Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])=[CH:4][CH:3]=1.[C:20]([NH:28][NH2:29])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)/[C:10](=[N:29]/[NH:28][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(Cc2ccc(Cl)cc2)c2ccccc21
Reactant: NNC(=O)c1ccccc1
Product: O=C(N/N=C1\C(=O)N(Cc2ccc(Cl)cc2)c2ccccc21)c1ccccc1
Yield: 86 %

Procedure:
The title compound was prepared as a yellow solid, using 1-(4-chlorobenzyl)-isatin and benzhydrazide according to the synthetic method D. The resulting solid was purified by crystallization in ethyl alcohol. Yield: 86%. 1H NMR (DMSO-d6): δ 5.03 (s, 2H), 7.08 (d, J=7.8 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 7.39-7.47 (m, 5H), 7.60-7.74 (m, 4H), 7.94 (m, 2H), 13.84 (br s, 1H). 13C NMR (DMSO-d6): δ 42.43 (CH2), 110.97 (CH), 119.87 (C), 121.35 (CH), 123.99 (CH), 127.93 (CH), 129.15 (CH), 129.70 (CH), 129.88 (CH), 132.14 (CH), 132.45 (C), 132.78 (C), 133.44 (CH), 135.15 (C), 143.04 (C═N), 161.74 (C═O). HRMS (ES+) calcd for C22H17N3O2Cl (M+H+), m/e, 390.1018. found, 390.1004.
Reaction SMILES: [CH:1]([Si:4]([CH:7]([CH3:9])[CH3:8])(Cl)[Cl:5])([CH3:3])[CH3:2].C([Si](C(C)C)(OC)[O:14][CH3:15])(C)C>>[CH:1]([Si:4]([CH:7]([CH3:9])[CH3:8])([O:14][CH3:15])[Cl:5])([CH3:3])[CH3:2]
Reactant: CO[Si](OC)(C(C)C)C(C)C
Reactant: CC(C)[Si](Cl)(Cl)C(C)C
Product: CO[Si](Cl)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
A 500 ml-capacity, four-necked flask was charged with 18.5 g (0.1 moles) of diisopropyldichlorosilane and 17.6 g (0.1 moles) of diisopropyldimethoxysilane, and the resulting mixture was stirred at 20° C.-30° C. for 1 hour. There occurred a disproportionation reaction, thus giving a mixture comprising diisopropylmethoxychlorosilane, the unreacted diisopropyldichlorosilane and the unreacted diisopropyldimethoxysilane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:16]/[C:14]([O:13][CH3:12])=[O:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc2cc[nH]c2c1
Yield: 72.4 %

Procedure:
To a solution of indole-6-carboxaldehyde (499 mg) in tetrahydrofuran (20 mL), methyl (triphenylphosphoranylidene) acetate (2.5 g) was added at room temperature, and then the reaction mixture was subjected to microwave irradiation at 200° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the titled compound (501 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:16]=[C:15]([C:17]([C:19]2[C:20](Cl)=[N:21][CH:22]=[CH:23][CH:24]=2)=O)[NH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>C(O)C>[CH2:1]([NH:8][S:9]([C:12]1[CH:16]=[C:15]([C:17]2[C:19]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:28][N:27]=2)[NH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1cc(S(=O)(=O)NCc2ccccc2)c[nH]1)c1cccnc1Cl
Solvent: CCO
Solvent: O
Product: O=S(=O)(NCc1ccccc1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 80 °C

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonic acid benzylamide (100 mg), hydrazine hydrate (excess) in ethanol (10 mL) was heated at 80° C. for 48 hours. The reaction was concentrated, mixed with water, the precipitate was filtered off, the filtrate was washed with dilute HCl, water, dried and concentrated to give the titled compound as a light yellow solid.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2].[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH2:23][NH:28][CH2:27][C:26]([F:30])([F:29])[F:25])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(CNCC(F)(F)F)ccc1-2
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a solution of 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde (180 mg, 0.53 mmol) in DCE (7 mL+5% AcOH) was added trifluoroethylamine (46 μL, 0.58 mmol) and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (134 mg, 0.64 mmol) was added and the solution was stirred under nitrogen for 65 hours. The reaction mixture was diluted with aqueous saturated sodium bicarbonate solution and DCM and the phases were separated. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% 2M NH3/MeOH in DCM) to give a colourless oil. The oil was triturated with ether/cyclohexane to give 119 as a grey solid (138 mg, 61%). LCMS: RT=9.52 min, [M+H]+=424. 1H NMR δ (ppm) (DMSO-d6): 8.91 (1H, s), 8.22 (1H, d, J=8.10 Hz), 7.09 (1H, dd, J=8.16, 1.68 Hz), 7.00 (1H, d, J=1.64 Hz), 5.49-5.39 (1H, m), 4.33-4.27 (2H, m), 3.74 (2H, s), 3.40-3.32 (2H, m), 3.21-3.09 (2H, m), 2.92 (1H, s), 1.52 (6H, d, J=6.71 Hz)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][P:12](=[O:16])([CH3:15])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:37][C:27]1[CH:28]=[C:29]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:30]=[C:31]([F:32])[C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:9]3[CH2:14][CH2:13][P:12]([CH3:15])(=[O:16])[CH2:11][CH2:10]3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CP1(=O)CCN(Cc2cccc(Br)n2)CC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CN4CCP(C)(=O)CC4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 1-[(6-bromopyridin-2-yl)methyl]-4-methyl-1,4-azaphosphinane 4-oxide (121 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the general procedure in Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)CCC>[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:24][CH2:23]1
Reactant: Nc1cc(Cl)ncn1
Reactant: COCCN1CCNCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCN(c2cc(N)ncn2)CC1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.3 g, 2.32 mmol) and diisopropylethylamine (0.30 g, 2.32 mmol) were suspended in n-butanol and then 1-(2-methoxyethyl)piperazine 5-2 (0.334 g, 2.32 mmol) was added. The reaction was stirred at 125° C. for 18 hours. The butanol was removed under reduced pressure, diluted with DCM and loaded onto a silica column eluted with DCM (100 mL), DCM:MeOH (99:4) and then DCM:MeOH:NH4OH (9:1:0.1). The product 5-3 was isolated after evaporation. 1H-NMR (DMSO): 7.95 ppm (s, 1H); 6.23 ppm (s, 2H); 5.59 ppm (s, 1H); 3.43 ppm (m, 4H); 3.33 ppm (m, 2H); 3.25 ppm (s, 3H); 2.59 ppm (m, 2H); 2.54 ppm (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:21]([OH:25])[CH2:22][C:23]#[CH:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]#[C:23][CH2:22][CH2:21][OH:25])=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[NH:12][C:13](=[O:20])[C:14]=1[C:18]#[N:19]
Reactant: N#Cc1c(O)c2c(-c3ccc(Br)cc3)csc2[nH]c1=O
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N#Cc1c(O)c2c(-c3ccc(C#CCCO)cc3)csc2[nH]c1=O
Temperature: 120 °C

Procedure:
To an ambient slurry of 3-(4-bromophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.050 g, 0.14 mmol), but-3-yn-1-ol (0.030 g, 0.42 mmol), copper(I) iodide (0.005 g), triphenylphosphine (0.009 g, 0.03 mmol) and diethyl amine (0.15 mL, 1.4 mmol) in DMF (1.5 mL) was added dichlorobis(triphenylphosphine)palladium(II) (0.002 g, 0.003 mmol) in a single portion. The reaction was heated at 120° C. for 20 min in a microwave, cooled to room temperature, filtered, concentrated and purified by RP-HPLC to afford the title compound. MS (ESI) m/e 334.9 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ ppm 12.02 (br s, 1H), 7.39 (d, J=9, 2H), 7.35 (d, J=9, 2H), 6.94 (s, 1H), 3.59 (t, J=9, 2H), 2.57 (t, J=9, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:23])=[N:4][C:5]2[CH:6]=[C:7]([N+:20]([O-])=O)[C:8]3[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1.Cl>CN(C)C=O.[Ni]>[NH2:20][C:7]1[C:8]2[C:15]([S:16](=[O:18])(=[O:19])[NH2:17])=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]2[N:11]=[C:2]([OH:1])[C:3]([OH:23])=[N:4][C:5]=2[CH:6]=1
Reactant: NS(=O)(=O)c1cccc2c1c([N+](=O)[O-])cc1nc(O)c(O)nc12
Agent: [Ni]
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1cc2nc(O)c(O)nc2c2cccc(S(N)(=O)=O)c12
Yield: 43.8 %

Procedure:
A solution of 0,5 g (1,49 mmol) 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline in 5 ml dimethylformamide was hydrogenated at atm. pressure by using ca. 1 g Ra-Ni as a catalyst. The filtered reaction mixture was added 5 ml 1N hydrochloric acid, and then evaporated in vacuo. The crude product was recrystallized (dimethylformamide-water) to give 0,2 g (40%) 6-amino-2,3-dihydroxy-7-sulphamoyl-benzo[f]quinoxaline as a hydrochloride salt. MS: (m/e) 306 (M+ ; 75%). NMR (DMSO-6): 11,8 (2H, broad s), 8.7 (1H,d), 8.2 (1H,d), 7.6 (3H,m), 6.93 (1H,s), 6.1 (2H, broad s).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:24]2[C:25](=[O:34])[NH:26][C:27]4[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:18]3)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[O:34]=[C:25]1[C:24]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:14][CH2:13][CH2:12][N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[CH:23][CH:22]=3)=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26]1
Reactant: CCOC(=O)C1CCN(CCOc2ccc3[nH]c(-c4cc5ccccc5[nH]c4=O)cc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(CCOc2ccc3[nH]c(-c4cc5ccccc5[nH]c4=O)cc3c2)CC1
Temperature: 50 °C

Procedure:
1-(2-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]oxy}ethyl)-4-piperidinecarboxylic acid ethyl ester (4-1, 138 mg, 0.30 mmol, 1 equiv) was dissolved in MeOH (20 mL). 1 N NaOH (6 mL, 20 equiv) was added and the solution warmed at 50° C. for 5 h. The reaction was concentrated, and the residue was suspended in 4 mL of water. This suspension was neutralized with 1 N HCl to provide 1-(2-{[2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indol-5-yl]oxy}ethyl)4-piperidinecarboxylic acid (4-2) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ8.45 (s, 1H), 7.74 (d, 1H, J=8 Hz), 7.53 (t, 1H, J=8 Hz), 7.38 (m, 2H), 7.28 (t, 1H, J=8 Hz), 7.19 (s, 1H), 7.16 (s, 1H), 6.88 (dd, 1H, J=9, 2 Hz), 4.34 (t, 2H, J=5 Hz), 3.53 (m, 2H), 3.47 (m, 2 H), 2.42 (m, 1H), 2.11 (m, 2H), 1.95 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](C=NO)[CH:5]=[CH:4][N:3]=1.CO.[CH2:13]([N:15](CC)CC)C>>[CH3:1][C:2]1[N:7]=[C:6]([NH:15][CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc(C=NO)n1
Reactant: CCN(CC)CC
Solvent: CO
Product: CNc1ccnc(C)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
An autoclave was charged with 2-methyl-pyrimidine-4-carbaldehyde oxime (13 g) from I.1.2, 150 ml of methanol and 70 ml of triethylamine. The autoclave was purged with nitrogen. To this mixture was added 3 g of a 10% palladium-on-carbon catalyst. The autoclave was sealed and purged twice with hydrogen gas. The hydrogenation was run for 2 h. In doing this, the reaction mixture was warmed up to 40° C. in the meantime. The precipitate was filtered off, washed with methanol to yield the title compound as light red solid (11 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=4[F:11])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1c(F)cccc1F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3c(F)cccc3F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,6-difluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (44% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 8.07-7.99, 7.44-7.38, 7.02-6.96, 4.0-3.99, 3.86-3.83, 3.58-3.50, 3.39-3.38, 1.52, 1.15-1.10, 0.77-0.74, 0.49-0.45, 0.11-0.08.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH2:12](OC(OCC)CBr)[CH3:13].Br>C(O)C>[F:10][C:8]([F:11])([F:9])[C:6]1[CH:5]=[CH:4][N:3]2[CH:12]=[CH:13][N:1]=[C:2]2[N:7]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1nccc(C(F)(F)F)n1
Agent: Br
Solvent: CCO
Product: FC(F)(F)c1ccn2ccnc2n1
Temperature: 70 °C
Yield: 86.2 %

Procedure:
A mixture of 2-amino-4-(trifluoromethyl)pyrimidine (prepared according to Zanatta et al. in J. Heterocyclic Chem., 1997, 34(2), 509-513) (500 mg, 3.1 mmol) and bromoacetaldehyde diethyl acetal (1.38 ml, 9.2 mmol) in ethanol (10 ml) was treated with hydrobromic acid (0.5 ml of a 48% aqueous solution) and then heated at 70° C. for 12 h. The reaction was cooled to ambient temperature then pre-adsorbed onto silica. Purification by chromatography on silica eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-5%) afforded 7-trifluoromethylimidazo[1,2-α]pyrimidine (500 mg, 87%) as a cream-coloured solid: δH (400 MHz, CDCl3) 7.22 (1H, d, J 7), 7.74 (1H, d, J 1), 8.03 (1H, d, J 1), 8.67 (1H, d, J 7).
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)=[O:5])C.[ClH:29]>C(O)C>[ClH:29].[C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:9][CH:8]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(OCC(O)CNC(C)CCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CC(CCc1ccccc1)NCC(O)COc1ccc(CC(=O)O)cc1
Yield: 49 %

Procedure:
In this example, 3 g of 1-(4-ethoxycarbonylmethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol (Compound 14) is dissolved in 20 ml of ethanol and then 20 ml of concentrated hydrochloric acid is added thereto. The mixture is heated under reflux for 3 hours. The solvent is then distilled away from the reaction solution under reduced pressure, and the residue is recrystallized from tetrahydrofuran-ether to obtain 1.5 g of 1-(4-carboxymethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol hydrochloride. (Yield: 49%)
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([OH:20])[CH2:17][CH2:18][OH:19].[OH-].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([O:19][CH2:18][CH2:17][CH2:16][OH:20])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCO
Reactant: O=c1cc(Cl)cnn1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(OCCCO)cnn1Cc1ccccc1
Yield: 79.7 %

Procedure:
The mixture of 10 g of 2-benzyl-5-chloro-3(2H)-pyridazinone, 50 g of 1,3-propanediol, 3.0 g of 85 % potassium hydroxide and 50 ml of N,N-dimethylformamide was reacted for 24 hours at room temperature, then to the reaction solution was added water and extracted with ethyl acetate, dried and freed of solvent to obtain 9.4 g of the intended compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:18]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1

Procedure:
12.7 Grams (0.0917 mol) of p-hydroxybenzoic acid was added to 150 ml of dichloromethane, and to this suspension was added 10.2 g (0.0917 mol) of triethylamine. The mixture was stirred until a homogeneous solution was formed. 19.7 Grams (0.096 mol) of undecanoyl chloride was added to the solution at such a rate that the dichloromethane was not refluxed. Then, 1.0 g (0.0085 mol) of 4-dimethylaminopyridine was added, and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to the reaction mixture and the mixture was subjected to extraction with ether. The ether was distilled off, and the resultant crude product was washed with hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.Cl.[Cl:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[ClH:11].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: ClCCNCc1ccccc1
Agent: Cl
Product: COc1cccc(NCCNCc2ccccc2)c1

Procedure:
Combine 3-methoxybenzenamine (81.2 g, 0.66 mol) with N-(2-chloroethyl)-benzenemethanamine hydrochloride (45.3 g, 0.22 mol) and heat to 190° C. for 13 h. Add methylene chloride to precipitate a solid. Filter the solid and wash with methylene chloride. Triturate the solid with 100 mL of ethanol, filter the solid and wash with ethanol to give the title compound.
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=[N:28][C:29]1([CH2:44][C:45]#[CH:46])[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:30]1=[O:43])(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[NH2:28][C:29]1([CH2:44][C:45]#[CH:46])[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])[C:30]1=[O:43]
Reactant: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCCN(COCC[Si](C)(C)C)C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C#CCC1(N)CCCN(COCC[Si](C)(C)C)C1=O
Reaction time: 120 h
Yield: 77.7 %

Procedure:
Citric acid monohydrate (1.58 g, 7.5 mmol) was added to a solution of 3-(benzhydrylideneamino)-3-prop-2-ynyl-1-(2-trimethylsilylethoxymethyl)piperidin-2-one (which may be prepared as described in Description 23) (1.34 g, 3 mmol) in THF (30 mL) at 20° C. and the reaction was stirred for 5 days. The solution was evaporated and loaded onto an SCX cartridge (10 g) then eluted with MeOH, followed by 2M NH3 in MeOH. The fractions containing the desired product were collected and evaporated to afford 3-amino-3-prop-2-ynyl-1-(2-trimethylsilylethoxymethyl)piperidin-2-one (658 mg, 2.3296 mmol, 77.7% yield) as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CS([Cl:37])(=O)=O>C(Cl)Cl>[Cl:37][CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(CO)n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(CCl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 4-(6-hydroxymethylpyridine-2-carbonyl)-piperazine-1-carboxylate (1.26 g) and diisopropylethylamine (1.0 g) were dissolved in 20 mL of methylene chloride, 0.1 mL of methanesulfonyl chloride was added dropwise into the above solution at ice temperature, and the mixture was stirred at room temperature overnight. After the solvent was removed under reduced pressure from the reaction mixture, the residue was purified by chromatography on silica gel (methylene chloride-ethanol=40:1) to give 1.07 g of t-butyl 4-(6-chloromethylpyridine-2-carbonyl)piperazine-1-carboxylate as a colorless oil.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=O.C([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)C.[N+](C1C=CC=CC=1)([O-])=O>>[N+:8]([C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[N:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:13]=1)[O-:10]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: CCc1ccccc1[N+](=O)[O-]
Solvent: O=[N+]([O-])c1ccccc1
Product: [O-][N+](=Nc1ccccc1)c1ccccc1

Procedure:
The reduction reaction was carried out in the same manner as set forth in Example 6 except for using a mixture of 1.0 mmol of o-methyl nitrobenzene and 1.0 mmol of o-ethyl nitrobenzene instead of using nitrobenzene alone, and using 19.5 mg (the amount required for swelling of the reactant in 100%) of Polymer supported reagent-2, and thereby an azoxybenzene derivative of a symmetrical structure and an azoxybenzene derivative of an asymmetrical structure were obtained as a main product, respectively.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([CH3:15])([CH3:14])[S:4]1)[OH:2].[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([CH3:15])([CH3:14])[S:4]1)=[O:19]
Reactant: CN=C=O
Reactant: CC1(C)SC(=NO)N=C1C1CCCCC1
Product: CNC(=O)ON=C1N=C(C2CCCCC2)C(C)(C)S1

Procedure:
2-oxo-4-cyclohexyl-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-cyclohexyl-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 158°-160° C. The 2-oxo-4-cyclohexyl-5,5-dimethyl-3-thiazoline-oxime starting material melts at 159°-162° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([C@H:13]2[C@H:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]3)=[O:23])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 95.7 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (130 mg, 0.24 mmol) in CH2Cl2 (5 ml) was added TFA (1 ml) at RT. Stirring was continued over night. The reaction mixture was then concentrated under vacuo, the crude dissolved in CH2Cl2, washed with aq.NaHCO3 and the organic phase was dried over Na2SO4. Purification by flash chromatography (SiO2, CH2Cl2/MeOH 95:5) yielded 100 mg (92%) of the title compound as light yellow oil. ES-MS m/e: 435.37 (M+H+).