Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])=[O:7].[OH-].[K+].Br[CH2:22][CH:23]([CH3:25])[CH3:24]>CS(C)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])=[O:7]
Reactant: Cc1c(NC(=O)c2ccco2)cccc1[N+](=O)[O-]
Reactant: CC(C)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1c(N(CC(C)C)C(=O)c2ccco2)cccc1[N+](=O)[O-]

Procedure:
The N-(2-furoyl)-2-methyl-3-nitroaniline (1 mmol) in DMSO was treated with potassium hydroxide (2.0 mmol) and 1-bromo-2-methylpropane (1.1 mmol) at 25° C. for 12 hr. Extraction and chromatography afforded N-(2-furoyl)-N-isobutyl-2-methyl-3-nitroaniline as a yellow syrup. TLC: Rf=0.40, 30% EtOAc-hexane.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[O:26])=[CH:23][C:22]=1[O:36][CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[O:26])=[CH:23][C:22]=3[O:36][CH3:37])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)NCCCN(C)C)ccc1N
Reactant: CC(C)N1CC(F)(F)C(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Yield: 53.6 %

Procedure:
A mixture of 0.07 g (0.24 mmole) of 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292), 0.067 g (0.26 mmole) of 4-amino-N-(3-dimethylamino-propyl)-3-methoxy-benzamide, 0.069 g (0.36 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-0:100) gave 0.065 g of give 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-296) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].C(S/[N:12]=[N:13]/[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([OH:19])=[O:18])(C)(C)C>CS(C)=O>[NH:13]1[C:14]2[C:22](=[CH:21][CH:20]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:23]=[N:12]1
Reactant: Cc1ccc(C(=O)O)cc1/N=N/SC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc2cn[nH]c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a stirred solution of potassium tert-butoxide (8.1 g, 73 mmol) in DMSO (30 mL) was added a solution of 3-[(E)-(tert-butylthio)diazenyl]-4-methylbenzoic acid (1.9 g, 7.3 mmol) at RT. The mixture was stirred overnight, followed by the adition of ice water. The aqueous layer was extracted with ethyl acetate. The organic layer was dicarded. The pH of the aqueous layer was adjusted to 4-5 with aqueous 1N HCl. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford 800 mg (97%) of 1H-indazole-6-carboxylic acid as a tan solid: 1H NMR (400 MHz. DMSO-d6) δ 13.4, 13.0, 8.2, 8.1, 7.9, 7.7.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Reactant: CC[C@H](N)C(O)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1)C(O)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.20 mL, 11 eq, 1.14 mmol) followed by (3RS,4S)-4-amino-2-methyl-hexan-3-ol (28 mg, 2.0 eq, 0.21 mmol). The reaction mixture was placed in a preheated oil bath at 160° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSo4) and evaporated in vacuo. The residue was purified by gradient column chromatography, on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid; Yield: 5.7 mg (14%). (50% de 4S,3R: 50% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.90-1.06 (m, 9H, —NHCH(CH2CH3)CH(CH3)2OH), 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.64-1.93 (m, 4H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.24-3.37 (m, 1H, —NHCH(CH2CH3) CH(CH (CH3)2)OH), 3.80-3.95 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.57-4.71 (m, 1H, —CH(CH3)2), 4.84-4.96 (m, 2H, —HNCH2-Pyr), 5.13-5.24 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 6.65-6.80 (m, 1H, —HNCH2-Pyr), 7.12-7.23 (m, 1H, Pyr-H), 7.30-7.40 (m, 1H, Pyr-H), 7.56 (s, 1H, —N═CH—N—), 7.59-7.74 (m, 1H, Pyr-H), 8.61 (d, 1H, J=4.42 Hz, Pyr-H). FABMS m/z (relative intensity): 398 ([M+H]+, 100), 324 (55). Accurate Mass (M+H): Actual: 398.2668, Measured: 398.2654.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[CH:2].[CH3:12][N:13]1[C:17]([NH2:18])=[CH:16][C:15]([CH3:19])=[N:14]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:12][N:13]1[C:17]([NH:18][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[CH:2])[CH:4]=2)=[CH:16][C:15]([CH3:19])=[N:14]1
Reactant: C#Cc1cccc(C(=O)O)c1
Reactant: Cc1cc(N)n(C)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#Cc1cccc(C(=O)Nc2cc(C)nn2C)c1
Temperature: 50 °C
Yield: 78.1 %

Procedure:
3-Ethynylbenzoic acid (0.1 g, 0.685 mmol) was added to a dry 50 mL round bottom flask and dissolved in DMF (6.85 mL). To the resulting solution was added 1,3-dimethyl-1H-pyrazol-5-amine (0.076 g, 0.685 mmol), followed by BOP (0.393 g, 0.890 mmol), and 0.238 mL of DIPEA (1.37 mmol). This reaction mixture was heated to 50° C. for 3 h. After allowing the reaction to cool to room temperature it was taken up in EtOAc (15 mL) and extracted with brine (3×15 mL). The EtOAc layer was then washed with saturated aqueous NaHCO3 (2×15 mL). The organics were dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude residue was purified via column chromatography (silica gel, gradient eluant mixture of EtOAc in Hexanes: 0% to 100% EtOAc) affording N-(1,3-dimethyl-1H-pyrazol-5-yl)-3-ethynylbenzamide (0.128 g, 78%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:10]([CH2:18]CC)[N:11]=[C:12](Br)[C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-]>CN1CCCC1=O.[Cu]I>[CH2:1]([NH:8][C:9]1[N:10]([CH3:18])[N:11]=[C:12]([O:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Reactant: Oc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cn1nc(Oc2ccccc2)c([N+](=O)[O-])c1NCc1ccccc1

Procedure:
Treatment of 3,5-dibromo-4-nitro-1H-pyrazole 1 with MeI and NaH in DMF affords 3,5-dibromo-1-methyl-4-nitro-1H-pyrazole 2. Nucleophilic aromatic substitution of the compound 2 with benzylamine in DMSO produces benzyl-(5-bromo-2-methyl-4-nitro-2H-pyrazol-3-yl)-amine 3. Treatment of the compound 3 with phenol in the presence of copper (I) iodide and cecium carbonate in N-methylpyrrolidinone (NMP) under microwave irradiation provides N-benzyl-1-methyl-4-nitro-3-phenoxy-1H-pyrazol-5-amine 4 (Tetrahedron Lett, 2003, 44, 3445). Hydrogenation of the compound 4 with Pd/C at 60 psi hydrogen in ethanol affords 1-methyl-3-phenoxy-1H-pyrazole-4,5-diamine 5. II. Keratin Dyeing Composition Components
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]O)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCCCC1CCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: BrCCCCCCC1CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
To a solution of 6-cyclobutyl-hexan-1-ol (0.47 g, 3.0 mmol) in DMF (10 mL) was added triphenylphosphine (0.88 g, 3.4 mmol). The solution was cooled to 0° C. and NBS (0.57 g, 3.2 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (0.5 mL). The solution was diluted with ether (60 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford (6-bromo-hexyl)-cyclobutane (0.60 g, 91%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.40 (2H, t, J=6.9 Hz), 2.23 (1H, m), 2.02 (2H, m), 1.82 (4H, m), 1.55 (2H, m), 1.12–1.46 (8H, m); 13C NMR (75 MHz, CDCl3) δ 37.19, 36.39, 34.40, 33.11, 29.07, 28.68, 28.51, 27.26, 18.80.
Reaction SMILES: [CH3:1][C:2]([O:14][CH2:15][CH2:16][CH3:17])([CH3:13])[CH2:3][NH:4][C:5]1[N:6]=[CH:7][NH:8][C:9]=1[C:10]([NH2:12])=[O:11].C(N=[C:27]=[S:28])(=O)C1C=CC=CC=1>ClCCl>[CH2:15]([O:14][C:2]([CH3:1])([CH3:13])[CH2:3][N:4]1[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[C:10](=[O:11])[NH:12][C:27]1=[S:28])[CH2:16][CH3:17]
Reactant: CCCOC(C)(C)CNc1nc[nH]c1C(N)=O
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CCCOC(C)(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-[(2-Methyl-2-propoxypropyl)amino]-1H-imidazole-5-carboxamide obtained from Example 2(c) was dissolved (0.19 g, 0.78 mmol) in 7 mL of dichloromethane. The obtained solution was stirred at ambient temperature. Benzoyl isothiocyanate (0.50 g, 3.1 mmol) was added in portions during 6 h. The reaction mixture was stirred over night and the solvent was then removed in vacuo. Ammonia in methanol (7 mL of 7 M solution) was added and the obtained solution was heated at 50° C. for 3 h and then at 80° C. for 3 h in a pressure flask. The cooled reaction mixture was concentrated and the crude product was purified by reverse phase HPLC. The product was obtained in 22% (48 mg) yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[N:12]=[C:11]([CH3:13])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH:20]1N(C)C(=O)N(C)C(=O)N1C.[OH-:31].[Na+]>O>[CH3:13][C:11]1[C:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:9][N:8]([C:6]2[CH:7]=[C:2]([OH:1])[C:3](=[CH:4][CH:5]=2)[CH:20]=[O:31])[N:12]=1
Reactant: Cc1nn(-c2ccc(C3N(C)C(=O)N(C)C(=O)N3C)c(O)c2)nc1-c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1nn(-c2ccc(C=O)c(O)c2)nc1-c1ccccc1
Temperature: 102 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A mixture of 570 g of 6-[2-hydroxy-4-(4-methyl-5-phenyl-1,2,3-triazol-2-yl)-phenyl]-2,4-dioxo-1,3,5-trimethyl-hexahydro-s-triazine, 2,940 ml of water and 560 g of sodium hydroxide is heated for 22 hours at 102° C. It is then cooled to 15° C. and the sodium salt which has separated out is filtered off and introduced into a mixture of 700 g of ice, 700 ml of water and 237 ml of 37% strength hydrochloric acid. After stirring for four hours, the salicylaldehyde produced is filtered off, washed with ice water and dried at 80° C. This gives 353 g of product of melting point 121°-123° C., the product being 98.6% pure, according to analysis. The yield is 89% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[CH:14]1([CH2:20][NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:21][CH2:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:5])[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Product: CCOC(=O)c1cnc(Cl)cc1NCC1CCCCC1

Procedure:
From 4,6-dichloropyridine-3-carboxylic acid ethyl ester synthesized according to the method described in US2006/0217417 and cyclohexylmethylamine in a manner similar to Example 339, the title compound was obtained as a slight yellow oil (yield 85%).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1CC1N=CC2C(C)=CC=CC=2N(C(C)C)C1=O.[N+:27]([C:30]1[CH:31]=[CH:32][C:33]2[N:39](C)[C:38](=[O:41])[CH:37]([CH2:42][C:43]3[NH:44][C:45]4[C:50]([CH:51]=3)=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:36]=[C:35]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:34]=2[CH:58]=1)([O-:29])=[O:28]>>[NH:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:51]=[C:43]1[CH2:42][CH:37]1[N:36]=[C:35]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:34]2[CH:58]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=[CH:32][C:33]=2[NH:39][C:38]1=[O:41]
Reactant: CN1C(=O)C(Cc2cc3ccccc3[nH]2)N=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: Cc1cccc2c1C=NC(Cc1cc3ccccc3[nH]1)C(=O)N2C(C)C
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1Cc1cc2ccccc2[nH]1

Procedure:
1,3-dihydro-3-(1H-indol-2-ylmethyl)-1-isopropyl-6-methyl-2H-1,4-benzodiazepin-2-one; 7-nitro-1,3-dihydro-3-(1H-indol-2-ylmethyl)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one;
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH3:38])[O:33][C:14]2=[N:15][C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:18]=[C:13]2[CH:12]([NH:34][C:35](=[O:37])[CH3:36])[CH2:11]1)C1C=CC=CC=1>C(Cl)Cl>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:16]1[N:15]=[C:14]2[O:33][C:10]([CH2:9][OH:8])([CH3:38])[CH2:11][CH:12]([NH:34][C:35](=[O:37])[CH3:36])[C:13]2=[CH:18][C:17]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1
Reactant: CC(=O)NC1CC(C)(COCc2ccccc2)Oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc21
Solvent: ClCCl
Product: CC(=O)NC1CC(C)(CO)Oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of step B (20 mg, 0.037 mmol) was dissolved in CH2Cl2 (1 mL) and FeCl3 (25 mg, 0.15 mmol) was added. The reaction was stirred at rt for 30 min and was concentrated. The residue was added to a silica gel flash chromatography column and eluted with 0-100% EtOAc in hexane. After concentration of the desired fractions the product was repurified by semi preparative reverse phase HPLC on a C18 column, eluting with 10 to 80% MeCN/H2O (each containing 0.5% TFA). The desired fractions were neutralized with a saturated solution of NaHCO3 and extracted with EtOAc. Evaporation and drying in vacuo afforded the title compound. (LC-2) HPLC/MS: 457.3 (M+1), 459.3 (M+3); Rt=3.11 min.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])C1C=CC=CC=1.C>C(O)C.[Pd]>[CH2:24]([O:23][C:21]([CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1)=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCOC(=O)C1CNCCN1
Temperature: 40 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
A solution of 25 g (63.5 mmoles) of the compound prepared in step A and 200 mg Pd(10%)/charcoal in 200 ml of ethanol was treated by H2 under pressure of 2.8 bars under stirring at 40° C. overnight. After filtration, the ethanol was evaporated off under reduced pressure and the crude residue, purified on a silica gel column using MeOH/CHCl3 (5:95, in vol.) as eluent, yielded 12.5 g (92%) of the title compound as a highly hygroscopic compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]2[CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=[C:4]2[NH:3]1.[OH-].[Na+]>C(O)C>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=[C:4]2[NH:3]1
Reactant: CCOC(=O)c1cn2c(n1)NC(=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCn2cc(C(=O)O)nc2N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 191 %

Procedure:
Ethyl 7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-2-carboxylate (1.711 mmol, 0.358 g) was dissolved in ethanol (5 ml) and cooled to 0° C. 1N solution of NaOH (5 ml) was slowly added. The resulting mixture was heated to 60° C. for 1.5 h. Ethanol was evaporated, the residue diluted with tert-butyl methyl ether and acidified with 2 N HCl solution under cold conditions. The mixture was stirred for overnight. DCM and water was added and the precipitate was filtered. Phases in the filtrate were separated and the water phase was evaporated. The residue from water and precipitate were combined. 0.592 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 2.73 (t, 2H), 4.12 (t, 2H), 7.58 (s, 1H), 11.09 (bs, 1H).
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([OH:30])[CH2:22][CH2:21][CH2:20][CH:19]2[NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:14][CH:13]=1>>[OH:30][C:18]1([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:13][CH:14]=2)[CH2:22][CH2:21][CH2:20][CH:19]1[NH:23][S:24]([CH:27]([CH3:28])[CH3:29])(=[O:26])=[O:25]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCCN)cc1
Product: CC(C)S(=O)(=O)NCCOc1ccc(C2(O)CCCC2NS(=O)(=O)C(C)C)cc1

Procedure:
The title compound is prepared in a manner analogous to the procedure set forth in example 51 from 2-propanesulfonyl chloride and {2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclopentyl}[(methylethyl)sulfonyl]amine.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:30])=[N:6][C:7]([C:19](=[O:29])[NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[OH:3][CH:1]([C:4]1[C:5]([CH3:30])=[N:6][C:7]([C:19](=[O:29])[NH:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH3:2]
Reactant: CC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(C(=O)NCCN2CCOCC2)nc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc(C(=O)NCCN2CCOCC2)cc(-c2cccc([N+](=O)[O-])c2)c1C(C)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a solution of 3-acetyl-2-methyl-6-(2-morpholinoethylcarbamoyl)-4-(3-nitrophenyl)pyridine (3 g) in methanol (30 ml) was added sodium borohydride (0.28 g) under ice-cooling. After stirring for 1 hour at same temperature, the solution was poured into a mixture of ice water (50 ml) and chloroform (50 ml). The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the residue was recrystallized from a mixture of ethanol and ethyl acetate to give 3-(1-hydroxyethyl)-2-methyl-6-(2-morpholinoethylcarbamoyl)-4- (3-nitrophenyl)pyridine (1.53 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([S:15]([CH3:18])(=[O:17])=[O:16])([CH3:14])[C:11]([OH:13])=O)=[C:4]([F:19])[CH:3]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][NH2:27].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:14])([S:15]([CH3:18])(=[O:17])=[O:16])[C:11]([NH:27][O:26][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)=[O:13])=[C:4]([F:19])[CH:3]=1
Reactant: NOC1CCCCO1
Reactant: CC(CCc1ccc(Br)cc1F)(C(=O)O)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(CCc1ccc(Br)cc1F)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
4-(4-Bromo-2-fluoro-phenyl)-2-methanesulfonyl-2-methyl-butyric acid (1.96 g, 5.55 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.910 g, 7.77 mmol), 1-hydroxy benzotriazole monohydrate (1.53 g, 9.99 mmol), triethylamine (1.39 mL, 9.99 mmol) and 1, (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.49 g, 7.77 mmol) were combined followed by the addition 60 mL of dichloromethane. The reaction was allowed to stir at room temperature overnight, was then diluted with 20 mL of dichloromethane and 60 mL of water. The aqueous layer was re-extracted with DCM (2×40 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated onto silica gel. Silica chromatography (40% ethyl acetate 60% heptane to 40% ethyl acetate 60% heptane to 80% ethyl acetate 20% heptane for 60 minutes) afforded the title compound as a white foam 2.0 g, (79.9%). LC-MS m/z 452.1 (M−1)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:8]=1[C:15]1[CH:20]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=1[CH3:25])[CH3:6].C(O)(=O)C.N([O-])=O.[Na+]>O>[CH2:13]([C:9]1[CH:10]=[C:11]([N+:1]([O-:4])=[O:2])[CH:12]=[C:7]([CH2:5][CH3:6])[C:8]=1[C:15]1[CH:20]=[C:19]([S:21]([NH2:24])(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=1[CH3:25])[CH3:14]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc(CC)c1-c1cc(S(N)(=O)=O)ccc1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc([N+](=O)[O-])cc(CC)c1-c1cc(S(N)(=O)=O)ccc1C
Temperature: 0 °C
Yield: 36.2 %

Procedure:
To 13 ml of 70% nitric acid in 100 ml of water was added 15.17 g (50.0 mmol) of the -toluenesulfonate obtained in step A, followed by the addition of 100 ml of glacial acetic acid and 0.37 g (5.0 mmol) of sodium nitrite. The mixture was heated on a steam bath for 1.5 hrs, cooled, diluted with 250 g of ice, and the precipitate was collected to yield 8.82 g of crude product. The crude product was chromatographed on 300 g of silica gel with 5:1 and 3:1 hexane:ethyl acetate to yield 6.30 g (36.2%) of 2,6-diethyl-4-nitrophenyl-p-toluenesulfonamide. NMR (CDCl3):δ 1.10 (t, 6H), 2.5 (m, 7H), 6.5 (s, 1H), 7.2-7.7 (dd, 4H), 7.97 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[N:6][CH:7]=1.[CH:13](O)=O>C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])[CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncc(C2CCCN2)c1
Reactant: O=CO
Agent: C=O
Product: CN1CCCC1c1cncc(Br)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Enantiomerically enriched 5-bromo-3-(2-pyrrolidinyl)pyridine (1.82 g, 8 mmol) was dissolved in a mixture of 98% formic acid (16 mL) and 37% aqueous formaldehyde (8 mL). The solution was heated with stirring for 3 h at 80° C. After cooling to 25° C. the mixture was concentrated in vacuo and water (30 mL) added. The mixture was basified with solid NaOH to pH 12 and extracted with methylene chloride (3×40 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed on silica gel with ethyl acetate:hexane (1:3) as eluant to afford 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine as an oil, 1.63 g,84%. LRMS (EI) m/e 242 (C10H13N281Br), 241 (C10 H13N279Br--+H), 240 (C10H13 N279Br), 239 (C10H13N2Br--+H); 1H NMR (DMSO-d6, 300 MHz) δ 8.55 (d, J=2.1 Hz, 1H), 8.44 (d, J=1.9 Hz, 1H), 7.88 (t, J=1.9 Hz, 1H), 3.24 (b-dt, J=8.1 Hz, 1H), 3.10 (t, J=8.0 Hz, 1H), 2.36 (m, 1H), 2.18 (s, 3H), 1.95 (m, 1H), 1.85 (m, 1H), 1.70 (m, 1H).