Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:38][NH:39][CH3:40]>>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][N:39]([CH3:40])[CH3:38])[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Yield: 67.1 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.341 g, 0.722 mmol) in 2.0 N dimethylamine in THF (9 mL, 18 mmol) of was stirred at 70° C. for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was partitioned in ethyl acetate/aqueous potassium carbonate. The organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. [2-(3-Benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-dimethyl-amine as a light yellow-brown solid (0.167 g, 67.1%) resulted. The compound was dissolved in methanol, and ethereal hydrochloride was added. After concentrating and drying in vacuo for 12 hours at 70° C., the hydrochloride as a light orange foam (94.0 mg) was obtained; Mass Spectrum (+EI, [M+H]+) m/z 346. 1HNMR (500 MHz, DMSO-d6): δ14.22 (s, 1H), 10.00 (br, 1H), 7.97-7.99 (m, 2H), 7.56-7.68 (m, 4H), 7.42 (d, 1H, J=2.20 Hz), 7.17-7.20 (m, 1H), 4.39-4.42 (m, 2H), 3.52-3.53 (m, 2H), 2.84 ppm (s, 6H).
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(=O)CN1C2C(=C(N)C=CC=2)C=C1)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CCOC(=O)Cn1ccc2c(N)cccc21
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (4-amino-indol-1-yl)-acetic acid ethyl ester (prepared in two steps from 4-nitroindole) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.47 (1H, s), 7.84 (1H, d), 7.47 (2H, m), 7.27 (1H, m), 7.15 (1H, t), 7.05 (1H, d), 6.96 (1H, d), 6.87 (1H, t), 5.69 (1H, d), 4.75 (4H, m), 4.57 (1H, d), 4.25 (1H, d), 2.79 (1H, m), 1.99-1.09 (19H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 58.46; H, 7.08; N, 9.78%; C32H37N5O5.C7H17NO5.1.6H2O.0.5C4H8O2 requires: C, 58.64; H, 7.35; N, 10.01%.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[C:5]([NH2:12])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH3:25])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([C:22](=[O:23])[NH:12][C:5]1[C:6]2[NH:7][CH2:8][CH2:9][O:10][C:11]=2[C:2]([F:1])=[CH:3][CH:4]=1)[CH3:25])([CH3:14])([CH3:15])[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)c2c1NCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c2c1NCCO2
Temperature: 0 °C
Yield: 89.7 %

Procedure:
To an ice-cooled mixture of 8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamine (243 mg, 1.445 mmol), (S)-2-tert-butoxycarbonylaminopropionic acid (305 mg, 1.61 mmol) and HOAt (200 mg, 1.463 mmol) in DCM (15 mL) was added EDCI HCl (337 mg, 1.76 mmol). The reaction mixture was stirred in the ice bath for 90 min, then diluted with DCM, washed with aqueous Na2CO3 and then water. The organic layer was dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 50-70% EtOAc in cyclohexane) affording the title compound as a pale yellow foam (440 mg, 89%). LCMS (Method B): RT 3.02 min [M+H]+ 340
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:32])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[N:25][C:26]([CH3:32])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc2c(N)cccc2n1
Reactant: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 135 mg (0.46 mmol) of (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal, 100 mg (0.63 mmol) of 5-amino-2-methylquinazoline and 0.23 ml of titanium tetraethoxide are reacted to give (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 260 mg of resultant crude imine are cyclized in the same way as in Example 1 at −30° C. using 5 ml (5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 56 mg of product.
Reaction SMILES: N1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH:21][C:22]([N:24]4C=CN=C4)=[O:23])=[N:18][C:17]=3[CH3:29])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])C=CN=C1.[F:30]C1C=C(C2SC(N)=NC=2C)C=CC=1S(C)(=O)=O>>[F:30][C:6]1[CH:7]=[C:8]([C:16]2[S:20][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[N:18][C:17]=2[CH3:29])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Product: Cc1nc(NC(N)=O)sc1-c1ccc(S(C)(=O)=O)c(F)c1

Procedure:
The title compound is prepared by the same procedure as imidazole-1-carboxylic acid [5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (Example 150a) by replacing 5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) with 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72)
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]([O:27][C:28](=[O:33])[CH:29](Br)[CH2:30]Br)[CH3:26]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:30][CH:29]2[C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CNCCNc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)CBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1c1ccccc1
Temperature: 40 °C
Yield: 29.2 %

Procedure:
A mixture of this ethylenediamine (31 g, 0.137 mole) and triethylamine (28 g, 0.277 mole) was added dropwise over 30 minutes to a stirred solution of ethyl-2,3-dibromopropionate (35.0 g, 0.135 mole) dissolved in 200 mL of toluene and heated to 40° C. After the addition was complete, the reaction was heated at 80°-85° C. for 7 hours, cooled to room temperature, and partitioned between water and toluene. The organic layer was separated, dried, and stripped of all solvent under reduced pressure to yield 38 g of the crude product. Chromatographic purification gave 12.8 g of ethyl 1-phenyl-4-(phenylmethyl)-2-piperazinecarboxylate.
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[N+:26]([O-])=O)[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[CH2:3])=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCc1c(N)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C

Procedure:
(2R)-Toluene-4-sulfonic acid 8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester (5.3 g, 13 mmole) and tin (II) chloride dihydrate (14.7 g, 65 mmole) were combined in 500 mL of ethyl acetate and the mixture refluxed for 3 hours under nitrogen. The reaction was allowed to cool to room temperature and was quenched by the addition of 300 mL of saturated aqueous sodium bicarbonate. The biphasic mixture was filtered through celite, the phases separated and the aqueous back-extracted with 200 mL of ethyl acetate. The combined organic phases were washed with 250 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with methylene chloride as eluant to give 2.2 g of the (R)-enantiomer of the title compound as an orange oil. 1H-NMR (CDCl3): doublet 7.8 δ (2 H); doublet 7.35 δ (2 H); doublet 6.6 δ (1 H); doublet 6.25 δ (1 H); multiplet 5.8 δ (1 H); singlet 5.05 δ(1 H); doublet 5.0 δ (1 H); multiplet 4.4 δ (1 H); multiplet 4.2 δ (3 H); doublet of doublets 4.0 δ (1 H); doublet 3.25 δ (2 H); singlet 2.45 δ (3 H).
Reaction SMILES: CC(OC[C:6]1[C:19]2[C:14](=CC=CC=2)[C:13]([CH2:20][O:21]C(C)=O)=[C:12]2[C:7]=1C=CC=C2)=O.C(Cl)(=[O:32])C1C=CC=CC=1>>[C:20]([OH:21])(=[O:32])[C:13]1[CH:12]=[CH:7][CH:6]=[CH:19][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: O=C(O)c1ccccc1

Procedure:
Preferred acylation agents are acetic, propanoic, benzoic, monochloroacetyl, and dichloroacetyl anhydride, also benzoyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-methyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M68) (0.42 g, 0.80 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (242 mg, 74%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26].ClCCl>C(O)C.C(=O)(O)[O-].[Na+]>[N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][C:25]([C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)=[NH:26])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(ccn2CCN2CCCCC2)c1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: N=C(Nc1ccc2c(ccn2CCN2CCCCC2)c1)c1cccs1
Reaction time: 3 h
Yield: 44.9 %

Procedure:
A solution of compound 95 (0.200 mg, 0.822 mmol) in absolute ethanol (3 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.350 g, 1.23 mmol) at room temperature and the resulting mixture was stirred for 3 hours. The reaction was diluted with saturated aqueous sodium bicarbonate (5 mL) followed by dichloromethane (30 mL) and transferred to a separatory funnel. The aqueous was extracted twice more with dichloromethane (2×30 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 5:95) to obtain compound 96 (130 mg, 45%) as a yellow oil. 1H NMR (CDCl3) δ 7.43 (d, J=2.7 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.21 (d, J=1.2 Hz, 1H), 7.14 (d, J=3.0 Hz, 1H), 7.08 (t, J=4.2 Hz, 1H), 6.67 (dd, J=1.8, 8.7 Hz, 1H), 6.42 (d, J=3.0 Hz, 1H), 4.24 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.47 (m, 4H), 1.61 (m, 4H); ESI-MS (m/z, %): 353 (M+1); ESI-HRMS calculated for C20H25N4S (MH+): 353.1794, Observed: 353.1796.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([C@@:10]1([CH2:24][CH:25]=[O:26])[CH2:14][C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>CO>[C:3]([O:7][C:8]([C@@:10]1([CH2:24][CH2:25][OH:26])[CH2:14][C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CC=O)(C(=O)OC(C)(C)C)CC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1C[C@@](CCO)(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Sodium borohydride (465 mg) was added to a solution of (3S)-5-oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.71 g, 8.19 mmol) in methanol at −40° C. After heating to room temperature, a 10% citric acid solution was added to the reaction solution, and the mixture was stirred. The reaction solution was poured into a mixture of ethyl acetate (50 mL) and a 10% citric acid solution (10 mL), followed by extraction with ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL), and then the organic layers were combined and washed with brine (50 mL×2). The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→0:1→ethyl acetate-methanol=10:1) to give 2.20 g (81%) of the title compound as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1([Mg]Cl)C=CC=CC=1.[CH3:21][C:22]([CH3:26])([CH3:25])[CH:23]=[O:24]>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:23]([OH:24])[C:22]([CH3:26])([CH3:25])[CH3:21])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Reactant: CC(C)(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(C)(C)C)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 4-iodo-3-nitroanisole (2.38 g, 8.50 mmol) in anhydrous THF (10 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium chloride (2 M in THF, 4.7 mL, 9.4 mmol) was added dropwise at a rate such that the temperature would not exceed minus 35° C. Upon completion of the addition, the mixture was stirred at minus 40° C. for one hour, followed by addition of trimethylacetaldehyde (1.13 mL, 10.2 mmol). The mixture was stirred at minus 40° C. for two hours and then at room temperature for another one hour. The reaction was quenched with brine (100 mL), and the mixture was extracted with CH2Cl2 (40 mL) three times. The combined organic phase was dried over Na2SO4 and concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield racemic (R/S)-1-(4-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (1.52 g, 74%). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, 1H, J=9.2 Hz, Ph-H), 7.22 (d, 1H, J=2.4 Hz, Ph-H), 7.12 (dd, 1H, J=8.8 and 2.8 Hz, Ph-H), 5.27 (d, 1H, J=4.0 Hz, Ph-CH), 3.86 (s, 3H, OCH3), 2.01 (d, 1H, J=4.0 Hz, OH), 0.86 (s, 9H, C(CH3)3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:16][S:17]([O:15][CH2:14][C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H](COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7.96 g of {(3S)-1-(tert-butoxycarbonyl)-3-piperidyl}methanol in 150 ml of chloroform, 3.4 ml of methanesulfonyl chloride and 6.7 ml of triethylamine were added under cooling with ice, followed by an hour's stirring at room temperature. The reaction liquid was distilled off under reduced pressure, diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution was added, followed by 1.5 hours' stirring. Thereafter the reaction liquid was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. Distilling the solvent off, 10.50 g of the title compound was obtained.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[OH-].[K+:16]>C(O)C.O>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5]([O-:7])=[O:6])([CH3:3])[CH3:2].[K+:16]
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(C(=O)[O-])c1ccc(Cl)cc1

Procedure:
α-Isopropyl-4-chlorophenylacetic acid (1.3 g) was dissolved in ethanol (10 ml) and a solution of potassium hydroxide (0.34 g) in water (5 ml) was added to the ethanolic solution. The solvents were then removed by distillation under reduced pressure to give anhydrous potassium α-isopropyl-4-chlorophenylacetate.
Reaction SMILES: [Li].N.[O:3]1[C@H:5]2[C:6](=[O:27])[CH:7]=[C:8]3[C@:24]([CH3:25])([C@@H:4]12)[C@@H:23]1[C@H:11]([C@H:12]2[C@:20]([CH3:26])([CH2:21][CH2:22]1)[C@@H:15]([C@H:16]([CH3:19])[CH2:17][OH:18])[CH2:14][CH2:13]2)[CH:10]=[CH:9]3.C=CC(=C)C.[Cl-].[NH4+]>CCOCC.O1CCCC1.CCOCC>[OH:3][C@@H:4]1[C@@:24]2([CH3:25])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:26])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:19])[CH2:17][OH:18])[CH2:7][C@@H:6]([OH:27])[CH2:5]1
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C=CC(=C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
0.334 g (48 mg-atom) of lithium are added while stirring and gassing with argon to 170 ml of dry liquid ammonia at -31° C. to -33° C. The resulting dark blue mixture is stirred for 15 minutes and then treated dropwise within 40 minutes with a solution of 3.0 g (8.76 mmol) of (20S)-1α,2α-epoxy-21-hydroxy-20-methyl-pregna-4,6-dien-3-one in 208 ml of ether/tetrahydrofuran (4.2:1). After stirring for an additional 15 minutes, 0.2 ml of isoprene are added to the blue mixture and the resulting pink mixture is subsequently treated, while stirring and gassing with argon, first with 3.045 g (57 mmol) of ammonium chloride in portions and then with 0.0608 g (8.7 mg-atom) of lithium. As soon as the lithium has dissolved, 0.468 g (8.7 mmol) of ammonium chloride and then a further 0.0608 g (8.7 mg-atom) of lithium are added. This procedure, i.e. the addition of 8.7 mmol of ammonium chloride followed by 8.7 mg-atom of lithium, is repeated a further fourteen times, for which a total of 6.552 g (122 mmol) of ammonium chloride and 0.851 g (122 mg-atom) of lithium are required. As soon as the lithium of the last addition has dissolved, 10.8 g (180 mmol) of ammonium chloride and then 150 ml of ether are added, and the ammonia is evaporated with stirring. The resulting suspension is diluted at 0° C. with 200 ml of water and extracted with ethyl acetate. The extract is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated at 40° C./11 Torr. Chromatography of the residue on 90 g of silica gel with benzene/ethyl acetate (1:1) and ethyl acetate yields 1.93 g (63%) of uniform, crystalline (20S)-1α,3β,21-trihydroxy-20-methyl-pregn-5-ene of melting point 205°-207° C.; [α]D25 =-25.8° (c=0.5 in methanol). The analytical sample is prepared by recrystallisation from acetone; melting point 206°-208° C., [α]D25 =-27° (c=0.5 in methanol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][F:23]>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][N:12]([CH2:21][CH2:22][F:23])[NH:11][N:10]=1
Reactant: Clc1cccc(-c2nnn[nH]2)c1Cl
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FCCN1NN=C(c2cccc(Cl)c2Cl)N1
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To 100 mL of acetonitrile was added 5 g of 5-(2,3-dichlorophenyl)-1H-tetrazole (Lancester Synthesis Inc., Windham, N.H.) followed by 2.5 g of potassium carbonate. After stirring for 15 min, 5 g of 1-bromo-2-fluoroethane was added dropwise. After the addition, the resulting mixture was then heated to reflux for 3 hours and then filtered. The solvent was then evaporated under reduced pressure leaving 4 g of 5-(2,3-dichlorophenyl)-2-(2-fluoroethyl)-1H-tetrazole as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C([N:19]1[CH2:25][CH2:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[CH2:21][CH2:20]1)C1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:22]1[CH2:21][CH2:20][N:19]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:25][CH2:24][C:23]=1[C:26]#[N:27]
Reactant: N#CC1=C(Cl)CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: N#CC1=C(Cl)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.3 gm=3.9 ml (0.025 mol) of benzyl chloroformate dissolved in 15 ml of methylene chloride, were added dropwise to a solution of 4.9 gm (0.02 mol) of 1-benzyl-4-chloro-5-cyano-2,3,6,7-tetrahydro-1H-azepine in 500 ml of methylene chloride while stirring at room temperature, whereby the temperature rose by 5° C. The mixture was stirred for 5 hours at room temperature and then allowed to stand overnight. The solvent was then removed in a rotary evaporator, and the residue was purified on a silicagel column (toluene/ethyl acetate=8:2). After the corresponding fractions had been concentrated by evaporation, a slightly yellowish oil was obtained with solidified upon standing.