Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:28][CH:29]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
To a solution of 1-[4-(4-formylbenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.3 g) in methanol (10 ml) is added gradually sodium borohydride (59 mg) under ice-cooling and the mixture is stirred at room temperature for 2 hours. Water is added to the mixture and the solvent is distilled off under reduced pressure. The resulting residue is extracted with dichloromenhane, washed with water, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane methanol=50: 1), and recrystallized from methanol to give 1-[4-(4-hydroxymethylbenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (165 mg) as white powder, m.p. 224.5°-225.5° C.
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])Cl)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>CCCCCC>[CH2:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])[NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC(C)(C)N
Reactant: C[Si](C)(Cl)C1=Cc2c(c3ccccc3c3ccccc23)C1
Solvent: CCCCCC
Product: CC(C)(C)N[Si](C)(C)C1=Cc2c(c3ccccc3c3ccccc23)C1

Procedure:
To a 500 ml round bottom flask containing 1.98 g (0.0064 mole) of (1H-cyclopenta[1]phenanthrene-2-yl)dimethylchlorosilane and 250 ml of hexane was added 2.00 ml (0.0160 mole) of t-butylamine. The reaction mixture was allowed to stir for several days, then filtered using diatomaceous earth filter aid (Celite™), washed twice with hexane. The product was isolated by removing residual solvent under reduced pressure. The isolated yield was 1.98 g (88.9 percent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[O:14][C:15]=1[CH3:16].O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[O:14][C:15]=1[CH3:16])[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: COc1cc(CO)ccc1OCc1nc(-c2cccnc2)oc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccnc2)oc1C
Reaction time: 15 h
Yield: 47.3 %

Procedure:
To a mixture of {3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]phenyl}methanol (1.00 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.58 g), tributylphosphine (0.95 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.19 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.72 g, 47%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 161-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]1[CH2:19][N:18]3[C:13](=[CH:14][C:15]([C:22](=[O:25])[CH2:23][CH3:24])=[C:16]([CH3:21])[C:17]3=[O:20])[C:7]1=[N:8]2.C(Cl)Cl.C1COCC1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]1[CH2:19][N:18]3[C:13](=[CH:14][C:15]([CH:22]([OH:25])[CH2:23][CH3:24])=[C:16]([CH3:21])[C:17]3=[O:20])[C:7]1=[N:8]2
Reactant: CCC(=O)c1cc2n(c(=O)c1C)Cc1cc3c(OC)cccc3nc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3c(OC)cccc3nc1-2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1-methoxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one (5.0 mg, 15 μmol) in a mixture of MeOH (0.2 mL), CH2Cl2 (0.6 mL) and THF (0.2 mL) was treated with a single portion of sodium borohydride (4.0 mg, 110 ,μmol). After stirring at room temperature for 1.5 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with 10% aqueous NH4Cl (350 μL) and allowed to stand at 4° C. overnight. The solid which formed was collected by filtration, washed sparingly with H2O and dried to afford the title compound. 1H NMR (CDCl3 /MeOH-d4) d 8.77 (s, 1H), 7.69 (m, 2H), 7.59 (s, 1H), 6.92 (dd, J=6.8, 1.7 Hz, 1H), 5.23 (br s, 2H), 4.89 (m, 1H), 4.05 (s, 3H), 2.24 (s, 3H), 1.79 (m, 2H), 1.03 (t, J=7.4 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.N1C=CC=CC=1.[Cl:15][C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29]C)=[CH:20][CH:19]=[CH:18][N:17]=1>O>[ClH:15].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[C:16]2[O:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1Oc1cccnc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: c1ccc2c(c1)Oc1cccnc1O2
Temperature: 100 °C

Procedure:
Anhydrous pyridine hydrochloride is prepared by distillation to a temperature of 220° C. from a mixture of 42 g of pyridine and 50 ml of concentrated hydrochloric acid. Under a nitrogen atmosphere, the pyridine hydrochloride is allowed to cool to 100° C. and 5 g of 2-chloro-3-(2-methoxyphenoxy)pyridine is added and the mixture is refluxed 1 hour. The mixture is cooled and 200 ml of water is added. The mixture is extracted with 250 ml diethyl ether and the extracts are washed with 10 ml of concentrated ammonium hydroxide. The ether layer is dried and evaporated to yield the pyrido[2,3-B][1,4]benzodioxin, mp 95°-97° C., after sublimation at 0.1 mm pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:42]([NH:50][C:51]1[CH:63]=[C:62](Br)[CH:61]=[CH:60][C:52]=1[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:42]([NH:50][C:51]1[CH:63]=[C:62]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:61]=[CH:60][C:52]=1[C:53]([O:55][C:56]([CH3:58])([CH3:59])[CH3:57])=[O:54])(=[O:49])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: Oc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccc(F)cc2F)cc1NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
0.018 mL of 2,4-difluorophenol was added to 1 mL of toluene suspension containing 10 mg of 60% sodium hydride at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 15 minutes. After the reaction mixture was cooled to room temperature, 0.5 mL of toluene solution containing 4.7 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl, 1.7 mg of palladium acetate and 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate was added and the resulting mixture was heated to reflux under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, 4.5 mg of 60% sodium hydride, 4.7 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl and 1.7 mg of palladium acetate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 0.018 mL of 2,4-difluorophenol, 7.4 mg of 60% sodium hydride, 4.7 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl and 1.7 mg of palladium acetate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 1.6 mg of tri-tert-butylphosphine tetrafluoroborate and 5.1 mg of tris(dibenzylideneacetone)dipalladium(0) were added, and the resulting mixture was heated to reflux under nitrogen atmosphere for 1 hour and 30 minutes. 10% citric acid aqueous solution and ethyl acetate were added after the reaction mixture was cooled to room temperature. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 2-(benzamido)-4-(2,4-difluorophenoxy)benzoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>C(Cl)Cl>[C:16]([Si:20]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(OCc2ccccc2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A mixture of 4-benzyloxyphenol (100 g, 360 mmol), t-butylchlorodiphenylsilane (72.8 g, 360 mmol), and imidazole (24.5 g, 360 mmol) in 1 L of methylene chloride was stirred overnight at ambient temperature. The reaction mixture was washed with water, sat'd NaHCO3 and brine. After drying (Na2SO4), the solvent was evaporated to provide, 155 g of the title compound
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)[N:4]2[C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:18]=[C:3]12>[C].[Pd].C(O)(=O)C>[O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([F:14])([F:13])[F:15])[CH:9]=2)[N:4]2[C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:18]=[C:3]12
Reactant: CCOC(=O)/C=C/c1ccc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl(E)-3-(4-oxo-7-trifluoromethyl-4,5-dihydropyrrolo[1,2-a]-quinoxalin-1-yl)acrylate as synthesized in Example 188, 182 mg, 5% palladium carbon 80 mg and acetic acid 6 mL were mixed and stirred under hydrogen atmosphere at room temperature for 16 hours. Filtering the reaction liquid through Celite, 50 mL of water was added to the filtrate and the precipitated crystals were recovered by filtration. The crystals were washed successively with water and diethyl ether, and dried in flowing air under heating to provide 120 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)=[CH:12][N:11]3[C:25]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.[C:30]1([C:36]([NH2:39])([CH3:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:21])[NH:39][C:36]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)([CH3:38])[CH3:37])[CH:17]=4)=[CH:12][N:11]3[C:25]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:4][CH:3]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)O)c3)cn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)imidazo[1,2-a]pyridin-6-yl)benzoic acid (40 mg, 0.10 mmol) and 2-phenylpropan-2-amine (21 mg, 0.15 mmol) were dissolved into DMF (0.7 mL) and TEA (0.1 mL). HATU (59 mg, 0.15 mmol) was added to this solution (solution became yellow). The reaction was stirred at rt for 2 hrs (complete by LCMS). The reaction was diluted with MeOH (0.7 mL), filtered and purified by prep HPLC (acetonitrile/water, with 10 mM ammonium acetate buffer) to yield 2-(4-fluorophenyl)-N-methyl-6-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)imidazo-[1,2-a]pyridine-3-carboxamide (24.1 mg, 0.045 mmol, 44% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 9.25 (br s, 1H), 8.14 (br s, 1H), 7.92-7.86 (m 3H), 7.81-7.79 (m, 3H), 7.63 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.35 (d, J=7.3 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H), 7.22 (t, J=7.2 Hz, 1H), 2.90 (s, 3H), 1.81 (s, 6H). LC-MS retention time 1.74 min; m/z 507 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% acetonitrile/90% H2O/0.1% TFA and solvent B was 10% H2O/90% acetonitrile/0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]1([C:7]2C=C(C=CC=2)N)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.NC1C=C2C(CCCC2=O)=CC=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][CH2:43][C:44]3=[O:47])=[CH:39][CH:38]=2)=[O:35])=[CH:29][C:28]=1[O:48][CH3:49].C(=O)C1C=CC=CC=1>Cl.C(O)C>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[CH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:44]3=[O:47])=[CH:39][CH:38]=2)=[O:35])=[CH:29][C:28]=1[O:48][CH3:49]
Reactant: Nc1cccc(C2=CCCCC2)c1
Reactant: COc1cc(CC(=O)Nc2ccc3c(c2)C(=O)CCC3)ccc1O
Agent: Cl
Agent: Nc1ccc2c(c1)C(=O)CCC2
Solvent: O=Cc1ccccc1
Solvent: CCO
Product: COc1cc(CC(=O)Nc2ccc3c(c2)C(=O)C(=Cc2ccccc2)CC3)ccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Instead of 3-(cyclohexen-1-yl)aniline (Intermediate 2) in Example 9, 7-amino-1-tetralone is treated in a similar manner to Example 9. The resulting 4-hydroxy-3-methoxy-N-[1-oxo-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide (1 g) is dissolved in 30% hydrogen chloride-ethanol (5 ml), and thereto is added benzaldehyde (433 mg). The mixture is stirred at 25° C. for 18 hours. The precipitated crystals are collected by filtration, and washed with diethyl ether to give the desired compound (700 mg).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH2:20][O:21][C:22]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=4[CH:24]=3)(=[O:18])=[O:17])[CH2:12][C:11]2=[O:30])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>ClCCl>[Cl:29][C:27]1[CH:26]=[CH:25][C:23]2[CH:24]=[C:19]([S:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][C:8]4[CH:7]=[CH:6][C:5]([C:2](=[NH:3])[NH:4][C:40]([O:41][CH3:42])=[O:43])=[CH:32][CH:31]=4)[C:11](=[O:30])[CH2:12]3)(=[O:18])=[O:17])[CH2:20][O:21][C:22]=2[CH:28]=1
Reactant: N=C(N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC(=N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 1-(4-amidinobenzyl)-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone hydrochloride (99 mg) and triethylamine (0.084 ml) in dichloromethane (10 ml) was added dropwise a solution of methyl chlorocarbonate (0.023 g) in dichloromethane (2 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with dichloromethane, washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated. Precipitated crystals were washed with ether to give colorless crystals of the title compound (95 mg).
Reaction SMILES: [CH:1]1([C:7]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:27][CH:26]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[OH:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:12][CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(CN(C(=O)C3CCCCC3)c3ccc(OCCN4CCCC4)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C1CCCCC1)N(Cc1ccc(O)cc1)c1ccc(OCCN2CCCC2)cc1
Yield: 41 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-({cyclohexanecarbonyl-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amino}-methyl)-phenyl ester in 5 mL methanol was added 5N NaOH (0.50 mL). The reaction mixture was heated at reflux until complete as judged by TLC and MS. The reaction mixture was washed with methylene chloride. The organic layer was concentrated to afford 0.045 g (41%) of the title compound. MS 423.2 (M+1)+
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH2:9]([S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[CH3:10].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[NH2:1][C:2]1[N:3]=[N:4][C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCSc1ccccc1-c1ccc(N)nn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
A mixture of 700 mg of 3-amino-6-chloropyridazine, 1.42 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 148 mg of tris(dibenzylideneacetone)dipalladiuim(0), 603 mg of tricyclohexylphosphine (18% toluene solution), 3.43 g of tripotassium phosphate, 4.5 ml of 1,4-dioxane and 1.5 ml of water was stirred at 100° C. for 3 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 927 mg of 3-amino-6-(2-ethylsulfanylphenyl)pyridazine.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]([CH3:28])=[C:15]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]2)[N:16]=1.[OH-].[Na+].O>C(O)C.O1CCCC1>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]([CH3:28])=[C:15]([CH2:17][N:18]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]2)[N:16]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3F)sc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1sc(-c2cccc(C(F)(F)F)c2F)nc1Cn1cc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a mixed solution of the compound (200 mg, 0.48 mmol) obtained in Example 80f in ethanol/tetrahydrofuran (v/v=1/1, 4 mL) was added 2N aqueous sodium hydroxide solution (0.97 mL, 1.9 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (150 mg, 81%) as colorless crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12](=O)[NH:13][CH2:14][C@@H:15]1[C@@H:19]([CH2:20][S:21][CH3:22])[O:18][C:17]([CH3:24])([CH3:23])[O:16]1)(C)(C)C>O1CCCC1>[CH3:23][C:17]1([CH3:24])[O:16][C@H:15]([CH2:14][NH:13][CH3:12])[C@@H:19]([CH2:20][S:21][CH3:22])[O:18]1
Reactant: CSC[C@H]1OC(C)(C)O[C@@H]1CNC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC[C@H]1OC(C)(C)O[C@@H]1CSC
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
Lithium aluminium hydride (3 ml, 2M in THF, 6.0 mmol) was added dropwise to a solution of tert-butyl((4R,5S)-2,2-dimethyl-5-(methylthiomethyl)-1,3-dioxolan-4-yl)methylcarbamate (620 mg, 2.1 mmol) in tetrahydrofuran (5 ml) and the resulting suspension heated to reflux and monitored by TLC. After 1 h at reflux the reaction appeared complete by TLC analysis therefore cool to ambient and quench with water (0.25 ml), 15% aq NaOH (0.25 ml), and water (0.75 ml) and stir the resulting white suspension for 30 minutes. The suspension was then filtered through Celite®, washed with hot ethyl acetate, and the filtrate concentrated in vacuo to afford a mobile oil. The residue was purified by flash chromatography on silica gel eluting with Purify the resulting oil by flash chromatography on silica gel eluting with 5% 7 N NH3 in MeOH/DCM to afford ((4R,5S)-2,2-dimethyl-5-(methylthiomethyl)-1,3-dioxolan-4-yl)-N-methylmethanamine (330 mg, 76%) as a colourless oil. 1H NMR (CDCl3) δ 3.94 (m, 2H), 2.85 (dd, J=12.3, 3.2 Hz, 1H), 2.75 (m, 3H), 2.47 (s, 3H), 2.18 (s, 3H), 1.41 (s, 3H), 1.41 (s, 3H). 13C NMR (CDCl3) δ 109.4, 80.7, 79.0, 54.8, 37.6, 37.5, 28.1, 27.9, 17.3.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>>[CH2:3]([N:2]([CH3:1])[C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: O=[N+]([O-])c1ncccc1Cl
Product: CN(Cc1ccccc1)c1cccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The mixture of N-methylbenzylamine (6.085 mL), TEA (13.19 ml) and 3-chloro-2-nitropyridine (5 g) was stirred at 60° C. under N2 overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give N-benzyl-N-methyl-2-nitropyridin-3-amine (2.6 g) as dark yellow oil.