Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1F)[CH3:2].Cl.Cl.[CH3:17][S:18]([N:21]1[CH2:26][CH2:25][N:24]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)(=[O:20])=[O:19].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:30]1[CH2:29][CH2:28][CH:27]([N:24]2[CH2:25][CH2:26][N:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH2:22][CH2:23]2)[CH2:32][CH2:31]1)[CH3:2]
Reactant: CS(=O)(=O)N1CCN(C2CCNCC2)CC1
Reactant: CCc1cc([N+](=O)[O-])c(OC)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc([N+](=O)[O-])c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 90 °C
Yield: 56.2 %

Procedure:
A mixture of 1-ethyl-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 187, step C) (0.93 g, 4.67 mmol), 1-(methylsulfonyl)-4-(4-piperidinyl)piperazine (Example 204, step C) (1.16 g, 4.67 mmol) and K2CO3 (0.774 g, 5.60 mmol) in DMSO (20 mL) was heated at 90° C. for 48 h. The reaction had not progressed sufficiently so the reaction was then heated at 120° C. for an additional 4 h. The reaction was cooled to rt, poured into H2O and extracted with DCM. Some saturated brine solution was added and the resultant was exhaustively extracted with DCM. The combined organics were washed with H2O then dried over MgSO4. The resultant solution was concentrated onto silica and purified by flash chromatography to afford 1-{1-[2-ethyl-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.12 g, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73-7.80 (m, 1H), 6.75 (s, 1H), 3.91 (s, 3H), 3.23-3.30 (m, 1H), 3.05-3.19 (m, 3H), 2.87 (s, 2H), 2.70-2.84 (m, 2H), 2.53-2.67 (m, 5H), 1.77-1.94 (m, 2H), 1.48-1.67 (m, 2H), 1.19 (t, J=7.42 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]2)[CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:28][C:26]1[CH:25]=[N:24][N:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:27]=1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN1CCC(n2cc(N)cn2)CC1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cnn(C2CCN(C)CC2)c1
Yield: 52.1 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.0 mmol) was reacted with 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (0.30 g, 1.66 mmol) to afford the desired product (223 mg, 52%) as a light yellow solid. ESI MS m/z 428 [C20H22BrN5O+H]+
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:19](=[O:25])[CH:18]([CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:17]2.C(Br)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[CH2:17][CH:18]([CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH2:11][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:29][CH2:28]3)[C:19](=[O:25])[C:20]2=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCNCC1)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Yield: 95.3 %

Procedure:
0.18 g of 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one p-toluenesulfonic acid salt were dissolved in 10 mL of dry N,N′-dimethylformamide. 0.073 g of benzyl bromide and 0.3 g of potassium carbonate were added thereto. The resulted mixture was stirred until the reaction completed. Then 60 mL of water were added and the solution was extracted with 4×30 mL of ethyl acetate. The extracts were combined, washed with 15 mL of Na2CO3 solution and with 15 mL NaCl solution, and dried over anhydrous MgSO4. Drying agent was then filtered off. The solvent was removed in vacuo yielding 0.141 g of product, 96% yield. 1H NMR (CDCl3), 7.15-7.35 (m, 5H), 7.09 (s, 1H), 6.78 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.48 (s, 2H), 3.17 (dd, 1H, J=8.0 Hz, J=17.6 Hz), 2.82-2.92 (m, 2H), 2.58-2.74 (m, 2H), 1.80-2.03 (m, 3H), 1.57-1.76 (m, 2H), 1.40-1.56 (m, 1H), 1.18-1.40 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:18](=[O:20])[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:12](=[O:22])[CH:11]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=1[N+:41]([O-:43])=[O:42]>CN(C=O)C>[N+:38]([C:35]1[CH:34]=[C:33]([N+:41]([O-:43])=[O:42])[CH:32]=[CH:37][C:36]=1[N:17]1[C:18](=[O:20])[C:19]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:11][C:12](=[O:22])[N:13]([CH3:21])[C:14]=2[N:15]=[CH:16]1)([O-:40])=[O:39]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 5F (41 mg, 0.1 mmol, 1 eq) and catalytic amount of potassium iodide in DMF (1 mL) was added potassium carbonate (21 mg, 0.15 mmol, 1.5 eq). The reaction mixture was stirred at ambient temperature for 5 minutes. 1-Chloro-2,4-dinitrobenzene (22 mg, 0.11 mmol, 1.1 eq) was then added and the reaction mixture was irradiated with microwave at 80° C. for 30 minutes and then at 100° C. for 30 minutes. The reaction mixture was filtered and the filtrate was purified by preparatory LC/MS (50-75% CH3CN in H2O) to give 3-(2,4-dinitrophenyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione compound 24A as a yellow solid (18 mg, 31% yield). 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3H) 6.09 (s, 1H) 7.17-7.24 (m, 1H) 7.52 (d, J=8.34 Hz, 2H) 7.72-7.80 (m, 1H) 8.23 (s, 1H) 8.75 (dd, J=8.46, 2.65 Hz, 1H) 9.12 (d, J=2.53 Hz, 1H) 9.83 (s, 1H). [M+H] calc'd for C20H12FIN6O6, 579. found, 579.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Product: COc1cccc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)c1

Procedure:
Prepared from 2-benzyl-benzo[b]thiophene and m-anisoyl chloride according to the procedure in Example 8. White solid: MS (EI): [M+], 358.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH2:10][C@H:9]([CH2:12][OH:13])[CH2:8]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][C@H:9]1[CH2:10][CH2:11][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8]1)(=[O:24])=[O:23]
Reactant: OC[C@H]1CCN(c2ccccn2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CCN(c2ccccn2)C1
Temperature: 25 °C

Procedure:
(S)-(1-(Pyridin-2-yl)pyrrolidin-3-yl)methanol (1.683 mmol, 0.3 g) and triethylamine (5.05 mmol, 0.702 ml, 0.511 g) were stirred in DCM (10 ml) at 0° C. Methanesulfonyl chloride (2.52 mmol, 0.195 ml, 0.289 g) was added and the reaction allowed to warm to room temperature over 1 hour. The reaction mixture was washed with water, dried over Na2SO4 and concentrated at reduced pressure to afford (S)-(1-(pyridin-2-yl)pyrrolidin-3-yl)methyl methanesulfonate. (0.38 g)
Reaction SMILES: [C:1]1([C:7]2([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][I:20]>CO>[I-:20].[CH3:19][N+:13]1([CH2:12][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CI
Reactant: c1ccc(C2(CN3CCCCC3)CCCC2)cc1
Solvent: CO
Product: C[N+]1(CC2(c3ccccc3)CCCC2)CCCCC1
Product: [I-]
Reaction time: 48 h
Yield: 96.6 %

Procedure:
To a mechanically stirred solution of [(1-phenylcyclopentyl)methyl]piperidine (115 gm; 0.47 mole) in 1000 ml methanol (ACS reagent), methyl iodide (100 gm; 0.7 mole) were added. The resulting mixture was stirred for 48 hrs. Then an additional 35 gm (0.5 mole equivalent) of methyl iodide was added and the reaction was heated for 1 hr. The resulting solution was concentrated under reduced pressure on a rotary evaporator to give 175 gm of a tan solid material. The obtained solid was re-crystallized by dissolving in hot isopropyl alcohol and allowed to re-crystallize overnight. Re-crystallization afforded 171 gm of the product (NMR analysis) as shinny white needles.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([S:18][CH3:19])[NH:12]4)[CH:5]=[C:4]([CH3:20])[CH2:3]1.[OH2:21].[CH2:22]=O>>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([S:18][CH3:19])[N:12]4[CH2:22][OH:21])[CH:5]=[C:4]([CH3:20])[CH2:3]1
Reactant: O
Reactant: C=O
Reactant: CSc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C=C(C)CN1C
Product: CSc1c2c3c(cccc3n1CO)[C@H]1C=C(C)CN(C)[C@@H]1C2

Procedure:
A solution of 8,9-didehydro-6,8-dimethyl-2-methylthio ergoline (see Example 1) (2.84 g) in aqueous formaldehyde (40%, 35 ml) was refluxed for 2 hours. On cooling, water (100 ml) was added and the solution extracted several times with ethyl acetate. The organic extracts were collected, washed with water, dried over anhydrous magnesium sulphate and the solution filtered. It was reduced in vacuo to give a yellow oil which solidified on standing (2.2 g). This was passed through a dry neutral alumina column (100 g), eluting with chloroform and the final product, 8,9-didehydro-6,8-dimethyl-1-hydroxymethyl-2-methyl thioergoline recyrstallised from acetonitrile, m.p. 133°-135°.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[C:46]([CH3:49])[C:45]([F:50])=[C:44]([NH:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[N:43]=1>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[C:46]([CH3:49])[C:45]([F:50])=[C:44]([NH:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=3)[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: COc1ccc(CNc2nc(N)c(F)c(C)c2F)cc1
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)c(C)c2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 3 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.78 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.90 g of 2-amino-3,5-difluoro-6-(p-methoxybenzylamino)-4-methylpyridine. The solution was concentrated under reduced pressure, and to the residue were added 1.3 g of anhydrous potassium carbonate and 3 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound as a brown crude oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.C(O[C:12](=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](OCC)=O)[CH3:13])C.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:15]1[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]([CH3:13])[N:1]=[C:2]2[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=12
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)OCC
Reactant: CCn1nccc1N
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)nc2c(cnn2CC)c1Cl
Temperature: 150 °C

Procedure:
A mixture of 5-amino-1-ethylpyrazole (1.614 g, 14.5 mmol) and diethyl 2-(1-ethoxyethylidene)malonate (3.68 g, 16.0 mmol, as described by P. P. T. Sah, J. Amer. Chem. Soc., 1931, 5, 1836) was heated at 150° C. under Dean Stark conditions for 5 hours. Phosphorous oxychloride (25 ml) was carefully added to the mixture and the resulting solution was heated at 130° C. under reflux for 18 hours. The mixture was concentrated in vacuo, then the residual oil was carefully added, with cooling, to water (100 ml). The resulting mixture was extracted with DCM (3×100 ml) and the combined organic extracts were dried over anhydrous sodium sulphate and concentrated in vacuo. The residual oil was purified by Biotage chromatography (silica, 90 g) eluting with ethyl acetate-petrol (1:19). Fractions containing the desired product were combined and concentrated in vacuo to afford Intermediate 58 (1.15 g). LCMS showed MH+=268; TRET=3.18 min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]1[O:14][CH2:13][CH2:12][O:5]1
Reactant: COc1ccc(C=O)c(F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCCO2)c(F)c1
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of 2-fluoro-4-methoxy-benzaldehyde (13.98 g, 90.7 mmol) in toluene (100 mL) was added ethylene glycol (101 mL, 1.81 mol) and p-toluenesulfonic acid monohydrate (1.04 g, 5.44 mmol). The reaction mixture was heated at reflux for 16 hrs. The water was removed using a Dean Starck apparatus. After cooling, aqueous potassium carbonate (10%, 200 mL) was added and the mixture stirred for 30 minutes. The solution was extracted with ethyl acetate. The organic phase was washed successively with 10% aqueous potassium carbonate, brine and dried (MgSO4). The residue was purified on silica gel (eluent: 10% ethyl acetate in hexane) to give 9.187 g of 2-(2-fluoro-4-methoxy-phenyl)-[1,3] dioxolane (51%). 1H NMR (300 MHz; CDCl3): 3.81 (s, 3 H), 4.06 (m, 2 H), 4.15 (m, 2 H), 6.03 (s, 1 H), 6.60 (dd, J=12.3 and 2.7 Hz, 1 H), 6.72 (d, J=8.4 Hz, 1 H), 7.44 (t, J=8.4 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:33]([N:35]([C@@H:47]([CH3:55])[CH:48]([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[N:45]=[CH:44][CH:43]=[CH:42]2)=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([NH:19][C@H:20]([C:33]([N:35]([C@@H:47]([CH3:55])[CH:48]([O:49][CH2:50][CH3:51])[O:52][CH2:53][CH3:54])[CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:46]=2[N:45]=[CH:44][CH:43]=[CH:42]3)=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:16])[CH3:12])=[O:9])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 79 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)-(quinolin-8-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-14) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: Cl.[CH3:2][NH2:3].O=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3([N:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:29][CH2:28]4)[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)[CH:15]=2)=[O:12])[CH2:7][CH2:6]1>C1COCC1.CO>[CH3:2][NH:3][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3([N:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:31][CH2:32]4)[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]3)[CH:15]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: CN
Reactant: CC1CCC(c2cccc(NC(=O)N3CCC(=O)CC3)c2)(N2CCN(c3ccccc3)CC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNC1CCN(C(=O)Nc2cccc(C3(N4CCN(c5ccccc5)CC4)CCC(C)CC3)c2)CC1
Temperature: 25 °C

Procedure:
Methylamine hydrochloride (37 mg, 0.546 mmol) was added to a solution of 4-(oxo)-N-[3-[4-methyl-1-(4-phenyl-1-piperazinyl)cyclohexyl]phenyl]-1-piperidinecarboxamide (cis isomer) (43 mg, 0.091 mmol) in THF/MeOH (1:1) and stirred at room temperature. When all the methylamine hydrochloride had dissolved, NaCNBH4 (6 mg, 0.091 mmol) was added and the reaction allowed to stir overnight at room temperature. The reaction mixture was concentrated, dissolved in an excess of 3N HCl, and the aqueous solution washed with ether (3×). The aqueous solution was made basic with 10N NaOH, extracted with EtOAc (4×), dried (Na2SO4), and concentrated to give 4-(methylamino)-N-[3-[4-methyl-1-(4-phenyl-1-piperazinyl)-cyclohexyl]phenyl]-1-piperidinecarboxamide (cis isomer) as a clear oil. The HCl salt was prepared by adding excess saturated EtOAc/HCl solution to the free base in dry MeOH. Concentration of the homogeneous solution yielded a white solid which was washed with EtOAc. mp=154-155° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:21])([CH3:20])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O)[C:4]=2[O:3][CH2:2]1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][C:27]2=[O:32]>C(O)(=O)C>[OH:19][C:12]1([C:15]([F:16])([F:17])[F:18])[CH2:11][C:10]([CH3:20])([CH3:21])[C:9]2[C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=[CH:7][C:8]=2[CH:13]1[NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][C:27]2=[O:32]
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cccc2c1OCO2
Reactant: Nc1cccc2c1CNC2=O
Solvent: CC(=O)O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c2CNC3=O)c2ccc3c(c21)OCO3
Yield: 63.5 %

Procedure:
800 mg (2.63 mmol) of 4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is stirred in 5.2 ml of glacial acetic acid with 389 mg (2.63 mmol) of 4-amino-2,3-dihydroisoindol-1-one overnight at room temperature. The reaction mixture is spun in until a dry state is reached, and the residue is chromatographed on a Flashmaster. 725 mg (62.8%) of the desired compound is isolated as a racemate. Racemate cleavage (Chiralpak AD 20μ; mobile solvent:hexane/ethanol/diethylamine) yields 279.2 mg of the (+)-enantiomer {[α]D=+20.7 (c=1.03, methanol)} and 297.5 mg of the (−)-enantiomer {[α]D=−23.4 (c=1.02, methanol)}.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[O:15]=[C:16]([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:17]([C:16](=[O:15])[CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
5 g (26.57 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 3.4 ml (26.57 mmol) of ethyl 3-oxobutanoate, 1.9 ml (33.21 mmol) of acetic acid and 263 μl (2.66 mmol) of piperidine in 50 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the solution is diluted with dichloromethane (50 ml) and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from isopropanol. 7.63 g (91% of theory) of the title compound are obtained as an E/Z mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(OCC)(=O)C>C1COCC1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=2)(=[O:28])=[O:27])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 2 h

Procedure:
4′-Amino acetophenone (0.375 g, 2.78 mmol) was dissolved in THF (5 ml) before pyridine (0.674 ml, 8.34 mmol) was added, leaving a yellow solution. 4-trifluoromethoxy benzenesulfonylchloride (0.871 g, 3.34 mmol) was then added dropwise with stirring. After strirring for 2 h, THF and pyridine were removed. The desired sulfonamide (0.848 g, 2.36 mmol, 85%) was recrystallized from ethyl acetate and hexanes. 1H-NMR: (400 MHz, CDCl3) 7.89 (m, 4H), 7.29 (d, 1H), 7.16 (d, 2H), 6.88 (s, 1H), 2.55 (s, 3H). LC-MS (ES+): 360 [MH]+ m/e.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[NH2:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[NH:16][N:15]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[Cl:30][C:26]1[CH:25]=[C:24]([NH:23][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[NH:16][N:15]=[C:14]([NH:13][CH2:6][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=4)[C:22]=23)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc(OC)c1
Reaction time: 5 h

Procedure:
99.7 mg (0.60 mmol) of 3,5-dimethoxy-benzaldehyde are added to a solution of 130 mg (0.50 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol and 120 mg (2.0 mmol) of acetic acid. As the reaction mixture is stirred, a solid precipitates which can be dissolved again by the addition of 52 ml of DMEU. 220 mg (3.5 mmol) of NaCNBH3 are added thereto and stirring is then continued for 5 hours at RT. Since not all of the 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine has been reacted (HPLC), 220 mg of NaCNBH3 are added twice more and stirring is continued for 5 hours each time. The reaction solution is then poured into 1 liter of water, stirred vigorously for 1 hour and filtered. Crystallization of the filtration residue from acetone yields 4-(3-chloro-phenylamino)-3-(3,5-dimethoxybenzylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 208-209° C.; HPLC: TRet (Grad20-100)=11.7; FAB-MS: (M+H)+ =411.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:10][CH2:11][N:12]([CH:32]([CH3:34])[CH3:33])[C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:17]=[C:16]([CH3:30])[CH:15]=1)#[N:9]>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:10][CH2:11][N:12]([CH:32]([CH3:34])[CH3:33])[C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][NH:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH:17]=[C:16]([CH3:30])[CH:15]=1)(=[O:4])[NH2:9]
Reactant: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC#N)C(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC(N)=O)C(C)C)c1

Procedure:
A solution of N-(2-cyano-ethyl)-N-isopropyl-3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzamide trifluoroacetate (0.011 g) in dichloromethane (1.5 ml) and trifluoroacetic acid (0.5 ml) was stored at room temperature overnight and then concentrated under reduced pressure. The title compound was obtained as a pale yellow foam (0.012 g).