Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[O:9][C@H:10]2[CH2:16][NH:17][CH:18]=[O:19])([CH3:3])[CH3:2].[C:26]1([CH:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl>ClCCl>[CH:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH:20]1[CH2:21][CH2:22][N:23]([C:33](=[O:34])[CH:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:36][CH3:37])[CH2:24][CH2:25]1)[O:9][C@H:10]2[CH2:16][NH:17][CH:18]=[O:19])([CH3:3])[CH3:2]
Reactant: CCC(C(=O)Cl)c1ccccc1
Reactant: Cc1ccc2c(c1OC(C)C)C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C(=O)N1CCC([C@@H]2Cc3c(ccc(C)c3OC(C)C)[C@H](CNC=O)O2)CC1)c1ccccc1
Temperature: 10 °C

Procedure:
Stir a solution of N-((1R,3S)-5-isopropoxy-6-methyl-3-(4-piperidinyl)-1-isochromanyl-methyl)formamide (200 mg, 0.58 mmole) in dichloromethane (3 mL), cool to 10° C. and add 2-phenylbutyryl chloride (115 mg, 0.64 mmole) and triethylamine (88 mg, 0.87 mmole). Allow to warm to room temperature and pour into dilute HCl. Separate the layers an extract the aqueous layer two times with 4 mL of dichloromethane. Wash the combined organic extracts with water and dry over Na2SO4. Purify the crude product on a 10 g silica gel column (eluting with ethyl acetate:heptane 3:1). Collect the appropriate fractions and concentrate to obtain the title compound. It was used without further purification in the next step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1.C(N(C(C)C)C(C)C)C>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[CH:20][CH:21]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CBr)cc1
Reactant: CC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccc(F)cc4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(4-Fluoro-benzyloxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 7.1c from 80 mg (0.19 mmol) 1-[2-(4-bromomethyl-phenyl)ethyl]-4-(4-fluoro-benzyloxy)-1H-pyridin-2-one (example 7.1b), 41 mg (0.29 mmol) N-piperidin-4-yl-acetamide and 70 μL (0.40 mmol) N-ethyl-diisopropylamine as base.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C)c(I)c1

Procedure:
40.61 g of 3-iodo-4-methylbenzoic acid was suspended in 406 ml of ethanol and 9.1 ml of concentrated sulfuric acid was added, and then the mixture was heated at reflux for 24 hours. After the solvent was distilled off under reduced pressure, the residue was mixed with iced water, made basic with an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate twice. The extracts were washed in turn with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 44.44 g of a crude product as a brown oily product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:7]2.[CH:18]([O-])([O-])OC.Cl.CO>CO>[N:1]1[C:2]2[C:10]3[CH:9]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[O:17][CH:18]=1
Reactant: CC(=O)NCCC1CCc2ccc(O)c(N)c21
Reactant: COC([O-])[O-]
Agent: Cl
Solvent: CO
Product: CC(=O)NCCC1CCc2ccc3ocnc3c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of N-[2-(7-amino-6-hydroxyindan-1-yl)ethyl]acetamide (630 mg, 2.7 mmol.) in methanol (5 mL) were added dropwise, under ice-cooling, methyl orthoformate (7.4 mL, 67.3 mmol.) and a saturated HCl/methanol (1.4 mL) solution. The reaction mixture was stirred for 30 minutes at room temperature and for further one hour at 60° C. The reaction mixture was cooled, which was poured into ice-water, followed by extracting the organic matter with chloroform. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of silica gel column chromatography (chloroform:methanol=20:1) to afford the title compound (yield 520 mg, 79%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[C:34][Si](C)(C)C)=[CH:29][CH:28]=2)([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][Si](C)(C)C)=[CH:17][CH:16]=2)[OH:14])=[CH:9][CH:8]=1)(C)C.[OH-].[K+]>CO>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[CH:34])=[CH:29][CH:28]=2)([C:10]2[CH:11]=[CH:12][C:7]([C:6]#[CH:5])=[CH:8][CH:9]=2)[OH:14])=[CH:20][CH:19]=1)#[CH:22]
Reactant: C[Si](C)(C)C#Cc1ccc(C(O)(c2ccc(C#C[Si](C)(C)C)cc2)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(C(O)(c2ccc(C#C)cc2)c2ccc(C#C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A solution of n-BuLi (2.1 mL, 3.36 mmol, 1.6 M in hexane) was added to a solution of (4-bromophenylethynyl)trimethylsilane (0.69 mg, 2.74 mmol) in 50 mL of Et2O prechilled to -78° C. The solution was then stirred at -30° C. for 15 minutes. The solution was warmed to room temperature, stirred for 1 hour, and cooled to -30° C. A THF solution (20 mL) of 4,4'-bis(trimethylsilylethynyl)benzophenone (0.83 g, 2.19 nmol) prechilled to -30° C. was added slowly and the resulting mixture was stirred for 15 minutes. The solution was warmed to 0° C. and stirred for 2 hours. After addition of 1 mL of H2O the solution was pumped dry. The residue was chromatographed using CH2Cl2 /hexane (1:5 to 2:1) as eluent to afford tri(4-(trimethylsilylethynyl)phenyl)methanol as a colorless powder in 77% yield (0.92 q). 1H NMR (300 MHz, CDCL3, 25° C., TMS): 0.22 (s, 27 H, CH3), 2.72 (s, 1 h, OH), 7.13 (d, J=8.4 Hz, 6 H, C6H4), 7.38 (d, 6 H, C6H4). To a mixture of tri (4-(trimethylsilylethynyl)phenyl)methanol (0.92 g, 1.68 mmol) and KOH (0.28 g, 5.0 mmol) was added 50 mL of MeOH and the solution was stirred at room temperature for 3 hours. The solution was then extracted with Et2O solution was pumped dry and the residue was chromatographed using EtOAc/hexane (1:50 to 1:5) as eluent to afford tri(4-ethynylphenyl)methanol as a colorless powder in 84% yield (0.47 g). Anal. Calcd for C34H40Si3O: C 74.39, H 7.34. Found: C 74.03, H 7.28. 1H NMR (300 MHz, CDCl3, 25° C., TMS) : 2.73 (s, 1 H, OH), 3.06 (s, 3 H, ≡CH), 7.19 (d, J=8.2 Hz, 6 H, C6H4), 7.43 (d, 6 H, C6H4) ; IR (KBr, cm-1): 1018 (m, C--O), 2107 (w, C≡C); 3554 (m, O--H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C@H:10]3[CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C@H:9]3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:1][C:2]1[C:11]2[C@@H:10]3[CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C@H:9]3[C:8]([CH3:17])([CH3:18])[O:7][C:6]=2[CH:5]=[C:4]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1
Reactant: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@H]21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@@H]21

Procedure:
The process according to claim 1, said process comprising reacting dl-cis-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]-pyran-9-one with aluminum chloride in dichloromethane to form dl-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]-pyran-9-one.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:28])=[CH:17]/[C:18]2[NH:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[K+]>C(O)C>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:28])=[CH:17]/[C:18]2[NH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1cnc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C/C(=C\c1ncc(C(=O)O)[nH]1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 20 h
Yield: 74.2 %

Procedure:
Ethyl (E)-2-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-5imidazolecarboxylate (Compound 5, 0.043 g, 0.153 mmol) was dissolved in ethanol (2 mL) and treated with 2N aqueous KOH (0.5 mL). The solution was stirred for 20 hours at 50° C. and concentrated under vacuum. The residue was treated with ether (10 mL) and water (1 mL) and neutralized with saturated aqueous NH4Cl. The layers were separated and the aqueous layer extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was passed through a small plug of silica gel (methanol) to give the title compound as a pale yellow powder (40 mg, 80%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=[O:21].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[CH:18]=[CH:19][C:20]([NH:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4])=[O:21]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: N[C@@H](CO)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1F)N[C@@H](CO)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.5 %

Procedure:
A mixture of (R)-2-amino-2-naphthalen-2-yl-ethanol (0.2 mmol), 2-fluorocinnamic acid (0.2 mmol), EDC HCl (0.4 mmol), DMAP (0.2 mmol), triethyl amine (0.6 mmol) in dichloromethane (4 mL) was stirred at room temperature for 14 h. The reaction mixture was purified by flash chromatography with 50% ethyl acetate in hexanes to provide the desired product (56 mg) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[OH:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)C(O)CC2
Yield: 100.7 %

Procedure:
6-Methoxyindan-1-one (5.0 g) was dissolved in methanol (50 ml). Next, sodium tetrahydroborate (1.41 g) was added thereto at 0° C., and the resultant mixture was reacted at room temperature for 5 hr. The reaction solution was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, dried and concentrated under reduced pressure to give 6-methoxyindan-1-ol (5.1 g) as an oil. This alcohol was not purified but reacted as such with thionyl chloride (4.5 ml) in ether at room temperature for 6 hr. The reaction solution was poured into ice water and extracted with ether. The ether layer was washed with water, dried and concentrated under reduced pressure to give the title compound (2.76 g). (251-2) 1-(4-Acetylpiperazin-1-yl)-6-methoxyindan
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:15][C@@H:16]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:18][C:17]1([C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([CH2:64][CH3:65])=[CH:60][CH:59]=2)[CH:49]=1)O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:64]([C:61]1[CH:60]=[CH:59][C:58]([CH2:57][N:50]2[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:48]([C@@H:17]3[CH2:18][C@H:19]([CH2:38][O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C@@H:20]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@H:21]([O:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@H:16]3[O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:49]2)=[CH:63][CH:62]=1)[CH3:65]
Reactant: CCc1ccc(Cn2cc(C3(O)C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc(Cn2cc([C@@H]3C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.3 %

Procedure:
In a nitrogen stream, triethylsilane (0.21 mL, 1.22 mmol) was added dropwise to a solution of (2R,3S,4R,5R)-2,3,4-trisbenzyloxy-5-benzyloxymethyl-1-[1-(4-ethylbenzyl)-1H-indol-3-yl]cyclohexanol (469 mg, 0.61 mmol) in methylene chloride (6 mL) at 0° C. A boron trifluoride-diethyl ether complex (0.093 mL, 0.73 mmol) was added dropwise thereto over five minutes and the reaction mixture was stirred at 0° C. for two hours. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:15)] to obtain the title compound (232 mg, 51%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[CH:10]=1)[CH2:2][CH3:3]>[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)[CH2:19][CH2:20]2)[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cc(OCCC)cc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: [Ti+3]
Agent: [Cl-]
Product: CCCOc1cc(OCCC)cc(N2CCN(Cc3ccc(N)cc3)CC2)c1

Procedure:
In the manner given in Example 1B, 1-(3,5-dipropoxyphenyl)-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(3,5-dipropoxyphenyl)-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:21]([CH:22]=O)=[CH:20][C:11]3[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][O:14][C:10]=3[C:9]=2[F:24])[CH2:5][C@H:4]([CH3:25])[O:3]1.[NH:26]1[C:33](=[O:34])[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28]>C(O)C>[F:24][C:9]1[C:10]2[O:14][N:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]=2[CH:20]=[C:21]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:25])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:32]1([C:30](=[O:31])[NH:29][C:27](=[O:28])[NH:26][C:33]1=[O:34])[CH2:22]2
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CCO
Product: CCOC(=O)c1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Yield: 89.5 %

Procedure:
Ethyl 6-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-5-formylbenzo[d]isoxazole-3-carboxylate (Intermediate 439, 350 mg, 1.00 mmol) and barbituric acid (141 mg, 1.10 mmol) were heated to reflux in ethanol (45 ml) for 64 hours. The reaction was concentrated. The residue was dissolved in DCM, absorbed onto silica and purified by silica gel column chromatography using a gradient of DCM to ethyl acetate, to give the title compound (412 mg, 76%) as a racemic mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[C:4]([CH3:16])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([C:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]=2[O:15][CH3:17])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)cc(C)c1C1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COC1=C(c2c(C)cc(F)cc2C)C(=O)CC1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
To a solution of 2-(4-fluoro-2,6-dimethylphenyl)-cyclopentane-1,3-dione (2.9 g, 13.3 mmol) in tetrahydrofuran (290 ml) is added anhydrous potassium carbonate (22 g, 159 mmol) and iodomethane (22.6 g, 159 mmol. The resulting mixture is stirred at 25-30° C. for 16 hours. The organic layer is evaporated, reaction mixture is quenched with water (150 ml) and extracted with ethylacetate (3×100 ml). The combined organic extracts are combined, washed with water and brine, dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel to give 2-(4-fluoro-2,6-dimethylphenyl)-3-methoxy-cyclopent-2-enone (2 g).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[C:10]([NH2:29])=[CH:11][C:12]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31]>C1COCC1>[CH:1]1([CH2:7][N:8]2[C:9]3[CH:14]=[C:13]([N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[C:12]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:11][C:10]=3[NH:29][C:30]2=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(c2cc(NCC3CCCCC3)c(N)cc2Nc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCN(c2cc3c(cc2Nc2ccccc2)[nH]c(=O)n3CC2CCCCC2)CC1
Yield: 66.7 %

Procedure:
A solution of N1-cyclohexylmethyl-5-(4-methyl-piperazin-1-yl)-N4-phenyl-benzene-1,2,4-triamine (0.10 g, 0.25 mmol) and 1,1′-carbonyldiimidazole (0.12 g, 0.76 mmol) in THF (3 mL) was stirred at room temperature for 17.5 h. The solvent was evaporated and the resulting residue was chromatographed (FCC, 5% MeOH/CH2Cl2) to give the title compound as a white solid (0.07 g, 61.6% yield). M+, 420.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[O:19]1C=CC(CO)=C1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[O:19]1[CH:4]=[CH:3][CH:2]=[C:1]1[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]2
Reactant: OCc1ccoc1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: O=C(O)c1cc2c(OCc3ccco3)cccc2[nH]1

Procedure:
4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid (16c) is synthesized analogous to 16a from furan-3-yl-methanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(COc2cccnc2N)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cccnc2NC(=S)Nc2ccccc2)cc1

Procedure:
A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (1.91 g, 0.0083 mol), phenyl isothiocyanate (1.4 g, 0.01 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.18 g (72%), m.p. 123°-125 ° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:45])[C@H:33]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH:34][C:35](=[O:37])[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:45])[C@H:33]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[NH:34][C:35](=[O:37])[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
160 mg (0.259 mmol) of the mixture of (2R*,4S*)-2-benzyl-1-((S)-N-acetyl-phenylalanyl)N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine diastereomers are reacted with 39 mg (1.04 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR57## is obtained as mixture of diastereomers as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.22, FD-MS: M+ =520.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[CH2:8]([N:10]([CH2:18][CH3:19])[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH3:9].C(=O)([O-])O.[Na+]>ClCCl>[CH2:5]([O:4][C:2]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([N:10]([CH2:18][CH3:19])[CH2:8][CH3:9])=[CH:16][CH:15]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(N(CC)CC)cc1
Reaction time: 96 h
Yield: 72.4 %

Procedure:
Ethyl chloroformate (5.0 mL, 52 mmol) was added to a stirred mixture of N,N-diethyl-p-phenylenediamine hydrochloride (10 g, 50 mmol) and sodium hydrogen carbonate (23.0 g) in dichloromethane (120 mL) at room temperature under nitrogen. After four days at room temperature, the precipitate which had formed was removed by filtration through a pad of celite. The solid residue was washed with dichloromethane and the combined dichloromethane extracts were concentrated to produce a black oil, which was redissolved in dichloromethane (110 mL) and stirred with silica (100 cc) for 30 minutes. The silica was then removed by filtration through celite. The residue was washed with additional dichloromethane (3×30 mL) and the combined dichloromethane extracts were concentrated to give N-ethoxycarbonyl-4-diethylaminoaniline (8.55 g, 73% yield) as a pale gray solid which melted at 31°-33° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:13]([CH2:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)#[N:14]
Reactant: c1ccc2c(c1)CCCN2
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CCN1CCCc2ccccc21

Procedure:
162 parts of 1,2,3,4-tetrahydroquinoline, 126 parts of chloroacetonitrile and 66 parts of sodium carbonate are stirred for 6 hours at a temperature of 105°-115° C. After cooling, the thick brown suspension is diluted with methylene chloride and filtered. After washing thoroughly with methylene chloride, the filtrate is concentrated as far as possible in a water jet vacuum and the residue is subsequently distilled. The main fraction boils at 148°-150° C. at a pressure of 1 torr.