Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1>>[Br-:1].[CH3:28][C:23]1[CH:22]=[N+:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:26]=[CH:25][C:24]=1[CH3:27]
Reactant: BrCCCCCCCCCCCCCc1cccnc1
Reactant: Cc1ccncc1C
Product: Cc1cc[n+](CCCCCCCCCCCCCc2cccnc2)cc1C
Product: [Br-]
Yield: 60 %

Procedure:
3-(13-Bromo-tridecyl)-pyridine (1 mmol) was added to 3,4-lutidine (5 ml), and the mixture was heated at 50 C overnight. The excess picoline was removed in a vacuum, and the resulting residue was partitioned between water and ether. The aqueous layer was washed extensively with ether until no 3,4-lutidine was left in the aqueous layer, and then the aqueous layer was extracted with chloroform. The chloroform was removed to afford the product (60%). 1HNMR (300 MHz, CDCl3, ppm), 9.23 (s, 1H), 9.04 (d, J=6.3, 1H), 8.40 (br, 2H), 7.79 (d, J=6.0, 1H), 7.48 (d, 8.1, 1H), 7.18-7.20 (m, 1H), 4.83 (t, J=7.5, 2H), 2.58 (t, J=7.5, 2H), 2.52 (s, 3H), 2.49 (s, 3H), 2.21 (br, 1H), 1.82-2.02 (m, 2H), 1.54-1.62 (m, 2H), 1.15-1.35 (br, 12H). 13CNMR, 157.61, 149.68, 146.92, 143.35, 141.91, 138.45, 138.33, 136.32, 128.65, 123.57, 61.37, 33.31, 32.19, 31.41, 29.85, 29.80, 29.68, 29.41, 26.45, 20.69, 17.40.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C(C)=CC=CC=1>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C1CCc2ccc(O)cc21
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Under argon atmosphere, 6-methoxy-1-indanone (10.0 g) was dissolved in xylene (100 ml), and to the mixture was added aluminum chloride (16.4 g). The mixture was refluxed for 2 hours and then cooled to room temperature. To the mixture was added 3N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 6-hydroxy-1-indanone (7.36 g) as pale brown crystals.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](N2CCN(S(C)(=O)=O)CC2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:33][N:34]([CH3:43])[C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36]>>[CH3:33][N:34]([CH3:43])[C:35]([N:37]1[CH2:38][CH2:39][N:40]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:41][CH2:42]1)=[O:36]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: CN(C)C(=O)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)N(C)C)CC4)cc3c2)CC1
Yield: 59 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and piperazine-1-carboxylic acid dimethylamide to afford the desired product as light-brown foam (59%). MS (ISP): 455.4 (M+H)+.
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CC=1N.[Cl:15]C1C=C(C=CC=1)/C=C/C(Cl)=O.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1/[CH:42]=[CH:43]/[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[ClH:50]>CO>[ClH:15].[Cl:50][C:46]1[CH:45]=[C:44]([CH:49]=[CH:48][CH:47]=1)/[CH:43]=[CH:42]/[C:34]1[N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Reactant: O=C(Cl)/C=C/c1cccc(Cl)c1
Agent: Cl
Agent: Nc1ccccc1Nc1ccccn1
Solvent: CO
Product: Clc1cccc(/C=C/c2nc3ccccc3n2-c2ccccn2)c1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-chlorocinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull., 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Br:12]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:12]
Reactant: COC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1CBr
Yield: 102.6 %

Procedure:
To a solution of methyl-2-methylbenzoate (3.00 g, 20.0 mmol) in carbon tetrachloride (15 mL) was added N-Bromosuccinimide (3.55 g, 20.00 mmol). The reaction was allowed to stirr at reflux for 3 h. The mixture was cooled and then partioned between 1:1 ethyl acetate/hexane and the combine organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure afforded the title compound as a yellowish liquid (4.70 g, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 1H), 7.54-7.35 (mm, 3H), 4.98 (s, 2H), 3.98 (s, 3H).
Reaction SMILES: O(S(C)(=O)=O)S(C)(=O)=O.[CH2:10]([O:12][C:13]([C:15]1[N:16]=[C:17]([Br:32])[N:18]([CH:29]([CH3:31])[CH3:30])[C:19]=1C(C1C=CC(Cl)=CC=1)O)=[O:14])[CH3:11].[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:41])=[C:38]([CH:40]=1)[NH2:39]>C(Cl)Cl.C(Cl)Cl.O>[CH2:10]([O:12][C:13]([C:15]1[N:16]=[C:17]([Br:32])[N:18]([CH:29]([CH3:30])[CH3:31])[C:19]=1[N:39]([C:37]1[CH:36]=[CH:35][C:34]([Cl:33])=[CH:40][CH:38]=1)[C:38]1[CH:40]=[C:34]([Cl:33])[CH:35]=[CH:36][C:37]=1[CH3:41])=[O:14])[CH3:11]
Reactant: Cc1ccc(Cl)cc1N
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1N(c1ccc(Cl)cc1)c1cc(Cl)ccc1C
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Ms2O (3.6 g, 20.9 mmol) was added to a stirred solution of 2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B; 4.2 g, 20.9 mmol) and TEA (5.3 g, 52.0 mmol) in DCM (80 mL) at 5° C. and the reaction mixture was stirred at 5° C. for 15 min. 5-Chloro-2-methyl aniline (2.2 g, 15.7 mmol) was then added. The reaction mixture was allowed to reach rt in 45 min and stirred at rt for 2 h. The reaction mixture was diluted in DCM/water, extracted twice with DCM and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The crude was purified by flash chromatography (silica gel, EtOAc/hexanes 2:8) to afford the title compound as a white foam; ESI-MS: 526.2 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 1.15 (dd, J=9.97, 4.11 Hz, 2 H) 1.15 (s, 1 H) 1.24 (t, J=7.23 Hz, 3 H) 1.45 (d, J=7.04 Hz, 3 H) 2.17 (s, 3 H) 4.24 (quin, J=6.74 Hz, 2 H) 4.83-5.04 (m, 1 H) 5.92 (d, J=5.47 Hz, 1 H) 6.47 (bs, 1 H) 6.63 (dd, J=7.82, 1.95 Hz, 1H) 6.79 (bs, 1H) 7.04 (d, J=8.21 Hz, 1 H) 7.26 (m, J=8.60 Hz, 2 H) 7.43 (m, J=8.60 Hz, 2 H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.C(Cl)Cl>CN(C)C1C=CN=CC=1>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH:10]1[CH2:9][CH2:8][CH:7]([N:5]2[CH:6]=[C:2]([I:1])[CH:3]=[N:4]2)[CH2:12][CH2:11]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O[C@H]1CC[C@H](n2cc(I)cn2)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(I)cn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of trans-4-(4-Iodo-pyrazol-1-yl)-cyclohexanol (Compound 137 D, 1.00 g, 3.42 mmol), tert-butyldimethylsilyl chloride (1.03 g, 6.85 mmol), 4-dimethylaminopyridine (80 mg, 0.7 mmol), 1H-imidazole (699 mg, 10.3 mmol) and DCM (20 mL, 300 mmol) was stirred room temperature for 20 min. The material was transferred to a separatory funnel, extracting with DCM and sat. NaHCO3. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 3% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as clear oil. 1H NMR (400 MHz, DMSO-d6): δ=0.05 (s, 6H), 0.86 (s, 9H), 1.33-1.47 (m, 2H), 1.70-1.91 (m, 4H), 1.96 (d, J=11.9 Hz, 2H), 3.58-3.75 (m, 1H), 4.11-4.21 (m, 1H), 7.49 (s, 1H), 7.92 (s, 1H). MS (ES+): m/z=407.05 [MH+]. HPLC: tR=3.22 min (polar—5 min, ZQ3).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+]([O-])([O-])=O.[NH4+].[Br:17]N1C(=O)CCC1=O.CCOC(C)=O>CC#N>[Br:17][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C(C)C)cc1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C(C)C)cc1Br
Yield: 99.7 %

Procedure:
A solution of 20.0 g of 1-isopropyl-4-methoxy benzene, 1.07 g of ammonium nitrate, and 23.7 g of N-bromosuccinimide in MeCN (66.5 ml) was stirred at room temperature for one hour. To the reaction solution was added EtOAc and a saturated aqueous solution of NaHCO3, liquid separation was performed, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/9, v/v) to obtain 30.4 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=O)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][C:47]=1[O:58][C:59]([F:62])([F:61])[F:60].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:16](=[O:18])[CH2:15][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[N:7]3)[CH2:54][CH2:53]2)=[CH:48][C:47]=1[O:58][C:59]([F:62])([F:60])[F:61]
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: FC(F)(F)Oc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2ccc(Cl)c(OC(F)(F)F)c2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A vial was charged with 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (55 mg, 0.226 mmol), HBTU (125 mg, 0.33 mmol), 1-(4-Chloro-3-trifluoromethoxy-phenyl)-piperazine dihydrochloride (177 mg, 0.50 mmol), anhydrous DMF (2.0 mL), and DIPEA (0.4 mL). The vial was capped, heated to 45° C., and stirred overnight. The following day, the volatiles were removed in vacuo and separation by preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-trifluoromethoxy-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone. MS (ES) [M+H]+ found: 506.4.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1.C(N(CC)CC)C>CN1CCCC1=O>[NH:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:3]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)cn1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(Nc2cc(NCC3CCNCC3)ncn2)cn1
Temperature: 145 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
A mixture of 5-(6-chloropyrimidin-4-ylamino)pyrazine-2-carbonitrile (124 mg, 0.533 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (228 mg, 1.066 mmol) and triethylamine (150 μL, 1.07 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated at 145° C. for 15 minutes using microwave irradiation. The mixture was concentrated in vacuo and the residue purified by preparative HPLC. The purified solid was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (3 mL) and was stirred for 1 hour at room temperature before being applied to a MP-TsOH cartridge. After washing with methanol, the pure product was eluted using 7M ammonia to give 5-(6-(piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazine-2-carbonitrile (10.3 mg, 6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][N:19]=1.O>C1COCC1>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12][O:13][C:18]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][N:19]=1)[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CCCN(CCO)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCOc1ncc([N+](=O)[O-])c(OC)n1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-hydroxy-ethyl)-propyl-carbamic acid tert-butyl ester (1.07 g, 5.28 mmol) in THF (40 ml) at 0° C. was added NaH (0.25 g, 5.80 mmol). After stirring the suspension at 0° C. for 30 minutes a solution of 2-chloro-4-methoxy-5-nitropyrimidine (1 g, 5.28 mmol) in THF (10 ml) was added and the mixture was stirred at room temperature for 16 h. The mixture was added to water, which was extracted three times with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=1
Reactant: Cc1cc(Cl)ccc1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Cl)cc2C)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (9.4 mg) with purity >90%. LCMS (pos) m/z 375.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1N.Cl.N([O-])=O.[Na+].[S:18](=[O:20])=[O:19].[NH3:21]>O.C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:18]([NH2:21])(=[O:20])=[O:19]
Reactant: N
Reactant: COCCSc1ccccc1N
Reactant: O=S=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCSc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
To a suspension of 2-(2-methoxyethylthio)benzenamine (91.5 g, 0.500 mol) in a mixture of concentrated hydrochloric acid (175 ml) and glacial acetic acid (80 ml) was added a solution of sodium nitrite (39.3 g, 0.550 mol) in water (75 ml) at -5° to 0°. The solution was stirred at 0° for 1/2 hour and then poured, in several portions, into a mixture of cupric chloride dihydrate (10.0 g, 0.059 mol) and liquid sulfur dioxide (77.5 ml, 1.76 mol), in glacial acetic acid (500 ml) at 0°. The resulting solution was stirred at 0° for one hour and then allowed to warm to room temperature. After four hours, ice-water (2000 ml) was added and the resulting oil was extracted into 1-chlorobutane (4×500 ml). The organic extracts were washed with water (5×500 ml) and saturated sodium bicarbonate (until neutral), dried (MgSO4), filtered and reduced in volume to 1000 ml. The sulfonyl chloride solution was cooled to 0° under nitrogen and treated with liquid anhydrous ammonia (50 ml, 2.0 mol). After 1 hour at 0°, the mixture was allowed to warm to room temperature and stirred for 21/2 hours. The reaction mixture was filtered and the resulting solid washed with 1-chlorobutane and water. 2-(2-methoxyethylthio)benzenesulfonamide (84 g, 68%) was obtained as a light-orange solid: m.p. 127°-130°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:9](=[O:13])[CH:10]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[BrH:25]>C1COCC1>[Br:25][CH2:10][C:9](=[O:13])[C@@H:8]([NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Br
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)C=[N+]=[N-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)CBr
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture is stirred at 0° C. for 1.5 hours then the reaction is quenched at 0° C. with sat. Na2CO3. The mixture is extracted with EtOAc (3×25 mL) and the combined organic extracts are washed with brine, dried (Na2SO4), filtered and concentrated to obtain 0.400 g of the product which is used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H), 4.80 (q, J=6.3 Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+]([O-])=O)[C:16]=1[C:17]#[N:18])([O-:14])=[O:13]>>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[C:16]=1[C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOCc1ccccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(NCCOCc2ccccc2)cccc1[N+](=O)[O-]
Yield: 77 %

Procedure:
Prepared as in Example 90c from 2-(benzyloxy)ethanamine and 2,6-dinitrobenzonitrile in 77% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.49 (q, J=5.2 Hz, J=5.6 Hz, 2H), 3.59 (t, J=5.6 Hz, 2H), 4.49 (s, 2H), 6.47 (t, J=5.8 Hz, NH), 7.23-7.31 (m, 6H), 7.43 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.4 Hz, 1H).
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:28][CH2:27][CH2:26][C@H:15]1[C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:13])[CH3:11])=[O:8])=[O:4]>C(O)(=O)C.[Pd]>[NH:1]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:28][CH2:27][CH2:26][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11])=[O:8])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 6 h

Procedure:
Boc-Gly-Gly-Ala-Pro-OBzl (30.0 g, 0.061 mole) was dissolved in glacial acetic acid (300 mL) and 3.0 g of 10% Palladium on activated charcoal was added. This mixture was hydrogenated at 40 psi for 6 h. The reaction mixture was filtered through celite and the solvent was removed in vacuum. The resulting residue was triturated with ether, faltered, washed with ether, and dried to obtain Boc-Gly-Gly-Ala-Pro-OH.
Reaction SMILES: ClCCC1C=C(F)C=[CH:6][C:5]=1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1CCCl)(=[O:13])=[O:12].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[F:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([CH2:5][CH2:6][N:34]2[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:35]2)(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: O=S(=O)(c1ccc(F)cc1CCCl)c1ccc(F)cc1CCCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloroethyl-4-fluorophenyl sulfone (2.5 g), N-(t-butoxycarbonyl)piperazine (2.3 g) and triethylamine (1.7 ml) were dissolved in tetrahydrofuran (30 ml) and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried, and evaporated. The residue was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (4.4 g, quantitatively) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=1
Reactant: O=C(CBr)c1ccsc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccsc1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 3-bromoacetylthiophene (1.025 g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 1 h. the mixture was cooled to 3° C., the resulting precipitate was collected, then dried and recrystallised twice from ethanol to give the title pyrimidinone (460 mg), m.p. 227°-230° C., λmax (EtOH) 250 nm (ε 15,770), 333 nm (ε 2,690).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=[N:29][C:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:38](N(CC)C(C)C)(C)[CH3:39]>CN(C=O)C>[ClH:1].[N:28]12[CH2:27][CH2:26][CH:25]([CH2:38][CH2:39]1)[C@@H:24]([NH:29][C:11]([C:8]1[S:9][C:10]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:23]2
Reactant: O=C(O)c1cc2cccc(Cl)c2s1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Cl)c2s1

Procedure:
176.2 mg (0.83 mmol) of 7-chloro-1-benzothiophene-2-carboxylic acid, 150 mg (0.75 mmol) of R-3-aminoquinuclidine dihydrochloride, 343.7 mg (0.90 mmol) of HATU, 350.5 mg (2.71 mmol) of N,N-diisopropylethylamine and 3.0 ml of DMF are reacted according to the general procedure (variant B). The reaction mixture is purified by preparative HPLC. The product is dissolved in a mixture of 4M HCl in dioxane and methanol and then concentrated. 175.2 mg (65.1% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([CH3:20])=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:21]([NH:23][CH3:24])[CH3:22])=[CH:5][CH:4]=1.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:23]([CH:21]([C:10]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([CH3:20])=[CH:15][CH:16]=3)[N:11]=2)[CH3:22])[CH3:24])(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CNC(C)c1nc2cc(C)ccc2c(=O)n1-c1ccc(OC)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(-n2c(C(C)N(C)S(=O)(=O)c3ccc(C(C)(C)C)cc3)nc3cc(C)ccc3c2=O)cc1

Procedure:
In a similar manner as described above in Paragraph A, 3-(4-methoxyphenyl)-7-methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-one, as prepared above in Example 5, was condensed with 4-tert-butylbenzenesulfonyl chloride to yield 4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide; MS (ESI) 520 (MH+).