Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][C@H:25]3[C@H:29]([CH2:30][O:31][CH3:32])[CH2:28][NH:27][CH2:26]3)[N:20]=[N:19][C:18]=2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C=O.O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.C(O)(=O)C.CCOCC>[ClH:1].[ClH:1].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][C@H:25]3[C@H:29]([CH2:30][O:31][CH3:32])[CH2:28][N:27]([CH3:40])[CH2:26]3)[N:20]=[N:19][C:18]=2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC[C@@H]2CNC[C@H]2COC)cc1-c1ccc(OCc2ccccc2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nnc(OC[C@@H]2CN(C)C[C@H]2COC)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 153.9 %

Procedure:
To a solution of the above pyridazine dihydrochloride (0.5 mmol, 267 mg) in dichloromethane (2.0 mL) was added formaldehyde solution in water (37%, 10 mmol, 1.0 mL), and 2 drops of acetic acid. Then sodium triacetoxyborohydride (10 mmol, 2.12 g) was added. The mixture was stirred at room temperature for 0.5 hour then concentrated. The mixture was then diluted with water/EtOAc, and neutralized with NaHCO3 powder. The organic layers were combined and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N ammonia in MeOH) to give a solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (211 mg). LCMS: m/z 477 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.83 and 7.93 (1H, s), 7.45-7.55 (4H, m), 7.36-7.40 (2H, m), 7.31-7.35 (1H, m), 7.20-7.24 (2H, m), 5.20 (2H, s), 4.59-4.63 (2H, m), 3.63-3.95 (4H, m), 3.44 (3H, s), 2.58-3.23 (9H, m), 1.44-1.53 (2H, m), 1.25-1.33 (2H, m), 0.81 (3H, t).
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>ClCCl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:1][CH:2]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc(CC(N)c2cccnc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To 0.11 g of methyl 4-[2-amino-2- (3-pyridyl)ethyl]phenylacetate in 10 ml of dichloromethane were added 0.07 ml of triethylamine (0.07 ml) and 0.11 g of p-chlorobenzenesulfonyl chloride, and stirred overnight at room temperature. After completion of reaction, water was added to the reaction mixture, which was then extracted with dichloromethane, followed by washing in saturated aqueous sodium chloride solution and dried over magnesium sulfate to obtain residue of 0.31 g. The residue was subjected to chromatography on a silica gel column, which was then eluted with chloroform-methanol (10:1 v/v) to produce 0.1 g of methyl 4-[2-(4-chlorobenzenesulfonamido)-2-(3-pyridyl)ethyl]phenylacetate. The spectrometric data thereof supports the structure of [28] as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][CH:4]=1.OOS([O-])=O.[K+].[K+].[Br-:27]>C(#N)C.O>[Br:27][C:8]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: [Br-]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)c(C)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC)c(Br)c2)c(C)c1
Reaction time: 2.5 h

Procedure:
To a solution of methyl 4′-methoxy-2-methylbiphenyl-4-carboxylate (71.5 g, 0.279 mol) in acetonitrile (1.43 L) and water (572 mL) was added oxone (180.1 g, 0.293 mol). Then a solution of KBr (38.2 g, 0.321 mol) in water (143 mL) was slowly added over 30 minutes. The reaction was stirred for 2.5 hours, then water (715 mL) was added and the mixture was left standing for 1 hour. The solids were filtered and washed as follows: with a solution of MeCN/water (1:1, 350 mL, twice), water (700 mL, twice, then 350 mL) and dried to afford methyl 3′-bromo-4′-methoxy-2-methylbiphenyl-4-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.3-7.2 (m, 2H), 6.97 (d, J=8.4 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:23](=[O:25])=[O:24].[OH-].[Na+]>O.CCOCC>[S:12]1[CH:13]=[C:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([C:23]([OH:25])=[O:24])=[CH:3][CH:4]=2)[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]1=2
Reactant: O=C=O
Reactant: Brc1ccc(C=Cc2csc3ccccc23)s1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1ccc(C=Cc2csc3ccccc23)s1
Reaction time: 1.5 h
Yield: 52.8 %

Procedure:
To a stirred, chilled (-70° C.) solution of 3-[2-(5-bromo-2-thienyl)-ethenyl]benzo[b]thiophene (15.0 g) and ether (500 ml) was added n-butyl lithium (20.5 ml, 2.5M solution in hexanes) over 15 mins., under a nitrogen atmosphere. The mixture was stirred 1.5 hr, and was transferred under nitrogen to a vessel containing a large excess of dry ice and ether (500 ml). The suspension was stirred at room temperature overnight. The mixture was poured into water (1 L) and the mixture was basified with 2.5N sodium hydroxide solution. The organic phase was removed. The aqueous phase was acidified with 10% hydrochloric acid and extracted with dichloromethane. The combined, dried over anhydrous sodium sulfate, organic phase was concentrated, and the residue was recrystallized from toluene to give 7.10 g (52.8%) of product, mp 196°-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[C:22]1([C:19]2[CH:20]=[CH:21][C:15]3[O:14][C:13]([C:4]4[CH:5]=[CH:6][C:7]([C:8]5[CH:12]=[CH:11][S:10][CH:9]=5)=[C:2]([N:1]5[C:37](=[O:38])[C:31]6[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=6)[C:40]5=[O:39])[CH:3]=4)=[N:17][C:16]=3[CH:18]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(-c2nc3cc(-c4ccccc4)ccc3o2)ccc1-c1ccsc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cc(-c3nc4cc(-c5ccccc5)ccc4o3)ccc1-c1ccsc1)C2=O

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-4-(3-thienyl)phenyl)-5-phenylbenzoxazole (61 mg, 0.16 mmol) and 1,2,4-benzenetricarboxylic anhydride (32 mg, 0.16 mmol) the title compound was obtained (66 mg, 75%). 1H NMR (DMSO) δ 8.50(d, 1H), 8.41(m, 2H), 8.30(s, 1H), 8.07(m, 2H), 7.90(m, 2H), 7.75(m, 3H), 7.62(m, 1H), 7.55(m, 1H), 7.50(m, 2H), 7.40(t, 1H), 7.11(dd, 1H). MS 540.7 m/z (M−H)−.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[CH:5]([CH3:7])[CH3:6]>CCOCC.O1CCCC1>[CH2:4]([C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[CH3:1])[CH:13]=[CH:14][CH:15]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: C[Mg]Br
Reactant: CC(C)Cc1cccc(C=O)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Cc1cccc(C(C)O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methylmagnesium bromide in ether (4 ml) was added to a solution of 3-isobutylbenzaldehyde (1.0 g) in tetrahydrofuran (10 ml) at 0° C. After stirred at 0° C. for 30 minutes, the mixture was partitioned between ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (30 g) eluting with a mixture of ethyl acetate and hexane (1:10) to give 1-(3-isobutylphenyl)ethanol (1.12 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29](O)=[O:30])[CH:9]=2)[C:5]([C:32]#[CH:33])=[CH:4][N:3]=1.CC[N:36](C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.N>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29]([NH2:36])=[O:30])[CH:9]=2)[C:5]([C:32]#[CH:33])=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C#Cc1cnc(N)nc1-c1cc(C(=O)O)c(-c2cc(Cl)ccc2C)n1COCC[Si](C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: C#Cc1cnc(N)nc1-c1cc(C(N)=O)c(-c2cc(Cl)ccc2C)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 5-(2-amino-5-ethynylpyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylic acid (338 mg, 0.7 mmol) in dry THF (5 mL) and DIPEA (0.48 mL, 2.8 mmol) was stirred at 0° C. EDCl (268 mg, 1.4 mmol), HOBT.NH3 (213 mg, 1.4 mmol) were added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, the residue taken-up in saturated solution of NaHCO3 and extracted with EtOAc. The combined organic layers were dried over sodium sulfate to obtain the title compound as a light-orange oil (334 mg, 99%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]([CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[N:12][C:11]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:10]1=2)[CH:6]=O.[NH2:22][CH2:23][C@@H:24]1[CH2:28][N:27]([C:29]2[CH:30]=[CH:31][C:32]3[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=3[N:38]=2)[C:26](=[O:40])[CH2:25]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][CH:5]([CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[N:12][C:11]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:10]1=2)[CH2:6][NH:22][CH2:23][C@@H:24]1[CH2:28][N:27]([C:29]2[CH:30]=[CH:31][C:32]3[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=3[N:38]=2)[C:26](=[O:40])[CH2:25]1
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COCOC(C=O)Cn1c(=O)cnc2ccc(OC)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCOC(CNC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1)Cn1c(=O)cnc2ccc(OC)nc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 35 %

Procedure:
In a mixed solvent (6 ml) of dichloromethane/N,N dimethylformamide (5:1) were dissolved 2-(methoxymethoxy)-3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal (as 0.217 mmol) and 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 54; 57 mg, 0.217 mmol). Acetic acid (0.025 ml, 0.434 mmol) and anhydrous sodium sulfate (100 mg) were added to the solution and the mixture was stirred at room temperature for 14 hours. Sodium triacetoxyborohydride (92 mg, 0.434 mmol) was added to the reaction solution, the mixture was stirred for 8 hours and then the solvent was removed under reduced pressure. A lower layer solvent of chloroform/methanol/water (7:3:1) was added to the residue, the resultant was alkalized by adding saturated sodium bicarbonate water under cooling on ice and extracted with a lower layer solvent of chloroform/methanol/water (7:3:1). After drying the extract with anhydrous sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to yield 41 mg (35%) of the title compound in the form of an orange oily product.
Reaction SMILES: [I-:1].[NH4+].P([O-])(O)(O)=O.[NH4+].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.O=O>[Cu](I)I.O.C1C=CC=CC=1>[I:1][C:11]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=1[NH2:9]
Reactant: [I-]
Reactant: Cc1ccc(N)cc1
Agent: I[Cu]I
Agent: O=O
Agent: O=P([O-])(O)O
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(N)c(I)c1
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a 500-ml pressure-proof glass autoclave were added 150 g (1.03 mole) of ammonium iodide, 5 g (0.0262 mole) of copper iodide, 50 g (0.435 mole) of ammonium dihydrogenphosphate, 70 g (0.654 mole) of p-toluidine, 250 ml of benzene and 100 ml of pure water, and reaction was carried out with stirring under a condition that the oxygen pressure be 3 to 8 kg/cm2 (gauge pressure) and the temperature be 70° C. At the point when the oxygen pressure decreased from 8 kg/cm2 to 3 kg/cm2, oxygen was supplied again to 8 kg/cm2. After 3 hours, the organic layer was taken out, and 83.1 g (0.357 mole) of 2-iodo-4-methylaniline was obtained from this layer. The yield was 82%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31]>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[N:19][C:18]([NH2:21])=[N:17][CH:16]=2)=[N:13][CH:14]=1
Reactant: COc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Product: COc1ccccc1-c1ccc(-c2cnc(N)nc2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and 1-bromo-2-methoxybenzene. MS (ESI): mass calcd. for C16H14N4O. C2HF3O2, 278.12; m/z found, 279.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.00 (s, 2H), 8.81 (d, J=2.2, 1H), 8.28 (dd, J=8.4, 2.2, 1H), 8.02 (d, J=8.4, 1H), 7.48-7.41 (m, 2H), 7.16 (d, J=8.4, 1H), 7.11 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][NH2:14])=[N:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O[CH:18]=[C:19]([C:22]#[N:23])[C:20]#[N:21])C>C(O)C>[NH2:23][C:22]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[C:5]([Cl:12])[N:4]=2)[N:14]=[CH:18][C:19]=1[C:20]#[N:21]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1nc(Cl)c(C(F)(F)F)cc1Cl
Solvent: CCO
Product: N#Cc1cnn(-c2nc(Cl)c(C(F)(F)F)cc2Cl)c1N
Temperature: 20 °C

Procedure:
24.6 g (0.1 mol) of 3,6-dichloro-2-hydrazino-5-trifluoromethylpyridine were added to a mixture of 12.2 g (0.1 mol) of ethoxymethylenemalononitrile and 200 ml of ethanol with stirring at 20° C. and it was stirred at 78° C. for 10 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was taken up in methylene chloride. It was extracted 3× with water and the organic phase separated off was dried over magnesium sulfate, filtered off with suction through neutral alumina and then concentrated under reduced pressure. After stirring in ether/pentane, 13.3 g (41.3% of theory) of the title compound of m.p. 168-171° C. were obtained (Active Compound Example No. 2a.002).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11]([O:14][C:15](=O)[CH3:16])(=[O:13])[CH3:12]>C(O)C>[C:11]([O:14][CH2:15][C:16]1[NH:10][C:8](=[O:9])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nccnc1N
Solvent: CCO
Product: CC(=O)OCc1nc2nccnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in Example 1, starting with 5.3 g (0.038 mole) of 3-amino-2-pyrazinecarboxamide, 34.5 g (0.157 mole) of triethyl orthopropoxyacetate and 34.5 ml of acetic anhydride. Refluxing time: 1 hour 45 minutes. Yld: 5.4 g (65%), m.p. 210°-212° C. (ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]2[C:6]([CH2:7][C:8]3[C:13]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:12]([C:20]#[N:21])[C:11](=O)O[C:9]=32)=[CH:5][CH:4]=1.[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[CH2:7][C:8]3[C:13]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:12]([C:20]#[N:21])[C:11]4[CH2:7][C:6]5[CH:5]=[CH:4][CH:3]=[CH:24][C:23]=5[C:9]=4[C:9]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)-c1oc(=O)c(C#N)c(N3CCCCC3)c1C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)-c1c(c(N3CCCCC3)c(C#N)c3c1-c1ccccc1C3)C2

Procedure:
A mixture of 8-methoxy-2-oxo-4-(piperidin-1-yl)-2,5-dihydroindeno[1,2-b]pyran-3-carbonitrile (322 mg), indanone-2 (132 mg) and NaH (39 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid mp 180-182° C.; IR (KBr) 2212 cm−1 (CN); MS (ESI) 393 (M++1); 13C NMR (150 MHz, CDCl3) δ 26.22, 35.46, 38.54, 51.70, 94.61, 119.87, 122.42, 122.68, 124.68, 124.79, 127.09, 127.17, 127.64, 127.77, 129.66, 132.09, 139.48, 140.39, 142.58, 144.25, 144.40, 144.54, 149.42.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.[OH-].[Na+].Cl>CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH:11]=[CH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][C:6]=2[N+:21]([O-:23])=[O:22])=[N:13]1
Reactant: COC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C=Cc2n[nH]c3ccccc23)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of (E)-4-[2-(1H-indazol-3-yl)vinyl]-3-nitrobenzoic acid methyl ester (1.0 g, 3.1 mmol) obtained in Step 1 of Example 217 in methanol (20 mL) was added with 2 mol/L aqueous sodium hydroxide solution (10 mL) and stirred at 60° C. for 1 hour. The reaction mixture was acidified by hydrochloric acid (6 mol/L) and the precipitated crystal was collected by filtration to obtain 4-[2-(1H-indazol-3-yl)vinyl]-3-nitrobenzoic acid.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:15]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1)=[CH:8]2)=[O:17])([CH3:27])[CH3:26]
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: CC(C)N
Product: Cc1cc(Nc2cc3cc(C(=O)NC(C)C)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and isopropylamine to give 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid isopropylamide. LC-MS: m/e 368 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:24][C:25](=[O:40])[CH2:26][CH2:27][NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:10]([N:12]([CH2:16][CH:17](OCC)OCC)[CH:13]([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[N:24]3[C:25](=[O:40])[CH2:26][CH2:27][N:28]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[CH:17]3[CH2:16][N:12]([CH:13]([CH3:14])[CH3:15])[C:10]2=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)CCNS(=O)(=O)c1ccc(OC)cc1)C(C)C)OCC
Solvent: O=CO
Product: COc1ccc(S(=O)(=O)N2CCC(=O)N3C(Cc4ccc(Cl)cc4)C(=O)N(C(C)C)CC32)cc1

Procedure:
A solution of 167 mg of 3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-methoxybenzenesulfonylamino)propionylamino]propionamide in 3 ml of formic acid is stirred at room temperature for 12 h. The reaction solution is concentrated under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20 →10/90). The desired product is obtained with MW=506.02 (calculated); measured value (M+H)+: 506.34
Reaction SMILES: C(OC([NH:8][CH:9]([CH3:34])[C:10]([N:12]1[C:16](=[O:17])[CH2:15][N:14]([N:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)=[CH:22][CH:21]=2)[C:13]1=[O:33])=[O:11])=O)(C)(C)C.Cl.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>>[ClH:31].[NH2:8][CH:9]([CH3:34])[C:10]([N:12]1[C:16](=[O:17])[CH2:15][N:14]([N:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)=[CH:22][CH:21]=2)[C:13]1=[O:33])=[O:11]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1C(=O)CN(N=Cc2ccc(-c3ccc(Cl)c(Cl)c3)o2)C1=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Product: CC(N)C(=O)N1C(=O)CN(N=Cc2ccc(-c3ccc(Cl)c(Cl)c3)o2)C1=O
Reaction time: 2 h

Procedure:
The 3-[2-(t-butoxycarbonyl-amino)propionyl]-1-{[5-(3,4-dichlorophenyl)furfurylidene]amino}hydantoin (15.1 g, 0.033 mole) was added to 3% hydrochloric acid/acetic (185 ml) and was stirred for 2 hours. The mixture was filtered and the collected solid was washed with nitromethane and ether which yielded 10.4 g (70%, 25% overall), m.p. 192°-196°.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@H:11]([OH:26])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>O1CCOCC1>[N+:7]([C:5]1[N:6]=[C:2]2[N:3]([CH:4]=1)[CH2:10][C@@H:11]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[O:26]2)([O-:9])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H]2Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
Tert-butyl (R)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxypropyl]piperazine-1-carboxylate prepared in Example 364 (6.43 g, 16.49 mmol) was dissolved in 1,4-dioxane (35 ml). To the solution, sodium hydride (730 mg, 18.25 mmol) was added with cooling on ice-bath, and the resulting solution was stirred at room temperature overnight and then stirred under reflux for 24 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added slowly, the mixture was extracted with methylene chloride twice, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to afford tert-butyl (R)-4-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (1.23 g, yield 21%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C[Al](C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:21][CH2:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Reactant: C1COCCN1
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(N2CCOCC2)nc2c1CCC(=O)N2c1ccccc1C

Procedure:
Following the general procedure outlined in Example 193, the product of Example 121 (100 mg, 0.22 mmol), morpholine (58 mg, 0.66 mmol) and trimethylaluminum (0.33 mL, 0.66 mmol) were reacted to give the desired product, 61 mg (64%). LC-MS: 431.2 (MH+, m/z), 2.46 (Rt, min).