Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:11][C:12]1[CH:19]=[CH:18][C:17]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:35])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH2:31][NH:30][CH2:29][CH2:28]4)[N:21]=2)=[CH:16][C:13]=1[C:14]#[N:15])[CH3:10].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][N:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([C:22]3[N:21]=[C:20]([C:17]4[CH:18]=[CH:19][C:12]([O:11][CH:9]([CH3:8])[CH3:10])=[C:13]([C:14]#[N:15])[CH:16]=4)[O:24][N:23]=3)[C:26]=2[CH3:35])[CH2:31]1)[CH3:42]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCNC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)CN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A mixture of 2-[(1-methylethyl)oxy]-5-[3-(5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl)-1,2,4-oxadiazol-5-yl]benzonitrile trifluoroacetic acid salt (Example 11; 100 mg, 0.20 mmol), ethyl bromoacetate (44 mg, 30 μl, 0.26 mmol) and caesium carbonate (200 mg, 0.61 mmol) in dry DMF (3 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3×5 ml). The combined extracts were dried and evaporated. Purification by chromatography on silica gel, eluting with 10% ethyl acetate in cyclohexane gave the title compound as a colourless oil (85 mg). MS m/z 461 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.CC1C=C(C)N2N=C(C=O)N=C2N=1.[CH:26]1([C:31]2([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=3[O:49][CH3:50])[O:36][C:35](=[O:37])[CH:34]=[C:33]([OH:38])[CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC>>[CH:26]1([C:31]2([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=3[O:49][CH3:50])[O:36][C:35](=[O:37])[C:34]([CH2:11][C:9]3[N:10]=[C:5]4[N:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]4[N:8]=3)=[C:33]([OH:38])[CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1cnc2nc(C=O)nn2c1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)c(OC)c1
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(C)cn4n3)C(=O)O2)c(OC)c1

Procedure:
The title compound was prepared analogously to Example B(97) where 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-Cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dione of that example. 1H NMR (400 MHz, DMSO-d6): δ 1.36–1.72 (m, 8H), 1.93–2.02 (m, 2H), 2.35 (s, 3H), 2.42–2.58 (m, 2H), 2.76 (d, J=16 Hz, 1H), 3.34 (s, 6H), 3.69 (s, 2H), 3.73 (s, 2H), 6.46 (dd, J=8, 2.5 Hz, 1H), 6.49 (d, J=2.5 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.70 (d, J=2.5 Hz, 1H), 8.85–8.87 (m, 1H), 10.8 (s, 1H). Anal. Calcd. For C27H32N4O5: 0.1H2O: C, 63.51; H, 6.71; N, 10.97. Found: C, 63.50; H, 6.70; N, 10.87. MS (ESI): 493 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][S:10][C:11]2[C:21]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:29])=[CH:7][CH:6]=1)(=O)[CH3:2].[CH:32]1(O)[CH2:38][CH2:37]CC[CH2:34][CH2:33]1>>[ClH:29].[Cl:29][C:12]1[CH:13]=[CH:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[C:11]=1[S:10][CH2:9][C:8]1[CH:30]=[CH:31][C:5]([O:4][CH:1]2[CH2:2][CH2:37][CH2:38][CH2:32][CH2:33][CH2:34]2)=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: OC1CCCCCC1
Product: Cl
Product: Clc1ccc2c(c1SCc1ccc(OC3CCCCCC3)cc1)CCNCC2

Procedure:
Use a method similar to the Example 423 to react 6-(4-acetoxybenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine with cycloheptanol. Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 416 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CS(=O)(=O)Cl
Product: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Yield: 34.3 %

Procedure:
Using the general method of Example 245, 1-(4-aminobutyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 4.6 mmol) was reacted with methanesulfonyl chloride (0.57 mL, 7.4 mmol) to provide 636 mg of N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as an off white solid, m.p. 136.8-138.1° C. Analysis: Calculated for C20H29N5O2S: %C, 59.53; %H, 7.24; %N, 17.35; Found: %C, 59.50; %H, 7.31; %N, 16.80.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[O:12][C:11]([CH2:13][NH:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][NH:19][C:18]3=[C:22]([C:25]#[N:26])[C:23]#[N:24])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:29]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:29][N:14]([CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[C:22]([C:23]#[N:24])[C:25]#[N:26])[CH2:13][C:11]1[O:12][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1
Reactant: N#CC(C#N)=C1NCCN1CCNCc1ccc(CN2CCCCC2)o1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(CCN1CCNC1=C(C#N)C#N)Cc1ccc(CN2CCCCC2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
In 15 ml of acetonitrile were dissolved 904 mg (2.55 mmol) of Compound 28 and 1 ml (12.3 mmol) of 37% aqueous formalin followed by gradual addition of 271 mg (4.30 mmol) of sodium cyanoborohydride at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and, then, adjusted to pH 7.2 with acetic acid. The reaction mixture was further stirred at room temperature for 45 minutes, at the end of which time the solvent was distilled off under reduced pressure. The residue was diluted with 2N sodium hydroxide solution and extracted with methylene chloride. The organic layer was washed with 0.1N sodium hydroxide solution once and, then, extracted with 1N hydrochloric acid twice. The aqueous layer was adjusted to pH 7.8 with 1N sodium hydroxide solution and re-extracted with 4 portions of methylene chloride. The pooled organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. Finally the residue was purified by silica gel column chromatography (chloroform-methanol=10:1) to give 244 mg (26.0%) of Compound 45 as colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([Cl:8])=[O:7])[N:3]=[CH:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>O1CCOCC1>[ClH:8].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)c1cocn1
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=O)c4cocn4)CC3)nc(N)c2cc1OC
Product: Cl
Temperature: 20 °C
Reaction time: 64 h

Procedure:
A solution of oxazole-4-carbonyl chloride (0.73 g., 5.53 mmole) in dioxane was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.60 g., 5.53 mmole) in dioxane. The mixture was heated at reflux for 0.5 hour, then was stirred at 20° C. for 64 hours. Filtration gave the title compound having a m.p. of 291°-294° C. with decomposition after recrystallization from acqueous ethanol.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[CH:10]=[C:11]([CH2:19][C:20]([NH2:22])=[O:21])[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.C[O:24][C:25](=O)[C:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH3:37])[CH:29]=1)=O.CC([O-])(C)C.[K+]>C1COCC1>[CH2:2]1[C:3]2([CH2:8][N:7]([C:9]3[CH:10]=[C:11]([C:19]4[C:20](=[O:21])[NH:22][C:25](=[O:24])[C:26]=4[C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:1]1
Reactant: COC(=O)C(=O)c1cn(C)c2ccccc12
Reactant: NC(=O)Cc1cc(N2CCNC3(CC3)C2)cc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3cc(N4CCNC5(CC5)C4)cc4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 0.08 h

Procedure:
2-[3-(4,7-Diaza-spiro[2.5]oct-7-yl)-naphthalen-1-yl]-acetamide (100 mg, 0.30 mmol) and (1-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (97 mg, 0.44 mmol) are azeotroped three times with dry THF and then dissolved in dry THF (3 ml). A solution of 1.0 M KOtBu in THF (1.2 ml) is added dropwise over 20 minutes at RT. After 5 minutes, TLC analysis indicates complete conversion of starting materials. The reaction is quenched by the additon of water (5 ml). The mixture is diluted with EtOAc and washed twice with saturated aq. NH4Cl. The aqueous layers are back extracted twice with EtOAc. The combined organic layers are dried over Na2SO4 and the solvent is evaporated. The residue is purified by FCC EtO/Ac/AcOH/H2O 800:55:45) to afford the title compound as its acetate salt. The compound is dissolved in MeOH/TFA and the solvent is removed to yield the title compound as its trifluoroacetate salt. 1H NMR (DMSO, 400 MHz) δ 0.95 (M, 4H), 3.39 (br, 4H), 3.49 (br, 2H), 3.86 (s, 3H), 6.16 (d, J=7.9 Hz, 1H), 6.46 (dd, J=6.6/7.9 Hz, 1H), 7.00 (dd, J=/7.9 Hz, 1H), 7.13 (dd, J=7.6/7.6 Hz, 1H), 7.40 (m, 4H), 7.55 (d, J=8.5 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 8.14 (s, 1H), 9.10 (br, 2H), 11.17 (s, 1H); ES-MS: 463 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:38])([CH2:32]OS(C)(=O)=O)[CH2:25][CH2:26]OS(C)(=O)=O)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:39])=[N:5]1)([CH3:3])[CH3:2]>C(N)(C)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][C:24]5([CH3:38])[CH2:25][CH2:26][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:32]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:39])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CCOS(C)(=O)=O)COS(C)(=O)=O)cc2OCC3)n(C(C)C)n1
Solvent: CC(C)N
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(C)CCN(C(C)C)C4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C

Procedure:
A solution of methanesulfonic acid 3-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-4-methanesulfonyloxy-3-methylbutyl ester from Example 51 (0.0318 mmol) in isopropylamine (0.7 mL) was heated at 90° C. for 1 h in a sealed vial and then at 130° C. for 2 h using microwave irradiation. After cooling to RT, the crude reaction mixture was purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH affording 261 as a colorless gum (10 mg, 69% over two steps). LCMS: RT 2.80 min [M+H]+ 451.1. 1H NMR (CD3OD, 400 MHz): δ 8.33 (1H, d, J=8.96 Hz), 7.68 (1H, s), 6.75 (1H, dd, J=8.96, 2.51 Hz), 6.60 (1H, d, J=2.49 Hz), 5.93-5.82 (1H, m), 4.49 (4H, s), 3.24 (1H, bd, J=10.84 Hz), 2.99-2.89 (1H, m), 2.76 (1H, bd, J=10.76 Hz), 2.73-2.64 (1H, m), 2.53-2.37 (2H, m), 2.36 (3H, s), 2.11-2.02 (1H, m), 1.60 (3H, s), 1.53 (6H, d, J=6.65 Hz), 1.14 (6H, d, J=6.35 Hz)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[OH-].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
A mixture of 5.04 g (40 mmol) 3-fluorobenzyl alcohol and 1.29 g (4 mmol) tris-(dioxa-3,6-heptyl)amine is treated with 2.47 g (44 mmol) of potassium hydroxide. The mixture is stirred at room temperature for 10 min, then 5.55 g (44 mmol) of 4-fluoro-nitrobenzene is slowly added through a dropping funnel. The mixture is kept for 45 min at 80° C., cooled to room temperature and diluted with about 75 ml water. Extraction with ethyl acetate and washing with 2M aqueous hydrochloric acid yields a yellowish organic phase, which is dried and evaporated. The residue is recrystallised from methanol to give 6.07 g (61%) of the title compound. Yellow crystals, mp=104-105° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:15][NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:52]=[N+:53]=[N-:54].CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:15][NH:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:13][N:52]=[N+:53]=[N-:54])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N
Reactant: O=C(N[C@H](CO)CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC[C@H](CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-2-(benzyloxycarbonylamino)-3-(4-phenoxybenzene sulfonamido) propanol (0.45 g, 1.0 mmol) in toluene (10 mL) was added PPh3 (0.28 g, 1.1 mmol) and the mixture was stirred at RT for 5 min. After adding hydrazoic acid (1.25 M in toluene, 1.04 mL, 1.3 mmol), DEAD (0.17 mL, 1.1 mmol) was added dropwise. The reaction mixture was stirred at RT for 30 min, filtered and solvent was evaporated. The crude residue was chromatographed (silica gel, 30% EtOAc in n-hexane) to afford (R)-2-(benzyloxycarbonylamino)-3-(4-phenoxybenzenesulfon amido) propyl azide as white solid in 60% (0.29 g) yield.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=2)[N:10]1[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)C.[Pt](=O)=O>[CH2:6]([O:5][P:4]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=2)[N:10]1[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:28])[Cl:29])=[O:24])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)C1C=Cc2cc(C(F)(F)F)ccc2N1C(=O)OCC(Cl)(Cl)Cl
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOP(=O)(OCC)C1CCc2cc(C(F)(F)F)ccc2N1C(=O)OCC(Cl)(Cl)Cl

Procedure:
71.6 g of 1-(2,2,2-trichloroethoxycarbonyl)-6-trifluoromethyl-1,2-dihydroquinoline-2-phosphonic acid diethyl ester is dissolved in 800 ml of ethanol, mixed with 3.6 g of platinum(IV)-oxide and hydrogenated at normal pressure. It is filtered, concentrated by evaporation and recrystallized from isopropyl ether.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:16])[C:13]([CH3:15])([CH3:14])[O:12][BH:11][O:10]1.O1CCOCC1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:36][C:37]1[CH:42]=[CH:41][C:40](I)=[CH:39][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([B:11]2[O:12][C:13]([CH3:15])([CH3:14])[C:9]([CH3:16])([CH3:8])[O:10]2)=[CH:41][CH:42]=1)[C:32]([O:34][CH3:35])=[O:33])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC1(C)OBOC1(C)C
Reactant: COC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 14 h

Procedure:
PdCl2(dppf) (127 mg), triethylamine (2.14 ml), 4,4,5,5-tetramethyl-1,3,2-dioxaborolan (1.13 ml) and 1,4-dioxane (21 ml) were added to methyl (2S)-2-[(t-butoxycarbonyl)amino]-3-(4-iodophenyl)propionate (1.8 g) and stirred at 100° C. for 14 hours. The reaction solution was diluted with ethyl acetate, washed with water and dried over magnesium sulfate to remove the solvent. The residue was purified with a silica gel chromatography (hexane-ethyl acetate) to obtain the title compound (1.05 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[OH:11].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.ClCCCl.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(NCc2ccc(Br)cc2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of 4-amino-2-hydroxy benzoic acid methyl ester (836 mg; 5 mmol) and 4-bromobenzaldehyde (926 mg; 5 mmol) in 1 M HOAc in 1,2-dichloroethane (5 mL) was added at once NaBH(OAc)3 (1.49 g; 7 mmol) and the reaction mixture was stirred at room temperature overnight. Water (25 mL) was added and the inhomogeneous mixture was neutralized using solid NaHCO3. The organic layer was isolated, dried, evaporated to dryness and recrystallised from isopropyl ether/dichloromethane/heptane to yield 970 mg (58%) of a yellow solid. NMR and GC-MS in accordance with structure.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:2].C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:19][CH:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ncsc1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COC(=O)c1scnc1C(C)Br

Procedure:
Following the procedure of Example 28, methyl 4-ethyl-5-thiazolecarboxylate is reacted with NBS and AIBN to give methyl 4-(1-bromoethyl)-5-thiazolecarboxylate, which is then reacted with sodium bicarbonate, or alteratively with potassium carbonate, and DMSO and the resulting methyl 4-acetyl-5-thiazolecarboxylate is treated with lithium hydroxide monohydrate to yield 4-acetyl-5-thiazolecarboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(O)C.[CH3:14][NH:15][CH3:16]>O1CCCC1.O>[CH3:14][N:15]([CH3:16])[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(=O)c1ccc(Cl)nc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)c1ccc(N(C)C)nc1
Yield: 99 %

Procedure:
500 mg (2.89 mmol) of 1-(6-chloropyrid-3-yl)ethanone, 2 mL of ethanol and 7.23 mL (14.46 mmol) of 2 M dimethylamine in tetrahydrofuran are placed in a 20 mL microwave reactor. The solution is irradiated with microwaves for 10 minutes at 130° C. The mixture obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to dryness to give 470 mg of 1-(6-dimethylaminopyrid-3-yl)ethanone, the characteristics of which are as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[NH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:17][N:8]1[C:7]2[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[N:10]=[C:9]1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2[nH]c(C(F)(F)F)nc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(C(F)(F)F)nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
5-Nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (4.45 g, 19.1 mmol, 1.0 eq.), K2CO3 (3.2 g, 23.0 mmol, 1.2 eq.) and methyliodide (1.2 ml, 19.1 mmol, 1.0 eq.) were dissolved in DMF (anhydrous, 50 ml). The reaction was stirred at RT for 2 h. TLC showed mostly starting material. The mixture was stirred at RT for another 16 h. The DMF was removed in vacuo and the residue redissolved in a minimum of hot EtOAc and recrystallized (gave mixture). Crystals and mother liquor were combined and evaporated down. Purification by column chromatography (0-25% EtOAc/Hex) yielded 1-methyl-5-Nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (1 g) and 1-methyl-6-Nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole. Structures confirmed by NOESY NMR.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[C@@H:24]([OH:25])[C@:23]([F:27])([CH3:26])[CH:22]([O:28][CH3:29])[O:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Si:1]([O:18][CH2:19][C@@H:20]1[C:24](=[O:25])[C@:23]([F:27])([CH3:26])[CH:22]([O:28][CH3:29])[O:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@@]1(C)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)[C@@]1(C)F
Yield: 150.8 %

Procedure:
A solution of (2R,3R,4R)-2-((tert-butyldiphenylsilyloxy)methyl)-4-fluoro-5-methoxy-4-methyl-tetrahydrofuran-3-ol (about 16 g, 38.2 mmol) and Dess-Martin periodinane (about 24.3 g, 57.4 mmol) in dichloromethane (about 150 ml) stirred at about 0° C. to room temperature under Nitrogen atmosphere. Completion of the reaction monitored by thin-layer chromatography and quenched by the saturated solution of sodium sulphate and sodium bicarbonate in equal volumes (100 ml+100 ml). The aqueous layers were extracted with dichloromethane and the combined organic extracts were washed with water, brine and dried over sodium sulphate and concentrated under reduced pressure to yield the title compound (24 g as crude). 1H NMR (300 MHz, CDCl3): δ 7.69-7.67 (m, 4H), 7.42-7.39 (m, 6H), 5.07 (d, 1H, J=12.3 Hz), 4.38 (dd, 1H, J=5.1 Hz, 3.3 Hz), 3.889-3.83 (m, 2H), 3.46 (s, 3H), 1.42 (d, 3H, J=24 Hz), 1.03 (s, 9H); Mass: [M+Na]+: 439 (65%); IR cm−: 2934, 2859, 1783, 1382, 1114, 998, 703.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.C(N(CC)CC)C.[CH2:24](Br)[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>C(Cl)(Cl)Cl>[O:26]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[NH:3][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccc1
Yield: 82.2 %

Procedure:
To a solution comprising 2.3 g of 4-(2-keto-1-benzimidazolinyl)-piperidine, 1.1 g of triethylamine, and 20 ml of chloroform is added 2.2 g of phenacyl bromide, and the reaction is carried out under the same conditions as in Example 1. The same post-treatment as in Example 1 is conducted to obtain 3.2 g of a crude product. Recrystallization of the product from a mixture solution of ethanol and ethyl acetate (2:3 by volume) yields 2.92 g of 1-[2-oxo-2-phenyl-1-ethyl]-4-(2-keto-1-benzimidazolinyl)-piperidine.