Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:13]([C:14](=[O:20])[C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:21].[BH4-].[K+]>O>[Cl:1][C:2]1[C:13]([CH:14]([OH:20])[C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:21]
Reactant: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Agent: [BH4-]
Agent: [K+]
Solvent: O
Product: O=C(O)C1Cc2cc(C(O)c3cccs3)c(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A magnetically stirred suspension of 3.4 g. (0.01 M) of 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)-benzofuran-2-carboxylic acid and 100 ml. water is cooled to 5° C. in an icewater bath. A solution of 0.8 g. (0.0148 M) potassium borohydride and 20 ml. water is added dropwise to the above suspension over one-half hour. The resulting solution is stirred 2 hours at 25° C., filtered to remove some cloudiness and acidified with 6N HCl to give 6,7-dichloro-2,3-dihydro-5-[hydroxy-(2-thienyl)methyl]benzofuran-2-carboxylic acid as a yellow gum. The product is purified by precipitating it from 2N NaOH with 6N HCl. The aqueous solution is decanted from the gum which is triturated with 6N HCl to give a pale yellow solid. This solid is washed with water and air dried. It is then dried 24 hours at 25° C. and lmm Hg over P2O5.
Reaction SMILES: [NH2:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15]Br.ClCCl>CN(C=O)C>[N+:7]([C:6]1[CH:5]=[N:4][N:3]2[CH2:15][CH2:14][CH2:13][NH:1][C:2]=12)([O-:9])=[O:8]
Reactant: BrCCCBr
Reactant: Nc1n[nH]cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnn2c1NCCC2
Temperature: 0 °C
Yield: 87.7 %

Procedure:
A solution of 51.2 g (0.4 moles) 3-amino-4-nitropyrazole in 650 ml dried DMF is slowly added by drops to a suspension of 10 g (0.4 moles) sodium hydride in 200 ml dried DMF. After the reaction is concluded, 121 g (0.6 moles) 1,3-dibromopropane in 250 ml DMF are added. The mixture is then heated for 5 hours accompanied by reflux. After cooling, the preparation is reduced to dryness. When the residue is treated with 300 ml dichloromethane and subsequently cooled to 0° C. the product is precipitated out together with NaBr. The raw product is recrystallized from 1200 ml ethanol. 59 g (38%) ocher-colored crystals with a melting point of 251°-252° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.[NH2:29][C@H:30]([CH2:47][C:48]1[CH:57]=[CH:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=1)[C:31]([N:33]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH2:44][CH2:45][OH:46])[CH3:34])=[O:32].C(OCC)(=O)C>CN(C)C=O.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:29][C@@H:30]([C:31](=[O:32])[N:33]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH2:44][CH2:45][OH:46])[CH3:34])[CH2:47][C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH:49]=2)[CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCc1ccccc1OCCO)C(=O)[C@H](N)Cc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
3-(tert-Butoxycarbonylaminomethyl)benzoic acid (113 mg, 0.45 mmol) and 7-aza-1-hydroxybenzotriazole (61 mg, 0.45 mmol) were dissolved in N,N-dimethylformamide (1 ml) and dichloromethane (1 ml). The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodilmide hydrochloride (86 mg, 0.45 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of (2R)-2-amino-N-{2-[2-(2-hydroxyethoxy)phenyl]ethyl}-N-methyl-3-(2naphthyl)propionamide (175 mg, 0.45 mmol) and ethylduisopropylamine (0.08 ml, 0.45 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted %With ethyl acetate (50 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (50 ml). The aqueous phase was extracted with ethyl acetate (2×15 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using ethyl acetate/heptane 3:1 as eluent, to give 211 mg of ((3-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl)phenyl)methyl)carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([C:18](O)([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.C(N(S(F)(F)[F:28])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18]([F:28])([CH3:20])[CH3:19])=[N:9][N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Temperature: 25 °C

Procedure:
To a solution of 2-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]propan-2-ol (200 mg, 0.57 mmol) in dry DCM (2 mL) at 0° C. under an atmosphere of nitrogen was introduced (diethylamino)sulphur trifluoride (0.14 mL, 1.15 mmol). The reaction was left to warm to RT for 1 hr. Following addition of sodium bicarbonate (5 mL of a saturated aqueous solution), the reaction mixture was washed with DCM (2×5 mL), and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Biotage, eluent heptane:EtOAc [0-100%] gradient) to furnish the title compound as a yellow solid: 1H NMR (500 MHz, CDCl3) delta 1.81-1.97 (6H, m), 5.18 (2H, br. s.), 7.28 (1H, s), 7.40-7.50 (1H, m), 7.78-7.92 (1H, m), 8.32 (1H, d, J=5.67 Hz), 9.01 (1H, d, J=1.10 Hz); LC-MS: m/z=+349.95/351.80 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]=2[N+:14]([O-:16])=[O:15])=[CH:29][CH:28]=1)#[N:26]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Product: COC(=O)Cn1c(C)cc(Cc2ccc(C#N)cc2)c([N+](=O)[O-])c1=O

Procedure:
This compound is prepared from 15.3 g (40.9 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate and 10 g (51 mmol) of (4-cyanophenyl)methyl bromide according to the method described in Example 1.5.
Reaction SMILES: Br[CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21])[CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Reactant: Nc1cccc(Cl)c1
Product: CC(C)[C@H](Nc1cccc(Cl)c1)C(=O)O

Procedure:
Following the procedure of Example 1, m-phenoxybenzyl α-bromoisovalerate is reacted with 3-chloroaniline to yield the m-phenoxybenzyl ester of N-(3-chlorophenyl)valine, MS m/e 409.2 (M+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][S:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[N:4]1[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][S:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)[CH2:6][CH2:5]1
Reactant: Clc1ncccn1
Reactant: c1ccn2c(SCCN3CCNCC3)nnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: c1cnc(N2CCN(CCSc3nnc4ccccn34)CC2)nc1
Yield: 45 %

Procedure:
4.8 g of 3-[2-(piperazin-1-yl)ethylmercapto]1,2,4-triazolo(4,3-a)pyridine, prepared in Example 79, and 2.1 g of 2-chloropyrimidine are heated under reflux in 140 ml of isopropanol in the presence of 2.5 g of potassium carbonate. After heating for 2 hours, the medium is cooled, the mineral substances are filtered off and the filtrate is concentrated. The oily residue is filtered on silica gel (eluent: chloroform/methanol 90/10). The resulting residue crystallizes from an ethyl ether/isopropyl ether mixture to give 2.8 g of 3-[2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethylmercapto]1,2,4-triazolo(4,3-a)pyridine in the form of crystals melting at 126°-7° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([S:7]([OH:10])(=[O:9])=[O:8])[CH:4]=[C:3]([NH2:11])[CH:2]=1.[C:12]([O-])(=[O:14])[CH3:13].[Na+:16].C(OC(=O)C)(=O)C>>[Na+:16].[C:12]([NH:11][C:3]1[CH:4]=[C:5]([S:7]([O-:10])(=[O:8])=[O:9])[CH:6]=[CH:1][CH:2]=1)(=[O:14])[CH3:13]
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(S(=O)(=O)[O-])c1
Yield: 95 %

Procedure:
Metanilic acid (3-aminobenzenesulfonic acid) in an amount of 37.5 parts, and 18.7 parts of sodium acetate are charged into the kneader and the procedure described and 32 parts of acetic anhydride are added to the reaction mixture. The powdery reaction mass is mixed for one hour and then dried at 85° C. in a stream of air to give a 95% yield of 3-acetylaminobenzenesulfonic acid sodium salt. Liquid chromatography and titration analysis indicated a purity of greater than 97% and the presence of about 0.5% metanilic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](=O)[NH:15][CH2:16][CH2:17][C:18]1[N:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[S:21][CH:22]=1)[CH3:2].O=P(Cl)(Cl)Cl>CC#N>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27])=[C:8]([C:14]2[C:22]3[S:21][C:20]([CH:23]([CH3:25])[CH3:24])=[N:19][C:18]=3[CH2:17][CH2:16][N:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C(=O)NCCc1csc(C(C)C)n1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)COc1ccc(Cl)cc1C1=NCCc2nc(C(C)C)sc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of {4-chloro-2-[2-(2-isopropyl-thiazol-4-yl)-ethylcarbamoyl]-phenoxy}-acetic acid ethyl ester (100 mg, 0.24 mmol, 1 eq.) and POCl3 (0.34 mL, 3.65 mmol, 15 eq.) in MeCN (2 mL) was stirred at 80° C. for 18 hours. The mixture was allowed to cool down to r.t. and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give ethyl 2-(4-chloro-2-(2-isopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-4-yl)phenoxy)acetate as a yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[F:12])(=[O:3])[CH3:2].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[CH:16][NH:11][C:9]1[CH:8]=[CH:7][C:6]([F:12])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: CC(=O)Nc1cc(N)ccc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(F)c(NC(C)=O)c1)C(=O)OCC
Temperature: 130 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
A mixture of 26.56 g (0.1579 mol) of 2-(N-acetylamino)-4-amino-1-fluorobenzene, 35.89 ml (0.1776 mol) of diethyl ethoxymethylenemalonate, and 30 ml of toluene is stirred at 130° C. for 3 hours. After cooling, the precipitate which forms is triturated with ether to yield 50.64 g (94.8%) of title compound as a white solid:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]2([CH3:31])[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].C(C1C=CC=CC=1B1OC(C)(C)C(C)(C)O1)(C)C>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]2([CH3:31])[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)Cc3cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C)Cc3cc(Cl)cc(-c4ccccc4)c3O2)cc1

Procedure:
Treatment of (±)-(5-chloro-2-methyl-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 10.0 mmol) with phenylboronic acid (1.83 g, 15.0 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.82 g, 1.0 mmol), and potassium carbonate (2.76 g, 20.0 mmol) generally according to the procedure described for Intermediate 35 gave (±)-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of (±)-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.1 g, 9.5 mmol) with sodium azide (3.9 g, 60.0 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.350 g, 5 wt. %) generally according to the procedure described for Example 1 provided 2.0 g (64%) of (±)-1-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 222-225° C.; Anal. calcd. for C16H16ClNOHCl: C, 61.95; H, 5.52; N, 4.52. Found: C, 60.82; H, 5.67; N, 4.37.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].O>CCOCC>[C:5]1([O:4][C:2](=[O:3])[NH:12][OH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=C(NO)Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Phenyl chloroformate (10 g, 63.8 mmol) in ether (10 mL) was added dropwise to a stirred mixture of finely ground hydroxylamine hydrochloride (63.8 mmol, 4.43 g) and potassium carbonate (58.4 mmol, 8.07 g) in ether (10 mL) containing water (1 mL) at 0° C. The mixture was stirred at room temperature for three days, filtered, and the solvent evaporated to give the Phenyl-N-hydroxycarbamate as crystals, m.p. 99.5°-100.7° C. (9.20 g, 94%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([O:18][CH3:19])=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN([C:39]([O:43][N:44]1N=NC2C=CC=N[C:45]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CONC>CN(C=O)C>[CH3:19][O:18][C:10]1[C:9]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:17][C:13]([C:14](=[O:16])[N:44]([O:43][CH3:39])[CH3:45])=[CH:12][N:11]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ncc(C(=O)O)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncc(C(=O)N(C)OC)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-[bis(tert-butoxycarbonyl)amino]-6-methoxynicotinic acid (Preparation 70, 500 mg, 1.358 mmol) and DIPEA (730 uL, 4.076 mmol) in DMF (4 mL) was added HATU (774 mg, 2.038 mmol) and N-methoxy-methylamine hydrochloride (198 mg, 2.038 mmol) and the reaction stirred at room temperature for 16 hours. The reaction was partitioned between saturated aqueous NaHCO3 solution and EtOAc, the organic layer collected, dried over sodium sulfate and concentrated in vacuo to afford the title compound that was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:20])[N:8]2[CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[N:23]\[NH:24][C:25]([NH2:27])=[O:26])/[C:7](=[O:20])[N:8]2[CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: NNC(N)=O
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccc(Cl)cc21)C(C)C
Agent: Cl
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccc(Cl)cc21)C(C)C
Yield: 69.4 %

Procedure:
By using 6-chloro-1-(2-diisopropylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-6-chloro-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 205°-208° C. (yield: 69.4%, recrystallizing solvent: aqueous methanol).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:14](Br)[NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=2[NH2:40])O1.C(=O)([O-])O.[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>[C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:14]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=3[NH2:40])[NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(N)c1
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: Cc1ccc(-c2[nH]c3cc(S(=O)(=O)NC(C)(C)C)ccc3c2C2CCCCC2)c(N)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a suspension of N-tert-butyl-2-bromo-3-cyclohexyl-1H-indole-6-sulfonamide (2.10 g, 5.08 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-methylphenylamine (1.86 g, 8.00 mmol) in 1,2-dimethoxyethane (20 ml) and water (10 ml) were added sodium hydrogen carbonate (1.60 g, 19.2 mmol) and tetrakis(triphenylphosphine)palladium (176 mg, 0.15 mmol), and the mixture was heated under reflux for 14 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and diisopropy ether was added to the residue. The precipitated solid was collected by filtration and dried in vacuo to give N-tert-butyl-2-(2-amino-4-methylphenyl)-3-cyclohexyl-1H-indole-6-sulfonamide (2.14 g, yield 96.3%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([N:15]2[CH2:19][CH2:18][NH:17][C:16]2=[O:20])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:19][CH2:18][NH:17][C:16]2=[O:20])[CH:10]=1)[S:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:29])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCN1c1cccc(NCc2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1NCCN1c1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of 1-(3-benzylamino-phenyl)-imidazolidin-2-one (25 mg, 0.1 mmol), benzenesulphonyl chloride (39 μl, 31 mmol) and pyridine (27 μl, 34 mmol) in dry dichloromethane (1 ml) was heated to reflux for 15 hrs. The reaction mixture was then cooled to room temperature, quenched with water (10 ml) and extracted with dichloromethane (3×7 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo. The crude residue was purified by preparative TLC (eluent 1:1 ethyl acetate:dichloromethane) to afford the title compound as a off white solid (9 mg, 24%). HPLC retention time 8.8 mins. Mass spectrum (ES+) m/z 425 (M+NH4).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CCOC(C)=O>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:7]=2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCCCC3)c2)CC1
Temperature: 80 °C
Yield: 88 %

Procedure:
1-(5-Fluoro-2-nitro-phenyl)-piperidine (100 mg, 0.44 mmol) was treated with N-methylpiperizine (3 mL) and heated to 80° C. overnight. The reaction was diluted with EtOAc (10 mL), washed with water (2×10 mL), dried (Na2SO4) and concentrated in vacuo to afford 118 mg (88%) of 1-methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine as an oil. The 1-methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine (22 mg, 0.07 mmol) was stirred with 13 mg 5% Pd—C in 1 mL of MeOH under H2 for 2 h. The mixture was filtered through SiO2, eluting with 10% MeOH—CHCl3, and the solvent was concentrated in vacuo to give 17 mg (86%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C16H26N4, 275.22 (M+H), found 275.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:22]=[C:21]([O:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=4)[CH:20]=[CH:19][N:18]=3)=[O:15])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:14]([N:11]3[CH2:10][CH2:9][CH:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH2:13][CH2:12]3)=[O:15])[CH:22]=2)=[CH:29][CH:28]=1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cc4)ccn3)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
2-{[4-(1-Methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}-4-(4-nitrophenoxy)pyridine (163 mg) was dissolved in tetrahydrofuran (20 ml). After adding 20% palladium hydroxide-carbon (104 mg), the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered and washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated under reduced pressure, and the resultant residue was dried under reduced pressure to provide the title compound (149 mg, 98%) as pale yellow powder.