Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+:3].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:55][CH2:56][CH3:57])[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:12]=1[C:13]([O:15]CC)=[O:14])([CH3:7])[CH3:6].C(=O)=O>O.O1CCOCC1>[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:55][CH2:56][CH3:57])[N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:12]=1[C:13]([O-:15])=[O:14])([CH3:6])[CH3:7].[Li+:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 20 h

Procedure:
A solution of 2.65 g of lithium hydroxide monohydrate in 158 ml of water was added, whilst ice-cooling, to a solution of 30 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 18(a)] in 344 ml of dioxane, and the resulting mixture was stirred at 5°-10° C. for 20 hours. At the end of this time, small pieces of dry ice were added to the mixture, which was then concentrated by evaporation under reduced pressure to a volume of about 100 ml. Ethyl acetate and sodium chloride were added to the concentrate, and the mixture was stirred. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure, to give lithium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate as a glass. 6.08 g of potassium carbonate were added, whilst ice-cooling, to a solution of whole of this lithium carboxylate in 160 ml of N,N-dimethylacetamide, and then a solution of 11.2 g of 4-chloromethyl -5-methyl -2-oxo-1,3-dioxolene (74% purity) in 26 ml of N,N-dimethylacetamide was added dropwise, whilst ice-cooling, to the mixture. The resulting mixture was stirred at 50° C. for 3 hours. At the end of this time, water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was crystallized in diisopropyl ether, to give 29.3 g of the title compound as crystals, melting at 98°-100° C. (with decomposition).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1.[C-]#N.[K+].[CH3:24][N:25](C)C=O>O>[C:24]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)#[N:25]
Reactant: O=[N+]([O-])c1ccc(OCCc2ccc(CCl)cn2)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture of 5-chloromethyl-2-[2-(4-nitrophenoxy)-ethyl]pyridine (9.5 g), potassium cyanide (3.2 g) and N,N-dimethylformamide (100 ml) was stirred at 60° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 5-cyanomethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine (9.0 g, yield: 98%). This compound was recrystallized from ethyl acetate-hexane to obtain colorless prisms, m.p. 94°-95° C.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([CH2:22][OH:23])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:23][CH2:22][C:19]1[N:11]2[C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][CH2:9][C:10]2=[N:21][N:20]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: c1ccncc1
Product: CC(=O)OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 17 h

Procedure:
An amount of 7.0 g of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-methanol is dissolved in 50 ml of absolute pyridine; to the solution are added 2.4 ml of acetic anhydride, and the whole is then allowed to stand for 17 hours at 25°. The reaction mixture is afterwards concentrated in vacuo. The residue is dissolved in methylene chloride, and the solution washed with water and saturated sodium chloride solution, dried over sodium sulphate, and concentrated by evaporation. After crystallisation of the residue from ethyl/acetate is obtained 1-(acetoxymethyl)-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine, M.P. 210°-212°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21]>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[Cl:13]
Reactant: Oc1ccc(F)cc1Cl
Reactant: Clc1ccnc2c(Cl)cccc12
Product: Fc1ccc(Oc2ccnc3c(Cl)cccc23)c(Cl)c1
Temperature: 160 °C
Yield: 49.5 %

Procedure:
A mixture of 2.0 g of 4,8-dichloroquinoline and 2.96 g of 2-chloro-4-fluorophenol was heated to 160° C. and stirred. Progress of the reaction was monitored using TLC. When no 4,8-dichloroquinoline remained, the product was washed with base to remove phenol, then purified using HPLC. A brown solid resulted, which was recrystallized in heptane to give 1.54 g of the title product as yellow crystals. Yield: 49%. M.P. 99°-101° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[S:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5]1
Reactant: CCCCCCCC(=O)Cl
Reactant: NCc1ccsc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NCc1ccsc1
Yield: 88.8 %

Procedure:
Using the same reaction conditions as those of Example 4, 3-(aminomethyl)thiophene hydrochloride (4 mmol), triethylamine (4.4 mmol) and octanoyl chloride (40 mmol) were reacted to give N-(3-thienylmethyl)octanamide (0.85 g, 89%). M.p. 71°-72° C. (Found: C, 65.0; H, 8.4; N. 5.7; S, 13.2. Calculated for C13H21NOS: C, 65.3; H, 8.8; N, 5.9; S, 13.4%); EI m/e Intensity (%): 239 (19, M+), 97 (63, C4H3S.CH2+); δH(CDCl3) 7.03-7.33 (3H, m), 5.60 (1H, br,s), 4.44 (2H, d), 2.19 (2H, t), 1.61 (2H, m), 1.28 (8H, m), 0.87 (3H, t); δC(CDCl3): 14.2, 22.7, 25.8, 29.1, 29.3, 31.8, 36.9, 38.8, 122.3, 126.5, 127.1, 140.0, 173.1 ppm.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH:33]([C:37](O)=[O:38])[CH2:32]1>>[CH3:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH:33]([C:37]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:38])[CH2:32]1
Reactant: CC1CCCC(C(=O)O)C1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CC1CCCC(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)C1

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3-methyl-1-cyclohexanecarboxylic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3-methyl-1-cyclohexylcarbonyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 490 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([O:13][CH:14]=[CH:15][C:16]#[N:17])[CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:16]([C:15]([C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[CH:14][O:13][CH2:11][CH3:12])#[N:17]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CCOC=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC=C(C#N)c1cc(F)ccc1C#N
Temperature: 100 °C
Reaction time: 24 h
Yield: 81.1 %

Procedure:
Palladium acetate (II) (0.556 g, 2.5 mmol) is added to a degassed solution of 2-bromo-4-fluoro-benzonitrile (10 g, 50 mmol), 3-ethoxyacrylonitrile (10.3 mL, 100 mmol) and triethylamine (14 mL, 100 mmol) in toluene (75 mL). The reaction mixture is stirred in an oil bath at 100° C. for 1 day. The reaction mixture is cooled to RT, filtered through a pad of Celite, and the filter cake is rinsed with EtOAc. After evaporation of the solvent, the residue is purified using a Biotage column eluted with 0-50% EtOAc/hexanes (20 CV) to afford 8.77 g (94%) of 2-(1-cyano-2-ethoxy-vinyl)-4-fluoro-benzonitrile. LC/MS: RT=3.38 min, no ionization.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O>[CH2:12]([O:19][C:20]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To the solution of piperidine-4-carboxylic acid (1.3 g, 10 mmol) of water (20 ml) was added sodium hydroxide (1.6 g, 40 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. The resulting mixture was treated with 5N hydrochloric acid to pH=6 and extracted with ethyl acetate, the solvent was removed under reduced pressure and dried in vacuum. 2.2 g of crude 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid was obtained. To a stirred solution of crude 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (1.05 g, 4 mmol) in anhydrous dichloromethane (10 mL) was added dropwise thionyl chloride (0.573 g, 4.81 mmol) at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give crude benzyl-4-(chlorocarbonyl)piperidine-1-carboxylate. To a stirred solution of ethyl 3-amino-2-hydroxybenzoate (0.501 g, 3.0 mmol) and triethylamine (0.455 g, 4.5 mmol) in anhydrous dichloromethane (20 mL) was added dropwise a solution of crude benzyl-4-(chlorocarbonyl)piperidine-1-carboxylate (1.014 g, 3.6 mmol) in anhydrous dichloromethane (5 mL) at 0° C. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=30:1 to 5:1) to give benzyl-4-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)piperidine-1-carboxylate (0.25 g, yield 20%; LC-MS (ESI) m/z: 413 (M+1)+) and 1-benzyl 4-(2-(1-(benzyloxycarbonyl)piperidine-4-carboxamido)-6-(methoxycarbonyl)phenyl)piperidine-1,4-dicarboxylate (1.0 g, yield 51%; LC-MS (ESI) m/z: 658 (M+1)+).
Reaction SMILES: C(=O)([O-])[O-].[K+:5].[K+].[C:7]([C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:30][CH2:29][CH:28]([O:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:27][CH2:26]3)[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH:12]=[CH:13][CH:14]=1)#[N:8]>O.CO>[C:7]([C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:26][CH2:27][CH:28]([O:31][CH2:32][C:33]([O-:35])=[O:34])[CH2:29][CH2:30]3)[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH:12]=[CH:13][CH:14]=1)#[N:8].[K+:5]
Reactant: N#Cc1cccc(-c2nc(C3CCC(OCC(=O)O)CC3)cc3cccnc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#Cc1cccc(-c2nc(C3CCC(OCC(=O)[O-])CC3)cc3cccnc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (10.1 mg, 0.074 mmol) in water (1 ml) is added to a solution of {4-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]cyclohexyloxy}-acetic acid (59 mg, 0.15 mmol) in methanol (6 ml). The reaction mixture is stirred at room temperature for 30 minutes, filtered and concentrated. The product is lyophilised from water (×3) then dried at 40° C. in vacuo for 18 hours. Recrystallisation from CH2Cl2/ether gives the product. m.p 148-150° C. (decomp.) MS (ES+) [M+H]+ 388.1635
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11]NC(=O)CCC(N)=O>>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1ccccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccccc1CBr

Procedure:
1-Methyl-2-nitro-benzene was reacted with N-bromosuccinamide as described in the synthesis of Example 1e to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].C([O:13][C:14]([C@@H:16]1[CH2:20][C@@H:19](OS(C)(=O)=O)[CH2:18][C@H:17]1[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:15])C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C@H:19]1[CH2:20][C@@H:16]([C:14]([OH:15])=[O:13])[C@H:17]([CH2:26][N:27]2[CH2:28][CH2:29][CH:30]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:31][CH2:32]2)[CH2:18]1
Reactant: CCOC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1CN1CCC(c2ccc(F)cc2)CC1
Reactant: Sc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@H](Sc2ccccc2Cl)C[C@H]1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.4 %

Procedure:
To a solution of 2-chlorobenzenethiol (141 mg) in tetrahydrofuran (2 mL) was added sodium hydride (dispersion in oil, 55% w/w, 50 mg). The mixture was stirred 20 min at room temperature. Then the mixture was cooled down to 0° C. and a solution of (1R,2R,4S)-2-[4-(4-Fluoro-phenyl)-piperidin-1-ylmethyl]-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (example 148 step 4, 180 mg) in tetrahydrofuran (2 mL) was added dropwise. The reaction mixture was stirred at room temperature over 24 h then partitioned between hydrochloric acid (1N) and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with a saturated aqueous solution of sodium carbonate and brine then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of dichloromethane:methanol (98:2 to 9:1 v/v) as eluant to afford the title compound (31 mg, 16%) as a light brown solid. MS (EI): 448.1 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[C:54]([C:55](O)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:46][CH:45]=1>CN(C=O)C>[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[C:54]([C:55]([N:2]3[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]3)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:48][CH:49]=1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: CC(C)(O)[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nocc2C(=O)N2CCC[C@@H](C(C)(C)O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (7 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (10 mg). MS (ESI, pos. ion) m/z calcd for C19H24N2O3: 328.1787, found 328.1783.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[CH:25]=1>O1CCOCC1.ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:31]([NH:30][C:26]3[CH:25]=[C:24]([CH3:33])[CH:29]=[CH:28][CH:27]=3)=[O:32])[CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2c(-c3ccc(F)cc3)csc2n1
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccc(NC(=O)N2CCN(c3nc(N)nc4scc(-c5ccc(F)cc5)c34)CC2)c1
Reaction time: 8 h

Procedure:
To a solution of Example 1 (115 mg, 0.35 mmol) in 1,4-dioxane (15 mL) was added m-tolyl isocyanate (0.38 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane and the organic layer was extracted several times with water. The combined organic layers were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 0.5% to 1% methanol in dichloromethane), yielding the title compound as a white powder. MS (m/z) 463 [M+H]+.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]=2S[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[C:22]1(S(C=C)=O)C=CC=C[CH:23]=1.C(#N)C>C1(C)C(C)=CC=CC=1>[C:16]1([C:4]2[C:3](=[O:2])[N:7]3[C:6](=[CH:22][CH:23]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccccc1-2
Reactant: C=CS(=O)c1ccccc1
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CC#N
Product: O=c1c(-c2ccccc2)ccc2n1CCc1ccccc1-2

Procedure:
be) from 5,6-dihydro-3-hydroxy-2-phenylthiazolo[2,3-a]isoquinolinium hydroxide (internal salt) and phenylvinyl sulfoxide in xylene there was obtained 6,7-dihydro-3-phenyl-4H-benzo[a]quinolizine-4-one of m.p. 139.5°-140.5° (from acetonitrile):
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]=1[OH:15])[CH:2]=[CH2:3].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc(C2CCCC2)c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cccc(C2CCCC2)c1OCc1ccccc1
Yield: 91.7 %

Procedure:
90 g (0.44 mol) of 2-allyl-6-cyclopentylphenol, 62 g (0.49 mol) of benzyl chloride and 124 g (0.9 mol) of potassium carbonate are heated under reflux in 800 ml of acetone for 70 h. The cooled reaction mixture is filtered, and the filtrate is concentrated. The residue is taken up in petroleum ether, and the solution is washed three times with 2N sodium hydroxide solution and then once each with water and saturated brine. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is distilled in vacuo. 118 g (92% of theory) of 1-allyl-2-benzyloxy-3-cyclopentylbenzene are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[CH2:30][CH:29]([N:34]([CH3:36])[CH3:35])[CH2:28]5)[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=1[C:40](Cl)=[O:41]>C1COCC1.C(Cl)Cl>[CH3:35][N:34]([CH3:36])[CH:29]1[CH2:28][C:27]2[C:31](=[CH:32][CH:33]=[C:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[C:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:40](=[O:41])[C:39]6[C:38]([F:37])=[CH:46][CH:45]=[CH:44][C:43]=6[F:47])[CH:3]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:23]=[CH:22][N:21]=3)[CH:26]=2)[CH2:30]1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(N)c5)nn5ccccc45)n3)cc2C1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
To a solution of {4-[2-(3-amino-4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amine (80 mg, 0.17 mmol) in THF (3 mL) was added TEA (25 μL, 0.25 mmol) and 2,6-difluorobenzoyl chloride (22 μL, 0.18 mmol). The reaction was stirred at rt for 2 h, and the reaction was diluted with 30 mL DCM and adsorbed onto silica. The crude product was purified by flash chromatography and reversed-phase HPLC to generate, after lyophilization, the title compound as a TFA salt (38 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.84 (s, 1H), 9.59 (s, 1H), 8.88 (d, J=6.7 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.24 (d, J=7.0 Hz, 1H), 7.75 (s, 1H), 7.58-7.62 (m, 1H), 7.41-7.52 (m, 4H), 7.24 (t, J=8.0 Hz, 2H), 7.13-7.16 (m, 2H), 6.61 (d, J=5.3 Hz, 1H), 4.04-4.12 (m, 1H), 3.22-3.28 (m, 2H), 3.06-3.12 (m, 2H), 2.82 (s, 6H). MS (ESI) m/z=620 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O-])(=[O:13])[CH3:12].[Na+].O>C(O)(=O)C>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)O)cc1
Yield: 65.8 %

Procedure:
A mixture of 4-aminobenzoic acid (Aldrich, 50.0 g, 0.365 mol) and anhydrous sodium acetate (35.0 g, 0.427 mol) in glacial acetic acid (150 mL) was heated to reflux for 15 h. The mixture was poured into cold water (1 L). The precipitate was separated by filtration and washed several times with cold water. The cake was dried in oven at 70° C. and recrystallized from 2:1 water:ethanol to give 43.0 g (68%) of the title compound as off-white flakes, mp 258° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23].[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23]
Reactant: COCCN
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNCCOC)C1C

Procedure:
The procedure of Example 13 is repeated, starting with 3.21 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester and 890 mg. of methoxyethylamine in 30 ml., to give 1.5 g. of the crude product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(Cl)cc3)CC2)ccc1Cl
Yield: 66 %

Procedure:
The title compound (27 mg, 66%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 4-chlorobenzoyl chloride. MS: 407.4 (MH+).