19-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 8.06 (s, 1H), 8.02 (d, J=7.7 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.33-7.27 (m, 2H), 7.23-7.16 (m, 1H), 6.03 (br. s., 1H), 4.31 (br. s., 1H), 3.96-3.90 (m, 1H), 3.55 (t, J=11.2 Hz, 1H), 3.45 (br. s., 2H), 3.08 (d, J=8.4 Hz, 1H), 2.77 (br. s., 1H), 2.51 (s, 3H), 1.98-1.65 (m, 10H), 1.22 (s, 3H), 1.18 (s, 9H), 0.77 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 721.3.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]3[CH2:17][C:18]4[C:19]([O:27][CH3:28])=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[C:23]=4[O:24][C:14]=3[C:13]2=[O:29])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.[N:44]1(OC(N(C)C)=[N+](C)C)[C:48]2[N:49]=[CH:50][CH:51]=[CH:52][C:47]=2N=N1.NC1C=CC=CN=1>O1CCCC1.O>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]3[CH2:17][C:18]4[C:19]([O:27][CH3:28])=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[C:23]=4[O:24][C:14]=3[C:13]2=[O:29])[C:9]([NH:44][C:48]2[CH:47]=[CH:52][CH:51]=[CH:50][N:49]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccn1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccccn2)C1
Temperature: 90 °C
Yield: 16.6 %

Procedure:
A solution of (S)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionic acid (100 mg, 0.24 mmol), in tetrahydrofuran (5 mL) was treated with N-methylmorpholine (70 mg, 0.56 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (212 mg, 0.56 mmol) and commercially available 2-aminopyridine (25 mg, 0.26 mmol). The mixture was heated in a sealed tube was heated for 16 hours at 90° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-N-pyridin-2-yl-propionamide (19 mg, 17.8%), as a white solid. 1H NMR (DMSO-d6) δ: 10.83 (br. s., 1H), 8.34 (br. s., 1H), 8.00 (d, J=7.8 Hz, 1H), 7.77 (br. s., 1H), 7.12 (br. s., 1H), 6.92 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.09 (br. s., 1H), 4.39 (d, J=18.6 Hz, 1H), 4.02 (d, J=19.1 Hz, 1H), 3.76 (s, 6H), 3.55 (br. s., 2H), 1.50-1.89 (m, 7H), 0.87-1.28 (m, 6H).
Reaction SMILES: [C:1]([N:11]1[CH2:15][C@H:14](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][C@H:12]1[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:39][NH2:40]>CO>[C:1]([N:11]1[CH2:15][C@@H:14]2[CH2:13][C@H:12]1[CH2:27][N:40]2[CH3:39])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OCc2ccccc2)cc1
Solvent: CO
Product: CN1C[C@@H]2C[C@H]1CN2C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 91 %

Procedure:
A Parr bottle was charged with 22 g (40.2 mmol) of (2S,4R)-1-(carbobenzyloxy)-2-(p-toluenesulfonyloxymeth- yl)-4-(4-toluenesulfonyloxy)-pyrrolidine and 100 ml of methanol and the bottle was then tared. Methylamine gas was bubbled through the methanol solution until 12.4 g (402 mmol) of the gas had dissolved. The bottle was then sealed and heated to 80° C. After heating for 16 hours, the reaction was cooled and the solvent was evaporated at reduced pressure. The residual solids were then partitioned between 200 ml of methylene chloride and 150 ml of 10% aqueous NaOH solution. The layers were separated and the organic layer was washed with 100 additional ml of 10% aqueous NaOH solution, and then dried over Na2SO4. Evaporation of the solvent under reduced pressure provided 9.0 g of the desired product (oil) which represents a 91% yield. NMR(CDC13) 7.32 (aromatic, 5H), 5.1 (d,2H), 4.4 (d,13.58 (dd, 1H), 3 4 (d,1H), 3.22 (m,1H), 2.88 (m,1H), 2.7 (d,1H), 2.52 (d,1H), 2.40 (s,3H), 1.86 (d,1H), 1.7 (m,1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[N:10][OH:11])[NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.B(F)(F)F.CCOCC>O1CCOCC1>[C:15]1([C:14]2[O:11][N:10]=[C:8]([C:7]3[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[N:9]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=NO)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2noc(-c3ccccc3)n2)cc1

Procedure:
A solution of 10.8 g. (0.06 mole) of p-nitrobenzamidoxime and 8.5 g. (0.06 mole) of benzoyl chloride in 250 ml. of dioxane is heated on a steam bath for one hour, followed by the addition of 2 ml. of BF3 -Et2O. After refluxing the solution overnight, the reaction mixture is cooled and the material which precipitates is collected by filtration to yield 8.1 g. (50%) of 5-phenyl-3-(4-nitrophenyl)-1,2,4-oxadizole.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[CH3:25][O:26][C@@H:27]1[C@H:32]([O:33][CH3:34])[C@@H:31]([O:35][CH3:36])[C@H:30]([CH3:37])[O:29][C@H:28]1[O:38][NH2:39]>CCO>[CH3:25][O:26][C@@H:27]1[C@H:32]([O:33][CH3:34])[C@@H:31]([O:35][CH3:36])[C@H:30]([CH3:37])[O:29][C@H:28]1[O:38][N:39]=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([C:13]2[N:12]=[CH:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:23])([F:1])[F:24])=[CH:5][CH:6]=3)[CH:14]=2)=[CH:16][CH:17]=1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON)[C@@H]1OC
Reactant: O=Cc1ccc(-c2cn(-c3ccc(OC(F)(F)F)cc3)cn2)cc1
Solvent: CCO
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON=Cc2ccc(-c3cn(-c4ccc(OC(F)(F)F)cc4)cn3)cc2)[C@@H]1OC
Yield: 43.6 %

Procedure:
A solution of 4-[1-(4-trifluoromethoxyphenyl)-1H-imidazol-4-yl]-benzaldehyde (50 mg, 0.15 mmol) and O-(2S,3R,4R,5S,6S)-(3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl)-hydroxylamine (45 mg, 0.20 mmol) were combined in 5 mL of dry EtOH, and the solution heated at reflux under a N2 atmosphere for 12 h. The resulting solution was concentrated in vacuo and purified by chromatography (Biotage, 1:1:1 Hexanes/EtOAc/DCM) to furnish 35 mg (44%) of Compound 26 as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.90 (s, 1H), 7.85 (d, J=6 Hz, 2H), 7.68 (d, J=6 Hz, 2H), 7.60 (s, 1H), 7.68 (s, 1H), 7.50 (d, J=6 Hz, 2H), 7.38 (d, J=6 Hz, 2H), 3.77 (dd, J=3.2, 2.0 Hz, 1H), 3.68 (dd, J=9.6, 6.2 Hz, 1H), 3.59 (s, 3H), 3.56 (s, 3H), 3.55 (s, 3H), 3.51 (m, 1H), 3.21 (t, J=9.3 Hz, 1H), 1.33 (d, J=6.1 Hz, 3H); MS 536.1 (M+H); mp 178° C. Anal. Calcd. for C16H10F3N3O2: C, 59.01; H, 5.50; N, 7.65. Found: C, 58.86; H, 5.58; N, 7.63.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])[C:34]2=[O:45])[S:28][C:29]=1[C:30](O)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])[C:34]2=[O:45])[S:28][C:29]=1[C:30]([NH2:7])=[O:31]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(N)=O
Yield: 52 %

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)-imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 52% yield: 1H NMR (300 MHz, CDCl3) δ 5.58 (s, 2H), 4.17-4.11 (m, 2H), 3.64-3.59 (m, 2H), 3.44-3.39 (m, 2H), 2.61 (s, 3H), 2.22-2.08 (m, 2H), 1.92-1.82 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 164.3, 157.7, 155.6, 155.5, 153.8, 128.6, 124.9, 116.9, 42.9, 42.3, 42.0, 31.8, 31.4, 30.9, 30.6, 20.2, 20.1, 17.3; MS (ES+) m/z 336.8 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16]C)=[O:15])[CH:2]=1.[OH-].[Na+].Cl>O.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([OH:16])=[O:15])[CH:2]=1
Reactant: COC(=O)c1cccc(OCC=C(c2ccccc2)c2cccnc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(OCC=C(c2ccccc2)c2cccnc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Methyl 3-[3-(3-pyridyl)-3-phenyl-2-propenyloxy]benzoate (If-56, 1.5 g, 4.35 mmoles) was dissolved in a mixture of water (3 ml) and methanol (10 ml). To the solution was added sodium hydroxide (700 mg, 17.5 mmoles). The mixture was stirred for 2 hours at 60° C., which was then left standing for cooling. To the reaction solution was added water, the pH of which was adjusted to 5 with 1N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried and the solvent was evaporated off. The residue was subjected to silica-gel column chromatography using ethyl acetate as eluant to yield 3-[3-(3-pyridyl)-3-phenyl-2-propenyloxy]benzoic acid (Ie-46) (1.15 g, 80%). Hydrolysis analogous to the above afforded substituted vinyl carboxylic acid derivatives (Ie-45-Ie-51, Ie-53, Ie-54) shown in Table 4-1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:12][C@@H:13]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15].[BH4-].[Na+].O>CO>[CH2:22]([N:19]1[CH2:18][CH2:17][N:16]([C:14](=[O:15])[C@@H:13]([NH:12][CH2:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:21][CH2:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C([C@H](Cc1ccccc1)NCc1ccc2[nH]ccc2c1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
In an inert atmosphere, indole-5-carboxaldehyde (108 mg, 0.75 mmol) and 2-amino-1-(4-benzyl-piperazin-1-yl)-(S)-3-phenyl-propan-1-one (162 mg, 0.50 mmol) were dissolved in dry MeOH (4.0 mL) and refluxed for 4 h. The reaction mixture was cooled to rt followed by slow addition of sodium borohydride (28 mg, 0.75 mmol). Stirring was continued for 1 h. Water (1 mL) was added to the reaction mixture followed by evaporation of the solvent under reduced pressure. The residue was dissolved in EtOAc (10 mL) and washed with sat. sodium hydrogencarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 200 mg (80%) of 1-(4-benzyl-piperazin-1-yl)-2-[(1H-indol-5-ylmethyl)-amino]-(S)-3-phenyl-propan-1-one. LC-MS: tR=0.65 min; [M+H]+=453.39.
Reaction SMILES: [C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.OS(O)(=O)=O.[N+:23]([O-])([O-:25])=[O:24].[K+]>>[C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[C:7]([N+:23]([O-:25])=[O:24])[C:6]([Cl:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)Oc1ccc(Cl)cc1C1CCCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(Cl)cc1C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
4-Chloro-2-cyclopentylphenyl methyl carbonate (1.0 g, 3.93 mmol) was added portion wise to H2SO4 (2.9 mL, 54.1 mmol) to generate a colorless homogeneous solution. The solution was then cooled to 0° C. and KNO3 (476 mg, 4.71 mmol) was added portion-wise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice water. The aqueous layer was extracted with dichloromethane (3×10 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10% EtOAc/hexane) provided 4-chloro-2-cyclopentyl-5-nitrophenyl methyl carbonate (1021 mg, 87% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.39 (s, 1H), 5.23 (s, 1H), 3.92-3.88 (m, 3H), 3.13-3.06 (m, 2H), 2.04-1.96 (m, 2H), 1.81-1.62 (m, 2H), 1.53-1.44 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br.[N+](C1C2C(=CC=CC=2)NN=1)([O-])=O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1n[nH]c2ccccc12
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
5-nitro indazole (1 equiv.), cesium carbonate (1.1 equiv.) and DMF (5 volumes) were charged to a vessel. The mixture was heated to 70–80° C. and 3-fluoro benzyl bromide was added over 75 mins. The reaction was assayed by HPLC for completion (<2 AP of nitro indazole vs combined isomers) and then cooled to 20° C. The salts were filtered and the cake was washed with DMF (2.7 volumes). The product was crystallized by charging water (1.35 to 1.45 volumes) between 15–21° C. The crystal slurry was held for 4 h, crystals were filtered and washed with 2:1 DMF:water mix (2.1 volumes), water (2 volumes) and finally 3:1 cold ACN:water mix (1.5 volumes). The wet cake was dried <45° C. to LOD <1% and the yield was about 49%
Reaction SMILES: O[CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].CC1C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[K+]>C(OCC)C>[CH3:2][CH:3]1[CH2:4][N@:5]1[C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC1CN1C(=O)OC(C)(C)C

Procedure:
To a solution of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (756 mg, 4.31 mmol) and 4-methylbenzene-1-sulfonyl chloride (905 mg, 4.75 mmol) in ethyl ether (30 mL) was added powdered potassium hydroxide (968 mg, 17.26 mmol) and reaction was refluxed for 2 hr. The reaction mixture was poured into a separatory funnel that contained crushed ice and extracted with ether (2×20 mL). The organics were combined, dried with sodium sulfate, filtered, and concentrated. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.16 (d, J=5.43 Hz, 3 H) 1.38 (s, 9 H) 1.83 (d, J=3.73 Hz, 1 H) 2.17 (d, J=5.76 Hz, 1 H) 2.40 (qd, J=5.65, 3.73 Hz, 1 H).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].C[O-].[Na+].[CH:9]12[O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]2>CO>[OH:15][C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[S:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: C1CCC2OC2C1
Reactant: O=C(O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CS[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Mercaptoacetic acid (18.5 g), 0.20 mole) was added to methanol (125 ml) containing sodium methoxide [prepared from sodium (9.3 g, 0.40 mole)] cooled by an ice bath. After 20 minutes, cyclohexene oxide was added slowly during 20 minutes. The ice bath was removed, and the reaction mixture was stirred at room temperature for 4 hours at which time it was poured into water (250 ml) containing concentrated hydrochloric acid (50 ml) and brine (200 ml). The reaction mixture was extracted three times with 150 ml of diethyl ether. The combined diethyl ether extracts were washed twice with 50 ml of brine, dried over anhydrous magnesium sulfate, filtered and concentrated with a rotary evaporator to give the product as an oil. The structure was supported by NMR.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41].[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41].[NH+:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: c1ccncc1
Agent: CCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCO
Product: c1cc[nH+]cc1

Procedure:
C16E8 -Pyridinium was synthesized by tresylation of C16E8 followed by reaction with pyridine and purification by reverse phase HPLC as described in Examples 1-3 above.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]([NH:24][CH3:25])=[O:23]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([NH:20][C@@H:21]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]([NH:24][CH3:25])=[O:23])=[O:19])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:2][CH2:3]1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=404.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(NC(=NC(C)C)O[C:25]([CH3:28])([CH3:27])[CH3:26])(C)C.NC(=N)O>C(Cl)Cl>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Agent: N=C(N)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Reaction time: 16 h
Yield: 75 %

Procedure:
A solution of 3-cyclohexenyl-1H-indole-6-carboxylic acid (1 eq., prepared as described in Example 1, Step 1) in dry DCM (0.19 M) was treated with tert-butyl N,N′-diisopropylimidocarbamate (2 eq.). The resulting clear solution was heated at reflux for 36 h. Addition of a further equivalent of isourea was required after 16 h to drive the reaction to completion. After cooling down the solvent was evaporated giving a residue that was purified by silica gel chromatography (Flashmaster Personal, PE:EtOAc, 30:1) affording tert-butyl 3-cyclohexyl-1H-indole-6-carboxylate (75%) 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.22-1.53 (m, 5H), 1.54 (s, 9H), 1.70-1.86 (m, 3H), 1.95-1.98 (m, 2H), 2.69-2.86 (m, 1H), 7.29 (s, 1H), 7.49-7.57 (m, 2H), 7.93 (s, 1H), 11.09 (s, 1H); MS (ES+) m/z 300 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1.[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[C:15]([NH:23][CH3:24])[CH:14]=1.Cl>CCCCCC.O1CCCC1.O>[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:18])[CH2:6][C:7]2[NH:11][N:10]=[N:9][N:8]=2)=[C:15]([NH:23][CH3:24])[CH:14]=1
Reactant: CNc1cc(F)ccc1C(=O)OC
Reactant: Cc1nnn[nH]1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CNc1cc(F)ccc1C(=O)Cc1nnn[nH]1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of butyl lithium in hexane (2.7M, 53 ml) was added to a stirred suspension of 5-methyltetrazole (6.0 g) in dry tetrahydrofuran (250 ml) at 0° under nitrogen. A solution of methyl 4-fluoro-2-methylaminobenzoate (4.36 g) in dry tetrahydrofuran (20 ml) was added during 10 minutes. The mixture was stirred for 17 hours at room temperature and then for 3 hours at 40° to 70°. The mixture was cooled to room temperature and water (200 ml) was added. The mixture was neutralised with dilute aqueous hydrochloric acid and extracted with dichloromethane (3×100 ml). The combined extracts were dried and evaporated under reduced pressure. The residue was crystallised from industrial methylated spirit to give the novel compound 1-(4-fluoro-2-methylaminophenyl)-2-(1H-tetrazol-5-yl)ethanone, m.p. 214°-6°.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([OH:23])=O)[CH2:9]1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[F:29][C:28]([F:31])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([N:44]2[CH2:43][CH2:42][N:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[F:34])[CH2:46][CH2:45]2)=[O:23])[CH2:9]1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Reactant: Fc1ccccc1N1CCNCC1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3F)CC2)N(Cc2cccc(Cl)c2)C1
Yield: 11 %

Procedure:
As described for Example 64e, (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(3-chloro-benzyl)-pyrrolidine-2-carboxylic acid (μmol) was converted, using 1-(2-fluoro-phenyl)-piperazine instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (72 mg) in 11% yield as colorless oil.