Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[O:25]1[CH2:30][CH2:29][O:28][C:27]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:26]1=2.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[O:25]1[CH2:30][CH2:29][O:28][C:27]2[CH:31]=[C:32]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)[CH:33]=[CH:34][C:26]1=2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OCCO4)n2n1
Temperature: 110 °C
Yield: 74 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 2,3-dihydrobenzo[b][1,4]dioxin-6-ylboronic acid (41 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 9.5 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (55-65% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (57.2 mg, 74%). Melting point (99.5-99.6° C.). 1H NMR (DMSO-d6) δ: 11.14 (s, 1H), 8.02 (d, J=8.6 Hz, 2H), 7.95 (s, 1H), 7.75 (d, J=2.3 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.57 (dd, J=8.5, 2.1 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.36 (s, 1H), 4.31-4.40 (m, 4H), 2.41 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 445.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:32])[C:8]2[O:14][C:13]3[C:15]([Cl:28])=[CH:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([C:25](=O)[CH3:26])[CH2:21][CH2:20]4)=[CH:18][C:12]=3[CH2:11][S:10](=[O:30])(=[O:29])[C:9]=2[CH:31]=1)=O>C1COCC1>[Cl:28][C:15]1[C:13]2[O:14][C:8]3[C:7]([CH3:32])=[CH:6][C:5]([CH2:3][OH:2])=[CH:31][C:9]=3[S:10](=[O:29])(=[O:30])[CH2:11][C:12]=2[CH:18]=[C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH2:24]2)[CH:16]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(C)=O)CC3)cc(Cl)c1O2
Solvent: C1CCOC1
Product: CCN1CCN(c2cc(Cl)c3c(c2)CS(=O)(=O)c2cc(CO)cc(C)c2O3)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Boranedimethylsulphide complex (0.85 mL, 8.7 mmol) was added at 10° C. to a stirred solution of 2-(4-acetyl-piperazin-1-yl)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid (0.8 g, 1.7 mmol) [obtained by hydrolysis of compound of Example 21] in dry THF (70 mL) under nitrogen atmosphere. The reaction mixture was stirred at 60° C. for 2 h. Reaction mixture was cooled and quenched with methanol and the solvent was removed. Solid was suspended in ethylacetate (100 mL) and washed with water, brine and dried over sodium sulphate. The crude product obtained was purified by column chromatography (silica gel, 2% methanol-chloroform) to obtain the title compound. Yield: 0.5 g (67.74%); mp: 230-32° C.; 1H NMR (DMSO-d6, 300 MHz): δ 1.88 (t, 3H, CH3), 2.57 (s, 3H, CH3), 2.86 (t, 2H, CH2), 2.88-2.91 (m, 4H, 2CH2), 3.31-3.41 (m, 4H, 2CH2), 4.45 (d, 2H, CH2), 5.04 (s, 2H, CH2), 5.37 (t, 1H, OH), 7.07 (s, 1H, Ar), 7.13 (s, 1H, Ar), 7.43 (s, 1H, Ar), 7.58 (s, 1H, Ar); MS: m/e (ES+) 437 (M+1).
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([N+:21]([O-:23])=[O:22])=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=2)OC1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH:36]=[C:35](OS(C(F)(F)F)(=O)=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH:34]=[C:35]([C:8]2[CH:9]=[CH:10][C:11]([N+:21]([O-:23])=[O:22])=[C:12]([N:14]3[CH2:15][CH2:16][CH:17]([CH3:20])[CH2:18][CH2:19]3)[CH:13]=2)[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC1CCN(c2cc(B3OCC(C)(C)CO3)ccc2[N+](=O)[O-])CC1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC1CCN(c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 73.8 %

Procedure:
A flask is charged with 1-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-nitro-phenyl]-4-methyl-piperidine (0.090 g, 0.27 mmol) (as prepared in the previous step), 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.090 g, 0.27 mmol) (Synthesis, 993, (1991)), LiCl (0.022 g, 0.54 mmol), Pd(PPh3)4 (0.015 g, 5 mol %), 2 M Na2CO3 (0.34 mL), DME (0.80 mL) and heated at 80° C. for 30 min. The reaction was diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (2×10 mL) and brine (10 mL), and the organic layer dried over Na2SO4 and evaporated. The crude product was eluted from a 10-g SPE cartridge (silica) with 10% EtOAc/hexane to give 0.080 g (74%) of the title compound as a light yellow oil. Mass spectrum (ESI, m/z): Calcd. for C22H31N3O4, 402.2 (M+H), found 402.1.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C)=[N+]([O-:16])C=C(C)N=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1[C:27]([CH2:34][CH3:35])=[N:28][CH:29]=[C:30]([CH2:32][CH3:33])[N:31]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1[C:27]([CH2:34][CH3:35])=[N+:28]([O-:16])[CH:29]=[C:30]([CH2:32][CH3:33])[N:31]=1
Reactant: Cc1c[n+]([O-])c(C)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CCc1cnc(CC)c(-c2ccc(Cl)cc2Cl)n1
Product: CCc1c[n+]([O-])c(CC)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Following the procedure of 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine 1-oxide but substituting Preparation of 3-(2,4-dichlorophenyl)-2,5-diethylpyrazine and making non-critical variations, the title compound was obtained (quantitative). It was used without preparation. 1H NMR (CDCl3) δ 1.12, 1.34, 2.55, 2.81, 2.89, 7.28, 7.40, 7.55, 8.11.
Reaction SMILES: CS(O)(=O)=O.C(OC([N:13]1[CH2:18][CH2:17][N:16]2[C:19](=[O:31])[N:20]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)[C:21](=[O:22])[CH:15]2[CH2:14]1)=O)(C)(C)C>C(Cl)Cl>[Cl:29][C:27]1[CH:28]=[C:23]([N:20]2[C:21](=[O:22])[CH:15]3[CH2:14][NH:13][CH2:18][CH2:17][N:16]3[C:19]2=[O:31])[CH:24]=[C:25]([Cl:30])[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2C1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: O=C1C2CNCCN2C(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Methanesulfonic acid (2.1 mL, 32.7 mmol) was added to an ice-cold solution of 2-(3,5-Dichlorophenyl)-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (2.62 g, 6.54 mmol, Prep. 18) in methylene chloride (50 mL). After 1 h at RT, TEA (5 mL, 36 mmol) was added. The reaction mixture was washed twice with water, dried over sodium sulfate and concentrated in vacuo to yield the above compound (1.7 g) as a white solid. Mp=134° C. (crystallized from diethyl ether).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:53][O:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:60]4[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][O:54][CH3:53])[CH2:58][CH2:59]4)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN1CCNCC1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCN(CC(=O)Nc2cc(COc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c4ccccc34)ccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (22 μl, 0.13 mmol) was added N-methoxyethyl piperazine (12.5 μl, 0.08 mmol). The reaction mixture was stirred at RT for 3 hr. LC-MS indicated 20% conversion to product. The reaction mixture was heated to 40° C. and stirred for 12 hr. LC-MS indicated 78% conversion to product. A further portion of N-methoxyethyl piperazine (12.5 μl, 0.08 mmol) was added and the reaction mixture continued to stir at 40° C. for 5 hr. LC-MS indicated 89% conversion to product. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(4-(2-methoxyethyl)piperazin-1-yl)acetamide (Example 10) as a light orange solid (45 mg, 73%): m/z 705 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO) δ: 1.27 (9 H, s), 2.39 (3 H, s), 2.46-2.48 (3 H, m, obscured by DMSO), 2.57-2.50 (4 H, m), 3.17 (2 H, s), 3.23 (3 H, s), 3.42 (2 H, t), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.29 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.65-7.55 (3H, m), 7.93 (1H, d), 8.36-8.30 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 9.92 (1H, s).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:8]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:7]1)(=O)=O.[OH:76][C:77]1[CH:84]=[C:83]([O:85][CH3:86])[CH:82]=[CH:81][C:78]=1[CH:79]=[O:80].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:86][O:85][C:83]1[CH:82]=[CH:81][C:78]([CH:79]=[O:80])=[C:77]([O:76][CH2:5][CH:6]2[CH2:11][CH:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:8]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:7]2)[CH:84]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COS(=O)(=O)c2ccc(C)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2cc(OC)ccc2C=O)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
3,4,5-Tris(octadecyloxy)cyclohexylmethyl tosylate (76.9 g, 71.6 mmol), 2-hydroxy-4-methoxybenzaldehyde (16.9 g, 0.11 mol) and potassium carbonate (25.6 g, 0.18 mol) were suspended in DMF (700 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was dissolved in chloroform (700 ml), washed twice with 0.5N hydrochloric acid (300 ml), once with 5% aqueous sodium hydrogen carbonate solution (300 ml), and once with pure water (300 ml). The solvent was evaporated, and the residue was precipitated with methanol (700 ml) to give 4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzaldehyde (73.56 g, 69.8 mmol, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([CH:22](B(O)O)[CH2:21][CH2:20][CH2:19]2)[C:11]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][C:11](=[O:26])[C:12]23[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C1Nc2ccc(-c3ccc(F)c(Cl)c3)cc2C12CCCC2
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of 3-chloro-4-fluoro-bromobenzene (0.4 cm3, 0.66 g, 3.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0 g, 4.7 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.65 g, 66%) as a pale-yellow solid. mp: 202-204° C.; 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 7.9 (dd, 1H, J=2.3, 4.9 Hz), 7.7-7.6 (m, 1H), 7.6 (d, 1H, J=1.5 Hz), 7.5 (s, 1H), 7.4 (d, 1H, J=1.8 Hz), 6.9 (d, 1H, J=8.0 Hz), 2.0-1.9 (m, 8H); MS [M−H]−=314.
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[NH:14][C:15](=O)[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=2)[CH2:4][CH2:3]1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>>[CH3:22][C:20]1[S:21][C:16]2[C:15]([NH:26][CH2:25][CH2:24][NH2:27])=[N:14][C:13]([N:5]3[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[S:2](=[O:1])[CH2:3][CH2:4]3)=[N:18][C:17]=2[CH:19]=1
Reactant: NCCN
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NCCN)c2s1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 3 by using 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one and ethylenediamine. MS obsd. (ESI+) [(M+H)+] 388, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.68-7.75 (m, 2H), 7.41-7.51 (m, 2H), 6.81 (s, 1H), 5.21 (d, J=5.6 Hz, 1H), 4.65-4.81 (m, 2H), 4.48 (br. s., 1H), 3.68 (m, 2H), 3.32-3.47 (m, 2H), 2.50 (s, 3H).
Reaction SMILES: [Cl-].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5].[C:12]([OH:15])(=[O:14])[CH3:13]>[Ni]>[C:12]([O-:15])(=[O:14])[CH3:13].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)O
Agent: [Ni]
Agent: CCCC[n+]1ccn(C)c1
Agent: [Cl-]
Product: CC(=O)[O-]

Procedure:
In a second example, a two-compartment cell was constructed, using a DSA anode, a cation exchange membrane (Nafion 902 from DuPont) and a Ni cathode. 10 liters each of 2 M 1-Butyl-3-Methylimidazolium Chloride and 1.5 M acetic acid were added to the two compartments, and 10 amps current was applied to the cell until the pH of the solution containing the acetic acid had risen to 7.0. The catholyte was then removed from the cell, and the 1-Butyl-3-Methylimidazolium Acetate product isolated by removing the water by rotary distillation as described above. The yield was 70% and had 329 ppm sodium and 893 ppm Cl. The product also contained 19% water, which could not easily be removed by vacuum evaporation. However, the 1-Butyl-3-Methylimidazolium Acetate product could be further dried by azeotropic distillation. The wet product was heated to reflux in a round bottom flask, fitted with a Dean-Stark trap with benzene was added. When no more water was collected in the trap, the benzene was removed by rotoevaporation. The product now contained <0.5% H2O.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:11]1[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH:17]=1)[NH2:16]>>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH:17]=2)[NH2:16])[CH2:6][CH2:5]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Yield: 99 %

Procedure:
The mother liquor of the reaction was recycled by the addition of NaOH pellets (34.9 g, 869 mmol, 1 equiv) to the mother liquor, followed by stirring until the NaOH was dissolved. 1-Methylpiperazine (96.5 mL, 869 mmol, 1 equiv) and 5-chloro-2-nitroaniline (150 g, 869 mmol) were charged to the vessel. Purging, followed by heating to completion, cooling, filtration, and washing with heptane was repeated as above to yield 5-(4-methyl-piperazin-1-yl)-2-nitroaniline (203.2 g, 98.9% yield). Residual N-methylpiperazine was not detected by 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]=[O:22])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:23]([Mg]Br)#[CH:24].O.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([CH:21]([OH:22])[C:23]#[CH:24])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.2 %

Procedure:
To a cold (−78° C.) suspension of 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (11.4 g, 37.0 mmol) in tetrahydrofuran (100 mL) was added ethynylmagnesium bromide (111 mL, 0.5 M in tetrahydrofuran, 56 mmol). The reaction mixture was warmed to room temperature and stirred for 14 hours. The reaction mixture was poured into water and adjusted to neutral pH with 1N aqueous hydrochloric acid. The aqueous mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine. The organic layer was dried over magnesium sulfate. Filtration and concentration provided 1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (11.9 g, 96%) as a tan solid. Rf 0.18 (4:1 hexanes:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.81 (s, 1H), 8.15 (d, 1H), 7.75 (m, 2H), 7.35 (d, 1H), 7.19 (t, 2H), 5.76 (s, 1H), 2.71 (d, 1H), 2.60 (d, 1H); MS m/z 335 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[CH2:4][C:5]2([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:16])[C:11]=3[Br:15])[C:6]=12.C(N(CC)C(C)C)(C)C.[CH3:31][O:32][CH2:33]Cl>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3](=[O:21])[CH2:4][C:5]2([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:16][CH2:31][O:32][CH3:33])[C:11]=3[Br:15])[C:6]=12
Reactant: CCCCC12CCc3c(ccc(O)c3Br)C1=C(Br)C(=O)C2
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC12CCc3c(ccc(OCOC)c3Br)C1=C(Br)C(=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,6-dibromo-3a-butyl-7-hydroxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one (189 mg, 0.46 mmol) in anhydrous DMF (2.3 mL) was placed under a N2 atmosphere and stirred at room temperature while N,N-diisopropylethylamine (0.242 mL, 1.38 mmol) and chloromethyl methyl ether (0.070 mL, 0.92 mmol) were added successively. After stirring at room temperature for 16 hours, the mixture was diluted with EtOAc and washed with 1N HCl. The organic phase was washed with 5% NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under vacuum to provide crude 1,6-dibromo-3a-butyl-7-(methoxymethoxy)-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH:31]([OH:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][CH:31]([CH3:32])[CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 58.8 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-propyl)-amide (67 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 1-amino-2-propanol (20 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 466.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.86-7.66 (m, 2H), 7.48 (d, 1H), 7.36 (d, 1H), 4.77 (d, 1H), 3.87-3.77 (m, 1H), 3.64 (bs, 3H), 3.29-3.17 (m, 2H), 1.09 (d, 3H).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[CH3:32])[N:25]([CH3:33])[CH:24]=2)[C:10]1=[O:34])[CH2:5][CH2:6][CH2:7][CH3:8]>O1CCOCC1.O>[CH3:33][N:25]1[C:26]2[C:31](=[C:30]([CH3:32])[CH:29]=[CH:28][CH:27]=2)[C:23]([CH2:22][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[C:18](=[O:19])[N:9]([C@@H:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]([OH:35])=[O:2])[C:10]2=[O:34])=[CH:24]1
Reactant: CCCC[C@@H](C(=O)OC)n1c(=O)c2ccc(OC)cc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Solvent: C1COCCO1
Solvent: O
Product: CCCC[C@@H](C(=O)O)n1c(=O)c2ccc(OC)cc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-7-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-hexanoic acid methyl ester (145 mg, 0.30 mmol) in dioxane (2.5 ml) is added a solution of LiOH monohydrate (50 mg, 1.19 mmol) in H2O (2.5 mL). The resulting mixture is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, quenched with 4M HCl in dioxane (500 μL) and is concentrated. The resulting residue is triturated with H2O and MeOH to afford (S)-2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-7-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-hexanoic acid. LCMS (ESMS): m/z 464.22 (M+H+).