Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](O)=O.C1([N:37]=C=NC2CCCCC2)CCCCC1.C([O-])(=O)C.[NH4+]>CN(C)C1C=CN=CC=1.O.C(O)(=O)C.ClCCl>[C:11]1([C:9]2[N:37]=[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]([O:18][CH3:17])=[O:30])[O:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COC(=O)CCCCCCCC(=O)O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
A mixture of benzoin (6.00 g, 28 mmol), azelaic acid monomethyl ester (7.17 g of 92% pure material, 32 mmol), 1,3-dicyclohexylcarbodiimide (7.00 g, 34 mmol), 4-dimethylaminopyridine (catalytic amount) and dichloromethane (120 mL) was stirred at room temperature. After 16 hours, the mixture was filtered and the solvent evaporated. Ammonium acetate (10.90 g, 141 mmol) and acetic acid (150 mL) were added to the residue and the mixture heated at reflux for 65 minutes before being cooled and diluted with water. The mixture was extracted with diethyl ether, the combined extracts dried over sodium sulfate and concentrated in vacuo. The residual oil was chromatographed on a column of silica gel using a mixture of hexanes and diethyl ether (7:3) as eluent to give methyl 4,5-diphenyl-2-oxazoleoctanoate (8.24 g, 77%) as an oil.
Reaction SMILES: [C:1]1(=O)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[NH3:15].[ClH:16]>C(OCC)C>[ClH:16].[C:1]1(=[NH:15])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: N
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Agent: Cl
Solvent: CCOCC
Product: N=C1C=CC=C2C1=Cc1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
The fluorenone (4.0 g, 22.2 mmol) was stirred in an autoclave of 110° C. for three days in an ammonia atmosphere (7 to 8 atm). After the reaction, it was allowed to dissolve in diethyl ether. And, hydrogen chloride was blown into it. It was stirred for one hour at room temperature. The obtained suspension was filtered, and the filtrate was cleaned with the diethyl ether. With this, fluorenone imine hydrochloride (3.4 g, 71%) was obtained. This hydrochloride was allowed to decompose with an ammonia aqueous solution. And, it was recrystallized by using the methylene chloride and hexane. And, Fluoren-9-ylideneamine (2.3 g, 58%) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[S:12]1[C:16]([CH:17]=O)=[CH:15][N:14]=[CH:13]1>>[S:12]1[C:16]([CH2:17][NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]([OH:2])=[O:11])=[CH:15][N:14]=[CH:13]1
Reactant: COC(=O)c1ccccc1N
Reactant: O=Cc1cncs1
Product: O=C(O)c1ccccc1NCc1cncs1

Procedure:
Prepared by a similar procedure as described for preparation 1J, starting from anthranilic acid methyl ester and thiazole-5-carboxaldehyde (Combi-Blocks). 13C-NMR (DMSO-d6) δ 169.8, 153.6, 149.9, 140.8, 137.9, 134.3, 131.6, 115.0, 111.6, 110.7, 38.3.
Reaction SMILES: [CH2:1]([CH:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][NH:16]C(OC(C)(C)C)=O)[C:4]([NH2:6])=[O:5])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([CH:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][NH2:16])[C:4]([NH2:6])=[O:5])[CH3:2]
Reactant: CCC(Oc1ccc(Cl)cc1CNC(=O)OC(C)(C)C)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(Oc1ccc(Cl)cc1CN)C(N)=O

Procedure:
Ethyl-2-t-butoxycarbonylaminomethyl-4-chlorophenoxyacetamide from Step F was dissolved in 2:1 methylene chloride/TFA (3 ml) and after 15 min the solvent was evaporated in vacuo. The residue was dissolved in water and the solution was washed with methylene chloride (twice). The aqueous layer was then basified with saturated sodium carbonate solution and NaCl was added to saturation. The mixture was extracted with ethyl acetate, and the organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound as a crystalline solid:
Reaction SMILES: I[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:12][C:13]1[N:14]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:15]2[C:24]3[CH:23]=[CH:22][C:21]([OH:25])=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:12][C:13]1[N:14]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:15]2[C:24]3[CH:23]=[CH:22][C:21]([O:25][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:26]=1
Reactant: CC(C)(C)OC(=O)NCCI
Reactant: Cc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc2cnc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)C
Temperature: 60 °C
Yield: 82.4 %

Procedure:
tert-Butyl 2-iodoethylcarbamate (2.55 g, 9.41 mmol), prepared as described in Parts J and K of Example 2, was added to a mixture of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (2.00 g, 7.83 mmol) and cesium carbonate (3.83 g, 11.7 mmol) in DMF (30 mL), and the reaction was heated at 60° C. for four hours. The solvent was removed under reduced pressure, and the resulting solid was triturated with water and isolated by filtration to yield 2.57 g of tert-butyl 2-{[2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate as a light-brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.OC=[C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][C:17]2=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1CCCCC1=CO
Product: COc1ccc2[nH]c3c(c2c1)CCCC3=O

Procedure:
6-Methoxy-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared from p-anisidine and 2-(hydroxymethylene)cyclohexanone in a similar manner as described above to give a tan solid. 1H-NMR (CDCl3): δ 8.77 (br s, 1H), 7.32 (d, 1H), 7.06 (d, 1H), 7.03 (s, 1H), 3.88 (s, 3H), 2.98 (t, 2H), 2.66 (t, 2H), 2.28 (m, 2H); MS m/z 216 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]([NH:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])[N:16]=[C:15]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=2)[N:14]=1
Reactant: COC(=O)c1ccc(Nc2nc(NCCCCCCCCCCN)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: NCCCCCCCCCCNc1nc(Nc2ccc(C(=O)O)cc2)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Yield: 25.7 %

Procedure:
To a suspension of methyl 4-(4-(10-aminodecylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.1 g) in acetone (6 mL) was added potassium carbonate in water (6.00 mL). The mixture was heated to reflux overnight. After cooling to r.t., the reaction solution was acidified with 1N HCl to pH=3. All solvens were removed under vacuum. The residue was purified by prep. HPLC to give 4-(4-(10-aminodecylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (25 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C.[Si:27](OS(C(F)(F)F)(=O)=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl>[Si:27]([O:17][C:15]([C:14]1[C:9]([C:8]#[C:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH2:16])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cccnc1C#Cc1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccnc1C#Cc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Step 2 (=Reaction 4): 455 mg 1-(2-(pyridin-2-ylethynyl)pyridin-3-yl)ethanone was dissolved in 10 mL DCM, 1.069 mL of DIPEA was added, the solution was cooled 0° C. and 1.42 mL of tert-butyldimethylsilyltrifluormethansulfonate added slowly. The mixture was stirred 30 min at 0° C., warmed to 25° C. and filtrated over a plug of silica (cyclohexane/ethylacetate 1:1+small amount of TEA) to yield 1.025 g 3-(1-(tert-butyldimethylsilyloxy)vinyl)-2-(pyridin-2-ylethynyl)pyridine as oil. Analysis: HPLC-MS: Rt=1.59 min (method E) m+H=337.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:51]([O:53][C:54]1[CH:62]=[CH:61][CH:60]=[CH:59][C:55]=1[CH:56]([OH:58])[CH3:57])[CH3:52]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:58][CH:56]([C:55]2[CH:59]=[CH:60][CH:61]=[CH:62][C:54]=2[O:53][CH2:51][CH3:52])[CH3:57])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOc1ccccc1C(C)O
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOc1ccccc1C(C)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Temperature: 25 °C
Yield: 61.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (72 mg) was added to toluene/triethylamine=10/1 (7 ml) and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (100 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-ethoxy-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (71 mg, yield 58%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:34]/[CH:35]=[CH:36]/[C:37](Cl)=[O:38].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([NH:19][C:37](=[O:38])[CH:36]=[CH:35][CH2:34][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1N
Reactant: O=C(Cl)/C=C/CBr
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN1CCOCC1
Yield: 38.9 %

Procedure:
To a mixture of 0.69 g (1.87 mmol) of 4-[(3-Bromophenyl)amino]-7-methoxy-6-amino-3-quinolinecarbonitrile and 0.98 ml (5.6 mmol) of Hunig's base in 50 ml of dry THF at 0° C., with stirring, was added a THF solution containing 0.86 g (5 mmol) of 4-bromocrotonyl chloride dropwise. The mixture was stirred for a additional 0.5 hour and then was added to a solution of 4.89 ml (56 mmol) morpholine in 50 ml THF at 0° C. dropwise. The solution was stirred an additional 0.5 hour and then the mixture was poured into diluted sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate. The residue was chromatographed to give 0.38 g of grey solid: mass spectrum (electrospray, m/e): M+H 521.9 and 523.8.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH2:34]([C:36]1[S:40][C:39]([C:41](Cl)=O)=[CH:38][CH:37]=1)[CH3:35]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:41][C:39]1[S:40][C:36]([CH2:34][CH3:35])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CCc1ccc(C(=O)Cl)s1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Cl)c23)s1

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 1-(3) and 5-ethylthiophen-2-carbonyl chloride were treated in a manner similar to Example 2-(4), (5), (6) and (7) to give the titled compound as a pink powder. APCI-Mass m/Z 455/457 (M+NH4). 1H-NMR (DMSO-d6) δ 1.17 (t, J=7.4 Hz, 3H), 2.71 (q, J=7.4 Hz, 2H), 3.15-3.43 (m, 4H), 3.67 (m, 2H), 4.36 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.10 (d, J=5.3 Hz, 1H), 5.16 (d, J=5.0 Hz, 1H), 5.20 (d, J=5.9 Hz, 1H), 5.40 (d, J=9.1 Hz, 1H), 6.62 (m, 2H), 7.04 (m, 1H), 7.11 (t, J=7.9 Hz, 1H), 7.38 (s, 1H), 7.54 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:5][CH:6]([CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[C:22](OC(=O)C)(=O)[CH3:23]>>[CH2:1]([N:5]([CH2:22][CH3:23])[CH:6]([CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:7][OH:8])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCNC(CO)CCOc1cccc2ccccc12
Product: CCCCN(CC)C(CO)CCOc1cccc2ccccc12

Procedure:
2-(butylamino)-4-(1-naphthyloxy)-1-butanol, described in Example 6, with acetic anhydride, followed by reduction, gives 2-(butylethylamino)-4-(1-naphthyloxy)-1-butanol.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:69]([NH2:73])([CH3:72])([CH3:71])[CH3:70]>CN(C=O)C>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:73][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NC(C)(C)C)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and t-butylamine (9.54 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (17.4 mg, 52%). LC-MS m/z 563 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[O:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[O:7]1[CH2:12][CH2:11][CH:10]([NH:6][C:3]2[NH:4][CH:5]=[N:1][N:2]=2)[CH2:9][CH2:8]1
Reactant: Nc1nc[nH]n1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1nnc(NC2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
To a solution (70 mL) of 1H-1,2,4-triazol-3-amine (3.7 g) and tetrahydro-4H-pyran-4-one (5.2 g) in acetic acid was added sodium cyanoborohydride (14 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.92 g, 10%).
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[CH:7]([O:10][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)OC1CC(C)(CC)N(OC(C)c2ccccc2)C(C)(CC)C1C
Yield: 870.1 %

Procedure:
In analogy to example 1 were reacted 6.36 g (2 mmol) of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-ol with 1.81 g (2 mmol) of acryloyl chloride and 2.02 g (2 mmol) of triethylamine in toluene to give 6.5 g (87%) acrylic acid 2,6-di-ethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl ester as yellowish liquid.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]2[O:14][CH:15]=[CH:16][N:17]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[O:14][CH:15]=[CH:16][N:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ncco1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCSc1ncco1

Procedure:
Hydrazine hydrate (5.3 g.) was added carefully to a solution of 2-(3-phthalimidopropylthio)oxazole (10 g.) in ethanol (173 ml.) with stirring. The solution was then heated under reflux for 25 minutes. After cooling, and filtration from phthalhydrazide, the filtrate was concentrated under reduced pressure and the residue was re-evaporated with ethanol to yield crude 2-(3-aminopropylthio)oxazole which was washed twice with ether and dissolved in ethanol (60 ml.). Methyl isothiocyanate (2.54 g.) was added and the solution was heated under reflux for 30 minutes. Following cooling and filtration from insoluble material, the filtrate was concentrated to an oil which was chromatographed on a column of silica gel with ethyl acetate as eluant. The product obtained crystallised from ethanol-ether-n-hexane to give N-methyl-N'-[3-(2-oxazolyl)thiopropyl]thiourea (2.4 g.), m.p. 43°-45°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13]CC#N)=[CH:9][C:4]=2[CH:3]=[CH:2]1.O.S(=O)(=O)(O)O.C(OCC)(=O)C.[C:29]([OH:32])(=[O:31])[CH3:30]>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:30][C:29]([OH:32])=[O:31])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: N#CCCOCCc1ccc2sccc2c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CCOCCc1ccc2sccc2c1

Procedure:
In 0.6 mL of acetic acid was dissolved 200 mg of 3-[2-(1-benzothiophen-5-yl)ethoxy]propiononitrile, followed by adding thereto 0.4 mL of water and 0.184 mL of sulfuric acid, and the resulting mixture was stirred at 90 to 100° C. for 1 hour. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene ethyl acetate=3:1) to obtain 140 mg of 3-[2-(1-benzothiophen-5-yl)ethoxy]propionic acid as colorless crystals.
Reaction SMILES: C([O-])(=[O:5])CCC.[Na+].C([O-])(=O)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].S(=O)(=O)(O)O>>[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH3:9]
Reactant: CCCC(=O)[O-]
Reactant: O=C([O-])C=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
The same medium and parameters as the inoculum were used. A 500 ml flask containing 100 ml broth was sterilized for 20 min. at 121° C. A 2.5 ml aliquot of sterilized 20% sodium butyrate solution (pH 7.0) and 1 ml. of the 24 hours grown culture were added. The flask was incubated at 30° C. and 150 rpm for 24 hours. Sterile 10% sodium cinnamate (pH 7.0) was added to each flask as follows: 5 g/l at 24 hours, 4 g/l at 72 hours, and 6 g/l at 80 hours. Periodically, 2 ml. samples of broth were acidified to pH 4.0 using 50% sulfuric acid, extracted with an equal volume of ethyl acetate, and analyzed by GC. The acetophenone concentration was estimated by external standard. At the conclusion of the fermentation, the culture broth was acidified to pH 4 as above and extracted twice with ½ volume of ethyl acetate each time. The extracts were combined and solvent was removed under vacuum using a rotary evaporator. The crude product was distilled in a micro-distillation oven and the distillate analyzed by GC. The yield of 1.8 g/L having a purity of 94.3% was obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[C:7]2[CH3:19].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O>[CH3:29][O:28][C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:9]1[C:10]2[C:6](=[CH:5][C:4]([Cl:3])=[CH:12][CH:11]=2)[C:7]([CH3:19])=[C:8]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:27]
Reactant: COC(=O)CCCCCBr
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCn1c(-c2cccnc2)c(C)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.39 g of 50% sodium hydride (dispersion in mineral oil) in 30 ml of dimethylformamide is added under nitrogen at 0°-5° dropwise while stirring a solution of 6.59 g of 5-chloro-3-methyl-2-(3-pyridyl)-indole (prepared as described in U.S. Pat. No. 3,468,894) in 60 ml of dimethylformamide. After addition is complete the suspension is stirred at 0° for 1/2 hour. While maintaining the temperature at 0° a solution of 6.06 g of methyl 6-bromohexanoate in 10 ml of dimethylformamide is added dropwise. The reaction mixture is allowed to reach room temperature and is stirred at room temperature for 5 hours, and poured into 400 ml of ice water. The resulting mixture is extracted with ethyl acetate (3×300 ml). The ethyl acetate extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness to give 1-(5-methoxycarbonylpentyl)-5-chloro-3-methyl-2-(3-pyridyl)indole as an oil.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:5][C:4]=1[CH3:21])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=3)[CH2:31][CH2:32]2)=[O:20])=[CH:5][C:4]=1[CH3:21])[CH3:2]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C
Yield: 61 %

Procedure:
Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.