Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1.[CH3:39]I>CN(C=O)C>[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[N:38]([CH3:39])[N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)nc2c(OC)cccc12
Reactant: CI
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnnn4C)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
The sodium salt (15.7 mg) obtained in Example 18 was dissolved in 0.3 mL of DMF, 0.009 mL of methyl iodide was added to it, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with water and saturated brine in order, then dried over sodium sulfate, and concentrated. The residue was purified through silica gel chromatography (chloroform/methanol=10/1) to obtain 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1-methyltetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one (this is referred to as 1-isomer) and 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(2-methyltetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one (this is referred to as 2-isomer) both as colorless powders. 1-Isomer: 1H-NMR (CDCl3) δ: 8.20 (1H, d, J=2.3 Hz), 8.05 (1H, dd, J=8.5, 2.3 Hz), 7.78 (1H, d, J=8.4 Hz), 7.48 (1H, dd, J=8.4, 7.9 Hz), 7.25 (1H, d, J=8.5 Hz), 7.20 (1H, s), 7.09 (1H, d, J=7.9 Hz), 4.67-4.57 (1H, m), 4.29-4.18 (1H, m), 4.22 (3H, s), 4.09 (3H, s), 4.04 (3H, s), 3.69-3.58 (1H, m), 3.46-3.33 (1H, m), 2.91 (1H, d, J=16.8 Hz), 2.84 (1H, d, J=16.8 Hz), 2.30-2.20 (1H, m), 2.16-1.88 (3H, m). MS [M+H]+=515.2-Isomer: 1H-NMR (CDCl3) δ: 8.65 (1H, d, J=2.3 Hz), 8.29 (1H, dd, J=8.7, 2.3 Hz), 7.77 (1H, d, J=8.5 Hz), 7.47 (1H, dd, J=8.5, 7.6 Hz), 7.19 (1H, s), 7.15 (1H, d, J=8.7 Hz), 7.08 (1H, d, J=7.6 Hz), 4.65-4.54 (1H, m), 4.39 (3H, s), 4.23-4.13 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.69-3.57 (1H, m), 3.46-3.33 (1H, m), 2.88 (1H, d, J=16.7 Hz), 2.80 (1H, d, J=16.7 Hz), 2.28-2.19 (1H, m), 2.15-2.05 (1H, m), 2.01-1.85 (2H, m). MS [M+H]+=515.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>COC(C)(C)C>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[N:9][C@@H:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:24][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Solvent: COC(C)(C)C
Product: C[C@H](N=Cc1ccc(OCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.8 %

Procedure:
0.11 g (0.93 mmol) of (S)-α-methylbenzylamine and 0.26 g (1.23 mmol) of 4-benzyloxybenzaldehyde are mixed in 4 ml of t-butyl methyl ether and stirred for three days at room temperature, and then evaporated under reduced pressure to give a residue, which was then washed with 5 ml of n-hexane, filtered, and dried to give 0.24 g (0.77 mmol) of (S)-N-(4-benzyloxybenzylidene)-α-methylbenzylamine (Yield: 83%, purity 90%).
Reaction SMILES: [S:1]1[CH:5]=[C:4](C(C2CCN(C(OC(C)(C)C)=O)CC2)=O)[C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2.S1C=CC2C=CC=CC1=2.[Br:34]Br>C(Cl)(Cl)(Cl)Cl>[Br:34][C:4]1[C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=2[S:1][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2csc3ccccc23)CC1
Reactant: BrBr
Agent: c1ccc2sccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1csc2ccccc12
Yield: 48 %

Procedure:
4-[(Benzo[b]thiophene-3-yl)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester ##STR13## Dissolve benzo[b]thiophene (23 g, 0.170 mmol) in carbon tetrachloride (80 mL). Add, by dropwise addition, a solution of bromine (26.85 g, 0.168 mmol) in carbon tetrachloride (30 mL) and stir at room temperature for 2 days. Quench with a 1M solution of sodium thiosulfate and separate the organic phase. Extract the aqueous phase with carbon tetrachloride, combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo and purify by distillation to give 3-bromobenzo[b]thiophene as a pale yellow liquid (17.33 g, 48%); bp 64°-72° C. @0.02 mm Hg.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:9]([C:12]1[C:17](Cl)=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>>[N+:9]([C:12]1[C:17]([O:7][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[CH3:8])=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:11])=[O:10]
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1cccc(Oc2ccccc2C)c1[N+](=O)[O-]

Procedure:
A mixture of o-cresol (4.9 g.), ethyl 2-(2-nitro-3-chlorophenyl)acetate (10.0 g.), potassium carbonate (8.5 g.) and cupric oxide (1 g.) was treated in a similar manner to the above to give the captioned compound (3.4 g.). bp 173° to 176° C./0.2 to 0.4 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]([C:12]2[O:23][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:14]=2)[C@@H:24]([OH:26])[CH3:25])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 29 %

Procedure:
The crude material of N′-((2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 12b) (509 mg, 1.36 mmol) was added to THF (100 mL) stirred at room temperature. PS-BEMP (1.86 g, 4.09 mmol base) was added to the solution followed by slow addition of p-TSCl (286 mg, 1.50 mmol). The reaction mixture was stirred for 2 h and the progress of the reaction was monitored by TLC. After the completion of the reaction) the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to provide the title compound (140 mg). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.93 (d, J=9 Hz, 2H), 7.54 (m, 1H), 7.46 (m, 3M), 6.83 (s, 1H), 6.65 (d, J=9 Hz, 0.1H), 5.35 (d, J=9 Hz, 1H), 4.70 (d, J=9 Hz, 1H), 4.62 (m, 1H), 3.30 (d, J=5 Hz, 1H), 1.42 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5](F)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([CH3:24])=[N:22][CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:16][C:11]1[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]2[C:5]([NH:17][C:18]3[CH:19]=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([CH3:24])=[N:22][CH:23]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:10]=1
Reactant: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Reactant: Cc1ncc(N)cc1NS(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(Cl)cnc2Nc2cnc(C)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 113.7 %

Procedure:
To a 15 mL round-bottom flask was added 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.050 g, 0.209 mmol), N-(5-amino-2-methylpyridin-3-yl)methanesulfonamide (0.046 g, 0.230 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (0.169 mL, 0.835 mmol) was then added to the solution in one portion. The now burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl and partitioned between water and CHCl3. The aqueous layer was extracted with more CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 3% MeOH in DCM) to afford the desired product as a yellow solid (100 mg). MS (ESI pos. ion) m/z: 421.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (s, 6H) 3.06 (s, 3H) 7.84 (br. s., 1H) 7.97 (br. s., 1H) 8.24 (d, J=2.05 Hz, 1H) 8.38 (d, J=2.63 Hz, 1H) 8.64 (d, J=2.19 Hz, 1H) 8.75 (d, J=2.63Hz, 1H) 9.32 (br. s., 1H) 11.98 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:4][CH:3]=1.[O:40]1[CH2:44][CH2:43]OC1=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[OH:40][CH2:44][CH2:43][O:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(O)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(OCCO)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Temperature: 90 °C
Yield: 47.9 %

Procedure:
A mixture of (E)-ethyl 3-(4-((E)-2-(4-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (352 mg, 0.67 mmol; Compound 339, Step 1), 1,3-dioxolan-2-one (296 mg, 3.37 mmol), and potassium carbonate (185 mg, 1.34 mmol) in DMF (7 mL) was heated to 90° C. overnight. The mixture was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with brine (3×), dried over sodium sulfate, and purified by flash chromatography on silica gel eluting with 0 to 100% ethyl acetate/hexanes to afford 182 mg of the title compound as a yellow foam. NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.72 (d, 1H), 7.62 (s, 1H), 7.47 (d, 1H), 7.40 (d, 2H), 7.21 (dd, 1H), 7.08 (d, 2H), 6.88 (d, 2H), 6.78 (d, 2H), 6.48 (d, 1H), 5.85 (dd, 1H), 4.83 (t, 1H), 4.14 (qt, 2H), 4.17-3.88 (m, 3H), 3.76 (m, 1H), 3.69 (m, 2H), 2.44-2.37 (m, 3H), 2.00 (m, 2H), 1.75 (m, 1H), 1.60 (m, 2H), 1.21 (t, 3H), 0.89 (t, 3H). LCMS: 483 [(M-THP+H)+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[C:19]2[C:12]([NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+].C(O)(=O)C(O)=O>CO.O>[CH2:1]([O:8][C:9]1[CH:20]=[C:19]2[C:12](=[CH:11][CH:10]=1)[NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH:18][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: NCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(COc2ccc3[nH]cc(CCNCc4cccc(Oc5ccccc5)c4)c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 5-benzyloxy tryptamine (1.23 g, 4.6 mmol), 3-phenoxybenzaldehyde (97%, 1.09 g, 5.53 mmol) and molecular sieves 4 A (1.0 g) and stir in methanol (15 mL) for 4 h. Filter the molecular sieves and wash several times with MeOH. To this MeOH solution, add portionwise NaBH4 (174 mg, 4.60 mmol), stir the resulting mixture at room temperature for 1 h. Remove MeOH under vacuum, dilute the residue with CH2CL2/water, extract with CH2Cl2, combine organic layers, dry over Na2SO4 and concentrate the solvent in vacuo. Purification by silica gel chromatography(CH2Cl2/MeOH) to give the free base. Combine the free base with oxalic acid to form the salt: (300 MHz, DMSO-d6) 2.95–3.15 (m, 4H), 3.93 (s, 2H), 4.10 (br, 1H), 5.05 (s, 2H), 6.85–7.46 (m, 18H), 10.67 (br, 1H); ms (ELECTROSPRAY) m/e: 449.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:50])[C:30]([CH3:49])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:50])[C:30]([CH3:49])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.4 %

Procedure:
p-Methoxyaniline (0.043 g, 0.347 mmol), triethylamine (0.035 g, 0.347 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.059 g, 0.347 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-methoxybenzoic acid (0.060 g, 0.173 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) to obtain the titled compound (0.044 g, 0.0975 mmol, 56%).
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.C(O)C.[F:16][C:17]([F:50])([F:49])[C:18]1[CH:19]=[C:20]([CH:46]=[CH:47][CH:48]=1)[C:21]([NH:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:37]C(=O)OCC)=S)=[N:32][CH:33]=1)=[O:22]>CO>[NH2:37][C:35]1[N:34]=[C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[C:20]4[CH:46]=[CH:47][CH:48]=[C:18]([C:17]([F:16])([F:49])[F:50])[CH:19]=4)[CH:45]=[CH:44][CH:43]=3)=[CH:33][N:32]2[N:6]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2n1
Temperature: 60 °C
Yield: 122.2 %

Procedure:
To a solution of hydroxylamine hydrochloride (400 mg, 5.76 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.20 mL, 6.88 mmol) in methanol (8.0 mL)/ethanol (8.0 mL) was added ethyl ({[5-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (480 mg, 0.95 mmol) obtained above, and the mixture was stirred with heating at 60° C. for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and fractions containing the object product was concentrated under reduced pressure to give the title compound (0.48 g, quantitative) as a pale-yellow powder.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]3[CH:8]=[CH:9][CH:10]=[CH:11][C:2]2=3)[CH2:15][CH2:14]1
Reactant: CN1CCC(=O)CC1
Reactant: c1ccc2c(c1)CCCCN2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(N2CCCCc3ccccc32)CC1
Reaction time: 15 h
Yield: 49.4 %

Procedure:
A solution of compound 2 (1.0 g, 6.79 mmol), N-methyl-4-piperidone (1.00 mL, 8.15 mmol) and acetic acid (0.96 mL, 16.98 mmol) in dry methanol (10 mL) was treated with NaCNBH3 (0.51 g, 8.15 mmol) at 0° C. The reaction mixture was brought to room temperature and stirred overnight (15 hours). The reaction was quenched with 2N NaOH (100 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic fractions were washed with brine (30 mL), dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (2.0 N NH3 in MeOH:CH2Cl2, 3:97) to give compound 3 (0.82 g, 49.4%) as a yellow oil. 1H-NMR (DMSO-d6) δ 1.55 (m, 4H), 1.74 (m, 4H), 1.96 (td, 2H, J=11.3, 2.6 Hz), 2.15 (s, 3H), 2.66 (m, 2H), 2.78 (m, 2H), 2.93 (m, 2H), 3.17 (m, 1H), 6.74 (t, 1H, J=7.3 Hz), 6.90 (d, 1H, J=8.2 Hz), 7.01 (m, 2H); EI-MS (m/z, %): 244 (M+, 24), 97 (100), 71 (37).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[N+:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:6][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([O-:16])=[O:15]
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(CCN2CCCCC2)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a mixture of 0.49 g (2.0 mmol, 1.0 eq.) of 3-nitrophenethyl methanesulfonate (I-24) and 0.55 g (6.0 mmol, 3.0 eq.) of potassium carbonate in 20 mL of acetonitrile was added 0.4 mL (4.0 mmol, 2.0 eq.) of piperidine. The reaction mixture was stirred at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, filtered and the solvent removed in vacuo. The resulting residue was purified by preparative TLC to provide 0.35 g (1.5 mmol, 75%) of 1-(3-nitrophenethyl)piperidine (I-25).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=[O:16])[NH:12][CH2:13][CH2:14][CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18]C1C=CC(C(NN)=O)=CC=1.C(N=C=O)CC>>[CH3:17][O:18][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:9][NH:10][C:11](=[O:16])[NH:12][CH2:13][CH2:14][CH3:15])=[O:8])=[CH:7][CH:6]=1
Reactant: CCCNC(=O)NNC(=O)c1ccccc1
Reactant: COc1ccc(C(=O)NN)cc1
Agent: CCCN=C=O
Product: CCCNC(=O)NNC(=O)c1ccc(OC)cc1

Procedure:
Synthesis and isolation were same as for 1-benzoyl-2-(N-propylcarbamyl)hydrazine, using 1.3 g (7.8 mmol) 4-methoxybenzoylhydrazine and 0.9 g (10.5 mmol) of n-propylisocyanate. Yield was 1.8 g (92%). MS (EI, m/e) calcd for C12H17N3O3 251, found 251 (M+, 1.6); mp 176-179° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[I:21])[CH2:14][CH2:13]1>C(Cl)Cl>[CH:12]1([C:15]2[CH:20]=[CH:19][N+:18]([O-:9])=[CH:17][C:16]=2[I:21])[CH2:14][CH2:13]1
Reactant: Ic1cnccc1C1CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(C2CC2)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
m-Chloroperbenzoic acid (408 mg, 2.36 mmol) was added to the solution of 4-cyclopropyl-3-iodopyridine (I-30a: 200 mg. 0.816 mmol) in DCM (10 mL) and the resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. The reaction mixture was quenched with ice and diluted with DCM. The organic layer was washed with dilute NaOH solution, water and brine solution, dried over sodium sulphate and concentrated to afford 200 mg of the product (94.7% yield).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16]CC)=[O:15])[O:3]1.[Li+].[OH-].Cl>CO.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([OH:16])=[O:15])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500 mg, 2.0 mmol) in 2 mL MeOH was added LiOH (240 mg, 10 mmol) in 5 ml H2O dropwise at 0° C. The reaction mixture was stirred at room temperature for 1.5 h and acidified by 1 N HCl to pH=5.0. The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was used directly in next step reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5](=[O:19])[CH2:4][CH2:3]1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21].CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>O1CCCC1>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][N:8]2[C:2](=[O:1])[CH2:3][CH2:4][C:5](=[O:19])[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]2=3)[CH2:24][CH2:23]1)[CH3:21]
Reactant: CCN1CCNCC1
Reactant: O=C(O)CCCN1C(=O)CCC(=O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCN(C(=O)CCCN2C(=O)CCC(=O)c3ccccc32)CC1
Yield: 12.2 %

Procedure:
On the basis of the method described by M. K. Dhaon et al. in J. Org. Chem. 47 (1982) p. 1962, reaction of 4-(2,5-dioxo-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)butanoic acid (0.06 g) from step b and 1-ethylpiperazine (0.25 mmol, 0.03 g) in the presence of EDC.HCl (N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride) (0.36 mmol, 0.07 g), Et3N (0.48 mmol, 0.05 g) in tetrahydrofuran (5 ml) afforded 10.0 mg of the title compound.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH:3]1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
Ethyl (RS)-1-(2-Methoxyphenyl)-3-(3,4-methylene-dioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (100 mg, 0.23 mmol) in CH2Cl2 (5 ml) was added triethylsilane (32 mg, 0.28 mmol), followed by boron trifluoride etherate (0.13 ml, 1.05 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3 M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to provide the title compound (91 mg, 96%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8](O)=[O:9].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[CH:11]=[C:7]([C:8]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:9])[CH:6]=1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)O)cc2OCC(O)CO)c1
Reactant: C1COCCN1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)N3CCOCC3)cc2OCC(O)CO)c1

Procedure:
In analogy to Example 121, by coupling 3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoic acid with morpholine there was obtained N-[3-(2,3-dihydroxy-propoxy)-2-(3-methoxy-phenoxy)-5-(morpholine-4-carbonyl)-phenyl]-4 methylsulphanyl-benzenesulphonamide as a white foam.