Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:23](=O)[CH3:24]>C(Cl)Cl.CO>[CH2:23]([N:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH:14]=2)[CH2:19]1)[CH3:24]
Reactant: CC=O
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CCNC2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCN1CCc2cc(OCCCN3CCCCC3)ccc2C1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a 25 mL round-bottom flask is placed 6-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (700 mg, 2.01 mol), MP-CNBH3 (2.5 g, 6.05 mmol, 2.42 mmol/g) and DCM/MeOH (9 mL/1 mL). Then, acetaldehyde is added (0.7 mL, 12 mmol) and the reaction is allowed to stir overnight. The reaction is then filtered, washed with DCM/MeOH and concentrated. Column chromatography in 9:1 DCM:MeOH affords 2-ethyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline (493 mg, 71%) of a viscous oil. Mass spec hit M+1, 303; LCMS>95% @ 230 nm and ELSD. Array synthesis followed this general procedure in 4 mL vials to make the following compounds:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:25])[N:16]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=2)=O)=[C:4]([CH3:36])[CH:3]=1.Cl.[NH2:38][OH:39].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:28][CH:27]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:25])[N:16]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=2)=[N:38]\[OH:39])=[C:4]([CH3:36])[CH:3]=1
Reactant: NO
Reactant: COCCOCCn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCCOCCn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-1-(2-(2-methoxyethoxy)ethyl)pyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing 12% of the corresponding Z isomer as a light yellow solid, MS (ESI+): m/z=547.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:18][CH3:19])[C:9]=1OS(C(F)(F)F)(=O)=O)[CH:5]=[O:6].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:18][CH3:19])[CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(Cl)c1OS(=O)(=O)C(F)(F)F
Agent: [Fe+2]
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC#N
Product: COc1cc(Cl)cc(C=O)c1
Temperature: 90 °C
Yield: 88.5 %

Procedure:
Triflate 5 (9 g, 28 mmol) pallidum(II) acetate (120 mg, 0.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene (620 mg, 1 mmol) and hplc grad CH3CN (10 ml) were mixed well in a teflon-lined stainless steel bomb. After adding freshly made, pulverized proton sponge formate2 (7.84 g 30 mmol), the bomb was sealed and heated at 90° C. for 4 h. The cooled reaction was then filtered to remove proton sponge crystals, partitioned between EtOAc and 3 N HCl, washed once each with dilute brine and dilute NaHCO3, dried over Na2SO4, and evaporated. Silica gel chromatography (15% EtOAc/hexanes) yielded 4.25 g (88.5% of chloromethoxybenzaldehyde 6, mp 45° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][CH:3]1[C:17]([OH:19])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][CH:2]1[CH:3]([C:17]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:19])[CH2:4][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:6]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CC1O
Agent: CN(C)C(On1nnc2cccnc21)=[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(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)C1CN(C(=O)OCc2ccccc2)CC1O
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
To a solution of 4-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrrolidinecarboxylic acid (available from Fluorochem, 59 mg, 0.22 mmol) in DMF (1 ml) was added HATU (85 mg, 0.22 mmol) and the mixture stirred for 10 mins. Then 6-(1H-indol-4-yl)-1H-indazol-4-amine (46 mg, 0.19 mmol) and DIPEA (0.065 ml, 0.37 mmol) were added and the mixture allowed to stand for 18 h at 20° C. The solvent was removed under a stream of nitrogen and the residue purified by Mass Directed Automated Preparative HPLC (Method E), to give the title compound (6 mg) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:49][CH:50]1[NH:54][CH2:53][C:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([OH:55])[CH2:51]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:54]3[CH:50]([CH3:49])[CH2:51][C:52]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([OH:55])[CH2:53]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: CC1CC(O)(c2ccccc2)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CC(O)(c3ccccc3)CC2C)cc1Cl
Yield: 72.7 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)-isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 5-methyl-3-phenylpyrrolidin-3-ol (7 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (12 mg). MS (ESI, pos. ion) m/z: calcd for C22H21ClN2O4: 412.1190, found 412.1189.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[CH:11]=[CH:10][N:9]=N[C:7]=2[O:6][CH2:5]1.[CH3:13][C:14]1N=CC=C2C(=O)COC=12>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[C:13]([CH3:14])[N:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: Cc1nccc2c1OCC2=O
Reactant: CON=C1COc2nnccc21
Product: CON=C1COc2c1ccnc2C

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 7-methylfuro[2,3-c]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one;
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]2([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:4]=[CH:3]1.Cl.[F:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]2([NH:14][C:15](=[O:18])[CH2:16][N:30]3[CH2:31][CH2:32][CH:27]([C:25](=[O:26])[C:24]4[CH:23]=[CH:22][C:21]([F:20])=[CH:34][CH:33]=4)[CH2:28][CH2:29]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:4]=[CH:3]1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(CCl)NC1(c2ccc(=O)[nH]c2)CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CN1CCC(C(=O)c2ccc(F)cc2)CC1)NC1(c2ccc(=O)[nH]c2)CCCCC1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A mixture of N-[1-(1,6-dihydro-6-oxo-3-pyridinyl)cyclohexyl]chloroacetamide (1.74 g), 4-(4-fluorobenzoyl)piperidine hydrochloride (1.57 g) and diisopropylethylamine (1.67 g) was heated in 35 ml of refluxing acetonitrile for 1 hour. The resulting suspension was cooled to room temperature and the solid was collected, yielding 1.8 g of solid. Recrystallization from methanol gave 1.1 g of product as a solid, m.p. 243°-245° C. (dec).
Reaction SMILES: [CH2:1]([CH:11]([C:17]([O-:19])=O)[C:12]([O:14]CC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][NH2:29]>C(O)C>[CH2:1]([CH:11]1[C:12](=[O:14])[NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][NH:20][C:17]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCC(C(=O)[O-])C(=O)OCC
Reactant: NCCNCCNCCN
Solvent: CCO
Product: CCCCCCCCCCC1C(=O)NCCNCCNCCNC1=O

Procedure:
A one liter round bottomed flask was charged with 0.053 mol (15.9 g) of ethyl n-decylmalonate, 0.053 mol (7.738 g) triethylene tetramine, and 500 ml absolute ethanol. During refluxing for 42 days, 2 ml aloquotes were removed by hypodermic syringe on days 7, 15, 22, and 37 for NMR analysis to determine the completeness of the reaction. After termination of the reflux the ethanol was distilled away and the product recrystallized from cold acetonitrile to yield 10.89 g of a very light fluffy white precipitate representing approximately a 60.0% conversion to the titled compound.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:18]([O-:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[CH3:22][CH:23]([CH3:47])[CH2:24][NH:25][C@H:26]1[CH2:31][C@@H:30]([C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[CH2:29][N:28]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:27]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>C(#N)C>[CH3:22][CH:23]([CH3:47])[CH2:24][N:25]([C:18]([C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])[C@H:26]1[CH2:31][C@@H:30]([C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[CH2:29][N:28]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:27]1
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])c1nc2ccccn2c1COc1ccccc1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)CN(C(=O)c1nc2ccccn2c1COc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
Ethyl 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (889 mg) was dissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The precipitated crystals were collected by filtration, and washed with ethanol to give sodium 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (680 g). The obtained sodium 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (290 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (370 mg) and N,N-diisopropylethylamine (862 μl) were dissolved in acetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (561 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object product (563 mg).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15]C(C)C)=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1ccc2c(ccn2C(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)n1ccc2cc(C(=O)O)ccc21
Yield: 109.7 %

Procedure:
A mixture of 2.20 g (8.97 mmol) of isopropyl 1-isopropyl-5-indolecarboxylate, 100 ml of 2N sodium hydroxide solution and 100 ml of ethanol was refluxed for an hour. The solvent was then distilled off under reduced pressure. Thereafter water was added to the residue and the resulting mixture was acidified with conc. hydrochloric acid. The precipitated solid was filtered and dried under reduced pressure to give 2.00 g of crude 1-isopropyl-5-indole-carboxylic acid. The reaction was carried out in a manner similar to Reference Example 4 using 2.00 g of the crude 1-isopropyl-5-indolecarboxylic acid, 0.44 g (11.1 mmol) of 60% sodium hydride, 2.87 g (20.2 mmol) of methyl iodide and 50 ml of dimethyl-formamide. Thus, 1.64 g (84.2%; yield based on isopropyl 1-isopropyl-5-indolecarboxylic acid) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)(C)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: O=C1CN(Cc2c(O)ccc3c2OCC3=O)CCN1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1CN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CCN1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A solution of 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazin-2-one (0.0986 g, 0.376 mmol) in isopropanol (1.5 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.0550 g, 0.376 mmol) and piperidine (0.00320 g, 0.0376 mmol), and the mixture was refluxed by heating for 2 hours. The reaction mixture was cooled to room temperature, and then added with isopropanol (2 mL), and the precipitated solid was suspended in isopropanol and thereby washed. The solid was collected by filtration to obtain the objective (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazin-2-one (0.106 g, 72%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[C:5]([NH2:8])=[N:6][CH:7]=1.C(N(C(C)C)CC)C.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[O:30].O>C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[C:5]([NH:8][C:29](=[O:30])[C:28]([O:32][CH2:33][CH3:34])=[O:31])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1NCc1c(F)ccc(F)c1Cl
Reactant: CCOC(=O)C=O
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)Nc1ncc(Br)nc1NCc1c(F)ccc(F)c1Cl
Reaction time: 8 h
Yield: 52 %

Procedure:
To a stirred solution of 5-bromo-N3-(2-chloro-3,6-difluorobenzyl)pyrazine-2,3-diamine (5.15 mmol, 1.8 g) and N,N-diethylisopropylamine (9.30 mmol, 2 mL) in CH2Cl2 (20 mL) was added ethyl glyoxylate (5.41 mmol, 0.74 g) at 0° C. The suspension was warmed up naturally and stirred overnight. Water was added to dissolve the precipitation. The combined organic layers from extraction were combined, dried, concentrated, and then subjected to a silica gel column chromatography by using CH2Cl2/MeOH (9:1) as eluents, furnishing ethyl ({5-bromo-3-[(2-chloro-3,6-difluorobenzyl)amino]pyrazin-2-yl}amino)(oxo)acetate in 52% yield (1.20 g).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1)([O-:28])=[O:27]>C(O)C.O>[N+:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:11]2[CH2:10][CH2:9][CH:8]([CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH2:12]2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(CN2CCC(C(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 4 h

Procedure:
To a solution of 126 parts of 4-(diphenylmethyl)piperidine in 1200 parts of 95% ethanol is added a solution of 69 parts of sodium carbonate in 1500 parts of water. The resultant mixture is heated at the boiling point under reflux with vigorous stirring while a solution of 112 parts of 4-nitrobenzyl chloride in 800 parts of 95% ethanol is rapidly stirred in, and for 4 hours thereafter. Solvent is then removed by vacuum distillation, and the residue is partitioned between dichloromethane and water. The organic layer is separated, dried over anhydrous potassium carbonate, and stripped of solvent by vacuum distillation. The residue, recrystallized from anhydrous ethanol, affords 1-[(4-nitrophenyl)methyl]-4-(diphenylmethyl)piperidine melting at approximately 130°-131°.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]=[N:6][CH:5]=1.[BH4-].[Na+]>C(O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C:8]2[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cncc(-c2cccc(Cl)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(-c2cccc(Cl)c2)c1
Temperature: 50 °C
Yield: 29.4 %

Procedure:
A solution of 1.0 g (4.04 mmol) 5-(3-Chloro-phenyl)-nicotinic acid methyl ester in 60.0 ml Ethanol was treated at room temperature (r. t.) with 304 mg (80.7 mmol) of sodium borohydride. The mixture was stirred over night at 50° C. Then it was poured on ice and extracted tree times with ethyl acetate. The combined organic phases were washed with water, dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:1) gave 261 mg (26%) of [5-(3-Chloro-phenyl)-pyridin-3-yl]-methanol.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([O:27][Si](C(C)(C)C)(C)C)[C:16]4([CH3:36])[CH3:35])=[CH:10][CH2:9]1)[CH3:7].Cl>C(O)C>[CH3:38][N:2]([CH3:1])[C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([OH:27])[C:16]4([CH3:36])[CH3:35])=[CH:10][CH2:9]1)[CH3:7]
Reactant: C[C@H](CCC(=O)N(C)C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: Cl
Solvent: CCO
Product: C[C@H](CCC(=O)N(C)C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Yield: 74.8 %

Procedure:
3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid-N,N-dimethyl amide (0.10 g) is dissolved in 5 ml of ethanol, 0.2 ml of 6N hydrogen chloride is added and the mixture is stirred at room temperature the weekend over. The product is precipitated with 10 ml of water, filtered and recrystallized from ethanol/heptan to give the title compound (59 mg). M.p. 192-195° C. 1H-NMR (CDCl3, 400 MHz)): δ=5.36 (1H, s); 3.24 (1H, m); 3.02 (3H, s); 2.94 (3H, s). Molecular weight: Calculated: 427.7. Found (by mass spectroscopy): 427.4.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:18])=[CH:12][CH:11]=1)C1C=CC=CC=1.[OH-].[Na+]>[Pd].C(O)C>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([NH:19][CH2:20][CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:18])=[CH:14][CH:15]=1
Reactant: CC(Cc1ccc(OCc2ccccc2)cc1)NCC(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(Cc1ccc(O)cc1)NCC(c1ccccc1)c1ccccc1
Reaction time: 72 h

Procedure:
The starting material is prepared as follows: The mixture of 4.6 g of dl-1-(4-benzyloxyphenyl)-2-(2,2-diphenylethylamino)-propane hydrochloride, 0.4 g of sodium hydroxide, 50 ml of ethanol and 0.5 g of 10% palladium on carbon is shaken under hydrogen at 3 atmospheres for 72 hours. The mixture is filtered and the filtrate evaporated, to afford the 1-(4-hydroxyphenyl)-2-(2,2-diphenylethylamino)-propane, which is used without further purification.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]([C:13]3[N:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1.[H-].[Na+].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[CH2:31]([O:19][C:16]1[CH:15]=[N:14][C:13]([CH:9]2[C:10](=[O:12])[C:11]3[C:2]([F:1])=[N:3][C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:18][CH:17]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCOc1cc2c(c(F)n1)C(=O)C(c1ncc(O)cn1)CC2
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1cnc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2=O)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxy-6,7-dihydro-5H-isoquinolin-8-one are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1-fluoro-3-octyloxy-6,7-dihydro-5H-isoquinolin-8-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12].CCCCCCCCCCCCN>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH2:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:14])([F:15])[CH:11]([F:12])[F:13]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Agent: CCCCCCCCCCCCN
Product: NCc1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Yield: 87 %

Procedure:
The title compound is prepared in 87% yield (947 mg, colorless oil) from 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.61 g, 4.00 mmol, Step-2) in a similar manner to Step-5 of Amine-12.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH:4]([CH2:5][C:6]([S:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)=[C:7]2[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1>[Pd].C(O)C>[O:1]=[C:2]1[N:8]2[CH:4]([CH2:5][C:6]([S:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)=[C:7]2[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: O=C(OCc1ccccc1)C1=C(Sc2ccc([N+](=O)[O-])cc2)CC2CC(=O)N12
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(SC2=C(C(=O)OCc3ccccc3)N3C(=O)CC3C2)cc1
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
A catalyst of 10% palladium on charcoal (Engelhard 4505, 50 mg) suspended in 90% aqueous ethanol (10 ml) was prehydrogenated for 20 minutes at room temperature/atmospheric pressure. Benzyl 7-oxo-3-p-nitrophenylthio-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate (50 mg) partially dissolved in ethanol (10 ml) was added, and the mixture was hydrogenated at room temperature and atmospheric pressure for 1.5 hours. The catalyst was removed by filtration through "High-Flo", and the colourless filtrate was evaporated to give an oil (35 mg) identical by TLC, u.v. and I.R. to the product (22) obtained in Example 7.