Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].C(OC(=O)[CH:20]=[CH:21][C:22](=[O:30])[CH:23]=[CH:24]C(OCC)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:24][CH2:23][C:22](=[O:30])[CH2:21][CH2:20]1
Reactant: CCOC(=O)C(C)c1ccc(N)c(Cl)c1
Reactant: CCOC(=O)C=CC(=O)C=CC(=O)OCC
Product: CC(C(=O)O)c1ccc(N2CCC(=O)CC2)c(Cl)c1

Procedure:
Moreover, the 4-fluoro-phenyl-acetonitrile can be reacted with 4-oxo-piperidine, to yield the 4-(4-oxo-piperidino)-phenyl-acetonitrile, which can be hydrolyzed to the free acid and the acid esterified, or the ethyl α-(3-chloro-4-aminophenyl)-propionate reacted with 4-oxo-2,5-heptadienedioic acid diethyl ester, saponifying and decarboxylating the reaction product, to yield the α-[3-chloro-4-(4-oxo-piperidino)-phenyl]-propionic acid. In corresponding esters, the carbonyl group can be reduced with one equivalent of Grignard compounds, e.g. methyl-, ethyl-, n-propyl-, phenyl- or 4-chlorophenyl-magnesium bromide, to yield, inter alia, the ethyl 4-[4-hydroxy-4-(methyl, ethyl, n-propyl, phenyl or 4-chlorophenyl)-piperidino]-phenyl acetate or α-[3-chloro-4-(4-hydroxy-4-methylpiperidino)-phenyl]-propionate. Said esters or the corresponding acids can be dehydrated wtih sulfuric or phosphoric acid, to yield, for example, the 4-(3-n-propyl-pent-2-enyleneimino)-phenylacetic acid or the α-[3-chloro-4-(3-methylpent-2-enyleneimino)-phenyl]-phenyl]-propionic acid.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:6][CH:7]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: CC(C)(O)c1nc(C(=O)O)co1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1coc(C(C)(C)O)n1
Reaction time: 48 h
Yield: 72 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylic acid (2.153 mmol, 0.368 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (2.153 mmol, 0.6 g) and using HBTU (0.215 mmol, 0.082 g) instead of HOBt. DCM (15 ml) was used as the solvent. During the reaction a new batch of starting materials was added to the reaction mixture. The batch contained half the amount of starting materials used in the beginning of the reaction with the exception that (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile was not added at all. The resulting mixture was stirred for 2 days. The mixture was diluted with DCM and washed with Na2CO3 solution and water. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.669 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.13 (d, 3H), 1.52 (s, 6H), 4.27-4.54 (m, 3H), 5.63 (s, 1H), 7.02 (d, 1H), 7.83-7.89 (m, 2H), 7.98 (s, 1H), 8.10 (d, 1H), 8.48 (s, 1H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=[O:2].[NH+]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:12]=[C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1>>[O:12]=[C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.[O:2]=[CH:7][CH:8]=[C:9]1[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: c1cc[nH+]cc1
Agent: COC(=O)C1CCC(=O)CC1
Product: COC(=O)C1CCC(=CC=O)CC1

Procedure:
The epoxides used as the starting materials in the general process described above can be obtained from available starting materials using an appropriate series of reactions. Thus, methyl 4-hydroxybenzoate is hydrogenated using 5% rhodium on alumina as catalyst to give methyl 4-hydroxycyclohexanecarboxylate. This is then oxidized with pyridinium chlorochromate resulting in methyl 4-oxocyclohexanecarboxylate. The 2-carbon homologation of methyl 4-oxocyclohexanecarboxylate to give methyl 4-(oxoethylidene)cyclohexanecarboxylate is carried out using the method developed by A. I. Meyers. Acetaldehyde t-butylimine is metalated with lithium diisopropylamide and then treated with diethyl chlorophosphate to provide the lithioeneaminephosphonate. Addition of methyl 4-oxocyclohexanecarboxylate and subsequent acid hydrolysis gives methyl 4-(oxoethylidene)cyclohexanecarboxylate. The reduction of this oxoethylidene compound with sodium borohydride gives methyl 4-(2-hydroxyethylidene)cyclohexanecarboxylate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[ClH:9].CN.[CH2:12]([N:14](CC)CC)C>ClCCCl>[ClH:9].[CH3:12][NH:14][CH:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1CCC(=O)CC1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCCl
Product: CNC1CCC(C)CC1
Temperature: 25 °C

Procedure:
In 1,2-dichloroethane (35 ml) were suspended 4-methylcyclohexanone (2.5 g), methylamine hydrochloride (1.6 g) and triethylamine (3.3 ml), and to the suspension was added sodium triacetoxy boron hydride (6.6 g) under ice-cooling. The mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated. To the residue was added 4N hydrochloric acid-ethyl acetate, and the solvent was evaporated to give N, 4-dimethyl-cyclohexylamine hydrochloride (2.6 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][C:3]=1[NH:11][CH2:12][CH:13]([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](Cl)=[O:30])=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O>[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][C:3]=2[NH:11][CH2:12][CH:13]([CH3:14])[CH3:15])=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CCOc1ccc(N)c(NCC(C)C)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1ccc(NC(=O)COc2ccc(Cl)cc2)c(NCC(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
To a mixture of 55 (2.08 g, 0.01 mol) and K2CO3 (3.45 g, 0.025 mol) in CH3CN (25 mL) was added a solution of 56a (2.46 g, 0.012 mol) in CH3CN (25 mL) over 45 min at rt under Ar. After stirring at rt for 3 hr, EtOAc (100 mL) and saturated NaHCO3 (100 mL) where added. The resulting mixture was stirred at rt for 10 min. The organic phase was washed with saturated NaHCO3 (1×75 mL) and brine (1×100 mL), filtered through phase separation filter paper, and concentrated in vacuo to give a solid. The solid was triturated with hexanes (100 mL), filtered, and dried to give 3.5 g (93%) of 58a as a purple solid. HPLC analysis showed a purity of 91%. 1H NMR (60 MHz, CDCl3): δ 7.6 (brs, 1H), 7.3-6.7 (m, 5H), 6.2 (m, 2H), 4.6 (s, 2H), 4.0 (q, 2H), 3.6 (brs, 1H), 2.8 (brs, 2H), 2.0-1.6 (m, 1H), 1.4 (t, 3H), 1.0 (d, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[CH:9][N:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[N:11]=2)[CH:5]=[N+:6]([O-])[CH:7]=1.P(Br)(Br)([Br:22])=O>ClCCCl>[Br:22][C:5]1[C:4]2=[CH:9][N:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[N:11]=[C:3]2[C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: [O-][n+]1cc(Cl)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Solvent: ClCCCl
Product: Clc1cccc(Cl)c1-n1cc2c(Br)ncc(Cl)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
To a cooled (0° C.) suspension of 7-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-5-oxide (2.5 g, 8.0 mmol) in DCE (50 mL) was added phosphorus oxybromide (6.8 g, 24.0 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, warmed to room temperature, and stirred for a further 18 hours. The reaction mixture was partitioned between DCM and sodium carbonate (sat. aq.). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in cyclohexane) to afford the title compound as a white solid (850 mg, 28% yield). LCMS (Method D): RT=3.92 min, m/z: 377 [M+H+].
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:28](OCCC)[CH2:27][C@@:26]2([CH3:33])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:34])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH2:13][S:14]([CH2:17][CH2:18][CH2:19][OH:20])(=[O:16])=[O:15])[CH2:3]1.[CH3:35][CH2:36]CCCC.CC(C)=O>>[C:35]([C@@:2]1([OH:1])[CH2:28][CH2:27][C@@:26]2([CH3:33])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:34])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:21])[CH2:13][S:14]([CH2:17][CH2:18][CH2:19][OH:20])(=[O:16])=[O:15])[CH2:3]1)#[CH:36]
Reactant: CCCCCC
Reactant: CCCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CS(=O)(=O)CCCO)CC[C@@H]32)C[C@@H]1O
Solvent: CC(C)=O
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CS(=O)(=O)CCCO)CC[C@@H]32)C1

Procedure:
Similarly prepared was 3α-hydroxy-21-(3′-hydroxypropylsulfonyl)-2β-propoxy-5α-pregnan-20-one; TLC Rf (hexane:acetone 2:1)=0.26.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[C:10]([CH3:24])([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[CH:27]=[C:28]([N+:33]([O-:35])=[O:34])[C:29]([CH3:32])=[N:30][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:26]2[CH:31]=[N:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)[C:10]([CH3:23])([CH3:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C(C)(C)C1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ncc(C2=CCN(C(=O)OC(C)(C)C)CC2(C)C)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
To a solution of tert-butyl-3,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.12 g, 6.28 mmol) in 1,4-dioxane (90 mL) were added 5-bromo-2-methyl-3-nitropyridine (1.64 g, 7.54 mmol), tetrakis(triphenylphosphine)palladium (642 mg, 0.556 mmol), potassium phosphate (4.96 g, 23.4 mmol) and water (22 mL). The reaction mixture was flushed with nitrogen gas and allowed to stir for 24 h at 80° C. The reaction mixture was filtered through a Celite® pad and washed with DCM. The filtrate was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl-3′,3′,6-trimethyl-5-nitro-3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate (1.3 g, 60%) as a white solid. LCMS (FA): Rt=2.16 min, m/z=348.3 (M+H).
Reaction SMILES: C([N:8]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]([C:22]([C:24]3[CH:36]=[CH:35][C:27]([CH2:28][NH:29][C:30]([CH:32]4[CH2:34][CH2:33]4)=[O:31])=[C:26]([CH3:37])[CH:25]=3)=[O:23])[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]1[CH3:38])C1C=CC=CC=1.C1C=C2C(N/N=C3/C4C=CC(S([O-])(=O)=O)=CC=4C=C(S([O-])(=O)=O)C/3=O)=CC=C(S([O-])(=O)=O)C2=CC=1.[Na+].[Na+].[Na+].N1CCCC(=O)C2C=CC=CC1=2.C1CCCCC=1>C(O)C.[Pd]>[CH3:37][C:26]1[CH:25]=[C:24]([C:22]([N:14]2[CH2:13][CH2:12][C:11]3[N:10]=[C:9]([CH3:38])[NH:8][C:17]=3[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=3)=[O:23])[CH:36]=[CH:35][C:27]=1[CH2:28][NH:29][C:30]([CH:32]1[CH2:33][CH2:34]1)=[O:31]
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CNC(=O)C1CC1
Agent: [Pd]
Agent: O=C1C(S(=O)(=O)[O-])=Cc2cc(S(=O)(=O)[O-])ccc2/C1=N/Nc1ccc(S(=O)(=O)[O-])c2ccccc12
Agent: O=C1CCCNc2ccccc21
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccc(CNC(=O)C3CC3)c(C)c1)CC2
Temperature: 60 °C
Yield: 53 %

Procedure:
Cyclopropanecarboxylic acid 4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzylamide from Example E123.1 (155 mg, 0.31 mmol) was dissolved in absolute ethanol (10 ml) and placed under an inert atmosphere. 10% Palladium on car-bon (155 mg) and cyclohexene (0.311 ml, 3.1 mmol) were added and the mixture was heated at 60° C. for 18 h. The catalyst was filtered off through Celite® filter agent and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (67 mg, 53%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:15])[CH2:11][N+:12]([O-:14])=[O:13].[CH:16](OC(=O)C)=O>O>[N+:12]([C:11]1[C:10](=[O:15])[C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[O:1][CH:16]=1)([O-:14])=[O:13]
Reactant: CC(=O)OC=O
Reactant: COc1ccc(C(=O)C[N+](=O)[O-])c(O)c1
Solvent: O
Product: COc1ccc2c(=O)c([N+](=O)[O-])coc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3-Nitro-7-methoxy-4H-1-benzopyran-4-one was prepared by the addition of 1-(2-hydroxy-4-methoxyphenyl)-2nitro ethanone (2.11 g, 0.01m), prepared in Example 8, and sodium formate (0.68 g, 0.01m) to stirred acetic-formic anhydride (25 ml). The reaction was warmed to 80° C. and allowed to return to room temperature. After stirring at least an additional 1 hour, cold water (100 ml) was added. The product was filtered off, washed with fresh portions of water and sucked dry. Recrystallization from ethyl acetate gave yellow crystals (1.7 g, 77.5%), m.p. 185°-87° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:17]=[C:16](S(C)(=O)=O)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:34]#[N:35].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:17]=[C:16]([C:34]#[N:35])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(S(C)(=O)=O)n2)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.9 %

Procedure:
To a stirring solution of 4-[2-methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (720 mg) in dimethyl sulphoxide (17 ml) was added sodium cyanide (72.5 mg). The resulting solution was stirred at room temperature for 24 hrs. After diluting with ethyl acetate (100 ml), then washed with water (4×50 ml), brine (50 ml), dried over MgSO4 and concentrated in vacuo. The residual solid was columned on silica gel using heptane and ethyl acetate (2:1) as eluant to give a white solid (230 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:11])([CH2:9][CH3:10])[NH:3]1.[OH-].[K+]>C(O)COCCO.O>[CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][CH2:5][C:4]([CH3:11])([CH2:9][CH3:10])[NH:3]1
Reactant: CCC1(C)CC(=O)CC(C)(C)N1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCC1(C)CCCC(C)(C)N1
Yield: 19.4 %

Procedure:
33.8 g (02 mol) 2,2,6-trimethyl-6-ethyl-4-oxopiperidine, 14 g (0.28 mol) hydrazinhydrate and 13 g KOH in 80 ml diethylenglykol are stirred for 4 h at 160° C. Subsequently an aciditional amount of 30 g KOH dissolved In 30 ml water are acided. 30 ml are distilled off. To the residue two times 40 ml of water are acided and removed by distillation. The combined distillates are saturated with solid K2CO3 and extracted with methyl-tert.-butylether. From the extracts 6 g ( 19%) 2,2,6-trimethyl-6-ethyl-piperidine are isolated by fractionated distillation. A colorless liquid is obtained with a b. p. of 78-88° C./15 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2
Reactant: CCCCCCC(=O)c1cc2cc(Cl)ccc2n1C
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCC(Nc1ccc(C(=O)OC)cc1)c1cc2cc(Cl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a mixture of 1-(5-chloro-1-methyl-1H-indol-2-yl)heptan-1-one (1.05 g) synthesized above, methyl 4-aminobenzoate (629 mg), triethylamine (4.21 mL) and methylene chloride (10 mL) was added a 1.0M solution (4.54 mL) of titanium (IV) chloride in methylene chloride at 0° C., and the mixture was stirred overnight at room temperature under argon atmosphere. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown solid. To a solution (10 mL) of the obtained solid in tetrahydrofuran were added acetic acid (1.08 mL) and sodium cyanoborohydride (475 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexane) to give the title object compound (1.15 g, 74%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:3]=1[O:4][C@@H:5]([CH3:9])[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[NH2:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[CH:37]=[C:36]([CH2:38][CH3:39])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[C@@H:27]([F:40])[C@@H:26]1[OH:41]>C1(C)C=CC=CC=1.CN(C)C=O.[OH-].[Na+]>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:3]=1[O:4][C@@H:5]([CH3:9])[C:6]([NH:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[CH:37]=[C:36]([CH2:38][CH3:39])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[C@@H:27]([F:40])[C@@H:26]1[OH:41])=[O:8]
Reactant: CCc1cn([C@@H]2O[C@H](CN)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Reactant: COc1cc(O[C@@H](C)C(=O)O)c(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1cn([C@@H]2O[C@H](CNC(=O)[C@H](C)Oc3cc(OC)c(Cl)cc3Cl)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Yield: 70.7 %

Procedure:
24.2 g (0.091 mol) of (S)-2-(2,4-dichloro-5-methoxyphenoxy)-propionic acid were suspended in a mixture of 150 ml of toluene and 0.5 ml of dimethylformamide and the suspension was stirred under nitrogen. 15.0 ml (0.17 mol) of oxalyl chloride were added, with vigorous evolution of gas occurring. The mixture was stirred for 1 hour to give a homogeneous solution. The solvents were removed by evaporation, the residue was taken up in 100 ml of diethyl ether and the solution was added to a solution of 24.6 g (0.090 mol) of 1-(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil in 290 ml of 0.31M sodium hydroxide solution. The heterogeneous mixture was shaken vigorously for 10 minutes to give a white precipitate which was filtered off and washed firstly with water and then with diethyl ether. The crude product was recrystallized from hot methanol to give 33.1 g (69.7%) of 1-[5-[2(S)-(2,4-dichloro-5-methoxyphenoxy)propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a white crystalline solid, m.p. 195°-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:14]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:14]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: O[C@H]1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N1CC[C@H](O)C1)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
To a solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (50 mg, 0.25 mmol), (3S)-pyrrolidin-3-ol (24.4 mg, 0.28 mmol) and BOP (116.0 mg, 0.26 mmol) in 0.4 mL DMF was added hunig base (0.066 ml, 0.38 mmol). The mixture was stirred at room temperature overnight and directly purified by prep. HPLC to provide (3S)-1-((1-(4-chlorophenyl)cyclopropyl)carbonyl)pyrrolidin-3-ol (20 mg). LCMS: m/z 266.0 (M+H)+; 553.1 (2M+Na)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N+:6]=1[O-])(=[O:3])[CH3:2].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][C:7]1[C:8]([CH3:11])=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:6]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(C)c[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C)c(OC(C)=O)n1
Temperature: 25 °C

Procedure:
A solution of 2-acetamido-5-methylpyridine N-oxide (28.2 g, 170 mmol) in acetic anhydride (840 mL) was stirred at 70° C. for 4 h. After cooling to rt and concentration in vacuo Et2O (180 mL) was added and the resulting solids isolated by filtration and washed with MeOH to give 6-acetamido-3-methylpyridin-2-yl acetate (6.87 g, 33.0 mmol) as a pale brown solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:18]>CCOCC>[Br:18][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1SCc1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1ccccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
A solution of (2-Benzylsulfanyl)methanol 4 (120 mg, 0.522 mmol) in anhydrous Et2O was cooled to 4° C. A solution of PBr3 (49 μL, 0.52 mmol) in anhydrous Et2O was added dropwise, keeping the temperature below 10° C. The reaction was allowed to warm to ambient temperature and stirred for one hour. The reaction was filtered through silica gel (2.0 g) and washed with Et2O. The filtrate was washed with H2O saturated aqueous sodium bicarbonate and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give 95 mg of the named product as a yellow oil.