Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[C:10]([Si:14]([CH3:24])([CH3:23])[O:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][NH:21][CH:22]=1)([CH3:13])([CH3:12])[CH3:11].O>CN1C(=O)CCC1>[Si:14]([O:15][CH2:16][CH2:17][C:18]1[CH:22]=[N:21][N:20]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[CH:19]=1)([C:10]([CH3:11])([CH3:13])[CH3:12])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cn[nH]c1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1
Temperature: 150 °C
Reaction time: 5 h
Yield: 36.5 %

Procedure:
A mixture of 2-chloropyridine-4-carbonitrile (1.38 g, 10 mmol), tert-butyl-dimethyl-[2-(1H-pyrazol-4-yl)ethoxy]silane (2.48 lg, 11 mmol) in NMP (30 mL) was stirred for 5 hr at 150° C. Then the reaction mixture was cooled to room temperature and poured into water and extracted with ethyl acetate three times. Organic extracts collected and washed with water twice, brine and dried with anhydrous Na2SO4. It was then concentrated and purified by flash column chromatograph to give the title compound (1.2 g, 36%). [M+H] Calc'd for C17H24N4O3Si, 329. Found, 329.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23]>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([NH:23][C:22]3[C:21]([Cl:20])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:28])=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(O)C1c2ccccc2COc2ccc(Br)cc21
Reactant: Nc1c(Cl)cccc1Cl
Product: O=C(Nc1c(Cl)cccc1Cl)C1c2ccccc2COc2ccc(Br)cc21
Yield: 18.4 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.67 g of 2-bromo-6,11-dihydrodibenz[b,e]oxepin11-carboxylic acid obtained in Example 46 (Compound H) in place of Compound A and 0.76 g of 2,6-dichloroaniline in place of aniline to obtain 0.40 g of Compound 39.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5]([OH:7])=O.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][N:31]=[CH:30]1>>[N:29]1([CH2:34][CH2:35][CH2:36][NH:37][C:5]([C:4]2[CH:8]=[CH:9][C:10]([N:11]([CH3:28])[C:12]([C:14]3[S:27][C:17]4[C:18]5[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=5[O:20][CH2:21][CH2:22][C:16]=4[CH:15]=3)=[O:13])=[C:2]([Cl:1])[CH:3]=2)=[O:7])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: NCCCn1ccnc1
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)NCCCn2ccnc2)cc1Cl

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and 3-(1H-imidazol-1-yl)propan-1-amine were reacted by a procedure similar to that to prepare 137 in Example 47 to give 229. MS: (ESI+) 521.1
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10](=O)[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=O)[CH:7]=[CH:6][C:5]=12.C([O-])(O)=O.[Na+].CO[C:28]([CH3:31])([CH3:30])[CH3:29]>CO>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[N:1]=[C:5]([CH2:29][C:28]4[CH:31]=[C:11]([CH:10]=[CH:8][CH:30]=4)[C:13]#[N:14])[NH:4][C:11]=3[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)[CH:7]=[CH:6][C:5]=12
Reactant: Cc1cccc(C(=O)C(=O)c2ccc3ncnn3c2)n1
Reactant: COC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2[nH]c(Cc3cccc(C#N)c3)nc2-c2ccc3ncnn3c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33 %

Procedure:
To a stirred solution of 1-((1,2,4)triazolo(1,5-a)pyridin-6-yl)-2-(6-methylpyridin-2-yl)ethane-1,2-dione (4.00 g, 15.02 mmol) in a mixture of tert-butyl methyl ether (30 mL) and MeOH (30 mL) were added 3-(fomylmethyl)benzonitrile (prepared according to the method described in WO 02/096875 A1) (6.54 g, 45.07 mmol) and NH4OAc (11.58 g, 150.24 mmol), and the mixture was stirred at room temperature for 90 min. The pH of the mixture was adjusted to 8 with saturated aqueous NaHCO3 solution. After removal of solvent, the mixture was extracted with EtOAc (2×150 mL), and the EtOAc solution was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of MeOH and CH2Cl2 (1:19 (v/v)) as eluent to give the titled compound (1.92 g, 33%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.70 (br s, 1H), 9.53 (br s, 1H), 8.49 (s, 1H), 7.96 (dd, 1H, J=9.2, 1.8 Hz), 7.84 (d, 1H, J=2.0 Hz), 7.82 (d, 1H, J=9.2 Hz), 7.74-7.71 (m, 2H), 7.69 (t, 1H, overlapped, J=7.6 Hz), 7.56 (t, 1H, J=7.8 Hz), 7.47 (br s, 1H), 7.15 (d, 1H, J=7.6 Hz), 4.18 (s, 2H), 2.47 (s, 3H); MS (ESI) m/z 392.18 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccccc1N
Product: Cc1ccccc1NS(=O)(=O)c1ccccc1

Procedure:
The so far single industrially feasible synthesis is described by BIOS Final Report 986/2, No. 167, pages 297-306, and involves acylating 2-aminotoluene with benzenesulfonyl chloride to give N-(2-methylphenyl)-benzenesulfonamide, nitrating the latter in chlorobenzene, and, finally, splitting off the protective group by hydrolysis and isolating 2-amino-5-nitrotoluene. This synthesis gives a yield of about 75% of theory. In addition to this unsatisfactory yield, the numerous process stages and the associated consumption of chemicals, this process harbors further grave disadvantages which render its industrial application problematical from a processing and an ecological point of veiw
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][CH2:55][N:54]([C:57](=[O:62])[CH2:58][N:59]([CH3:61])[CH3:60])[CH2:53][CH2:52]2)=[CH:47][CH:46]=1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([CH:51]4[CH2:52][CH2:53][N:54]([C:57](=[O:62])[CH2:58][N:59]([CH3:60])[CH3:61])[CH2:55][CH2:56]4)=[CH:47][CH:46]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN(C)CC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(C4CCN(C(=O)CN(C)C)CC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20.5 mg, 0.050 mmol) and 1-[4-(4-amino-phenyl)-piperidin-1-yl]-2-dimethylamino-ethanone di-TFA salt (24 mg g, 0.050 mmol) were combined in i-PrOH (1 mL) and TEA (10.6 mg, 0.11 mmol) was added and the mixture was heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/1120 gradient over 10 min) and lyophilized to provide 24 mg (80%) of 2-{4-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.31 (s, 1H), 9.10 (br s, 1H), 8.48 (s, 1H), 7.51 (d, 2H, J=8.1 Hz), 7.22-7.34 (2H), 7.13-7.16 (m 3H), 4.38 (q, 2H, J=7.0 Hz), 3.09 (br s, 2H), 2.95-3.02 (m, 6H), 2.71-2.80 (m, 2H), 2.39 (s, 6H), 2.11-2.22 (m, 2H), 1.55-1.93 (m, 4H), 1.39 (t, 3H, J=7.2 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][C:20]([CH3:29])([CH2:24][C:25](=O)[CH2:26][CH3:27])[C:21]([OH:23])=[O:22]>C(O)(C)(C)C>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:26]([CH3:27])=[C:25]2[CH2:24][C:20]([CH3:29])([CH3:19])[C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1
Reactant: CCC(=O)CC(C)(C)C(=O)O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the method of Example 2, but using 1-[4-chlorobenzyl]-1-(4-fluorophenyl)hydrazine hydrochloride 1.9 g and 2,2-dimethyl-4-oxohexanoic acid (950 mg) as starting materials, in t-butanol as solvent, after 16 hrs. at reflux, the solvent was removed in vacuo, and the title compound was isolated by crystallization and filtration, followed by crystallization from hot ethyl acetate:hexane 9:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:10][C:41](=[O:42])[C:40]([S:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH:30]([CH3:31])[CH3:32])=[C:44]([OH:45])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(Cl)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4'-chloroacetophenone (2.33 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio] propanedioic acid (3.11 g, 10.0 mmol) m.p. 148°-151° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.41 (m, 1H), 6.86 (s, 1H), 6.92 (m, 1H), 7.08 (m, 2H), 7.27 (m, 1H), 7.62 (m, 2H), 7.86 (m, 2H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23]>>[CH2:25]([O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[CH:26]=[CH2:27]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: C=CCOC(=O)Cl
Product: C=CCOC(=O)N=C(OCC)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and allyl chloroformate, there is obtained ethyl N-allyloxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 76°-77.5° C.;
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C@H:9]([C:14]2[CH:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[C:10]([F:13])([F:12])[F:11])[CH2:6][C@@H:5]1O)=[N+:2]=[N-:3].C(N(S(F)(F)[F:28])CC)C>ClCCl>[N:1]([C@H:4]1[CH:5]([F:28])[CH2:6][N:7]([C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[N:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[CH2:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C[C@@H]1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)CC1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of (3S,4R)-4-azido-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ol (2.4 g, 7.5 mmol) in dichloromethane (30 mL) at −78° C., was added diethylaminosulfur trifluoride (1.17 mL, 8.95 mmol). The resulting solution was allowed to warm to ambient temperature and stirred overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and washed with water and brine, then dried (MgSO4), filtered and concentrated. The crude residue was purified by column chromatography (Biotage, 40M; 10-25% ethyl acetate/hexanes gradient) to afford 5-((1R)-1-((3R)-3-azido-4-fluoropyrrolidin-1-yl)-2,2,2-trifluoroethyl)-2-chloropyridine (1.02 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]CC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[Cl:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[Cl:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 70 °C

Procedure:
A mixture of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2-chloro-5-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (150 mg, 0.24 mmol), NaOH (70 mg, 1.75 mmol), H2O (2 mL) and THF (6 mL) was heated at 70° C. for 1 h. After cooled to room temperature, the solution was concentrated and the residue was acidified to “pH” 2-3 by addition of concentrated aqueous HCl. The white solid was collected by filtration to give the title compound which was used for next step reaction without further purification.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]1[CH:56]=[CH:55][CH:54]=[CH:53][C:49]=1[CH2:50][CH2:51][NH2:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:52][CH2:51][CH2:50][C:49]4[CH:53]=[CH:54][CH:55]=[CH:56][C:48]=4[CH3:47])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1ccccc1CCN
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCCc2ccccc2C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-methyl-phenethylamine (Oakwood) to give the title product. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12](Br)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][NH:29][CH3:30].CN>>[CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12]([N:29]([CH3:30])[CH3:28])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C1c2ccccc2CCc2c1nc1c(cnn1Cc1ccccc1)c2Br
Agent: CN
Product: CN(C)c1c2c(nc3c1cnn3Cc1ccccc1)C(=O)c1ccccc1CC2

Procedure:
By substituting the product of Example 11 in the procedure of Example 5 and substituting dimethylamine for the methylamine, 1-benzyl-4-(dimethylamino)-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])[C:7]2[C:16]3[CH:15]=[C:14]([CH2:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:24]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:46].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:46][C:9]1[C:8]2[N:24]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][C:29]3=[O:33])[C:7]=2[C:16]2[CH:15]=[C:14]([CH2:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: COCCc1nc2cnc3ccc(CCC(=O)N(C)C)cc3c2n1CCCN1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccc(CCC(=O)N(C)C)cc3c2n1CCCN1CCCC1=O
Reaction time: 0.17 h

Procedure:
To a stirring solution of 3-{2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}-N,N-dimethylpropanamide, (0.66 g) in dichloromethane (75 mL) was added 3-chloroperoxybenzoic acid (60% pure, 423 mg, 1.62 mmol). After 18 hours concentrated ammonium hydroxide (50 mL) was added and the reaction was vigorously stirred for 10 minutes. p-Toluenesulfonyl chloride (311 mg, 1.62 mmol) was then added in one portion. The fractions were separated and aqueous fraction was extracted with chloroform (3×50 mL). The combined organic fractions were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-30% gradient of CMA in chloroform). The resulting product was washed with a 1% aqueous sodium carbonate and then recrystallized from acetonitrile to provide 75 mg of 3-{4-amino-2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}-N,N-dimethylpropanamide as an off-white solid, mp 184-186° C.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16]=[C:17]=[O:18].[CH2:19]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:19]([C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:17]([NH:16][C:10]2[C:9]([Cl:8])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:15])=[O:18])=[CH:32][CH:33]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(NC(=O)Nc2c(Cl)cccc2Cl)cc1
Reaction time: 16 h
Yield: 68 %

Procedure:
To 10.6 ml (5.3 mmol) of a toluene solution of 0.50M 2,6-dichlorophenyl isocyanate was added 1.21 ml (5.32 mmol) of 4-octylaniline at room temperature and the whole was stirred for 16 hours. After removal of the solvent under reduced pressure, the residue was recrystallized from methanol to give 1.42 g (68% yield) of 1-(4-octylphenyl)-3-(2,6-dichlorophenyl)urea, the physical properties of which being shown in the following Table 3. The compounds No. 1, No. 13, No. 14, No. 17, and No. 18 listed in Table 3 were similarly prepared as above.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH3:23])[C:13]([O:19]C(=O)C)=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CN=C1>CCO>[OH:19][C:13]1[C:12]([CH3:23])=[C:11]2[C:16]([C:17](=[O:18])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[CH2:9][O:10]2)=[CH:15][CH:14]=1
Reactant: CC(=O)Oc1ccc2c(c1C)OCC(c1ccc(O)cc1)C2=O
Agent: c1c[nH]cn1
Solvent: CCO
Product: Cc1c(O)ccc2c1OCC(c1ccc(O)cc1)C2=O
Reaction time: 8 h

Procedure:
Acetic acid 3-(4-hydroxy-phenyl)-8-methyl-4-oxo-chroman-7-yl ester (18.37 g), imidazole (21.18 g, 6 equivalents) and 100% EtOH (536 ml) were added to a round bottom flask (2 L). The reaction mixture was refluxed and monitored by HPLC. The reaction was completed at 8 hours. The reaction mixture was reduced (˜130 ml) on a rotary evaporator and poured into stirred, chilled distilled water (1.9 L). The water crash out was left stirring in the cold room overnight. The pale pink solid was collected by suction filtration. NMR of the solid indicated it was 7-Hydroxy-3-(4-hydroxy-phenyl)-8-methyl-chroman-4-one with >95% purity. The solid was dried on the freeze dryer for 3 hours (8.31 g, 59%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:27]1>CN(C)C=O>[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:36][CH2:37][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:39][CH2:40]2)=[N:27]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 20 °C
Yield: 24.3 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (11 g), triethylamine (11 cc) and 4-(1,2-benzisothiazole-3-yl)piperazine (8.6 g) in dimethylformamide (120 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure with ethyl acetate as eluant, and recrystallization from boiling methyl ethyl ketone (160 cc), 2-{3-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.4 g) is obtained, m.p. 172°-173° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:31][C:30](=[O:32])[N:29](CC[Si](C)(C)C)[S:28]1(=[O:40])=[O:39])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:31][C:30](=[O:32])[NH:29][S:28]1(=[O:39])=[O:40])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][S:20]([CH3:23])(=[O:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3NS(C)(=O)=O)cc2OCc2ccccc2)S1(=O)=O
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of N-((1R*,2S*)-2-{3-Benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzyl}-cyclohexyl)-methanesulfonamide (118 mg, 0.194 mmol) in DMF (3 mL) is added CsF (118 mg, 0.78 mmol) and the mixture is stirred at 90° C. for 1 h. Ethyl acetate is added and the mixture is washed with 1N HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:4][CH:3]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([NH2:29])=[O:28])[CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(C2=C(c3ccc(F)cc3)CCCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)Nc1cc(C2=C(c3ccc(F)cc3)CCCC2)ccn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
A sealed 8 mL vial is charged with a solution of 4-[2-(4-Fluoro-phenyl)-cyclohex-1-enyl]-pyridin-2-ylamine (11 mg, 0.041 mmol) in methylene chloride (2 mL). Then benzoyl isocynate (9.0 mg, 0.06 mmol) is added. The resulting mixture is allowed to stir at 50° C. for 1 hour. The solvent is then carefully removed before potassium carbonate (6.8 mg, 0.049 mmol) and ethanol (1 mL) are added. The resulting reaction is allowed to stir at 85° C. for 30 min. Solvent is removed and the crude is purified by silica flash column chromatography using MeOH in DCM (gradient from 0% to 5%) to give 11 mg of the titled product.