Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-])=O.[CH2:16]=[CH:17][CH:18]=[CH2:19].[OH-].[Na+].[H][H]>[Pd].COCCO>[NH2:1][C:4]1[C:5]2[C:6](=[O:15])[C:7]3[C:8](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9](=[O:14])[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C=CC=C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 80 °C

Procedure:
6.1 Grams of 5-nitro-1,4-naphthoquinone, 140 grams of methyl cellosolve 2.4 grams of 1,3-butadiene were introduced into an autoclave, heated up to 80° C. and reacted for 2.5 hours. After the reaction solution was allowed to cool, 0.06 gram of a 5% palladium on carbon catalyst and 6 grams of a 20% aqueous sodium hydroxide solution were added to the solution, into which was fed hydrogen at room temperature under normal pressure with agitation to absorb hydrogen in the 5-nitro-1,4-naphthoquinone in an amount of 2 mols per mol of the nitro compound. Then, the catalyst was removed by filtration and hydrochloric acid was added to the resultant filtrate for neutralization. From the thus neutralized solution was removed methyl cellosolve by distillation for concentration, followed by allowing to cool to precipitate crystals. The crystals were separated by filtration, washed with water and dried to obtain 5.8 grams of 1-aminoanthraquinone with a purity of 98.7%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][CH:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH:9]1[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC1CN(c2ccc([N+](=O)[O-])nc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Product: CC1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Yield: 122.4 %

Procedure:
By repeating procedures described in Example B, 2-methyl-4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.52 mmol) is hydrogenated over Pd—C on an H-cube (Thales) (instead of under an atmosphere of hydrogen) to give 4-(6-amino-pyridin-3-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (544 mg, 98%). MS(ESI) m/z 293 (M+H)+
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20]([O:22]N1C(=O)CCC1=O)=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([N:32](CC)CC)C>C(Cl)Cl>[C:20]([C:8]([NH2:32])([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:9]([OH:11])=[O:10])([O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CCN(CC)CC
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Product: NC(C(=O)O)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a suspension of 4-amino phenylacetic acid (9 g, 60 mmol) and N-(benzyloxycarbonyloxy)-succinimide (15 g, 60 mmol) in CH2Cl2 was added enough triethylamine to form a homogeneous solution. The mixture was stirred at room temperature for 30 min and then CH2Cl2 was removed by rotavapor. The resulting residue was dissolved in water and acidified with 5% HCl. The solid thus formed was filtered and washed with 5% HCl, water, and diethyl ether to give 12 g (70%) of Cbz-aminophenylacetic acid as a brownish powder. 1H-NMR (300 MHz, DMSO-d6): 3.48 (s, 2H), 5.13 (s, 2H), 7.14 (d, 2H), 7.29-7.45 (m, 7H), 9.73 (s, 1H).
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([O:10][C@@H:11]([C@@H:14]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:24])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:12]=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O1CCCC1>[NH:1]([C:12]([C@H:11]([C@@H:14]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:24])[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:13])[NH2:2]
Reactant: O=C[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: NN
Solvent: CO
Solvent: C1CCOC1
Product: NNC(=O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1

Procedure:
To a solution of 3.8 g (119 mmoles) of anhydrous hydrazine in 10 ml of absolute methanol a solution of 5 g (11.9 mmoles) of 2,3,5-tri-O-benzyl-D-arabinose in 10 ml of absolute tetrahydrofuran (THF) is added dropwise while stirring and cooling in an ice bath at a moderate speed. After 10 minutes the ice bath is removed and the solution is stirred for 6 hours at room temperature. Then the solvent is removed with the superfluous hydrazine, and the remaining yellowish oil is dried for removal of the last traces of hydrazine for one day under a continuous oil pump vacuum.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:31][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC3CC3)c(=O)n12
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate dissolved in 40 ml of chloroform is dropped to the above mixture at a temperature between -10° C. and -17° C. during 25 minutes. After stirring for 5 minutes, 5.025 g (0.088 mol) of cyclopropylamine in 80 ml of chloroform are dropped to the above solution at the same temperature during 40 minutes. The reaction mixture is stirred for 1 hour below -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 14.5 g (74.5%) of the named compound as light yellow crystals after recrystallization from ethanol, m.p.: 174°-176° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]3[C:14](=[O:17])[NH:15][CH2:16][C:12]=3[CH:11]=[C:10]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]3[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:9]=2)[CH:5]=[N:4]1)[CH3:2].[B-](F)(F)(F)[F:34].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]3[C:14](=[O:17])[NH:15][CH2:16][C:12]=3[C:11]([F:34])=[C:10]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]3[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:9]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClCCl
Product: CCn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of tert-Butyl (1S,2R)-2-(4-(1-ethyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (69.7 mg, 0.158 mmol) in DCM (5 mL) was cooled to 0° C. SELECTFLUOR® (84 mg, 0.237 mmol) was added. The mixture was left stirring in an ice bath and was allowed to warm slowly to RT with stirring overnight. Additional SELECTFLUOR® (2 eq) was added and the reaction was stopped after 2 h. After removal of solvent, the residue was diluted with EtOAc (10 mL) and washed with saturated aq NaHCO3 (5 mL), water (5 mL), and brine (5 mL). The organic layers were combined, dried over Na2SO4, and concentrated to a brown residue. The resulting crude material was reconstituted in MeOH/DCM (6 mL) and was purified via preparative HPLC. The fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (20 mg, 28%). [M+H] calc'd for C23H31FN6O3, 459. found, 459.
Reaction SMILES: C(O)(=O)C.OO.[Cl:7][C:8]1[CH:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([CH3:19])=[C:12]2[C:17]=1S[CH2:15][CH2:14][C:13]2=[O:18].[S:25]([O-:28])(O)=[O:26].[Na+]>O>[Cl:7][C:8]1[CH:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([CH3:19])=[C:12]2[C:17]=1[S:25](=[O:28])(=[O:26])[CH2:15][CH2:14][C:13]2=[O:18]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2(=O)=O
Yield: 54 %

Procedure:
3 Milliliters of acetic acid and 1.75 g (15.47 mmol) of a 30 wt % hydrogen peroxide aqueous solution were added to 2.00 g (7.03 mmol) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one in a 50-ml round-bottomed flask, and the mixture was allowed to react at 70° C. for 2 hours. The reaction mixture was diluted with about 50 ml of water, and a sodium hydrogensulfite was added to decompose excess hydrogen peroxide. Then, the mixture was extracted with ethyl acetate. An organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to give 1.20 g (yield 54%) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]3)[C:21]=12.CCCP(=O)=O.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([NH:31][C@H:28]3[CH2:29][CH2:30][N:26]([C:22]4[C:21]5[N:20]([CH:19]=[CH:18][C:17]=5[CH3:16])[CH:25]=[CH:24][N:23]=4)[CH2:27]3)=[O:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccn2ccnc(N3CC[C@H](N)C3)c12
Reactant: O=C(O)c1ccn(-c2ccc(F)cc2)n1
Agent: CCCP(=O)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccn2ccnc(N3CC[C@H](NC(=O)c4ccn(-c5ccc(F)cc5)n4)C3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazole-3-carboxylic acid (0.04 g, 0.19 mmol, 1.5 eq) in 1 mL of DCM was added (S)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine (0.036 g, 0.13 mmol, 1 eq), propylphosphonic anhydride (0.3 mL, 0.47 mmol, 2.5 eq), and N-methylmorpholine (0.15 mL, 1.36 mmol, 10.5 eq). The reaction mixture was stirred at room temperature for 1 h then quenched with H2O and extracted with ethyl acetate. The combined organic layers were concentrated and purified by HPLC to afford (S)-1-(4-fluorophenyl)-N-(1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-1H-pyrazole-3-carboxamide (0.030 g, 0.074 mmol, 57%). 1H NMR (400 MHz, CDCCl3) δ 7.91 (d, J=7.3 Hz, 1 H), 7.82 (s, 1 H), 7.68 (dd, J=4.4, 8.8 Hz, 2 H), 7.33 (d, J=4.8 Hz, 1 H), 7.19 (t, J=8.8 Hz, 3 H), 7.00 (m, 2 H), 6.50 (s, 1 H), 4.75 (s, 1 H), 3.90-3.56 (m, 4 H), 2.57 (s, 3 H), 2.42-2.38 (m, 1 H), 2.02-1.80 (m, 1 H); MS: (ES) m/z calculated for C22H21FN6O[M+H]+ 405.2, found 405.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][CH2:29][S:30]([NH2:33])(=[O:32])=[O:31])[C:14]3=[O:34])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:37](Cl)(=[O:39])[CH3:38].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=4)[CH2:16][N:15]([CH2:28][CH2:29][S:30]([NH:33][C:37](=[O:39])[CH3:38])(=[O:32])=[O:31])[C:14]3=[O:34])=[CH:11][CH:12]=2)=[CH:35][CH:36]=1
Reactant: NS(=O)(=O)CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-2-[3-[4-(4-chloro-phenoxy)-phenyl]-2-oxo-4-(3-trifluoromethyl-phenyl)-imidazolidin-1-yl]ethanesulfonic acid amide (20 mg, 0.037 mmol) and acetyl chloride (6 mg, 0.076 mmol) in anhydrous CH2Cl2 (1 mL) is added triethylamine (7.7 mg, 0.076 mmol). The mixture is stirred at room temperature for 14 h and is then concentrated to dryness. The residue is dissolved in EtOH and treated with NaOH (0.074 mmol, 1 M aqueous solution) for 1 h. The mixture is then treated with water (3 mL) and extracted with EtOAc (3×3 mL). The combined organic layers are concentrated and purified by flash column chromatography to provide the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.56 (m, 3H), 7.48 (m, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 6.86 (d, J=9.2 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.26 (dd, J=9.2, 6.8 Hz, 1H), 4.00 (t, J=9.2 Hz, 1H), 3.75-3.90 (m, 2H), 3.55-3.65 (m, 2H), 3.36 (dd, J=8.8, 6.8 Hz, 1H), 2.17 (s, 3H); HPLC-MS calculated for C26H23ClF3N3O5S (M+H+) 582.1, found 582.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C1[CH2:17][O:16]CC1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.CN.Cl>O.CN(C=O)C>[CH3:17][O:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2]([C:10]([NH2:20])=[O:12])=[CH:3]2
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(C(N)=O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1H-indole-2-carboxylic acid 3 (X═H, 1.0 g, 6.21 mmol) and anhydrous THF (50 ml), add carbonyldiimidazole (1.10 equiv., 1.1 g, 6.83 mmol). Stir for 30 min at rt and then add MeNH2HCl (1.30 equiv., 541 mg, 8.07 mmol) in one portion. Add DMF (10 mL) to the reaction and stir at rt. After 2 h, pour the clear yellow reaction solution into H2O. Collect the precipitate by filtration and dry under vacuum at 40° C. to afford 1H-indole-2-carboxylic acid methylamide 4 (X═R2═H, R3═CH3; 860 mg, 80%) as a yellow solid, mp 222-223° C.; 1H NMR (DMSO-d6) δ 11.6 (brs, 1H), 8.45 (m, 1H), 7.60 (d, 1H, J=7.8 Hz), 7.44 (dd, 1H, J=1.05, 8.25 Hz), 7.20-7.14 (m, 1H), 7.60-7.00 (m, 1H), 2.82 (d, 3H, J=4.2 Hz). m/z obs=175 (M+1). Treat 1H-indole-2-carboxylic acid methylamide (174 mg, 1.0 mmol) with phenyldisulfide (1.1 equiv., 240 mg, 1.1 mmol) as described in General Synthetic Procedure VIIa to afford the title compound Ij (140 mg, 50%) as an ivory-colored solid, mp 201-204° C.; 1H NMR (DMSO-d6) δ 12.3 (brs, 1H), 8.3 (m, 1H), 7.48 (d, 1H), 7.42 (d, 1H), 7.3-7.0 (m, 7H), 2.9 (d, 3H).
Reaction SMILES: [C:1]([O:9][CH2:10]/[CH:11]=[C:12](\[CH3:26])/[CH2:13][CH2:14][C:15]1[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[C:17](=[O:24])[C:16]=1[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:9][CH2:10]/[CH:11]=[C:12](\[CH3:26])/[CH2:13][CH2:14][C:15]1[C:16]([CH3:25])=[C:17]([OH:24])[C:18]([CH3:23])=[C:19]([CH3:22])[C:20]=1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C)C(=O)C(CC/C(C)=C/COC(=O)c2ccccc2)=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C/C(=C\COC(=O)c1ccccc1)CCc1c(C)c(O)c(C)c(C)c1O
Yield: 84.6 %

Procedure:
A solution of 1.22 g (3.5 mmol) of (E)-3-methyl-5-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)-2-pentenyl benzoate in 10 ml of THF was treated dropwise with a solution of 0.9 g of sodium dithionite in 8 ml of water. After 1 hour the mixture was extracted with chloroform (2 x) and the combined extracts were washed three times with water. The residue remaining after removal of the solvent was washed with hexane and dried under vacuum, yielding 1.05 g of colourless (E)-5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl benzoate. M.P. 112°-114° C.
Reaction SMILES: I[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]2[S:4][CH2:3][CH2:2][N:14]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:6]=2[CH:7]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2SCCI)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 42.4 %

Procedure:
To a stirred solution of tert-butyl 4-(2-(2-iodoethylthio)-5-nitrophenylamino)piperidine-1-carboxylate (1.49 g, 2.94 mmol) in DMF (10 mL) was added potassium carbonate (0.812 g, 5.87 mmol). The resulting mixture was stirred at 90° C. for 3 hours. The reaction mixture was then diluted with ethyl acetate and washed sequentially with water and saturated sodium carbonate (2×). The organic phase was dried, filtered, concentrated, and then chromatographed in 1:4 ethyl acetate:hexanes, giving the desired product (473 mg, 42.4%) as an orange foam. 1H NMR (DMSO-d6) δ 7.57 (d, J=2.4 Hz, 1H), 7.41 (dd, J=8.7, 2.4 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 4.09-3.88 (m, 3H), 3.47-3.42 (m, 2H), 3.12-3.08 (m, 2H), 3.01-2.85 (m, 2H), 1.72-1.51 (m, 4H), 1.41 (s, 9H); ESI-MS (m/z, %): 402 (M+Na, 95), 380 (MH+, 28), 324 (100), 280 (55).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[N:6]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:7](=[O:29])[N:8]([CH:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10](=[O:22])[N:11]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12]3)[C:4]=2[CH:3]=1.[CH:43](=O)[CH3:44].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[N:6]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)(=[O:32])=[O:31])[C:7](=[O:29])[N:8]([CH:9]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:10]([N:11]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:17][CH2:18][N:19]([CH2:43][CH3:44])[CH2:20][CH2:21]4)[CH2:12]3)=[O:22])[C:4]=2[CH:3]=1
Reactant: CC=O
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CC[C@H](N4CCNCC4)C3)c3ccccc3)c3cc(Cl)ccc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: CCN1CCN([C@H]2CCN(C(=O)C(c3ccccc3)n3c(=O)n(S(=O)(=O)c4ccc(OC)cc4)c4ccc(Cl)cc43)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 99.0 mg (0.16 mmol) of 5-chloro-1-(4-methoxybenzenesulfonyl)-3-[2-oxo-1-phenyl-2-((S)-3-piperazin-1-yl-pyrrolidin-1-yl)ethyl]-1,3-dihydrobenzimidazol-2-one (example 149) in 4 ml of THF was mixed with 7.15 mg (0.16 mmol) of acetaldehyde and 160 mg of MP-triacetoxyborohydride resin (Argonaut, 2.55 mmol/g, 0.41 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (mobile phase: gradient from 10% to 80% acetonitrile in water, 0.1% trifluoroacetic acid as modulator). Yield: 38.6 mg (38%) of colorless solid
Reaction SMILES: [CH:1]([CH2:3][N:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])=[O:2].[Cl:19][C:20]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+].[CH3:38][S:39]([OH:42])(=[O:41])=[O:40]>C(OCC)(=O)C.CO>[OH2:2].[CH3:38][S:39]([OH:42])(=[O:41])=[O:40].[CH:7]1([C:5]([N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:3][CH2:1][N:26]2[CH2:25][CH2:24][N:23]([CH2:22][C:21]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:20]=3[Cl:19])[CH2:28][CH2:27]2)=[O:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:7]1([C:5]([N:4]([CH2:3][CH2:1][N:26]2[CH2:25][CH2:24][N:23]([CH2:22][C:21]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:20]=3[Cl:19])[CH2:28][CH2:27]2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:38][S:39]([OH:42])(=[O:41])=[O:40]
Reactant: O=CCN(C(=O)C1CCCCC1)c1ccccn1
Reactant: Clc1ccc(Cl)c(CN2CCNCC2)c1
Agent: CS(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O
Product: O=C(C1CCCCC1)N(CCN1CCN(Cc2cc(Cl)ccc2Cl)CC1)c1ccccn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 19 %

Procedure:
To a mixture comprising 0.164 g of Compound 1B of Example 1, 0.210 g of Compound 14B, and 4 mL methanol, continuously stirred under nitrogen, at room temperature, there was added 0.049 g of sodium cyanoborohydride. The resulting mixture was then stirred for 13 hr, at room temperature, followed by dilution with 10 mL water, and subsequent extraction with ethyl acetate (3×10 mL). The collected organic phases were then dried over anhydrous sodium sulphate, followed by vacuum evaporation, and subsequent purification of the obtained product residue by flash chromatography (chloroform—methanol 95:5). The solvents were then evaporated off, from the recovered fractions, yielding a residual substance which was then solubilized into 2 mL ethyl acetate. To this solution was then added 0.08 mL methanesulphonic acid (2 M solution of CH3SO3H, in ethanol) followed by diethyl ether, until the complete precipitation of the product. 0.071 g of this end-product precipitate was recovered here (yield 19%), through the use of vacuum filtration procedures.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH:21]([CH:10]2[CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)[CH3:22])=[N:25][CH:26]=1
Reactant: CC(Oc1ccc(Cl)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(Oc1ccc(Cl)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 3 h
Yield: 42.7 %

Procedure:
To a solution of 2-{(RS)-1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine (XIV-B-2) 1.57 g (3.40 mmol) dissolved in CH3CN (40 mL) was added 1.08 mL (5.10 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was continued for 3 hours at RT. Volatiles were removed under vacuo, and the residue was dissolved in AcOH (30 mL) before a total of 1.20 g of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by an extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 0.54 g (67%) of the title compound as a colorless oil. ES-MS m/e: 356.3 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]=[CH2:13])=[C:10]([C:14]([OH:16])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N+](=[CH2:19])=[N-].C(O)(=O)C>CO.C(OCC)C>[CH3:19][O:15][C:14]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:1])[C:11]=1[CH:12]=[CH2:13])=[O:16]
Reactant: C=[N+]=[N-]
Reactant: C=Cc1c(C(=O)O)c2ccccc2[nH]c1=O
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOCC
Product: C=Cc1c(C(=O)OC)c2ccccc2[nH]c1=O

Procedure:
To a solution of 4.4 g (20 mmol) 2-Oxo-3-vinyl-1,2-dihydroquinoline-4-carboxylic acid 4 in 200 mL methanol was added etheral diazomethane at ambient temperature until the vigorous evolution of nitrogen subsided and the starting material was used up. Then 10 mL acetic acid were added, the mixture was diluted with 200 mL diethylether and washed with a solution of sodium bicarbonate (5%) and brine. The organic layer was separated, dried over sodium sulfate and filtered. After evaporation the crude product was purified by chromatography on silica gel eluting with toluene/ethyl acetate/methanol 4:1:1, to give 2.6 g of 5 as a pale yellow solid.