Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:26][CH:27]([CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[CH:36]=[C:35]2[CH2:42][CH2:43][CH2:44][O:45][CH3:46])[CH:28]([CH3:30])[CH3:29])[CH:9]([OH:25])[CH2:10][CH:11]([C:15](=[O:24])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[CH:12]([CH3:14])[CH3:13])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15](=[O:24])[CH:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][CH:9]([OH:25])[CH:8]([NH2:7])[CH2:26][CH:27]([CH2:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[N:37]([CH3:41])[CH:36]=[C:35]3[CH2:42][CH2:43][CH2:44][O:45][CH3:46])[CH:28]([CH3:30])[CH3:29])=[N:18][CH:19]=1
Reactant: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CC(C(=O)Nc3ccc(F)cn3)C(C)C)C(C)C)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCc1cn(C)c2ccc(CC(CC(N)C(O)CC(C(=O)Nc3ccc(F)cn3)C(C)C)C(C)C)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of 0.090 g (4-(5-fluoro-pyridin-2-ylcarbamoyl)-2-hydroxy-1-{2-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-3-methyl-butyl}-5-methyl-hexyl)carbamic acid tert-butyl ester in 2.4 ml dichloromethane are added 1.2 ml trifluoroacetic acid at 0° C. The reaction mixture is stirred at 0° C. for 1 hour and then concentrated by evaporation. The title compound is obtained as a beige foam from the residue by means of flash chromatography (SiO2 60 F). Rf=0.35 (200:20:1 dichloromethane-methanol-25% conc. ammonia). Rt=4.58 (gradient I).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>>[CH:39]1([NH:42][C:33](=[O:35])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)(=[O:28])=[O:29])[CH:31]=2)[CH2:41][CH2:40]1
Reactant: NC1CC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: O=C(NC1CC1)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 77.2 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 44 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:29][C:28]#[CH:27])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])=[C:4]([F:20])[CH:3]=1
Reactant: C#CCBr
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-5-hydroxy-phenyl)-3,4,5,6-tetrahydrophthalimide (1 g) in dimethylformamide (10 ml), there was added anhydrous potassium carbonate (0.34 g) while stirring at room temperature. After stirring for 30 minutes at about 40° C., propargyl bromide (1 g) was added thereto, and the resultant mixture was stirred for 3 hours at 50°-60° C. After being allowed to cool to room temperature, the mixture was poured into water and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 0.8 g of N-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide (Compound No. 3). M.P., 136.4° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:11]([NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=3)[O:12][CH2:13][C:14]=2[CH:20]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Reactant: O=Cc1ccccc1
Product: c1ccc(CNc2ccc3c(c2)COC(Nc2cccc(C4CC4)c2)=N3)cc1
Yield: 55 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (200 mg, 0.72 mmol) and benzaldehyde (68 mg, 0.66 mmol) according to the procedure described for example 88. Obtained the title compound as a white foam (134 mg, 67%), MS (ISP) m/e=370.1 [(M+H)+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14](Cl)=[O:15])[CH3:8]>C(#N)C.C(Cl)Cl>[CH2:7]([C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:15])[CH3:8]
Reactant: C1CCNCC1
Reactant: CCc1oncc1C(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Product: CCc1oncc1C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.2 mol (17.0 g) of piperidine is added dropwise to 0.1 mol (16.0 g) of 5-ethyl-4-isoxazolecarboxylic acid chloride dissolved in 200 ml of acetonitrile, at room temperature with stirring. Stirring is continued for 20 minutes and the mixture is then cooled to room temperature and the piperidine hydrochloride precipitated is filtered off with suction. The filtrate is concentrated under reduced pressure. An oily residue is obtained, and is taken up in 200 ml of methylene chloride, and the mixture is washed first with 100 ml of 2N hydrochloric acid and then with water. After drying over sodium sulfate, the mixture is concentrated under reduced pressure and the oily residue is distilled under reduced pressure (bulb tube distillation). N-(5-Ethyl-4-isoxazolylcarbonyl)-piperidine of boiling point (7 mbar) 90°-110° C. is thus obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH:14]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.N1C=CC=CC=1>O>[CH:14]1([NH:21][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCCC1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC1CCCCCC1)c1cnc2ccccc2n1
Yield: 12.4 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), cycloheptylamine (115 μL, 102 mg, 0.90 mmol), pyridine (5 mL), and water (100 mL) yielding 30 mg (12%) of (229):
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH:8]1[O:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[CH3:2].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][O:13]1)[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CCOCCOCC1CCC(O)CO1
Product: CCOCCOCC1CCC(OCc2ccccc2)CO1

Procedure:
5 was prepared as a liquid, boiling point not determined, by treating 5B with benzyl chloride according to the procedure described in the last paragraph of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[CH:24]([CH:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1)([CH3:26])[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH:24]([CH:27]1[CH2:32][CH2:31][CH:30]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:6]=[CH:5]3)[CH2:29][CH2:28]1)([CH3:26])[CH3:25]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Reactant: CC(C)C1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(Cc2ccc3cc(OC4CCC(C(C)C)CC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 486.7 %

Procedure:
Into a 25 mL round bottom flask was added ethyl 1-((6-hydroxynaphthalen-2-yl)methyl)piperidine-4-carboxylate (313 mg, 0.1 mmol, 2 eq), 4-isopropylcyclohexanol (284 mg, 0.2 mmol, 2 eq), PPh3 (562 mg, 0.2 mmol, 2 eq) and dry toluene (0.5 mL) under N2. Then DIAD (404 mg, 0.2 mmol, 2 eq) was quickly added in one portion at room temperature. The reaction mixture was stirred at rt for 0.5 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (PE:EA=4:1) to give ethyl 1-((6-(4-isopropylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate (213 mg, yield: 51%) as slight yellow oil. ESI-MS (M+1)+: 438.1. 1H NMR (400 MHz, CDCl3) δ: 7.64-7.57 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.10-7.08 (m, 2H), 4.60-4.58 (m, 1H), 4.05 (q, J=7.2 Hz, 2H), 3.56 (s, 2H), 2.85-2.81 (m, 2H), 2.07-2.04 (m, 1H), 2.01-1.97 (m, 2H), 1.83-1.71 (m, 4H), 1.51-1.40 (m, 6H), 1.24-1.15 (m, 6H), 1.11-1.06 (m, 1H), 0.83 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Li+].[CH3:2][N:3]([CH3:26])[C:4]1[C:5]([F:25])=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O-])=[O:15])[C:10](=[O:21])[CH:9]=1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH:39][C:14](=[O:15])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[CH:22]=[CH:23][CH:24]=[C:4]([N:3]([CH3:2])[CH3:26])[C:5]=4[F:25])=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:35]2)[CH2:30][O:29]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)[O-])N1CC(Oc2cccc(N(C)C)c2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(N(C)C)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of (S)-2-[4-(3-dimethylamino-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid lithium salt (0.257 g, 0.73 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.160 g, 0.81 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.91 g, 4.32 mmol). The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with a saturated sodium chloride solution and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 10% to 75% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-dimethylamino-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.200 g, 51%) as a yellow solid: HR-ES-MS m/z calculated for C27H36FN5O5 [M+H]+ 530.2773, observed 530.2771, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.31 (d, J=3.0 Hz, 3H), 1.38-1.50 (m, 1H), 1.50-1.65 (m, 1H), 1.69-1.85 (m, 1H), 2.82 (s, 6H), 3.74 (dd, J=8.3, 5.9 Hz, 1H), 4.01 (dd, J=8.5, 6.3 Hz, 1H), 4.04-4.15 (m, 2H), 4.20 (d, J=18.4 Hz, 1H), 4.29-4.43 (m, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.86 (s, 1H), 4.87-4.95 (m, 1H), 6.44 (d, J=2.1 Hz, 1H), 6.79-6.98 (m, 2H), 7.12 (t, J=8.5 Hz, 1H), 7.61 (br. s., 1H), 10.80 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH:15]=2)C.C1C2N(CC3C=CC(C([NH:53][OH:54])=O)=CC=3)C3C(=CC=CC=3)C=2C=CC=1>>[OH:54][NH:53][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH:15]=2
Reactant: CCOC(=O)CCCCCn1c2c(c3cc(-c4ccc(N(C)C)cc4)ccc31)CCCC2
Reactant: O=C(NO)c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Product: CN(C)c1ccc(-c2ccc3c(c2)c2c(n3CCCCCC(=O)NO)CCCC2)cc1

Procedure:
Compound 33 was prepared from 6-(6-bromo-1,2,3,4-tetrahydro-carbazol-9-yl)-hexanoic acid ethyl ester (compound 32) using the procedure described above for compound 29 as a white solid (85%). 1H NMR (400 MHz, MeOD): δ 7.86 (d, 2H), 7.65 (m, 3H), 7.33 (s, 2H), 4.09 (t, 2H), 2.76 (m, 4H), 2.16 (s, 1H), 2.08 (t, 2H), 1.98 (m, 2H), 1.90 (m, 2H), 1.77 (m, 2H), 1.66 (m, 2H), 1.38 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH2:5][C:6]([C:8]1[S:9][C:10]([Br:13])=[CH:11][CH:12]=1)=O.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>CO>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:8]2[S:9][C:10]([Br:13])=[CH:11][CH:12]=2)[N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])[N:25]=1)=[O:15]
Reactant: COC(=O)C(=O)CC(=O)c1ccc(Br)s1
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(Br)s2)n(-c2ccccc2Cl)n1
Temperature: 20 °C
Yield: 100.6 %

Procedure:
A solution of 4-(5-bromo-thiophen-2-yl)-2,4-dioxo-butyric acid methyl ester (15 g, 50 mmol) and 2-chlorophenylhydrazine hydrochloride (10.75 g, 60 mmol) in dry MeOH (200 mL) was heated to reflux for 6 h. After cooling to 20° C., a white solid precipitated and was collected by filtration, washed with a small volume of cold MeOH and dried under high vacuum to afford 5-(5-bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-1H-pyrazole-3-carboxylic acid methyl ester (20 g, 100%). 1H-NMR (CDCl3): δ 7.48-7.55 (m, 3H), 7.43 (m, 1H), 7.11 (s, 1H), 6.90 (d, 2H), 6.65 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[S:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2ccccc2cc1NC(=S)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 79 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](C3C=CC4C(C=3)=NN(CC3C=CC=CC=3)C=4)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 152.9 %

Procedure:
To a solution of tert-butyl 4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate (325 mg, 0.62 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred (rt) for 17 h. The mixture was made basic (pH 9) with the addition of saturated aqueous NaHCO3 and the layers were separated. The aqueous phase was back extracted with dichloromethane (2×10 mL) and the combined organics were washed with brine, dried (Na2SO4), and evaporated to afford 299 mg (100%) of the desired product, which contained trace impurities. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.87 (s, 1 H), 7.78 (d, 1 H), 7.57 (s, 1 H), 7.36-7.30 (m, 5 H), 7.13 (d, 1 H), 6.55 (s, 1 H), 5.64 (s, 2 H), 3.41 (br s, 1 H), 3.30-3.18 (m, 1 H), 3.07 (d, 2 H), 2.75-2.64 (m, 2H), 1.97 (d, 2 H), 1.68-1.53 (m, 2 H); ES-MS m/z 424.3 [M+H]+, HPLC RT (min) 0.78.
Reaction SMILES: CS(O)(=O)=O.O[CH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2[NH:12][C:11]1=[O:20].[C:21]1([N:27]2[C:31]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:30](=[O:37])[NH:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:19][C:17]1[CH:16]=[CH:15][C:14]2[N:10]([CH2:9][CH2:8][CH2:7][N:34]3[CH2:33][CH2:32][C:31]4([N:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:28][NH:29][C:30]4=[O:37])[CH2:36][CH2:35]3)[C:11](=[O:20])[NH:12][C:13]=2[CH:18]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A mixture of 5.68 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one methanesulfonate, 4.62 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 3.7 parts of sodium carbonate and 45 parts of N,N-dimethylformamide is stirred for 1 hour at 60° C. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off and purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of N,N-dimethylformamide and water, yielding 2 parts (24%) of 8-[3-(1,3-dihydro-5-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 255.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH2:16][C:17]2[C:18]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])=[N:19][O:20][C:21]=2[CH:22]2[CH2:24][CH2:23]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:22]1([C:21]2[O:20][N:19]=[C:18]([C:25]3[C:26]([Cl:32])=[CH:27][CH:28]=[CH:29][C:30]=3[Cl:31])[C:17]=2[CH2:16][O:15][CH:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCCC(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(Cl)c1-c1noc(C2CC2)c1COC1CCCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
A solution of 56 g (116.32 mmol) of 4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepane-1-carboxylic acid tert-butyl ester in 150 mL of dichloromethane at 0° C. (ice bath) is treated with trifluoroacetic acid (150 mL, 1.98 mol). The mixture is stirred at room temperature under nitrogen for 2 hours. The reaction mixture is concentrated. The crude product is dissolved with EtOAc (300 mL), washed with a solution 2N—NaOH (2×100 mL) and washed with brine (1×100 mL). The organics are dried (Na2SO4), filtered and concentrated to afford 38 g of the desired compound as a yellow oil (86%). MS (m/e): 381 (M+1).
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([OH:13])=[O:12].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([CH:6]1[CH2:9][O:10][CH:18]([C:17]2[CH:20]=[CH:21][C:14]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)[O:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(CO)CO
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC1COC(c2ccc(C(=O)O)cc2)OC1
Yield: 80.9 %

Procedure:
A mixture of 2-n-pentylpropane-1,3diol (8 g, 0.054 m), 4-carboxybenzaldehyde (8 g, 0.053 m), benzene (200 ml) and a catalytic amount of 4-toluenesulfonic acid was azeotropically refluxed until no more water was collected. The cold reaction mixture was washed with saturated NaHCO3 solution and water and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to yield 4-(5-n-pentyl-1,3-dioxan-2-yl) benzoic acid (12 g, 80%)
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[I:24]I.S([O-])(O)=O.[Na+]>O1CCCC1.O>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[C:11]([I:24])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: II
Reactant: Cc1ccc(C)n1-c1ccn(-c2ccccc2)n1
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C)n1-c1cc(I)n(-c2ccccc2)n1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-phenyl-1H-pyrazole (14.6 g) in tetrahydrofuran (80 ml) cooled to −78° C. was added n-butyllithium (1.6M solution in n-hexane, 24 ml) over 5 minutes, and then the mixture was stirred for 1 hour. To this mixture was added a solution of iodine (15.7 g) in tetrahydrofuran (30 ml) over 10 minutes, and the mixture was stirred for additional 1.5 hours. To this mixture were sequentially added water (5 ml) and a saturated aqueous solution of sodium hydrogen sulfite (30 ml), and then the mixture was warmed to 0° C., and additional water (150 ml) was added thereto, and the mixture was stirred at room temperature for 1 hour. A precipitated solid was collected by filtration, washed with water and a small amount of methanol, and dried under reduced pressure to give the titled compound (13.0 g).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:5][NH:4][CH2:3][CH2:2]2.C(O)(=O)C.[CH:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH2:15]>CO>[N:19]1[CH:20]=[CH:21][C:16]([CH2:14][CH2:15][N:4]2[CH:3]=[CH:2][N:1]3[CH:9]=[CH:8][CH:7]=[C:6]3[CH2:5]2)=[CH:17][CH:18]=1
Reactant: C1CC2CNCCN2C1
Reactant: C=Cc1ccncc1
Solvent: CC(=O)O
Solvent: CO
Product: C1=Cn2cccc2CN1CCc1ccncc1

Procedure:
A solution of 12 g (0.095 mole) 1,4-diazabicyclo[4.3.0]-nonane, 10 ml of acetic acid and 12.5 ml of 4-vinylpyridine in 225 ml methanol was heated at reflux for 20 hours. The solvent was removed under vacuum and the residue distilled to yield 5.1 g of 2(4-pyridylethyl)pyrrolo[1,2-a]pyrazine; b.p. 126°-130/0.01 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH2:14])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
The product from step (iii) was dissolved in dichloromethane (200 ml) and trifluoroacetic acid (100 ml) added. After 18 hrs at room temperature the solvent was evaporated and the resultant gum triturated under ether to give the sub-titled product as a solid (5.7 g).